pediatric neurology, a color handbook bale jr., james f. [srg]

PediatricNeurology

James F. Bale, Jr, MD

Joshua L. Bonkowsky, MD, PhD

Francis M. Filloux, MD

Gary L. Hedlund, DO

Denise M. Nielsen, MD

All at the University of Utah School of Medicine, Salt Lake City, UT, USA

Paul D. Larsen, MD

University of Nebraska College of Medicine, Omaha, NE, USA

A Color Handbook

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Contents

Preface . . . . . . . . . . . . . . . . . . 5

SECTION 1: CORE CONCEPTSCHAPTER IThe pediatric neurologicalexamination . . . . . . . . . . . 9Introduction . . . . . . . . . . . . . . 9What is the lesion? . . . . . . . . 10Where is the lesion? . . . . . . . 11Adaptation of the neurological

examination to the child . 12Mental status: examining the

cortex . . . . . . . . . . . . . . . 13Cranial nerves . . . . . . . . . . . . 16Coordination . . . . . . . . . . . . 24Sensory examination . . . . . . . 26Motor examination . . . . . . . . 26Conclusions . . . . . . . . . . . . . 32

CHAPTER 2Neuroimaging . . . . . . . . . 33Introduction . . . . . . . . . . . . 33Patient safety and preparation

for imaging . . . . . . . . . . . 34Magnetic resonance imaging

(MRI) . . . . . . . . . . . . . . . 34Computed tomography (CT) 39Cranial ultrasound imaging . . 40Magnetoencephalography

(MEG) . . . . . . . . . . . . . . 40Nuclear medicine brain

imaging . . . . . . . . . . . . . . 41Catheter angiography . . . . . . 42

CHAPTER 3Electrophysiologicalevaluation of Infants,children, and adolescents . . . . . . . . . . . 43Introduction . . . . . . . . . . . . 44Electroencephalography . . . . 44Recognizable EEG

abnormalities in children . 50Video-EEG monitoring . . . . 55Brainstem auditory evoked

potentials . . . . . . . . . . . . 55Visual evoked potentials . . . . 55Electromyography and nerve

conduction studies . . . . . 56Polysomnography . . . . . . . . . 57Electronystagmography

and balance testing . . . . . 58

Electroretinography . . . . . . . 58

CHAPTER 4 Cerebrospinal fluid . . . . 59Introduction . . . . . . . . . . . . 59CSF production . . . . . . . . . . 60CSF pressure . . . . . . . . . . . . 60Lumbar puncture (spinal tap) 60CSF content . . . . . . . . . . . . . 63Specialized diagnostic testing

of CSF samples . . . . . . . . 64

CHAPTER 5Genetic evaluation . . . . . 67Introduction . . . . . . . . . . . . 68Human genetics: a primer . . . 69Diagnostic tools . . . . . . . . . . 72Future directions . . . . . . . . . 74

CHAPTER 6 Newborn screening andmetabolic testing . . . . . . 75Newborn screening . . . . . . . 76Abnormal results on a

newborn screen . . . . . . . . 76Inborn errors of metabolism . 76Inborn errors in newborns . . 77Laboratory screening . . . . . . 77Imaging . . . . . . . . . . . . . . . . 78Later clinical presentations . . 80

SECTION 2: A PROBLEM-BASEDAPPROACH TO PEDIATRICNEUROLOGICAL DISORDERSCHAPTER 7 Disorders of development . . . . . . . . . . 83Introduction . . . . . . . . . . . . 84Motor delay . . . . . . . . . . . . . 84Global developmental delay . 88Developmental regression . . . 88Management of

developmental delay . . . . 88

CHAPTER 8 Disorders of behavior and cognition . . . . . . . . . 91Introduction . . . . . . . . . . . . 92Disorders of attention . . . . . . 92Neurobehavioral toxicity of

antiepileptic drugs . . . . . . 92Disorders of cognition . . . . . 94

Learning disability . . . . . . . . 96Autism spectrum disorders (ASD)

and related conditions . . . 97Organic brain disorders of

childhood . . . . . . . . . . . . 98Conversion disorders . . . . . . 99

CHAPTER 9 Disorders of language and hearing . . . . . . . . . . 101Introduction . . . . . . . . . . . 102Language disorders . . . . . . 102Epileptic causes . . . . . . . . . 105Other causes . . . . . . . . . . . . 105Hearing disorders . . . . . . . . 110Conditions associated with

hearing loss . . . . . . . . . . 112

CHAPTER 10 Disorders of head size and shape . . . . . . . . . . . . 115Introduction . . . . . . . . . . . 116Macrocephaly . . . . . . . . . . . 118Microcephaly . . . . . . . . . . . 122Misshapen heads . . . . . . . . . 126

CHAPTER 11 Disorders of cranial nerves . . . . . . . . . . . . . . . 131Introduction . . . . . . . . . . . 132Cranial nerve 1

(olfactory nerve) . . . . . . 132Cranial nerve 2

(optic nerve) . . . . . . . . . 133Cranial nerve 3

(oculomotor nerve) . . . . 140Cranial nerve 4

(trochlear nerve) . . . . . . 143Cranial nerve 5

(trigeminal nerve) . . . . . 143Cranial nerve 6

(abducens nerve) . . . . . . 144Cranial nerve 7

(facial nerve) . . . . . . . . . 145Cranial nerve 8

(acoustic nerve) . . . . . . . 147Cranial nerves 9 and 10

(glossopharyngeal and vagus nerves) . . . . . . . . . 148

Cranial nerve 11 (spinal accessory nerve) . 149

Cranial nerve 12 (hypoglossal nerve) . . . . 149

CHAPTER 12 Disorders of peripheralnerves . . . . . . . . . . . . . . . 151Introduction . . . . . . . . . . . 152Neonatal brachial plexopathy 152Brachial plexopathy of

children or adolescents . . 154Lumbosacral plexopathy . . . 154Sacral neuropathy . . . . . . . . 155Hereditary neuropathy with

liability to pressure palsy 156Guillain–Barré syndrome . . 158Complex regional pain

syndrome . . . . . . . . . . . 159Inherited peripheral

neuropathy . . . . . . . . . . 160Critical illness polyneuropathy/

myopathy . . . . . . . . . . . 160Miscellaneous causes of

peripheral neuropathy . . 160

CHAPTER 13 Disorders of gait andbalance . . . . . . . . . . . . . . 161Introduction . . . . . . . . . . . 162Evaluation . . . . . . . . . . . . . 162Patterns of presentation . . . 166

CHAPTER 14 Disorders of sleep . . . . 173Introduction . . . . . . . . . . . 174Normal sleep of infants,

children, and adolescents 174Common sleep disorders . . 177Parasomnias . . . . . . . . . . . . 178Neonatal sleep myoclonus . 179Narcolepsy . . . . . . . . . . . . . 180Delayed sleep-phase

syndrome . . . . . . . . . . . 180Advanced sleep-phase

syndrome . . . . . . . . . . . 180

CHAPTER 15 Disorders of the newborn . . . . . . . . . . . . . 181Introduction . . . . . . . . . . . 182Assessing the neonate . . . . . 182Neuroimaging of the

newborn . . . . . . . . . . . . 184EEG in the newborn . . . . . 186EMG in the newborn . . . . . 186Specific conditions . . . . . . . 187

CHAPTER 16 Acute focal deficits . . . 199Introduction . . . . . . . . . . . 200Acute arm or leg weakness . 200Acute facial weakness . . . . . 204Acute visual loss . . . . . . . . . 205Acute double vision

(diplopia) . . . . . . . . . . . 206

CHAPTER 17 The dysmorphic child . 209Introduction . . . . . . . . . . . 210The hypotonic infant . . . . . 212The neonate with encephalopathy

or seizures . . . . . . . . . . . 215The child with seizures . . . . 219The child with language

impairment . . . . . . . . . . 222The child with global

developmental delay . . . 223The child with deafness . . . . 227The child with a stroke . . . . 227The child with neurological

signs or symptoms and birth marks . . . . . . . . . . 228

The infant with a neural tube defect . . . . . . . . . . 238

CHAPTER 18 Headaches . . . . . . . . . . . 241Introduction . . . . . . . . . . . 241Migraine . . . . . . . . . . . . . . 242Migraine variants . . . . . . . . 245Chronic daily headaches . . . 245Other headache syndromes . 246

CHAPTER 19 Hypotonia and weakness . . . . . . . . . . . . 253Introduction . . . . . . . . . . . 253The hypotonic infant . . . . . 254Selected disorders in infants 256Weakness in children and

adolescents . . . . . . . . . . 261Selected disorders in children

and adolescents . . . . . . . 262

CHAPTER 20 Infections of the nervous system . . . . . . . 269Introduction . . . . . . . . . . . 270Bacterial meningitis . . . . . . 270Viral meningitis . . . . . . . . . 275

Congenital infection . . . . . . 280Lyme disease . . . . . . . . . . . 284Cat-scratch disease . . . . . . . 285Neurocysticercosis . . . . . . . 285Cerebral malaria . . . . . . . . . 286HIV/AIDS . . . . . . . . . . . . 288

CHAPTER 21 Movement disorders . . 291Introduction . . . . . . . . . . . 291Stereotypy . . . . . . . . . . . . . 292Tremor . . . . . . . . . . . . . . . .293Tic disorders and Tourette

syndrome . . . . . . . . . . . 294Chorea . . . . . . . . . . . . . . . . 296Dystonia . . . . . . . . . . . . . . . 298Myoclonus . . . . . . . . . . . . . 299Hypokinetic movement

disorders in childhood . . 299

CHAPTER 22 Seizures and otherparoxysmal disorders . 301Introduction . . . . . . . . . . . 302Cardiac arrhythmia . . . . . . . 302Nonepileptic events . . . . . . 304Seizures and epilepsy . . . . . 306Specific seizure types and

pediatric epilepsy syndromes . . . . . . . . . . . 306

Management of seizures . . . 310Management of children

with epilepsy . . . . . . . . . 312

CHAPTER 23 Pediatric neurologicalemergencies . . . . . . . . . 313Introduction . . . . . . . . . . . 314Seizures . . . . . . . . . . . . . . . 314Status epilepticus . . . . . . . . 314Alterations of consciousness 317Acute CNS injury . . . . . . . . 322Acute neuromuscular

weakness . . . . . . . . . . . . 329Acute poisonings . . . . . . . . 330Hypertensive

encephalopathy . . . . . . . 332

Abbreviations . . . . . . . . 333Further reading andbibliography . . . . . . . . . 335Index . . . . . . . . . . . . . . . . 342

5Preface

Forty years ago Dr. Patrick Bray published thetext Neurology in Pediatrics. Among Dr. Bray’sgoals were to make his book practical andcomprehensive and to demystify the nervoussystem to trainees and practitioners. He realizedthat virtually all children with neurologicaldiseases are seen first by a primary care provider,whether pediatrician or family physician. Hadhospitalists, physician assistants, nursepractitioners, and pediatric emergency medicinephysicians existed then, Dr. Bray’s insightswould have applied equally well to them. Thisbook, A Color Handbook of Pediatric Neurology,has been prepared by the trainees of Dr. Brayand the trainees of his trainees. We have notforgotten the many lessons we learned fromhim, and these lessons inspired us as we preparedthis text. The past 40 years have seen remarkableadvances in pediatric neurology and in manyinterfacing disciplines, especially medicalimaging, genetics, and infectious diseases. Yet,the fundamentals of the neurological examin -ation and history remain essential in the accuratediagnosis of conditions affecting the child’snervous system.

The text is divided into two sections. Thefirst, Core Concepts, covers material basic to theformulation of differential diagnoses and themanagement of neurological conditions ofinfancy, childhood, and adolescence. Cognizantof the importance of accurate localization, webegin the book with a detailed discussion of theneurological examination. The material isabundantly illustrated, given our goal ofproviding more than simple narrative descrip -tions of these important techniques. The firstsection continues with succinct overviews ofneuroradiology, electrophysiology, and geneticand metabolic testing. During our practicecareers, amazing advances have occurred ingenetic diagnosis; more are yet to come. Wehave included a section on the cerebrospinalfluid, emphasizing that sampling this importantbody fluid still has an essential role in thediagnosis and management of infectiousconditions, demyelinating disease, and arcane,but potentially treatable, disorders of centralnervous system neurotransmitters.

The second section, A Problem-BasedApproach to Pediatric Neurological Disorders,describes neurological disease as it isencountered by practitioners. With very fewexceptions parents do not arrive at theirpractitioner’s office carrying a card that states‘my child has vanishing white matter disease’,unless, of course, they have already been to theirconsultant or researched their child’s conditionon the Internet. Rather, children come to careproviders because their parents are concernedabout certain signs or symptoms. Recognizinghow disease presents in the real world, thelonger second section employs practicalsymptom- and sign-based strategies for virtuallyall conditions that will be encountered by thepractitioner. In this section, we cover a widevariety of topics including ‘Disorders of HeadShape and Size’, ‘Seizures and other ParoxysmalDisorders’, ‘Disorders of Language andHearing’. Again, numerous illustrations, aunique attribute of this text, accompany thenarrative. We have used textboxes to drawreaders to key points that will enable them todiagnose and manage their patients moreeffectively. We conclude with a detaileddiscussion of neurological emergencies, againcognizant that children with such conditions willpresent first to someone other than a pediatricneurologist. Throughout the text, we emphasizehow recognizing patterns of disease, whetherbased on historical or physical signs, comprisesthe first step in successfully managing the childwith a neurological problem.

Such texts are not written without thecontributions of many. The parents and childrenof those with neurological disorders featured inthis book were unsparing in their patience andwillingness to provide clinical examples andphotographs. The parents provided permissionto show their children’s faces unmasked, thusenhancing the utility of this text. We thank Dr.Alan Rope of the Division of Medical Genetics,The University of Utah, for generously provid -ing many photographs of children with geneticand syndromic disorders. Our colleagues, Drs.David Dries and Robert Hoffman, the Divisionof Pediatric Ophthalmology, Primary Children’s

Medical Center, Dr. Bruce Herman, the Divisionof Emergency Medicine, the Department ofPediatrics, Dr. Steven Chin, the Department ofPathology, Dr. Richard Sontheimer, Departmentof Dermatology, and Dr. Mark Bromberg, theDepartment of Neurology, all at the Universityof Utah, each provided photographs andillustrations that contribute greatly to theinformation contained in this text. We thankseveral pediatricians, Drs. David Folland, ChuckNorlin, Tom Metcalf, and Wendy Hobson-

Rohrer, for their suggestions, advice, and readingof the manuscript. Finally, we appreciate the keenperspective of our trainees, Drs. RussellButterfield, Matthew Sweney, and WendyOsterling who read and critiqued this work. Afundamental goal of our effort is to providecomprehensive information about the child’snervous system that is as highly relevant to thoseembarking on careers in pediatric neurology as itwill be to the experienced practitioner.

PREFACE6

7SECTION 1

Chapter 1The pediatric neurological examination

Chapter 2Neuroimaging

Chapter 3Electrophysiological evaluation of infants,children, and adolescents

Chapter 4Cerebrospinal fluid

Chapter 5Genetic evaluation

Chapter 6Newborn screening and metabolic testing

CORECONCEPTS

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CHAPTER 19

The pediatricneurologicalexamination

Main Points• The clinician uses the history and diagnostic studies to answer ‘what

is the lesion?’ and the neurological examination to answer ‘where isthe lesion?’.

• The clinician hears and sees the effects of disease and uses powersof reasoning to identify the biologic cause.

• The temporal profile or chronology of disease enables clinicians tohypothesize the nature of the lesion.

• The elements of the adult neurological examination are thefoundation for the pediatric examination and the verbal child canbe taught the examination.

• The pediatric neurological examination must be conducted andinterpreted in the context of expected neurodevelopmentalmilestones.

• For the preverbal child, the examination must be tailored to theage-specific expectations of the developing nervous system.

• Many neurological deficits can be detected by watching the childwalk, talk, and play.

Introduction

A clinician hears and sees the effects of diseasein patients and uses this information anddeductive powers to identify the cause of thesigns and symptoms. This Sherlock Holmesianprocess is common to many areas of medicine,and neurology is no exception. Essential inthis diag nostic process is the clinician’s abilityto answer two basic questions: ‘Where inthe nervous system is the lesion?’ and ‘What is

the lesion?’. The first question can be answeredby combining historical information andthe neurological examination. The secondquestion, ‘What is the lesion?’, is often sug -gested by the patient’s history or examinationand confirmed by the appropriate laboratory orneurodiag nostic tests. Consequently, thischapter addresses first the key elements of theneurological history and then focuses on theneurological examination.

1The temporal profile ofneurological disease,depicting acute, subacute,chronic, or paroxysmalchanges from baseline.

a stroke. If it developed over a period of severalmonths, a brain tumor must be considered.Stroke is now unlikely. Not only do thesepathologies have typical temporal profiles, theycan be considered in terms of whether theyproduce focal or diffuse brain dysfunction andwhether the disease process is static or progres -sive. The typical temporal profile, local ization,and course of the most common path ologies thataffect the brain are summarized in Table 1.

Two additional aspects of the historydeserve special emphasis in pediatric neurology:the developmental history and the familyhistory. The child’s nervous system is a dynamicand maturing organ system. Whether the childreaches appropriate developmental milestonesand the rate at which they are achieved areimportant indicators of brain function. Theclinician must obtain a concise and reasonablyprecise history regarding when developmentalmilestones were achieved. Because manyconditions of the child’s nervous system have agenetic basis, it is also essential that a completefamily history be obtained. A useful question toask is: ‘Does anyone else in the family haveanything similar to the patient’s problem?’.Creating a family pedigree helps the family andthe clinician construct a thorough familyhistory.

SECTION 1 Core concepts10

1

Func

tion

Baseline function

Onset of symptoms or signs

Paroxysmal

Acute

Time

Subacute

Chronic

What is the lesion?

The pediatric patient presents with a chiefcomplaint and a history of the present illness.This complaint and present illness must beviewed in the context of the past medicalhistory, family history, and social history. Withthis information, the clinician constructs atemporal profile of the child’s illness. Thisprofile can be conceptualized as a graph with‘function’ on the vertical axis, and ‘time’ on thehorizontal axis (1). The patient’s baselinefunction is determined by his past history,family history, and social history. The chiefcomplaint and the present illness represent adeparture from this baseline level of function.The chronology or the period of time overwhich the present illness evolves is critical indetermining the most likely disease process thathas caused the symptoms.

The common pathologies of the nervoussystem have relatively stereotyped patterns inwhich they appear. The time line can be acute(seconds, minutes, hours), subacute (hours,days), chronic (days, months), or paroxysmal(episodes of illness with returns to baseline). Anadolescent, for example, can present with a lefthemiparesis. If the hemiparesis developed overa matter of seconds, it is most likely the result of

Where is the lesion?

The history provides important etiologicclues, but the neurological examination andneuroimaging studies confirm the anatomicallocation of the child’s chief complaint. Theneurological examination is the window throughwhich the clinician views the nervous system.When the examination is approached in asystematic and logical fashion organized byanatomical levels and systems, the clinician canuse clinical findings to determine the location ofthe lesion causing the child’s symptoms. Tofacilitate anatomical localization, the clinician canthink of a coronal view of the brain, spinal cord,and peripheral nerves superimposed on an ‘x, y’graph (2), with brain function on the vertical axisand location (left, right, and midline) on thehorizontal axis. Ascending and descendingsystems exist at multiple levels and cross themidline during their course, enablinglocalization on both vertical and horizontal axes.

Elements of the neurological examinationallow the physician to obtain x and y values so that an anatomical location can bedetermined. On the vertical axis are the cerebralcortex, brainstem, cerebellum, spinal cord,muscle, and peripheral nerves; each structurehas a left and right side. The correspondingelements of the neurological examination for each of these levels are: cortex: mental status examination; brainstem: cranial nerves;cerebellum: coordination; spinal cord, muscle,and peripheral nerves: sensory and motor. Themotor system involves all levels, includingperipheral nerve and muscle. The sensory andmotor systems are not only located in the spinalcord and peripheral nerves, but also ascend ordescend through the brainstem and the cerebralhemispheres. Because they decussate at the levelof the spinal cord or lower brainstem, findingson motor and sensory examinations havepowerful localizing value when combined withcranial nerve, cerebellar, or cortical findings.

A few examples help to illustrate the power ofthis paradigm in anatomical localization. A childpresents with a right hemiparesis and lefthemifacial weakness. The only place that thelesion can be located in the neuraxis is at the levelthe pons on the left side where the 7th cranialnerve nucleus and corticospinal tract are located.When the disorder begins insidiously, magneticresonance imaging (MRI) may confirm the

CHAPTER 1 The pediatric neurological examination 11

Table 1 Temporal profile and localization ofimportant pathologies affecting the brain

AcuteVascular/infarct – focal Hypoxic – diffuseTrauma – focal or diffuse

SubacuteInflammatory/infectious – focal or diffuseImmune – focal or multifocalToxic/metabolic – diffuse

ChronicCongenital – focal or diffuseDegenerative – diffuse or system relatedNeoplastic – focal

ParoxysmalSeizure – focal or diffuseVascular/syncope – diffusePain/headache – focal or diffuse

2

Cortex –mentalstatus

Brainstem –cranial nerve

Cerebellum –coordination

Somatosensorytracts – sensoryexam

Upper andlower motor

neuron –motor exam

Y

X

2The neuraxis of neurological localization.

presence of a brainstem glioma. If the child hasacute aphasia and a right hemiparesis, the lesionmust be at the level of the cerebral hemisphereson the left side where corticospinal tracts ormotor cortex is located near the speech centersof the brain. MRI, using diffusion-weightedimages, may demonstrate acute ischemiaaffecting the distribution of the left middlecerebral artery. Similarly, if the child has weakness of the legs, loss of sensation below the nipple line, and preserved arm function, thelesion must be at or near the T4 level of the spinal cord. MRI may show demyelinationcompatible with multiple sclerosis or acutedisseminated encephalomyelitis, an immune-mediated inflammatory disorder of the centralnervous system (CNS).

This approach to anatomical localization is necessary for evaluating children, but it is not sufficient alone. The interpretation of theneurological examination must be couched inthe context of neurodevelopmental milestones.What one expects from a newborn is vastlydifferent from what one expects from a child or adolescent. Expression of motor andcognitive function is influenced immensely bythe maturation of the nervous system. Patternsof development are important indictors ofchildhood brain dysfunction and must beconsidered when establishing anatomicallocalization.

In many instances the neurologicalexamination will be normal or nonspecific,leading some to question the value of theexamination in modern practice. What does the examination contribute to the evaluationand management of the patient? First, theneurological examination provides essential dataregarding anatomical localization, as outlinedabove. Second, the absence of an abnormality isoften equal in importance to the presence of anabnormality. The examination must be normal,for example, to conclude that headaches in ayoung child are not the result of a brain tumor.Third, a complete neurological examinationreassures the family and child that their concernshave been taken seriously. This is particularlyimportant when parents are worried that theirchild’s headaches are the result of a brain tumor.Finally, documenting the examination over time is essential in evaluating neurologicaldisorders that evolve over time. Rett syndrome,for example, becomes the likely cause of devel-

opmental delay in a young girl when headgrowth velocity slows and hand stereotypiesappear.

Adaptation of theneurologicalexamination to the child

The neurological examination of the adult is the foundation for the neurological examinationof the child. Many of the same techniques and maneuvers can be used in the verbal childwho can be taught what is needed in the exam-ination. On the other hand, forcing the infant orthe toddler to comply with the routine adult-based neurological examination leads to anunpleasant and unrewarding experience forboth child and examiner. The examination mustbe adapted to the child, his/her temperament, and developmental level. More can be learnedby watching spontaneous movement andinteractions than by having an uncooperative,crying child resist the examination.

With this in mind, the first thing to considerwhen examining the child is to resist touchingthem. Step back and observe. Divide what yousee into its parts. Is the child socially interactingand displaying a symmetric smile? Does aninfant have good head control, posture, andsymmetric movements? Does the infant reachfor items and explore the environment? Whatsounds or words does he or she make? Theseobservations can then be registered into themental matrix of the information that the clini -cian carries forward in building the differentialdiagnosis of the child’s condition.

After these spontaneous observations aremade, the second part of the examination starts.This is when the physician approaches the childfor the ‘hands-on’ part of the examination.Touching and examining the infant or toddlercan be very threatening, therefore the exam-ination is best performed with the infant in the parent’s lap for security. The tools of the examination can also be alarming. Forexample, the child sees the reflex hammer assomething that may be harmful. Distraction andimaginative suggestion are important skills thatcan reduce the child’s anxiety and facilitatecooperation. The reflex hammer, for example,can be turned into a stick horse with a puppetrider (3). Add sound effects and eliciting muscle


stretch reflexes becomes a nonthreateninggame. Finger puppets or brightly colored toysengage the child in play which maximizes theinformation for the clinician and makes theprocess pleasant for all.

The third and final part of the examination isall those things that are potentially unpleasantand unsettling for the child. This would includeundressing the child, looking at the fundus withthe ophthalmoscope, using the otoscope,testing for the gag reflex, and measuring thehead circumference.

After all the elements of the examination havebeen completed, the clinician should reflect onthe findings to organize them for analyticaldiagnostic reasoning. In keeping with theconcept of analyzing the neurological examina -tion in terms of levels and systems, informationshould be recorded in the following sequence:mental status (the cortex); cranial nerves (thebrainstem level); coordination (the cerebellarsystem); sensory (ascending system); motor(descending system); and gait (putting it alltogether). The following sections focus on eachof the elements of the examination in this order.

Mental status: examiningthe cortex

The purpose of the mental status examination is to interrogate the function of the cerebralcortex. The cortex, the highest level of the

neuraxis, integrates perception, cognition, and emotion and results in thought, feelings,and behavior. For the child, the cortex is the site of the most dynamic and age-dependentbrain development and growth. At birth, aninfant’s behavior is predominantly reflex driven, but as maturation and developmentprogress, the cortex determines and shapes allareas of behavior. The examination of mentalstatus should be tailored to the expected devel-opmental age of the child.

The first element of the mental statusexamination is to assess the child’s level ofalertness. Is the child alert, sleepy, lethargic, orunresponsive? Without appropriate arousal, thecontent of consciousness cannot be assessed.Does the child establish eye contact and attendto the environment? Is the child able tounderstand personal boundaries and are socialskills appropriate for the child’s age? Is the childcurious and interested in exploring theenvironment? Does the child laugh, appreciatehumor, and is he/she willing to engage in play?Does the child have odd or peculiar behaviors?Are there repetitive or self stimulationbehaviors such as hand flapping or twirling andstereotypic behavior such as hand clapping,patting, or wringing? Does the child uselanguage and gestures in a meaningful way tocommunicate and connect with parents and theexaminer? The answers to these questions createa gestalt of the patient’s mental status andcortical function.


33 Using a reflex hammer as a horse and apuppet as a rider to keep the child’s attentionand increase cooperation.

The order and the content of the examinationare determined by the developmental age of thechild; many elements of the mental statusexamination can be assessed while taking thehistory. Detailed assessment of cortical functionfrom infancy to adolescence is facilitated byutilizing standardized tests administered bytrained individuals. Table 2 lists age-appropriateinstruments available for assessing corticalfunction.

Because of the complexity and integration ofcortical function, any clinical method used toexamine the cortex will be over-simplified andartificially compartmentalized. It is useful,nonetheless, to organize the mental statusexamination in terms of anatomical localization.The cortical areas examined include functions ofthe frontal lobes, frontotemporal (language),temporal and parietal lobes; their generalfunctions are listed in Table 3.

In newborns the mental status examinationconsists mainly of observations of the infant’salertness, response to environmental stimulisuch as light and sound, sleep–wake cycles, and temperament. By 2–3 months of age, asocial smile develops, and the infant becomesmore attentive to the examiner and theenvironment. At 6 months, the infant laughs,

coos, jabbers, and works to reach for a toy orinteresting object, such as the reflex hammer.By 12 months, the infant imitates simple motortasks, indicates wants, plays simple games, andhas one or two meaningful words. As the childmatures, the ability to perform self-care skills such as eating and dressing, increases. Languageskills increase as well, corresponding to dramaticgrowth in vocabulary at 18–22 months of ageand the use of two word ‘sentences’ by24 months. As children reach preschool andschool levels, components of a standard, adult-type mental status examination can be utilized(Table 4).

Frontal lobe functionThe frontal lobes are important for attention,working memory, executive function, and socialjudgment. For the older child testing frontallobe function includes repeating 3–4 numbers,spelling a word backwards, or naming themonths of the year backwards. The frontal lobesare important for directing attention andignoring competing or distracting stimuli,organizing daily activities, regulating emotion,and establishing appropriate interpersonalboundaries, features that are considered execu-


Table 2 Standardized pediatricneurodevelopmental tests

NewbornNeonatal Behavioral Assessment Scale (Brazelton)

InfantBayley Scales of Infant DevelopmentCattell Infant Intelligence Scale

Young childMcCarthy Scales of Children’s AbilitiesStandford–Binet Intelligence Scale

Older childWechsler Preschool and Primary Scale of IntelligenceNEPSY: A Developmental NeuropsychologicalAssessment

Table 3 Cortical function tested by the mentalstatus examination

Frontal lobesAttention – working memoryExecutive functionMotivationSocial behavior

Frontotemporal lobes: languageDominant hemisphere

Receptive and expressive languageNondominant hemisphere

Prosody (affective and emotion quality oflanguage)

Receptive and expressiveTemporal lobes

Episodic and semantic memoryParietal lobes

Visuospatial processing

tive functions. Certain screening tests can testselected aspects of frontal lobe function. Thepatient is instructed to tap twice when the examiner taps once and tap once when theexaminer taps twice. A variation is the Go–NoGo test in which the patient is asked to tap whenthe examiner taps once and not to tap when theexaminer taps twice. The patient with frontallobe dysfunction will repeat the motor patterndemonstrated by the examiner rather thanfollowing the directions given for the test.Another test is to tell the patient not to grasp theexaminer’s hand and then to place your hand inthe patient’s outstretched hand. The patientshould be able to inhibit the impulse to graspthe examiner’s hand.

Frontotemporal function:languageReceptive language ability precedes and is moredevelopmentally advanced than expressivelanguage ability. At 12 months the child waves‘bye-bye’, plays simple games like pat-a-cake or

peek-a-boo, and is able to follow simpledirections when a task is demonstrated such asplacing a small object in cup or bottle. At thisage the child should have two meaningfulwords, such as mama and dada. By 18 monthsthe child’s vocabulary should include at least 10words and the child should be able to point toat least one or two pictures such as a cat or dogor other common or well-known animals orobjects. The child should also be able to pointto two body parts when asked. By 24 months ofage the child should have a 50 word vocabularyand speak in two word phrases. By 3–4 years ofage the child should speak in 3–4 wordsentences, using prepositions and pronouns.

The older child can be tested for age-appropriate reading and writing skills. Languageassessment is most often thought of as assessingdominant cerebral hemisphere function, but the affective and emotional aspect or prosody of language is a nondominant cerebral hemi-sphere function. The child should be able tocomprehend and express these importantprosodic elements of language. Does the childunderstand and express emotions in languagesuch as anger, joy, and sadness as well as theinflections used in questions and exclamations?

Temporal lobe: memoryThe hippocampi of the temporal lobesparticipate in the formation and consolidationof new memories. Recent memory can be testedby asking the older child or adolescent toremember three unrelated items, such asbanana, twelve, and paper cup, and 3 minuteslater asking the child or adolescent to recallthose items. Younger children can be shownthree pictures to remember and then later askedto identify the pictures from a larger selection ofpictures. Episodic memory can be tested byasking the child to recall recent personal events,such as the most recent meal. Semanticknowledge can be tested by asking the patientage-appropriate questions, such as the names ofimportant historical figures, nonpersonalhistorical events, or recent news items.


Table 4 Mental status examination for the olderchild or adolescent

AppearanceMood and affectOrientation to place, person, timeAttention/working memory – digit spanMemory:

List of three words, recall in 5 minutesQuestions about recent and remote events

Language – appropriate for age:Naming objectsMeaning of words Following commandsShow a picture and ask questions about the pictureReadingWriting

Visuospatial – appropriate for age:Copy a designDraw a personDraw clockName fingersLeft–right and examiner’s left and right

Parietal lobe: visualspatial processingThe parietal lobe function is assessed in three domains, discriminatory somatosensoryfunction, visual spatial processing, and symbol/spatial sequencing. Discriminatory somatosen-sory processing is assessed by having the childclose his/her eyes and name numbers that aredrawn on the child’s hand (graphesthesia) oridentify familiar objects placed in their hand(stereognosis).

The nondominant parietal lobe subservesvisual spatial processing. Patients with lesions inthis part of the brain will often neglect the sideopposite to the involved hemisphere and havetrouble drawing figures. Subtle neglect can bedetected by double simultaneous stimulation.With eyes closed, the patient is asked to identifyif they are being touched on the right, left, orboth sides. The patient may correctly identifysingle right and left touch but neglect the touchcontralateral to the involved parietal lobe withsimultaneous touch. The complexity of drawnobjects is age dependent (textbox).

Drawing tasks for screening parietallobe function

Age Object3 years circle4 years cross5 years triangle6 years diamond9 years cylinder11 years box

The dominant parietal lobe is important forsymbol and spatial sequencing tasks such asright–left identification, finger naming, math,and writing. Testing for these abilities is agedependent.

Cranial nerves

The cranial nerve examination provides a viewof the neuraxis from the level of the olfactorytracts and optic nerves in the telencephalon tothe level of the hypoglossal nerve nucleus in themedulla. Cranial nerve findings combined withlong tract signs (such as corticospinal orsomatosensory tracts) have powerful localizingvalue. Clinicians can become frustrated becauseof the lack of cooperation when examining thecranial nerves of the infant and young child.Even in the totally uncooperative newborn,however, most cranial nerves can be assessed by watching the infant’s spontaneous activityand response to stimuli (Table 5). This sectionfocuses on the cranial nerve examination and the adaption of the examination to thedevelopmental level of the child.


Table 5 Cranial nerve examination in infants

Cranial Testingnerve (CN)CN2 Observe the response to bright light (blink)

Elicit the red reflex (present and symmetric)CN3, 4, 6 Inspect for the eyes aligned in conjugate

gazePerform the Doll’s eye maneuver (rotatehead in horizontal and vertical planes andobserve conjugate eye rotation in theopposite direction)Elicit the pupillary response (CN2 and 3)

CN5 Observe suck (4)Test the corneal reflex; watch for a grimacewith a nasal tickle

CN7 Observe the face during grimacing andcrying

CN8 Observe the behavioral response to loudnoise

CN9, 10 Assess suck and swallow with feeding; suckon pacifier, the quality of cry; elicit the gagreflex

CN11 Observe the symmetry of neck movements,head control

CN12 Observe tongue movement during sucking

Olfactory nerve (CN1)Examining the olfactory nerve is unfeasible untilthe child has the cognitive and language capacityto identify odors. For the older child, a smallcontainer of a substance, such as lemon, orange,or vanilla flavoring, that emits a non-noxiousodor can be used. With eyes closed the child isasked if they smell something and can identifythe smell. Scratch and sniff cards can be usedeffectively in younger children. Documentingthe perception of the smell is more importantthen actually naming the smell.

Optic nerve (CN2)Optic nerve function is assessed in fourdomains:• Visual acuity.• Visual fields.• Pupillary responses.• Funduscopy.

Visual acuity for the child 4 years and oldercan be assessed by using the tumbling E oranimal picture Snellen chart. For the youngerchild who is verbal, the examiner can ask thechild to identify small objects. For the preverbal

infant, the examiner can present the infant withsmall objects and observe visual fixation and eyetracking movements. The clinician can coverone eye, then the other, while the infant looks atan object (5). If there is decreased visual acuityin one eye, the infant will resist having the eyewith normal vision covered. If the child isvisually inattentive, then assessment by anophthalmologist is required.

Visual fields are assessed by confrontation.Each eye is ideally tested separately, but forscreening purposes both eyes can be testedtogether. The simplest way to test the verbalchild is to ask the child to focus on the examiner’snose while facing the child. Holding up bothhands to the side, superiorly and inferiorly, heasks if the child can see normal hands on bothsides out of the corner of their eye. Anothertechnique is to have the child look at theexaminer’s nose and ask him to say ‘now’ as soonas he sees the tip of a cotton applicator move intohis side vision. For the infant who can’tcooperate, attract the infant’s attention to acolorful object held in front of him and then usea dangling measuring tape and slowly move thetape from outside of his peripheral vision towardsthe midline. When the infant notices the tape he


4 5

4Watching a newborn feed assesses alertnessand cranial nerve function.

5 Cover test using a finger puppet to keep thechild’s attention.

will turn his head and look at it (6). Thistechnique is most valuable when there isasymmetry in the response. Formal perimetrymay be required for accurate detailed visual fieldtesting.

Pupillary light response tests two cranialnerves. The afferent limb of the reflex dependson the perception of light by the optic nerve(CN2) while the efferent limb is mediated by theparasympathetic nerves that are associated withthe oculomotor nerve (CN3). Use a flashlight ina dimly lit room to test the child’s direct andconsensual pupillary constriction. If the pupilsare unequal and direct pupillary constriction isabsent, an oculomotor lesion is most likely. Ifboth pupils are equal, but one pupil constrictsless to light, an optic nerve lesion is presentcausing less light perception. This phenomenon,

known as an afferent pupillary defect, can bedetected best by the swinging flashlight test. Theflashlight is swung slowly back and forth fromeye to eye. The pupil of the eye with the afferentdefect will dilate when the flashlight strikes theaffected eye, indicating impaired transmission oflight by the optic nerve.

The last element of examining CN2 is usingthe ophthalmoscope to view the optic disk and the fundus. The first step is to elicit the redreflex. In uncooperative infants or children this may be the only thing that is accomplishedby the clinician. When viewed through anophthalmoscope held approximately 24 inches(61 cm) in front of the child, the pupils shouldappear uniformly round and red (7). Colorasymmetry can be caused by any opacitybetween the surface of the eye and the retina,


6

6 Using a dangling tape and a finger puppet toassess visual fields.

7

8 9

7Assessing for pupillary symmetry in a youngchild.

8A congenital cataract obscures the red reflex.

9 A normal-appearing fundus. Note the colorand shape of the optic nerve.


such as a cataract (8) or retinoblastoma, or bynear or far sightedness. Asymmetry of the redreflex must be further evaluated by anophthalmologist.

After the red reflex is assessed, the examinerfocuses on the retina and notes the appearanceof the optic disk, the cup, the vessels, and theretinal background (9). The optic disk willappear pale yellow or nearly white if there isatrophy. A small optic disk with a double ringsign indicates optic nerve hypoplasia. Everychild who presents with headaches or signs orsymptoms suggesting increased intracranialpressure must have an adequate funduscopicexamination to determine if papilledema ispresent (textbox).

Key findings in papilledema• Loss of venous pulsations.• Venous engorgement.• Disk hyperemia.• Blurring of disk margins.• Flame hemorrhages.• Loss of physiological cup.

All infants with suspected nonaccidentaltrauma must have a funduscopic examination tolook for retinal hemorrhages. Examination ofthe retina can detect chorioretinitis, indicatingcongenital infections, peripheral pigmentation,suggesting retinitis pigmentosa, or lacunarretinopathy, suggesting Aicardi syndrome. If anadequate view of the fundus cannot beobtained, referral to an ophthalmologist shouldbe considered.

Oculomotor, trochlear,and abducens nerves(CN3, 4, and 6)These three cranial nerves control eye move -ments and are considered together because theyare assessed together. The oculomotor nerveinnervates the eye muscles for adduction (medialrectus), elevation (superior rectus and inferioroblique), depression (inferior rectus), andelevation of the eyelid (levator palpebraesuperioris). Parasympathetic nerves for the pupilalso accompany CN3. The abducens nerveinnervates the lateral rectus for abduction of theeye, and the trochlear nerve innervates thesuperior oblique muscle which is essential forlooking down and inward toward the midline.

The first step in assessing these cranial nervesis to observe the child with the eyes lookingstraight ahead. The eyes should be aligned andthe light reflex should be on the same locationof each cornea. The pupils should be equal andthe width of the palpebral fissures should alsobe equal (10). The eye movements are thentested by having the child follow an object thatis moved through the six cardinal positions ofgaze (textbox [overleaf] and 11).

10 11

10 Inspecting for symmetry of the pupils andpalpebral fissures.

11Testing extraocular movements using a fingerpuppet.

Cardinal positions of gaze and the eyemuscles tested• Right up: right superior rectus and left

inferior oblique.• Right: right lateral rectus and left medial

rectus.• Right down: right inferior rectus and left

superior oblique.• Left up: left superior rectus and right

inferior oblique.• Left: left lateral rectus and right medial

rectus.• Left down: left inferior rectus and right

superior oblique.

If the corneal light reflex is not symmetric, theclinician should suspect strabismus. Strabismuscan be paralytic or nonparalytic. Paralyticstrabismus is caused by a cranial nerve palsy,while nonparalytic strabismus is caused bymisalignment of the eyes but with intact and fullaction of the eye muscles. The difference can besorted out by using versions (testing the sixcardinal positions with both eyes together) andductions (testing each eye individually with theother eye covered). With paralytic strabismus theabnormal eye movement will be present on bothversion and duction testing. With nonparalyticstrabismus misalignment is seen on versions, butfull range of motion is observed for each eye withductions. Nonparalytic strabismus in children israrely caused by neurological conditions, but can cause amblyopia; such children should beevaluated and managed by an ophthalmologist.

With an oculomotor palsy the affected eyewill deviate down and out; adduction, elevation,and depression of the eye will be limited. If thereis compression of CN3, ptosis and pupillarydilation occur ipsilaterally. A CN3 palsy fromischemia often spares the pupil and causesminimal ptosis. When a CN4 palsy is present theaffected eye deviates up and sometimes out. Theresulting diplopia is maximum when the childlooks down and toward the midline. The headis tilted to the opposite shoulder in order tominimize the double vision. For a CN6 palsy,the affected eye usually has some degree ofmedial deviation and cannot be fully abducted.The child will turn his head to the side of theaffected CN6 to reduce diplopia. Diplopia isusually the result of an acquired lesion of CN3,

4, or 6 (textbox), and occurs because the viewedimage no longer falls on the corresponding areasof both retinas; therefore, the brain interpretsthis as two images instead of one.

Rules for determining the cause ofdiplopia• Diplopia is greatest when gazing in the

direction of the paretic muscle.• The ghost image is always the most

peripheral image.• Weakness of the medial or lateral rectus

muscles causes horizontal diplopia.• Weakness of the depressor or elevator

muscles (inferior or superior obliqueand/or inferior or superior rectus) causesvertical diplopia.

When presented with a child with unequalpupils and ptosis, the clinician must decide if theabnormality is a pupil that is too small or a pupilthat is too large (textbox).

Distinguishing between Hornersyndrome and oculomotor palsy• Horner syndrome: mild ptosis; small,

reactive pupil; normal eye movements.• Oculomotor palsy: prominent ptosis; large,

unreactive pupil; restricted eye movements.

Trigeminal nerve (CN5)The trigeminal nerve has both sensory andmotor components. The sensory componentconsists of three divisions (ophthalmic,maxillary, and mandibular); somatosensoryfunction of each is tested with light touch andsharp/dull discrimination. The ophthalmicdivision (V1) is sensory for the forehead as wellas for the cornea and the mucosa of the nose.The corneal reflex tests both the sensory afferentlimb (V1 of CN5) and the motor efferent limb(branches of CN7). The edge of the cornea islightly touched using a small thread of cottonformed from a cotton tip applicator (12).A cotton tip applicator can also be used toirritate the nasal mucosa which tests the integrityof V1 and causes grimacing and eversion from the stimulus. The maxillary (V2) and


mandibular (V3) divisions are tested forsharp/dull sensation over the cheek and jaw,respectively.

The major muscles supplied by the motordivision of CN5 include the temporalis,masseter, and pterygoid muscles. Thetemporalis and masseter muscles can be palpatedas the child clenches the teeth or bites down.They are also tested as the child opens and closesthe mouth or when the child keeps the mouthopen as the examiner attempts to close it bypushing up on the chin. When unilateralweakness is present, the jaw deviates to the sideof the weakness. In young children who won’tcooperate, motor assessment of this cranialnerve consists only of palpating the muscles andobserving spontaneous jaw movement ormovement with chewing and eating.

The examination of CN5 should also includeassessment of the jaw jerk. The examiner placeshis finger on the jaw and taps it with a reflexhammer (13). Usually there is very little reflexmovement of the jaw. If there is prominentpalpable and observable movement, the jaw jerkis considered hyperactive; this may indicate anupper motor neuron lesion or corticobulbardysfunction as in pseudobulbar palsy (see discus -sion of pseudobulbar palsy under CN9 and 10).

Facial nerve (CN7)The facial nerve is examined by watching thechild’s facial expression particularly whensmiling, laughing, or crying (14). If the child isold enough to follow commands and iscooperative, the examiner asks the child tosmile, show his teeth, close his eyes tightly, andwrinkle his forehead. Another way to test labialmuscle action is to have the child say ‘pah-pah-pah’. With lesions at the level of the facialnucleus or nerve (so called, peripheral 7th), thechild has weakness of all muscles of facialexpression ipsilateral to the lesion. With acentral 7th or corticobulbar lesion affecting themuscles of facial expression, the weaknessinvolves the orbicularis oculi, buccinator, andorbicularis oris muscles but spares the frontalismuscle. The child can still wrinkle the forehead.This finding separates facial weakness due to anupper motor neuron lesion (as might occur ina stroke) from a lower motor neuron lesion (asmight occur in Bell’s palsy). CN7 also subservestaste to the anterior two-thirds of the tongue.


12

12Assessing the corneal reflex using a cotton-tipped applicator.

1313 Performingthe jaw jerkreflex.

14

14 Inspecting for facial symmetry in a laughingchild.

This sensory function is tested when there is aweakness from lesions of the facial nerve, as inBell’s palsy.

Vestibulocochlear nerve(CN8)Unless the child complains of vertigo orunsteadiness, the auditory portion of this cranialnerve is the main focus for a screeningneurological examination. Having the childidentify whispered words, a ticking watch, or the rubbing of the examiner’s fingers are thetypical ways for hearing screening. Hearing is compared in the right and left ears. Ifasymmetry is present, a tuning fork is used toperform the Weber and Rinne tests.

For the Weber test, the tuning fork is struckand placed at the midline of the forehead (15).The vibrations lateralize to the normal ear ifthere is a unilateral sensorineural hearingloss, and to the involved ear if there is aconductive hearing loss. For the Rinne test, thetuning fork is then struck again and placedon the mastoid bone and held there until thechild can no longer perceive any vibrations (16).The examiner then moves the tuning forkover the external ear and asks the child if he orshe can hear the vibrations. Because airconduction is more effective than bone, thechild should still be able to hear the sound ofthe vibrating tuning fork. The Rinne test helpsto confirm a conductive hearing loss becausebone conduction will be better than airconduction. By contrast, the air conduction will still be greater than bone conduction insensorineural hearing loss. The above screeningtests are inadequate, however, to assessaccurately auditory nerve function. Any childwith suspected hearing loss or language orspeech delay must have a formal audiometricevaluation.

With vestibular dysfunction, the childcomplains of vertigo. The examination revealsnystagmus with the slow component toward the involved nerve and the fast correctivecomponent away from the nerve. Formal testingcan be done with a rotational chair and ice watercaloric testing. With the latter testing, the slowcomponent of the nystagmus will be toward theirrigated ear, while the fast corrective componentis away from the irrigated ear. Ice water caloricsare most often done in assessing brainstemfunction in the comatose child. The comatosechild with intact brainstem function will have theeyes deviate toward the irrigated ear, but lackscorrective nystagmus away from the irrigated ear.The corrective or fast component of the

nystagmus is only seen in the conscious patientwith intact vestibular function. Lack of theresponse to ice water caloric testing is one of thecriteria used in establishing brain death.

Glossopharyngeal andvagus nerves (CN9 and 10)These two cranial nerves are considered togetherbecause they are tested together. They are testedby asking the child to say ‘ah’ or ‘cah’ andobserving the palate rise and occlude thenasopharynx (17). If there is unilateral weaknessthe uvula will deviate away from the side of thelesion and the arch of the palate will be lower onthe affected side. With upper motor neuronlesions that affect bilateral CN9 and 10 function,both sides of the palate fail to elevate when saying‘ah’ or ‘cah’, and there is excessive nasalization ofthe produced sound because of lack of occlusionof the nasophyarnx. If the palate fails to rise withvolitional activation, then the gag reflex is tested.The gag reflex assesses the sensory afferent limband the motor efferent limb for CN9 and 10.

With an upper motor neuron lesion, knownas pseudobulbar palsy, the gag reflex will behyperactive similar to the hyper-reflexia of thedeep tendon reflexes observed with upper motorneuron lesions. Pseudobulbar palsy is mostcommonly observed in conditions that causediffuse upper motor neuron disease, such asspastic quadraparetic cerebral palsy or traumaticbrain injury, or in frontal lobe dysfunction.Lower motor neuron lesions causing bilateralCN9 and 10 palsy are unusual because of thebilateral upper motor neuron input to thesecranial nerve nuclei. Bilateral lower motorneuron CN9 and 10 palsy can be a complicationof Guillain–Barré syndrome (GBS) or Möbiussyndrome.

Accessory nerve (CN11)The accessory nerve is tested by asking the childto shrug his shoulders and watching the actionof the trapezius muscles bilaterally. Thesternocleidomastoid muscles are then testedindividually by having the child turn his or herhead to one side and then the other side againstthe resistance of the examiner’s hand upon thecheek (18). The strength of resistance can befelt and the activated sternocleidomastoidmuscle in the neck can be palpated.


15 Performing the Weber testof hearing. The sound shouldbe heard equally in both ears.

16 Performing the Rinne testof hearing. When the child nolonger hears the sound of thetuning fork held against themastoid (bone conduction),the ability to hear the vibrationwhen the tuning fork is heldbeside the ear (air conduction)should be preserved.

17Assessing palate symmetry and uvula position. Note the midline uvula.

18Testing the strength of the sternocleidomastoid muscle by assessing the child’s lateral headmovement against resistance.

19Assessing tongue protrusion by watching the child spontaneously extend his tongue.


15 16 17

18 19

Hypoglossal nerve(CN12)The hypoglossal nerve is assessed by inspectingthe tongue for any evidence of atrophy andfasciculations; both occur with lower motorneuron lesions. The patient is then asked to stickout the tongue (19). With a lesion of CN12, thetongue will deviate to the side of the lesion.With bilateral upper motor neuron lesions(pseudobulbar palsy) the patient will slowly andincompletely protrude the tongue; side-to-side

tongue movements will be slow and accom -panied by jaw movement. A rapid screening testfor CN7, 9, 10, and 12 function is to ask thechild to repeat several times ‘lah-pah-cah’. Thesesounds require intact tongue, lip, and palatemuscles innervated by these CNs.

Coordination

The principal area of the brain examined byassessing coordination is the cerebellum and its connections. Incoordination is primarilycaused by cerebellar disorders, but there areother causes, including vestibular dysfunc-tion and weakness. Although the cerebellum isincreasingly recognized as important innonmotor brain function, including cognition,coordination is the main cerebellar functionassessed during the formal neurologicalexamination.

The cerebellum controls the timing ofagonist and antagonist muscle contractionacross multiple joints to ensure smooth, flowinggoal-directed movements. When cerebellardysfunction occurs, goal-directed movementsbecome uncoordinated, and missed timing ofmuscle contraction results in overshooting andundershooting of the intended movement.Terms used to describe these uncoordinatedmovements include dysmetria and ataxia.

The cerebellum supports the integration ofsensory input to correct and modulate motoroutput. The ability to experience cerebellardysfunction depends upon the maturity of themotor systems supported by the cerebellum.Testing coordination, for example, is not evenpart of the newborn neurological examination.Cerebellar assessment awaits the acquisition offine motor skills. As the baby acquires a pincergrasp and begins to manipulate small objects,fine motor testing assumes the characteristics ofcoordination testing. Maturing of the cerebellarsystem can be seen as the infant progresses fromsitting without support to cruising (taking steps

with support) and then walking independentlywith a wide-based or toddler’s gait. At 3 years ofage, the child is able to balance on one foot, andat 4 years the child can hop on one foot. By 6 years of age most children can narrow theirstation (stance) to the point of being able totandem walk and maintain sufficient balance toride a bicycle. Thus, cerebellar testing must takeinto account the developmental level of thechild and the acquisition of normal milestones.

Ataxia can be thought of in terms of twomain categories: gait and truncal ataxia orappendicular (extremity) ataxia. Stability of the trunk and coordination in walking ispredominantly a function of the midlinestructures of the cerebellum (the vestibulo -cerebellum and spinocerebellum). By contrast,fine motor coordination of the extremities isthe function of the cerebellar hemispheres(neocerebellum). Testing of cerebellar func -tion is usually directed toward assessment ofthe extremities and then assessment of trunkstability and gait coordination. The standardtests for appendicular coordination includerepetitive finger and foot tapping, front-to-back hand patting (20) (diadochokinesia),finger-to-nose and heel-to-shin testing. Trunkand gait assessment is accomplished byobserving the child get in and out of a sittingposition, noting stability in the sitting andstanding positions, and watching the childwalk and performing age-appropriate skillssuch as hopping, walking tandem, or balancingon one foot.

For the older child, the standard coordina -tion examination can be used, but adaptation isneeded for the infant and toddler. The key is to


20

20 Having the child perform rapid alternatingmovements to assess coordination.

21

21Assessing a child’s coordination by having herpick up small objects.


22

22Assessing for coordination by having thechild reach for an object.

23

23 Using a finger puppet to assess cerebellarfunction akin to the finger-to-nose test.

24

24–28Assessing the finger-to-nose maneuver in anadolescent. The movementsshould be performedsmoothly and accurately.

25 26

27 28

engage the child in playful activities that willinterrogate coordination. For example, pickingup a small object such as a small wad of papercan be used for testing extremity fine motorcoordination (21). The child can reach for andgrasp the examiner’s reflex hammer or the endof the measuring tape (22). For finger-to-nosetesting, ask the child to touch the nose or eyesof a finger puppet and then to touch their own

nose (23). Older children and adolescents canperform standard finger-to-nose testing(24–28). Using blocks or other stacking toys isanother useful assessment strategy. Because theunder- and over-shooting movement of ataxiaresembles a tremor, this type of ataxia is oftencalled an intention or ataxic tremor. Thistremor is greatest at the end point or the mostdemanding part of the movement.

Sensory examination

Two somatosensory pathways are examinedduring the sensory examination: the spino-thalamic and the dorsal column–mediallemniscus system. The spino-thalamic system istested by assessing responses to painful stimuli(such as a pin prick) and temperature. Thedorsal column–medial lemniscus system is testedby assessing vibratory, position sense, anddiscriminatory sensation. In order for these teststo be useful, the child must be old enough tocooperate and to report what they aresubjectively experiencing. Because of this,sensory examination is difficult to perform andoften neglected in young children.

For children, the sensory examination ismost important in suspected spinal cord orperipheral nerve conditions. Much of the time,the sensory examination of the young childassesses only whether the child localizes touchor pin prick and if there is an appropriateaffective response. Demonstrating a lack ofappropriate response in a peripheral nerve,dermatome, or sensory level pattern can be veryhelpful in making an anatomical diagnosis.

For the infant or young child, useful sensorydependent reflexes are the anal wink and thecremasteric reflex. The anal wink consists ofsphincter contraction when the skin adjacent tothe rectal sphincter is pricked with a pin. Thecremasteric reflex is seen when the skin of theinner thigh is stroked with a cotton tipapplicator and the ipsilateral testicle retractsupward. The afferent sensory limb of thesereflexes must be present in order to obtainthem. The Romberg, a test of dorsal columnfunction, becomes important when a child hasgait ataxia. The child must be old enough tocooperate and be able to stand still with his eyesopen and closed (29). If he or she can stand stillwith the eyes open, but becomes unstable orfalls when the eyes are closed, this indicatesabnormal proprioception, and is considered apositive Romberg sign.

Motor examination

The elements of the motor examination includeassessment of tone, strength, and reflexes(textbox).

• Inspection and palpation of muscles.• Assessment of tone:– Postural tone/range of motion.– Phasic tone/muscle stretch (deep tendon)

reflexes.• Muscle strength testing.• Observation of muscle stretch (deep

tendon) reflexes.• Assessment of developmental reflexes,

including:– Primitive reflexes.– Postural reflexes.• Assessment of motor milestones.• Detection of pathological reflexes.

Inspection and palpationThe motor examination begins with inspectionof muscle mass. The examiner must look forgrowth disparity of the extremities as well asevidence of atrophy of individual muscles orgroups of muscles. Prominent atrophy plusfasciculations indicate a lower motor neuronlesion. The pattern of the atrophy can indicate aperipheral nerve, nerve root, or an upper motorneuron lesion. Although atrophy and contrac-tures are most prominent with anterior horncell, nerve, and muscle disease, they can be seenwith upper motor neuron disease as well. Withan upper motor neuron lesion that occurs earlyin life there is often decreased muscle mass and impaired growth of the involved extremitywith the distal growth more affected than the proximal growth. If there is weakness, it isimportant to palpate the muscle. Muscle tender-ness can accompany inflammatory myopathiessuch as dermatomyostis. Calf muscles may have pseudohypertrophy and a woody orrubbery consistency in Duchenne–Beckermuscular dystrophy (DMD).

Assessment of toneTone indicates the resistance of the restingmuscle to stretch. Clinically there are two typesof tone: postural tone and phasic tone. Posturaltone, the bias or tension maintained by themuscle to resist gravity, is assessed by putting therelaxed muscle through a passive range ofmotion (30). When there is too muchresistance, hypertonia is present. Hypertonia


29The Romberg istested by havingthe child stand withhis/her eyes closedand hold the handsand arms at theside.

30Assessing thetone and range ofmotion of a youngchild by alternatelyabducting andadducting the hips.

usually results from upper motor neuron orbasal ganglia disease. Spasticity, hypertonia fromupper motor neuron disease, is rate and forcedependant, while rigidity, hypertonia from basalganglia disease, is constant throughout therange of motion and not dependent on the rateor the force of the range of motion.

When the child has too little resistance topassive movement, hypotonia is present.Hypotonia is usually seen with disease of themotor unit (anterior horn cell, nerve, andmuscle). Common exceptions are the hypo-tonias from upper motor neuron disease inyoung infants and children or immediately afteracute lesions at any age. When hypotonia resultsfrom upper motor neuron lesions, it is calledcerebral or central hypotonia. This type ofhypotonia occurs acutely in infants withhypoxic–ischemic encephalopathy and chron -ically in those with congenital brain malfor -mations, chromosomal disorders, metabolicdisease, or cerebral palsy. Hypotonia from acentral etiology can be distinguished from aneuromuscular cause by assessing tonevariability and phasic tone.

Phasic tone is assessed by delivering a quick,brisk stretch to the muscle which results in a fast,brief contraction of the corresponding muscle.By striking a muscle tendon with a reflexhammer, the deep tendon reflex (DTR) (alsoknown as a muscle stretch reflex [MSR]) iselicited. With upper motor neuron diseasesresulting in spasticity or central hypotonia, theDTRs are present and typically hyperactive.With hypotonia of neuromuscular disease, theDTRs are absent or decreased. Variability oftone also allows the clinician to distinguishcentral from neuromuscular hypotonia. Withneuromuscular hypotonia the low tone isinvariable, while tone in central hypotonia canbe variable. When a child with central hypotoniabecomes upset or irritated, the tone increasesand the child often stiffens. Pathologicalreflexes, such as the Babinski signs, are oftenobserved in children with central hypotonia.

Obtaining accurate DTRs in infants andchildren is an art. The muscle being testedshould be positioned so that it is midway in itsusual range of motion. This provides somebackground tension in the muscle. The childmust be relaxed and not tensing the muscle orfighting the examiner who is trying to obtainthe reflex. This can be difficult if the child is

apprehensive about being struck with the reflexhammer. The child’s fears can be calmed byconverting the process into a game. The reflexhammer can be an imaginary toy or a means toelicit the child’s ‘jumpers’. The examiner canfirst do the biceps jerk, in which the hammer


29

30

strikes his or her own thumb as it is held on thebiceps tendon (31). Reflexes can be elicited withthe child in either the supine or the sittingposition, but they are best obtained in the sittingposition. When the child is supine, the examinermust place the knee in a semi-flexed position(32). In infants the Achilles tendon responsecan be obtained easily by placing the examiner’sfingers on the ball of the foot and striking themwith the foot semi-dorsiflexed (33). The


31

31–33 Eliciting the biceps jerk (31), knee jerk (32), and ankle jerk (33).

32 33

Table 6 Testing and root innervation of major muscles

Upper extremityMuscle Testing Major nerve root levelDeltoid Abduction of upper arm C5Biceps Supinated arm flexion C6Triceps Extending forearm C7Extensor carpi muscles Extend wrist C6, C7Hand intrinsic muscles Hand grasp C8, T1

Lower extremityMuscle Testing Major nerve root levelIliopsoas Hip flexion L2Quadriceps femoris Leg extension L3, L4Hamstring muscles Leg flexion S1Gastrocnemius Foot extension S1Tibialis anterior and Foot and toe L5, S1toe extensors dorsiflexion

brachioradialis response, often the most painful,should be saved until last. The reflexes aregraded 0–4 according to the briskness of theresponse (textbox).

Grading reflexes0 = absent.1 = decreased but present.2 = normal.3 = brisk but without clonus.4 = clonus.

Muscle strength testingFor the child who can cooperate and followdirections, muscle strength testing is performedas it is in the adult examination. Muscle strengthis graded at all ages using the 0–5 scale(textbox). A rapid screen for upper extremitymuscle strength is to have the child grasp theexaminer’s fingers with both hands. Theexaminer then instructs the child, ‘Squeeze myfingers as hard as you can and don’t let me moveyour arms’. The examiner then tests the muscle


Table 7 Maneuvers and positions for infantstrength and tone assessment

Head and trunk control Newborn – in sitting position, the head should cometo the upright position at least for a few seconds3 months – some head wobbling but the head is heldupright with good control most of the time6 months – sits with a straight back and good headcontrol

TractionNewborn – while pulling to sitting position, armsshould be slightly flexed, mild head lag3 months – no or only slight head lag 6 months – when pulled to the sitting position thearms are well flexed, trunk and head are forward

Ventral suspensionNewborn – in the prone position with the examiner’shand under the chest, the head should stay in thesame plane, back has some resistance to gravity, andthe extremities are semi-flexed3 months – back should be straight, the headextended and looking forward

Vertical suspensionNewborn – holding the baby around the chest, theexaminer suspends the baby in the upright position.The baby’s shoulder girdle should be strong enoughto prevent slipping through the examiner’s hands3 months – supports its weight on the feet

Prone positionNewborn – turns the head side-to-side, theextremities should be in flexion3 months – lifts the head 45–90° off the mat,supports weight on the forearms (34)6 months – the chest is off the mat and the weight ison the hands.

34

34 Head elevation in a 3-month-old baby.

strength by moving in directions that force thechild to use the various muscles of the upperextremity. The strength of the lower extremitymuscles can be assessed well by watching thechild lift the weight of his/her own bodyagainst gravity and during squat/rise andheel/toe walk. Important muscles to test, theirmajor nerve root innervation, and the methodof testing are summarized in Table 6.

Grading muscle strength0 = no observable contraction.1 = slight contraction, but no movement.2 = full range of motion, but not against gravity.3 = full range of motion against gravity.4 = full range of motion against someresistance.5 = full range of motion against full resistance.

For the child who is too young to cooperateor follow directions, strength testing can be achallenge. Watching the child’s spontaneousactivity or movements during rolling, sitting, orpulling to stand provide the clinician with usefulinformation regarding strength. Most of themotor assessment of the newborn and theinfant is carried out this way. Table 7 listsmaneuvers and positions for strength and toneassessment of these infants. For the older,uncooperative child, strength testing isaccomplished by observing the child rise fromthe floor, climb, walk, run, and play.

Developmental reflexassessmentThe newborn infant operates predominantly ata reflex level (textbox). Primitive reflexes shouldbe present, and their absence can indicatesignificant neurological dysfunction. As theinfant’s nervous system matures, these primitivereflexes should diminish. By 4–6 months mostof the primitive reflexes are gone. As theprimitive reflexes are diminishing, posturalreflexes are emerging; the earliest postural reflexappears at 3–4 months and the last one appearsat 8 months. The postural reflexes are essentialfor the child to oppose gravity successfully andacquire the ability to walk (Table 8). Persistenceof primitive reflexes and absence of posturalreflexes are important indicators of upper motorneuron lesions in this age group.

Neonatal primitive reflexes• Moro: hold baby’s head and shoulders off

the mat. With a sudden drop towards themat, the arms will extend, abduct, handsform a C-shape and then arms return tomidline.

• Suck, root: strong suck with coordinatedstripping action of the tongue. Gentlystroking the cheek towards the lips, thebaby opens the mouth and turns towardsthe stimulus.

• Galant (trunk incurvation): hold the babyin ventral suspension and stroke the skinon one side of the lower back. The trunkand hips swing towards the side of thestimulus.

• Grasp: strong grasp with the fingers ortoes when pressure is applied to the palmof the hand or ball of the foot.

Assessment of motordevelopmentalmilestonesThe development of motor control proceeds ina head-to-toe fashion and reflects theprogressive myelination of the corticospinaltracts. The tracts with the shortest length, thosecontrolling head movement and cranial nervefunction, are myelinated first. Tracts ofintermediate length, affecting the arms and

trunk, are myelinated next. The longest and lasttracts to become fully myelinated are those ofthe lower extremities. Myelination for thesetracts typically occurs during the second year of life. Thus, the child’s gross motor devel-opmental sequence is head control first, trunkstability and upper extremity control next, andwalking and further maturing of the gait last.The latter allows running, hopping, and moredemanding motor skills. Acquisition of thesemilestones occurs at predictable times for thechild (textbox), and delay in obtaining motormilestones provides the clinician with importantindicators of neurological disease.

Major motor milestones of childhood• 2–4 months: rolling over.• 5–7 months: sitting without support.• 8–9 months: moving from lying to sitting.• 9–11 months: cruising.• 12–16 months: walking.• 14–18 months: running.• 3–4 years: hopping on one foot.• 3–4 years: can ride a tricycle.• 6–7 years: can ride a bicycle.

Detection of pathologicalreflexes The main pathological reflex sought in childrenis the Babinski sign, the response of the great toeelicited by stroking the plantar surface of thefoot. Because of the lack of myelination of thecorticospinal tracts for the lower extremities, aBabinski or an up going toe (also called theextensor plantar response) is the normal findingduring the first year of life. After the first year oflife the great toe should go down on plantarstimulation. The Babinski sign becomespathological after the first year of life and hasgreatest utility when the responses areasymmetrical. Proper testing for the Babinskisign consists of firmly stroking the lateral aspectof the foot starting at the heel and movingtoward the fifth toe (37). If the medialaspect of the foot is stimulated then a plantargrasp reflex rather than Babinski response iselicited. Confident elicitation of the Babinskiresponse can be extremely challenging in theyoung child who withdraws the foot during themaneuver.



Table 8 Postural reflexes

Reflex Age of Descriptionappearance

Positive 3–4 months Infant extends legs and support supports his weight when

held in the vertical position with feet touching a surface

Landau 4–5 months In ventral suspension, theinfant extends head and legs

Lateral 5–7 months Infant prevents falling to one propping side by extending the

appropriate arm and hand to catch himself (35)

Parachute 8–9 months When the infant is turnedface down and suspended inthe air, the arms and handsextend forward toward themat (36)

35 3635 Lateral proppingresponse in ahealthy young child.

36 Using theparachute responseto assess thesymmetry of upperextremity function.

37

37 Eliciting the Babinski sign.

38

38Watching for pronator drift, an upper motorneuron sign, by having the patient stand withtheir eyes closed and arms extended.

If the child is old enough to follow direc-tions, the examiner should test for the presenceof pronator drift. This sign is sometimes calledthe pronator Babinski because it has the clinicalsignificance similar to the Babinski sign. Thechild is asked to extend his or her arms in frontwith palms up. The child is then asked to closetheir eyes and to hold the arms still (38).Pronation and downward drift of either arm isabnormal. Pronator drift occurs in corticospinaltract disease because the supinators of theforearm are weak and pronator tone exceedssupinator tone.

GaitGait must be assessed in the context ofdevelopment. The infant first develops posturalreflexes and then gets in and out of the sittingposition and pulls to stand. After cruising, thechild begins to take steps on their own at 12–15months of age. In this early, toddler gait, thestation is wide based and arms are held in frontin the high guard position (39). During the nextfew months the station gradually narrows, thegait stabilizes, and arms drop into the mid andlow guard positions. By 18 months the arms areheld to the side and associated arm swingappears. As the child matures, other gait-relatedtesting can be preformed, such as toe, heel, hop,and tandem walking (40). In conditions such asAngelman syndrome, the gait remains toddler-like (41).

Conclusions

The neurological examination provides clinicianswith a window to the brain. Although theprocess is an indirect view, the neurologicalexamination, when conducted with anatomicallocalization in mind, becomes a powerfuldiagnostic tool. The neurological examination ofthe child must be couched in the context of age-appropriate neurodevelopmental expectations.Although it can be frustrating to examine anuncooperative child, patience and imaginationcan transform the examination into a rewardingexperience for examiner, child, and parent.Exploiting the child’s natural inclination towardplay facilitates the successful examination. Manysignificant neurological findings can be elicitedby the simplest of strategies, watching the childwalk, talk, and play.


4139

41A wide-based gait in a young childwith Angelman syndrome.

39A normal toddler’s gait.

40

40 Performing thetandem gait by havingthe adolescent walkheel-to-toe.

CHAPTER 233

Neuroimaging

Main Points• Several modalities, including magnetic resonance imaging (MRI),

computed tomography (CT), and ultrasonography can be used toimage the developing and mature brain.

• MRI provides sensitive and accurate information regardinginfection, neoplasms, hemorrhage, stroke, developmentalmalformations, and spinal cord lesions. Infants and young childrenor uncooperative older children require sedation to achieve optimalMRI studies.

• CT accurately detects hemorrhage, hydrocephalus and intracranialcalcifications and can be performed urgently, usually withoutsedation.

• Ultrasonography provides useful information regarding intracranialhemorrhage and hydrocephalus in neonates and tethered cord or other spinal anomalies in infants <6 months of age.Ultrasonography can be performed at the bedside in unstableinfants.

• Pediatric radiologists should be consulted when orderingneuroimaging studies in young children, especially those whorequire sedation.

Introduction

Many resources are currently available to imagethe developing and mature central nervoussystem. The modalities include: magneticresonance imaging (MRI) and MRI adjuncts(magnetic resonance angiography [MRA],magnetic resonance venography [MRV],diffusion-weighted magnetic resonance imaging[dMRI], diffusion tensor imaging [DTI] andfiber tracking, perfusion-weighted magneticresonance imaging [pMRI], magnetic reso -nance spectroscopy [MRS], and functional MRI[fMRI]); computed tomography (CT),including CT angiography and positron emis -

sion tomography (PET)-CT; nuclear medicinebrain imaging (single photon emissioncomputed tomography (SPECT) and PET);magnetoencephalography (MEG); sonography(cranium and spine); and conventional catheterangiography. This chapter describes themodalities and their utility, including their risksand benefits.

Although remarkable advances in imagingtechnology have been realized among allmodalities, MRI and advanced MRI adjunctivetechniques have had the greatest impact uponthe diagnosis of pediatric neurologicaldisorders. MRI provides an in vivo method toevaluate CNS structure, development, and

Models for sedating pediatric patientscan include the utilization of pediatricians,emergency medicine physicians, hospitalists,intensivists, radiologists, or pediatric nursepractitioners supervised by pediatric anesthe -siologists. Pediatric patients with complexmedical problems, such as severe developmentaldelay, obstructive airway symptoms, congenitalheart disease, and chronic pulmonary insuf -ficiency, are best served by having their MRIexamination conducted under the directsupervision of a pediatric anesthesiologist.Conventional angiography procedures aretypically performed using general anesthesia orconscious sedation with agents such asintravenous midazolam or ketamine.

Magnetic resonanceimaging (MRI)

MRI has become an integral component of theevaluation, diagnosis, and treatment surveillanceof many pediatric neurological disorders. Priorto entering the MRI scanning environment, thepatient and parent will be assessed for anycontraindications to performing the MRI, suchas the presence of a variety of implantable devicesand any history of penetrating trauma withforeign bodies (e.g. BB shot). The neurora -diologist must confirm that a patient with animplantable device or retained foreign body cansafely enter the MRI environment (textbox).

MRI can be safely performed on patients withmany types of implantable devices includingsome types of cardiac pacemakers. Certaindevices are safe at 1.5 Tesla (T) but not at 3.0 T. See: www.MRIsafety.com.

Conventional MRIConventional MRI accurately characterizesbrain organization and maturity, demonstratesmalformations of the brain and spine,comprehensively assesses traumatic injury to the brain, and characterizes neoplastic,inflammatory, infectious, metabolic, andneurode generative disorders. Contrast enhancedMRI contributes additional information in theevaluation of vascular malformations, neoplasms,leukoencephalopathies, complications of


disease. In addition to allowing exquisitedepiction of neuroanatomy, MRI and itsadjuncts provide physiological informationregarding vascular morphology, flow, tissueperfusion (MRA, MRV, and pMRI), cellularviability (dMRI), cellular biochemistry (MRS),and functional brain activation (fMRI).Additionally, advances in computer hardwareand software enable the fusion of large imagingdata sets from several imaging modalities,enabling clinicians to superimpose functionalinformation upon high-resolution structuralanatomy.

Patient safety andpreparation for imaging

In an age of medical subspecialization and withlegitimate concerns over quality, cost, andutilization of imaging technology, the pediatricpractitioner must rely heavily on the pediatricneuroimaging consultant to navigate throughthe maze of diagnostic neuroimaging tests.When questions arise, consultation with apediatric neuroradiologist is invaluable. Oncethe decision has been made to proceed with aneuroimaging examination, the successful andsafe completion of the diagnostic neuroimagingstudy rests in thoughtful patient preparation.

The majority of cranial and spinal ultrasound(US) and CT studies last seconds to minutesand can be successfully accomplished withoutsedation or with distraction techniques (e.g.involvement of play therapists or moviepresentations using television monitors or videogoggles). MRI and nuclear medicine brainimaging examinations tend to be of longerduration, often requiring 30–60 minutes. Inmany children between the ages of 4 years and8 years, motion can be limited by usingdistraction techniques. Children less than 4–6years of age commonly require sedation(textbox).

The initial step in obtaining high qualitydiagnostic neuroimaging studies is for theclinician to determine the necessity forsedation or anesthesia support. When in doubt,consult your medical imaging colleague.

www.MRIsafety.com

meningoencephalitis, neuroendocrine disorders,and the characterization of CNS vascularmorphology and patency (42). However, themodality has some drawbacks (textbox).

Magnetic resonance imaging data arecorrupted by the presence of dental braces,intracranial hemorrhage, and patient motion.All create susceptibility artifacts. MRI maymiss or underestimate calcification andsubarachnoid hemorrhage. Noncontrast CToffers greater sensitivity for calcium.

The common nomenclature are described inTable 9.

CHAPTER 2 Neuroimaging 35

42

42T2-weighted sagittal MRI showing a smallsessile hamartoma of the tuber cinereum(arrow). The child has gelastic seizures.

Advanced MRI adjunctsThe improvements in MRI hardware andsoftware have made it clinically feasibleand practical to complete a comprehensiveconventional MRI examination and includeMRI adjuncts such as MRS, MRA, MRV,dMRI, DTI, pMRI, and fMRI. Commu -nication between the pediatric practitioner andthe pediatric neuroradiologist facilitates atailored MRI strategy that best answers clinicalquestions. All advanced MRI adjuncts aremore robust at higher MRI field strengths, suchas 3.0 T.

Diffusion-weightedimagingThe rapid acquisition of diffusion-weightedimaging information during the MRI exam -ination (dMRI) adds significantly to the sensi -tivity and specificity of MRI findings (textbox).

Diffusion-weighted imaging• Diffusion-weighted imaging usually requires

less than 30 seconds of scanning time andshould be included in all brain MRIprotocols.

• Diffusion-weighted imaging is a sensitivemeans to detect hypoxic or ischemic injuries.

• Diffusion-weighted imaging can becorrupted by scalp IV sites, dental braces,and intracranial hemorrhage.

Table 9 MRI imaging nomenclatureNotation Description UseT1WI T1-weighted imaging Defines anatomyT2WI T2-weighted imaging Detects edema and pathologyGRE Gradient recall imaging Detects bloodSPGR Spoiled gradient recall imaging 3D techniques are particularly helpful to detect cortical malformationsFLAIR Fluid attenuated inversion recovery Sensitive to parenchymal lesions close to CSF spaces, good for

depicting demyelinating lesionsSWI Susceptibility-weighted imaging Detects blood, shear, and slow flowDWI Diffusion-weighted imaging Detects cytotoxic edema, shear strain, abscess characterizationADC Apparent diffusion coefficient Reflects ‘true diffusion’ restrictionDTI Diffusion tensor Characterizes white matter tracts; used for surgical planning,

imaging/tractography malformation characterization, assessment of trauma, ischemia

Signal alteration in a diffusion-weightedimage relates to diminished random translationalmovement of water molecules in tissue.Diffusion-weighted signal abnormality and thedecrease in apparent diffusion coefficient (ADC)of water in ischemic tissue reflects dysfunctionin cell membrane depolarization and resultantintracellular (cyotoxic) edema. Tissue ischemiaand infarction are common causes of cytotoxicedema (43, 44). Vasogenic edema (extracellular)is associated with increased ADC values. Othercauses of restricted diffusion and low ADCvalues include: shear strain axonal injury;necrotizing infections (e.g. herpes simplexencephalitis); mitochondrial cytopathies; toxicsubstances, such as intermediary metabolites andorganic acids; highly cellular anaplastic tumors;abscess; empyema; acute demyelination; andcongenital tumors such as epidermoid cysts.

Diffusion tensor imaging (DTI)Diffusion tensor imaging (DTI) and fibertractography provide unique informationregarding white matter microstructure andconnectivity within the human brain, thusimproving the clinician’s understanding ofdevelopmental anomalies, neurological disor -ders, and psychiatric conditions. DTI andtractography can be used for mapping eloquentwhite matter tracts prior to the resection ofintracranial masses. DTI and fiber tractographycan also characterize developmental malfor -mations such as agenesis of the corpus callosum,holoprosencephaly, and Joubert syndrome. DTIcan quantify axonal loss after CNS injury ofmany causes (45).

Perfusion-weightedMRI (pMRI)Current clinical MRI systems operating at 1.5and 3.0 T field strengths enable perfusionMRI techniques. These techniques can useendogenous (arterial spin labeling) or exoge -nous contrast (susceptibility-weighted contrastenhanced) techniques to investigate capillarydensity and angiogenesis. Characterization ofrelative cerebral blood volume and mean transittime of contrast through tissue reflects tissuecapillary density. Perfusion MRI facilitatesthe evaluation of stroke patients with

diffusion–perfusion mismatch. Here, pMRI canidentify the ischemic penumbra of salvageabletissue surrounding the infarct core. Otherapplications of pMRI include characterizationand grading of intracranial neoplasms,discrimination between neoplasm and post-treatment effects such as radiation therapy,distinction of tumefactive multiple sclerosis(MS) from neoplasm, and evaluation ofrevascularization of the brain following pialsynangiosis.


43

44

43 Diffusion-weighted image showinghyperintense signal in an acute thromboembolicstroke of the left putamen (arrow).

44 Corresponding ADC map to 43 showinghypointense signal reflecting cytotoxic edema(arrow).

MRI vascular imagingMagnetic resonance angiography (MRA) andmagnetic resonance venography (MRV) areuseful supplements to MRI and often substitutefor catheter angiography in the evaluation ofpediatric intracranial vascular disease. MRAreflects the signal generated from protons withinflowing blood. Flow direction, blood volume,and velocity of flow affect the quality of signal andthe apparent size of the vessel. The MRAtechniques most commonly utilized in theevaluation of pediatric neurological disorders aretime-of-flight (TOF) MRA, phase contrastangiography (PCA) and, more recently, dynamictime-resolved contrast enhanced MRA. TOFtechniques take advantage of differences in signalamplitude between stationary tissue from flowingblood, whereas PCA exploits the dif ference insignal phase between flowing and station ary spinsor protons. Factors that influence the appearanceof flow within blood vessels include the directionof flow relative to the plane of imaging, thegeometry of vessels, velocity of flow, and thecomplexity of flow patterns.

At MRI field strengths of 1.5 and 3.0 T,intravenous contrast is usually not necessary toimage cerebral arterial vasculature (textbox).However, contrast administration in MRA ofthe cervical vasculature can be useful. Dynamic


45

45 Diffusion tensor tractography showing lossof bifrontal white matter tracts (arrows).

46

46 MRA reveals a persistent trigeminal artery(arrow), a remnant of the embryonic carotid tobasilar artery connection.

contrast enhanced MRA techniques canvisualize the dynamic process of contrastpassing through the vascular system. T1relaxation (T1 shortening) with intracranialhemorrhages may create the false illusion offlow during routine MRA. Therefore, contrastenhanced MRA is preferred in a setting ofsuspected or known intracranial hemorrhage ordural venous sinus thrombosis. However,gadolinium should be avoided in patients withsevere renal failure, given the risk of nephro -genic systemic fibrosis.

The clinical applications of MRA includeinvestigation and evaluation of: developmentalvascular anomalies, such as embryonic basilarto carotid artery connections; unusual vesselturns that may mimic an aneurysm or varix; therelationship of tumors to vessels (displacementversus encasement); vessel occlusion; arterialdissection; vasculitis; and suspected arte -riovenous malformations (AVMs) (46).

Intracranial MRA can be accomplishedwithout or with contrast. However, evaluationof cervical arterial anatomy and intracranialvenous anatomy is best performed usingintravenous MRI contrast.

49 3D functionalMRI showsactivation of theauditory cortexbilaterally (arrows).(Courtesy ofBrandon ZielinskiM.D., Ph.D.)

MRV is commonly used to evaluate childrenor adolescents with suspected dural sinovenousthrombosis. In this setting, contrast enhanced3D spoiled gradient recall (SPGR) imaging withmultiplanar reformations has the greatestsensitivity in detecting venous sinus clots.Contrast enhanced, fluoro-triggered MRVelegantly depicts cortical veins as well as venoussinuses, thus aiding the neurosurgeon in tumorresection and repair of congenital lesions, suchas an encephalocele, that may be juxtaposed tovenous sinuses (47).


47

47 Coronal enhanced MRV showing a clot inthe sagittal venous sinus (arrow).

48

48 MRS showing elevated choline (1)and reduced N-acetylaspartate (2)peaks in a child with SSPE.

491

2

Magnetic resonancespectroscopy (MRS)MRS provides an additional window into brainimaging and evaluates brain metabolism in vivo.The broad and growing applications of MRSinclude the evaluation and characterizationof brain tumors, metabolic and geneticdisorders, epilepsy, chronic infection (especiallyHIV and subacute sclerosing panencephalitis[SSPE] [48]), demyelinating disorders, hypoxicischemic encephalopathy, head trauma, devel -opmental delay, and creatine deficiency states.Technical limitations for performing MRSinclude the presence of dental braces, intra -cranial hemorrhage, and patient motion.

Functional MRI (fMRI)Functional MRI exploits the blood oxygen leveldependent (BOLD) technique to detectalterations in the oxy/deoxyhemoglobin ratiofollowing activities (paradigms) that aredesigned to stimulate areas of the brain.Functional MRI can be used noninvasively tomap eloquent regions of brain function prior toresection of tumors or epileptogenic foci.Paradigms can exploit motor function, visualcortical activity, language, memory, andauditory pathways (49). In many pediatricmedical centers fMRI has replaced invasiveWada testing (textbox). Some fMRI paradigmscan be accomplished in sedated pediatricpatients.

Wada testing, named after the neurologistJuhn Wada, MD, is used to determine whichside of the brain subserves language andmemory. A short-acting barbiturate is givendirectly into the right or left carotid arteriesduring cerebral angiography to anesthetizeeach side of the brain independently while the child or adolescent is shown objects,pictures, or words. The responses enable the neurologist, neurosurgeon, andneuropsychologist to determine which side isthe dominant hemisphere.

Fetal MRIImproved MRI software and hardware andclinical scanning at higher field strengths allowingfast scanning sequences enable high-resolutionevaluation of the fetus. In many cases, MRIprovides considerable information that supple -ments the commonly performed fetal sono -graphy examination. Before therapeutic decisionsare made on the basis of sonographic ‘abnormal -ities’, fetal MRI should be strongly considered.


Table 10 CT imaging nomenclature

Notation Description Use NCCT Noncontrast CT Detects blood,

calcium, fractures, and skull base and calvarial malformations

CECT Contrast Shows tissue enhanced CT enhancement,

venous sinuses, neck and intracranialvessels

CTV CT venography Detects venous sinus maldevelopment, clot, or injury

CTA CT angiography Identifiesarterial dissection, aneurysm, AVM

50

50 Noncontrast CT showing focal globuspallidus calcifications (arrows) in a child withhypoparathyroidism.

Computedtomography (CT)

CT remains a highly useful test for evaluatingdisorders of the brain, orbits, face, neck, andspine. Common nomenclature is shown inTable 10. Common pediatric neurological appli -cations of CT technology include trauma to thecranial spinal axis, detection and localization ofintracranial hemorrhage and calcium, inter -rogation of complex anomalies in bony develop -ment of the skull, craniovertebral junction andspine, identification of cerebral calcifications(50), investigation of macro crania, and assess -ment of ventricular and extra ventricular fluidspaces in patients with shunted hydrocephalus.

The utility and benefits of CT in diagnosticimaging are counterbalanced by the knowledgethat CT contributes to a patient’s lifetimeionizing radiation exposure. The risk of adversehealth effects, including cancer, is proportionalto the amount of absorbed radiation (textbox).Concerns regarding the long-term effects ofradiation have fostered initiatives to reduce theabsorbed dose from medical imaging proce -dures, especially CT. Current CT equipmentallows flexibility for dose modulation and dosereduc tion while preserving useful diagnosticinformation.

Radiation exposure to children• Children are considerably more sensitive

to radiation than adults. • Children have a longer expected life than

adults, resulting in a larger window ofopportunity for radiation damage andtumor development.

• Children often receive a higher dose thannecessary when ‘adult CT settings’ areused. See: www.imagegently.org.

CT for vascular imagingCurrent multislice CT scanning equipmentallows for sub-millimeter slice thicknesses andisotropic reconstructions in multiple planes.This robust, high spatial resolution technologyis particularly valuable in the trauma setting forimmediate evaluation of vascular injury (dis -section, venous sinus disruption, or post-traumatic venous thrombosis) (51). CTangiography (CTA) and venography (CTV)may be used when MR vascular imaging yieldsequivocal results. Another useful application ofCTA is in the preoperative evaluation ofcomplex congenital anomalies of the cran -iovertebral junction and cervical spine. Here,characterizing arterial to vertebral foraminalrelationships may avert an operative mishap.

Cranial ultrasoundimaging

Cranial US is particularly helpful in newbornsand infants up to 6 months of age. The anteriorfontanelle, posterior fontanelle, andtransmastoid suture are acoustic windows thatallow imaging of the developing brain. Themajor US applications include: inves tigationfor neonatal intracranial hemorrhage andperiventricular white matter injury (textbox);evaluation of cerebral edema; screening forcerebral malformations, especially midlinemalformations, such as agenesis of the corpuscallosum; and the investigation of macro -cephaly (52). In addition to standard real timeimaging, transcranial Doppler sonography cannoninvasively measure velocity and pulsatility ofblood flow within the intracranial arteries andveins that are more centrally located. The


indications for transcranial Doppler in childreninclude the evaluation of sickle cell disease,moyamoya syndrome and disease, andarteriovenous malformations. In some centers,transcranial Doppler plays a role in theevaluation of suspected brain death. Otherindications include the evaluation of intracranialvasospasm following subarachnoid hemorrhageand the characterization of resistive indices inneonates with hydrocephalus.

Cranial sonography provides usefulinformation about the ventricles andperiventricular white matter, but limitedinformation about the peripheral brain andadjacent extra-axial spaces.

Ultrasound imaging ofthe spineUS of the pediatric brain and spine is mostuseful in the newborn and infants in the first6 months of life. A common clinical indicationfor spinal US is the evaluation of the newbornor infant up to 6 months of age with suspectedoccult spinal dysraphism. US of the lumbosacralspine can detect tethered cord and intraspinallipoma or neural tube defects (53). However,MRI remains the preferred imaging modalityfor complex lumbosacral skin abnormalities,such as verrucous hemangioma, combinationof dermal sinus and hemangioma, or dermalsinus alone.

Magnetoencephalo-graphy (MEG)

This noninvasive imaging technique measuresthe magnetic fields produced by electricalactivity in the brain. An instrument known as abiomagnetometer detects small magnetic fieldswithin the periphery of the brain. Mathematicalalgorithms applied to the data allow for relativelyaccurate estimation or mapping of the source ofthe field in three dimensional space. MEG thusprovides information that is entirely differentfrom that of CT or MRI. The latter modalitiesprovide structural and/or anatomicalinformation, whereas MEG provides functionalmapping information regarding potential

www.imagegently.org

51 CT venography showshomogeneousenhancement of thesagittal venous sinus(arrows).

52 Cranial sonography ina 7-day-old baby with anintraventricularhemorrhage (arrow).

53 Prone spinalsonography of an infantof a diabetic mothershows a truncatedtermination of the conusmedullaris at L3 (arrow)and thickening of thefilum terminale(arrowhead). At surgery athickenedfibrolipomatous filumwas found.

54 Nuclear medicinebrain death assessment.Anteroposterior early flow image from a TC-HMPAO scan shows no intracerebral blood flow(arrows).

epileptiform discharges. When superimposedupon 3D SPGR high-resolution brain MRI, theMEG information provides accurate anatomicallocalization of the electrical fields emanatingfrom the brain. MEG applications include:localizing the origin or pathological substrate forseizures; assisting researchers in determining thefunctions of the various parts of the brain; andproviding neurofeedback.

Nuclear medicine brainimaging

Select nuclear medicine brain imagingtechniques detect brain perfusion and metab -olism and neurochemistry (54). The mosthighly developed techniques are single photonemission computed tomography (SPECT)


51 52

53

and positron emission tomography (PET).Currently, SPECT offers spatial resolutionsimilar to PET imaging. Many of theSPECT and PET tracers take advantage ofthe tight coupling between cerebral perfusionand metabolism. SPECT tracers, such astechnetium-99-m-hexamethylpropylene amineoxime (Tc-HMPAO), are extracted by braintissue on the first arterial pass after intravenousinjection and remain within the brain for severalhours. This allows the patient to be imagedwithin hours of the administration of theradioisotope. SPECT imaging has been mostuseful in identifying a seizure focus. During orimmediately after a seizure (the ictal period),the epileptogenic focus demonstrates increasednuclear medicine tracer uptake. Betweenseizures (the interictal period) the seizure focusshows reduced tracer uptake, indicating reduced

54

perfusion or metabolism. PET displays similarfeatures, although clinically useful informationis usually derived from areas of reduced cerebralmetabolism. Current PET radiopharmaceuti -cals include fluorine-18 (F-18) fluorodeoxyglu -cose (FDG) (18-FFDG PET), 11-carbon(C)-flumazenil PET (useful in temporal lobeepilepsy) and α[11-C] methyl-L-tryptophanPET (used to identify epileptogenic tubers intuberous sclerosis). Finally, SPECT and PETimages can be coregistered with either CT orMRI to create multimodal images of functionand anatomy.

Catheter angiography

In many clinical situations, MRA, MRV, andCTA have supplanted catheter angiography.However, there remain several importantindications for catheter angiography (textbox).These include: the initial characterization andfollow-up evaluation of vascular malformations(55); the demonstration and stenting treatmentof suspected arterial injuries (dissection andpseudoaneurysm); the preoperative evaluationand transcatheter treatment of highly vascular

tumors; petrosal venous sampling in patientswith Cushing syndrome; and venous sinusmanometry for the evaluation of pseudotumorcerebri. In addition, catheter angiography hasimportant therapeutic applications, includingembolization of tumors and vascular malfor -mations, clot removal in the setting of venousthrombosis, and coil occlusion of congenitalvascular abnormalities, such as vein of Galenmalformations. The development of spiral 3Dangiographic techniques have shortenedexamination time and diminished radiation doseand contrast requirements.

Catheter angiography• Risk of femoral artery occlusion after

catheter angiography rises in children lessthan 10 kg.

• General anesthesia is commonly necessaryin pediatric patients who require cerebralangiography.

• AVM flow characteristics and associatedabnormalities (aneurysm, varix, andstenosis) are best evaluated with catheterangiography.


55 55 Catheter cerebral angiogram, obliqueanteroposterior, midarterial image shows asmall saccular aneurysm off the left middlecerebral artery.

CHAPTER 343

Electrophysiologicalevaluation ofinfants, children,and adolescents

Main Points• Clinicians should understand common electrophysiological

procedures including: brainstem auditory evoked potentials,polysomnography, electroencephalography, and electromyography.

• Electroencephalography is useful in the evaluation of thefollowing:

– Suspected seizures.

– Unexplained alterations of consciousness.

– Unexplained encephalopathy.

– Evaluation for neurosurgical procedures.

– Suspected brain death.

• An electroencephalogram, ‘a sample in time’, may demonstrate:

– Seizure-like (epileptiform) patterns.

– Asymmetries of amplitude or frequency.

– Slowing of EEG frequencies.

– Wave forms of potential clinical utility (e.g. triphasic waves,periodic lateralized epileptiform discharges).

• Electromyography and nerve conduction studies are difficult toperform well in young children; clinicians should be aware of theimplications of certain abnormal patterns.

• Other electrophysiological studies of value in pediatric patientsinclude: polysomnography, visual and somatosensory evokedpotentials, electroretinography, and electronystagmography.

scalp (57) collect electrical signals from theunderlying brain and muscle, and the signals areamplified and compared through a series of‘differential amplifiers’ in a manner comparableto ECG. In contrast to ECG, however, thesource signals are of much lower strength(amplitude); hence the ‘signal to noise ratio’ ismuch lower. The typical ECG source signals arein the millivolt (mV) range, while those fromthe brain are usually recorded in microvolts(μV). This causes considerably more artifacts inEEG, a situation not aided by the fact thatyoung children and those with neurologicalproblems are often less than enthusiastic abouthaving their heads covered with electrodes!

Likewise, the time scale of an EEG differsfrom that of an ECG. In ECG the typical timescale is 25 mm/sec, while in EEG one usuallyviews 10 sec of recorded time across a page orcomputer screen. An ECG represents 10 orfewer seconds of heart electrical activity, while aroutine EEG consists of 30–45 minutes or moreof brain wave activity. While ambulatorymonitoring is very common with ECG (‘eventrecorders’ or ‘Holter monitors’), ambulatoryEEG recordings are obtained infrequently inpediatrics, given that they are difficult tointerpret and limited to 3 days of data acquisi -tion. In contrast to ECG, in which video record -

Introduction

Electrophysiological tests, especially electroen -cephalography (EEG), can assist the clinician’sevaluation of pediatric patients with suspectedor proven neurological disorders. Given thedynamic development of young children andthe difficulty posed by the uncooperative child,however, obtaining high quality, valid resultscan be challenging. This chapter describescommon electrophysiological tests and focuseson the EEG, electromyography, and nerveconduction testing.

Electroencepha lography

Aside from brain imaging, the EEG is the mostwidely used tool for the investigation of chil-dren with neurological disorders (56). The toolprovides extraordinarily useful information inchildren with possible seizures, but interpretationof the results depends on a thorough knowledgeof the specificity and sensitivity of EEG.

Basics of EEGEEG is essentially an electrocardiogram (ECG)of the brain. Electrodes applied to the child’s


56

56 Obtaining an EEG in a cooperative child.

57

57 EEG electrodes affixed to a child’s scalp.

ings have no role currently, video-EEG can beimmensely useful, as discussed further below.

The EEG recording reflects the summedactivity of numerous postsynaptic braincurrents. The EEG signal (voltage) measured ateach electrode is compared with one or moreother electrodes in a pair-wise fashion. Thedifference in voltage between each pair isdetermined by a differential amplifier, and theoutput produces a recording that fluctuates upand down depending on this difference. Byconvention, an upward deflection of therecording indicates that the voltage at ‘input 1’is negative relative to that at ‘input 2’ (58A).

Multiple pair-wise comparisons are laid outin a presentation known as a ‘montage’ (fromthe French for ‘lay-out’). The locations ofelectrodes are noted by letters (F = frontal; Fp = frontal polar; T = temporal; C = central;P = parietal; and O = occipital) and numbers(even = right; odd = left). The montages aredescribed as either referential or bipolar(58B, C). In the referential montage each scalpelectrode is compared with a more distant,relatively silent or ‘reference’ electrode, such asan electrode applied to the ear lobe (58B). Forbipolar montages each scalp electrode iscompared to a neighboring and active scalpelectrode (58C). Since most epileptic focirepresent strong negative voltages, bipolararrays around a (negative) epileptic focus will‘point’ to the source of the discharge (58C).This pattern, known as a ‘phase reversal’, is avery useful feature of EEG facilitating patternrecognition of epileptiform discharges. EEGwaves are subdivided by convention intofrequency and amplitude ranges (textbox).

Categories of EEG activity• Delta: slow waves, <4 Hz; amplitude <5

to >200 μV; can be diffuse or localized.• Theta: slow to medium frequency waves,

4–7 Hz; amplitude 5–100 μV or greater;diffuse or central location.

• Alpha: medium frequency waves, 8–13 Hz; amplitude 20–100 μV; typicallyposterior in location, attenuates with eyeopening.

• Beta: high frequency waves, 14–25 Hz orhigher; amplitude 5–20 μV; usuallyfrontocentral in location.

CHAPTER 3 Electrophysiological evaluation of infants, children, and adolescents 45

Normal EEG patterns inchildrenPediatric EEG is made challenging by the factthat EEG patterns evolve dramatically over thecourse of brain development. Neonatal elec-troencephalographers recognize useful patternsin premature infants as young as 28 weeksgestation or less, but features resembling someadult patterns are not seen until well after6 months of age. Amplitudes, frequencies, andwake–sleep patterns continue to evolve untilreaching adult-like appearances at approx-imately 8 years of age (textbox).

58

58A EEG signal as measured at scalpelectrodes; B EEG signal referenced to theipsilateral ear; C Bipolar EEG signal.

Fp2–A2

C4–A2

O2–A2

Fp2

Fp2

O2

Fp2A2C4

C4

O2 A2

2

1

A

B

C

A2O2A2

Fp2C4C4O2

Fp2–C4

C4–O2


60 Sleep EEG in a healthy termnewborn infant.

59Awake EEG in a healthy termnewborn infant.

The evolution of normal EEG patterns frominfancy to childhood is depicted in Figures59–64. Amplitudes tend to be higher in younginfants, presumably due to the relatively thin

59

60

skull, and frequencies tend to be slower inyounger children, especially in wakefulness anddeeper stages of non-REM (rapid eyemovement) sleep.

Preterm infants• Different patterns for quiet and active

sleep emerge; discontinuous patterns(tracé discontinue) can be normal inextremely premature infants.

Term infants• Wake: low to medium amplitude activity

in mixed frequencies (activitée moyenne).• Active sleep: similar to wakefulness.• Quiet sleep: discontinuous pattern with

delta brushes (tracé alternant).First year of life• Wake: appearance of 4–5 Hz dominant

posterior frequency.

• Sleep: sleep spindles; becomebisynchronous by end of first year.

Second year of life• Wake: 4–8 Hz dominant posterior

frequency.• Sleep: vertex waves, sleep spindles.By 4 years of age• Wake: ≥8 Hz dominant posterior

frequency.• Sleep: Near-adult patterns.By 8 years of age• Generally similar to adult patterns.

Characteristic EEG features at various ages


6161Awake EEG in a healthy 3-month-oldinfant.

6262 Sleep EEG in a healthy 3-month-oldinfant.

6363Awake EEG in a healthy 6-year-old.

6464 Sleep EEG in a healthy 6-year-old.

65 EEG attenuation over the righthemisphere secondary to asubdural hematoma. Loweramplitudes are apparent from theright hemisphere (oval) than fromcorresponding areas of the lefthemisphere (box).

Abnormal EEG patternsin children: generalconsiderations

AMPLITUDEIn general, any tissue/material (e.g. accumu-lation of cerebrospinal fluid (CSF), subduralblood, or scalp edema) that occupies spacebetween the brain and the collecting electrodeswill reduce amplitude causing attenuation of theEEG activity (65, 66). In addition, variousdiseases that cause encephalopathy are oftenassociated with EEG attenuation (67).

FREQUENCYThe frequencies of EEG wave forms are reducedin most forms of brain dysfunction whichproduce acute or static encephalopathies (e.g.encephalitis, tumor, or ischemic injury). Theresultant abnormalities are described as slowingof the EEG (the presence of excessive slow wavesfor age). The background frequency may beuniformly slow (e.g. in a child with develop-mental delay) or focal slowing may be seen overa diseased area of brain (e.g. in a child with acortical malformation, stroke, or brain tumor).The main exceptions to this rule are epilepticencephalopathies (in which continuous epilep-tiform activity may occur) and intoxication withsedative medications (barbiturates and benzo-diazepines) in which excess fast (beta) activity isseen with therapeutic levels of these medications(68). Very high levels of these medications causeEEG flattening (attenuation) or a burstsuppression pattern.

EPILEPTIFORM ACTIVITYEpilepsy, a clinical condition, is defined simplyas a history of two or more unprovokedseizures. The EEG hallmark of epilepticconditions is ‘epileptiform activity’ which refersto particular patterns that abruptly deviate fromnormal background patterns. Epileptiformactivity is characterized as interictal or ictaldepending on whether the abnormal featureoccurs in between or during an epileptic event,respectively. Some times, the distinctionbetween these two may be very difficult,especially in children with markedly abnormalEEGs. Interictal abnormalities are usuallyisolated or brief, although they may recur veryfrequently, while ictal events are usuallysustained for at least several seconds.

Approximately 5% of normally developingchildren without known seizure disorders haveepileptiform EEGs. Likewise, 4–6% of childrenwith attention deficit hyperactivity disorder(ADHD) and higher percentages of childrenwith language impairments have epileptiformEEGs; up to 30–50% of children with autismhave an abnormal EEG. A potential clinicalpitfall is the presence of frequent epileptiformactivity in neurologically impaired children whodo not have clinical seizures. Children withcortical blindness due to remote occipital lobeinjury, for example, have occipital spikes(epileptiform discharges), but do not neces -sarily have ongoing epileptic seizures. A childwith hemiplegic cerebral palsy (CP) may havean epileptiform EEG while not clinicallysuffering from seizures. Thus, the routine use


65


6868 Medium amplitude frontal,fast activity (oval), as amedication effect.

66

66 FLAIR MRI showing the subdural hematoma(arrows) in 65.

6767 Low amplitude EEG in aninfant with hypoxic ischemicencephalopathy.

of EEG in children with these conditions canbe seriously misleading. An abnormal EEG isinsufficient to make a diagnosis of a seizuredisorder or epilepsy, unless electro graphic andclinical seizures are captured.


69A burst-suppression EEG, an ominous findingat any age.

Recognizable EEGabnormalities in children

Patterns of backgroundabnormalitiesBackground slowing of the EEG is usuallynonspecific. Irregular, unpatterned, localized orgeneralized slowing (often referred to aspolymorphic slowing) may result from virtuallyany pathological process. Background slowing,referred to as postictal slowing, is often seen inchildhood following seizures (febrile orotherwise). Other processes that result inlocalized or diffuse brain dysfunction, such ashypoxic or ischemic injury, global develop-mental impairments, encephalitis, metabolicencephalopathies, and so forth, will also often beassociated with focal or diffuse EEG slowing.The most severe encephalopathies typicallyfollow a continuum of diffuse slowing andattenuation, to episodic suppression (attenu-ation) of EEG activity interrupted by bursts ofactivity (burst-suppression pattern; 69), tomarked generalized attenuation, and ultimatelyto an isoelectric (or flat) pattern with absence ofall cerebrocortical activity (70).

Rarely, certain recognizable patterns of EEG slowing may suggest particular neuro-logical impairments. Regular, somewhat sharplycontoured frontally dominant periodic slowwaves (often known as triphasic waves) aretypical of hepatic and other metabolicencephalopathies, while periodic clusters offrontal slow waves (referred to as frontalintermittent rhythmic delta activity, FIRDA;71) may suggest structural disease, such as braintumor, or encephalopathy.

Patterns of epileptiformactivityIn neonates, a common pattern of epileptiformactivity consists of frequent electrographicseizures often seen in the setting of hypoxicischemic injury. Such protracted trains of epilep-tiform activity are not always associated withclinical seizure activity, but are still consideredictal events (subclinical seizures or electro-graphic seizures). They will often occur inde-pendently from both hemispheres at differenttimes. Typically, such findings suggest a poorprognosis. Likewise in the neonatal period andearly infancy, a pattern of alternating bursts ofchaotic high amplitude spikes and slow wavesinterrupted by periods of marked EEG atten-uation (so-called suppression-burst patterns)can be seen in several epileptic encephalopathiesassociated with metabolic or structural disease,such as nonketotic hyperglycinemia, also knownas glycine encephalopathy.

Later, the classic pattern of hypsarrhythmia isseen in infants with infantile spasms and closelyrelated clustered tonic spasms. This pattern,with a peak incidence in midinfancy, consists ofhigh amplitude, chaotic generalized andmultifocal spike and spike-wave discharges withloss of normal background patterns (72, 73).Often, brief periods (lasting seconds or less) of EEG attenuation (electrodecrementalresponses) can occur in association with theactual tonic spasms. A milder version of thisabnormality, variably defined by differentexperts, is known as modified hypsarrhythmia.

69


7272 Hypsarrhythmic EEG in aninfant with infantile spasms.

7373 EEG following treatment withACTH shows resolution ofhypsarrhythmia (same infant as 72).

7070 Isoelectric (flat) EEG in a childwith the clinical criteria of braindeath.

7171 Frontal intermittent rhythmicdelta activity (FIRDA) (oval).

76 EEG showing photic driving (smalloval) and photoparoxysmal response(large oval) in an adolescent with juvenilemyoclonic epilepsy (JME).

75A brief burst of slow (2.5 Hz) spike-wave activity in a child withLennox–Gastaut syndrome.

74 3 Hz spike-wave discharges in anadolescent with absence seizures.


A few fairly specific patterns are seen in olderchildren. The classic three cycle per second or 3Hz generalized spike-wave pattern (74) occurswith idiopathic general ized epilepsy, especiallychildhood absence (petit mal) epilepsy.Discharges are readily evoked by hyper -

ventilation and if they last more than a fewseconds, produce demon strable alteration ofconsciousness with amnesia for the spike-waveevent. Less regular generalized discharges occur -ring at slower frequencies (e.g. 1–2.5 cycles persecond) tend to be associated with more serious

74

75

76


7777A brief burst of irregularspike-wave activity in JME.

intractable epilepsies such as Lennox–Gastautsyndrome (75) or myo clonic–astatic epilepsy ofDoose. Irregular generalized spike-wavedischarges occurring at faster frequencies (4–5Hz) and photoparox ysmal responses, provokedby photic stimu lation, are seen in children or

adolescents with juvenile myoclonic epilepsy(JME) (76, 77).

Benign partial epilepsies of childhood producecharacteristic focal discharges that often occur inclusters or brief trains and increase markedly infrequency during drowsiness and sleep (78–80).

78 79

8078 Rhythmic sharp and slow waveactivity (circle) in a child with rolandicepilepsy.

79A train or run of sharp/slowdischarges in a child with rolandicepilepsy (oval).

80 Sleep EEG in a child with rolandicepilepsy shows sleep spindles (box)and centro-temporal sharp and slowwave discharges (oval). Sleep typicallyactivates epileptiform discharges inchildren with Rolandic epilepsy.

83An EEG control room for acontemporary epilepsy monitoringunit.


82 PLEDs in a young child with herpessimplex virus encephalitis (circled).

81 Electrical status epilepticus ofsleep.

81

82

83

Sometimes the discharges occur bilaterally in anindependent fashion (i.e not simultaneously fromboth hemispheres). Benign rolandic epilepsy(benign epilepsy with centrotemporal spikes,BECTS) is the most common of these so-calledbenign partial epilepsies. Benign occipital epilepsyof childhood is another example.

An unusual pattern referred to as continuousspike-wave of slow wave sleep (CSWS) orelectrical status epilepticus of sleep (ESES) isseen in a variety of children with mixed neurode-velopmental and neurobehavioral problems.A subset of these may have acquired epilepticaphasia (Landau–Kleffner syndrome), a disorder


Brainstem auditoryevoked potentials

Evoked potentials are less commonly used inpediatric neurology than in adult neurology.Brainstem auditory evoked potential (BAEP),also known as a brainstem auditory evokedresponse (BAER), is utilized commonly toevaluate hearing when other methods areequivocal or cannot be performed due to poorcooperation. This method assesses hearingthresholds at different frequencies and, whensuccessful, provides information regarding thefunctional and structural integrity of brainstemauditory pathways. Cerebral responses (essen-tially, a limited EEG) to repetitive auditorystimuli are summed such that responses, fixed intime relative to the stimulus, are amplified whilerandom noise tends to cancel out. The result, atracing of activity vs. time, depicts wavesattributed to the activation of several structuresalong brainstem auditory pathways. Abnor -malities such as absence of waves, delayedconduction between waves, or asymmetriesbetween ears may be clinically important.Because the procedure is technically chal-lenging, absence of wave I, generated by nervefibers as they exit the cochlea, can be due totechnical failure or can suggest profoundsensorineural hearing loss.

Visual evoked potentials

Similar to a BAEPs, a visual evoked potential(VEP) measures the cortical response to visualstimuli. VEP sums the EEG responses time-linked to a repeating visual stimulus. Themethod can assess visual function in infants andyoung children, and may detect delays inconduction from retina to occipital cortex, asmight occur in optic neuritis, multiple sclerosis,or acute disseminated encephalomyelitis.

in which a child with relatively normal earlylanguage acquisition appears to acutely orsubacutely lose language skills to the point ofappearing deaf (auditory agnosia). Such childrenmay have a few clinical seizures, but their EEGmay demonstrate nearly continuous epilep -tiform activity during slow wave sleep (81).

In acute CNS injuries, an unusual pattern ofperiodic, epileptiform-like discharges, consistingof sharply contoured, localized slow waves orsharp waves recurring at a slow frequency, can beseen. These are known as periodic lateralizedepileptiform discharges (PLEDs). This patternusually reflects acute localized structural injury,such as ischemic damage from profoundhypotension or focal infection/inflammationfrom herpes simplex virus encephalitis and othercauses (82).

Video-EEG monitoring

Well-designed EEG laboratories can recordEEG with video for extended periods (83). Insome cases, portable systems allow for longerterm recording of EEG in the ambulatorysetting without video. The former is usedprimarily in three settings: 1) evaluation ofchildren with ‘seizure-like’ spells of uncertainnature; 2) evaluation of children to characterizebetter the type of epilepsy/seizures; and3) presurgical evaluation of children withintractable localization-related epilepsy whomay be candidates for epilepsy surgery. Inpractical terms, 24-hour video-EEG, which isrelatively commonly available, is usuallyappropriate only if a child’s episodes of concernoccur more than once a day. Otherwise, for lessfrequent episodes, longer periods ofmonitoring may be required. Most ambulatorysystems, subject to greater degrees of artifact,are limited to 48 or 72 hours of continuousrecording. Higher quality data usually resultfrom inpatient monitoring, but capturing spellssometimes requires that the child be in theirown environment and necessitates ambulatorymonitoring.

Electromyography andnerve conduction studies

Electromyography (EMG) and nerve conduc-tion studies (nerve conduction velocity, NCV)are performed less frequently in children than inadults. These technically difficult studies shouldbe performed by a pediatric or adult neurologistwith considerable subspecialty training andexperience. Since the procedure producesmodest pain and apprehension, EMG and NCVstudies frequently require conscious sedation.The pediatrician and child neurologist shouldremember that interpretation of the EMG andNCV can be subjective and limited by thedifficulties noted above. Thus, findings mustalways be considered within the context of thechild’s clinical presentation. Often, musclebiopsy or specific genetic testing (e.g. testing forsurvival motor neuron [SMN1] mutations insuspected spinal muscular atrophy) providesmore useful diagnostic information.

When assessing the function of motornerves, the electromyographer delivers anelectrical shock at a specific point over aperipheral nerve (84, 85) and identifies theresultant contraction of muscle (the compoundmuscle action potential or CMAP). The NCV isthen calculated by dividing the distance inmeters separating stimulating and recordingelectrodes by the time interval in secondsbetween the stimulus and the appearance ofthe CMAP response. In similar fashion, theconduction velocities of sensory nerves can bedetermined by stimulating a sensory nerve andrecording the time it takes for the stim-ulus to reach a distal recording site. Gener-alized slowing of motor NCVs occurs inGuillain–Barré syndrome (GBS), whereaslocalized slowing may suggest compressionneuropathy, as in carpal tunnel syndrome.

The pattern of the CMAP can also be useful.Decreased amplitude occurs with diminishedmuscle activation or with marked muscleatrophy, while a broader, temporally dispersedCMAP can be seen when the various axonswithin a nerve bundle conduct electricalimpulses at different velocities. The latter can beobserved with peripheral demyelination inchildren or adolescents with GBS.

The electromyographer performs an EMGby inserting a very fine needle electrode into amuscle and measuring the muscle’s spontaneous

activity and response to activation. The muscleactivity is viewed on an oscilloscope, and thepattern of activity can be heard via a speaker.The electromyographer recognizes specificconditions not only by the appearances of waveforms (86), but also by their characteristicsounds.

When muscle innervation is diminished (i.e.the muscle is denervated) or muscles areinflamed, muscle fibers fire spontaneouslycreating fibrillations and positive waves. Inaddition, denervation is often accompanied byreinnervation of denervated muscle cells byfibers from healthy alpha motor neurons. Thisresults in the formation of large motor unitsbecause a given anterior horn cell nowinnervates more than the usual number ofmuscle fibers. Activation of these large motorunits is recognized as large polyphasic motorunit potentials (MUPs). Thus, denervationproduces fibrillations, positive waves, fascicu -lations and large polyphasic MUPs. In addition,purposeful activation of the muscle by thepatient is less effective since motor nerves arenot properly innervating their target musclecells. This results in decreased recruitment(fewer motor units are activated for a giveneffort), also known as an incomplete inter -ference pattern. The amount of electrical activitywith voluntary muscle contraction appearsincomplete on the oscilloscope screen.

By contrast, myopathy or dystrophyproduces small, polyphasic MUPs because themotor unit consists of many, weaker musclefibers that generate frequent and smalleramplitude responses. There is relatively normalrecruitment of motor units, but because each ofthese motor units produces small MUPs, theresulting interference pattern is irregular and oflow amplitude. Thus, the hallmarks of myo -pathic disorders are normal NCVs, small poly -phasic MUPs, and a low amplitude interferencepattern.



86

85 Recording nerve conductionvelocities in a young child.

86 Electromyogram showing: A Normal; B Myopathic responses(small polyphasic potentials); C Neurogenic responses (largepolyphasic potentials).

87 Polysomnography showingsimultaneous recordings of EEGand several physiologicalparameters.

A

B

C

84

84 Obtaining median nerve conduction velocity.

85

87

Polysomnography

Polysomnography is being used morefrequently in children to evaluate sleep dis -orders, nocturnal events, apnea, breathingdisorder in sleep, and narcolepsy. Continuousrecording of various physiological variablesoccurs overnight and sometimes duringdaytime sleep the next day (87). A typicalpolysomnogram includes recordings of airflow, oxygen saturation, muscle movement(usually chin and leg), eye movement,abdominal and chest wall movement, and anECG. Although some EEG data are collected


(usually via only two EEG leads), the typicalpolysomnogram provides limited informationregarding nocturnal epileptiform activity. Ifseizures are strongly considered as a potentialcause of a sleep disturbance, a full coverageEEG may be collected simultaneously with thepolysomnogram.

Electronystag mographyand balance testing

Formal evaluation of the vestibular system maybe useful when evaluating children andadolescents with vertigo or unexplained balancedisorders. Hearing and balance centers providecomprehensive data regarding hearing (usingBAEPs), and vestibular function, using electro -nystagmography, posturography, and the rotarychair test. Clinicians often receive a complexinterpretation from such centers and must relyon the conclusions provided by the individualsperforming these specialized studies. Theprocedure may be useful in the evaluation ofchildren with unexplained dizziness, vertigo, orbalance difficulties, as might occur in multiplesclerosis, a disorder that can be seen in childrenas young as 4 years of age. Absence of objec-tive abnormalities in children or adolescentswith episodic dizziness or vertigo often supports a diagnosis of migraine or migrainevariants. High-resolution MRI of the temporalbones can be a useful procedure in children with sensorineural hearing loss or balancedysfunction.

Electroretinography

The electroretinogram (ERG) consists of anevoked potential of the retina. A contact lensplaced on the eye records the response of rodsand cones to flash stimuli with white, red, andblue light. This response, the ERG, reflectsretinal function. The response can be altered ina useful manner by light or dark adaptation andby the nature or intensity of the flash stimulus.The ERG obtained in clinical retinal physiologylaboratories generally consists of an ‘a-wave’followed by a ‘b-wave’ that together reflect thefunctioning of various components of the retinalsystem.

Rod responses are enhanced under scotopic(dark adapted, red light stimulus) circum-stances, while cone responses are enhancedunder photopic conditions (bright ambient light,high flash intensity). In addition, repetitiveflashing of an intense light at 30 Hz normallyelicits a following response of the b-wave of the ERG. This pattern is known as the flickerresponse. The flicker response is believed to begenerated by retinal cones specifically.

The ERG, combined with VEP, can be usefulin identifying neurological disorders associ-ated with retinal involvement. These includedisorders associated with retinitis pigmentosa,such the mitochondrial disorder NARP(neuropathy, ataxia, and retinitis pigmentosa),rare neurodegenerative disorders, such asneuronal ceroid lipofuscinosis (e.g. Battendisease), and disorders of the optic nerve orretina, such as Leber congenital amaurosis orLeber hereditary optic neuropathy, anothermitochondrial disorder. By contrast, the ERGremains normal in children with Tay–Sachsdisease, an infantile disorder associated withseizures, exaggerated startle responses, and acherry-red spot at the macula. The ERG offersa reliable means of monitoring retinal toxicity invery young children treated with vigabatrin.

CHAPTER 459

Cerebrospinal fluid

Main Points• CSF examination (lumbar puncture or spinal tap) provides

diagnostic information when clinicians suspect meningitis,encephalitis, idiopathic intracranial hypertension (pseudotumorcerebri), and rare metabolic conditions, such as glucose transporter(GLUT1) deficiency, cerebral folate deficiency, and disorders ofneurotransmitters.

• The polymerase chain reaction performed on CSF samples is thegold standard for diagnosing many viral infections of the CNS,especially encephalitis due to herpes simplex virus type 1.

• CSF examination can provide supportive diagnostic information inMS, GBS, and CNS leukemia.

• CSF examination infrequently provides useful information inafebrile children or adolescents with seizures or headaches.

• CSF examination is contraindicated in patients with cerebral edemaand intracranial or intraspinal mass lesions, including tumors, brainabscess, and hemorrhage.

Introduction

This chapter describes the physiology ofcerebrospinal fluid (CSF) production and theutility of CSF examination. The latter examin -ation, usually consisting of a lumbar puncture or‘spinal tap’, provides supportive or definitivediagnostic information in several central nervous

system (CNS) conditions, including infections,demyelinating disorders, metabolic disorders,malignancies, and disorders of intracranialpressure. By contrast, lumbar puncture infre -quently provides useful informa tion in afebrile,otherwise healthy children with headache(including migraine) or seizures.

CSF pressure

CSF pressure varies according to the age of thechild, the location within the CNS, and the stateof the patient at the time of the measurement.CSF pressure is lowest within the lateral ventri -cles and highest in the lumbar region when aperson stands or lies in a lateral recumbentposition, the typical position for performing aspinal tap. As measured by a lumbar puncture,normal CSF pressure ranges between 100–250mmH2O. CSF pressures above 180 mmH2O inyoung children are generally considered elevated(intracranial hypertension) whereas pres suresbelow 60 mmH2O are considered low (intra -cranial hypotension). However, pres sures up to250 mmH2O may be normal in children over 8years of age and adolescents, provided thatpapilledema is not present.

Lumbar puncture (spinal tap)

Sampling the CSF by lumbar puncture providesuseful diagnostic information regarding manyconditions affecting the central and peripheralnervous systems. Before performing the lumbarpuncture, the clinician should reconfirm thegoal(s) of the CSF examination and assess thepatient for contraindications (textbox).

Contraindications to lumbar puncture• Papilledema: must have imaging performed

to exclude intracranial mass lesion.• Known or suspected intracranial mass

lesion, especially of the posterior fossa.• Cerebral edema with or without CT or MRI

features of central or uncal herniation.• Transtentorial herniation.• Spinal subarachnoid block by mass or

hemorrhage.• Chiari malformation (90).• Infection of the skin overlying the L3–L5

interspaces.• Platelet count <50,000/mm3 (a relative

contraindication). • INR >1.5.

A serum sample should be obtained prior tothe tap to measure the serum glucose content.The lumbar puncture is typically performed atthe L3–L4 or L4–L5 interspace (91).


CSF production

Humans produce approximately 0.3 ml of CSFper minute, corresponding to 400–500 ml perday for the average adult. CSF arises frommodified ependymal cells of the choroid plexus,a highly vascular structure within the lateral,third, and fourth ventricles. Modest amounts ofCSF are also produced by ependymal cells thatline the ventricular system within the brain.CSF largely represents an ultrafiltrate of blood;each cardiac systole facilitates production ofCSF, whereas each diastole allows resorption ofCSF into the systemic circulation. Certaincomponents of CSF, such as glucose andprotein, enter the CSF via facilitated or activetransport, as discussed further below. Theintracranial volume of CSF in adults averagesapproximately 75 ml; the volume in all CSFspaces is approximately 150 ml in adults. Bycontrast, the total CSF volume in young infantsis only 30–50 ml.

Most of the CSF originates from thechoroid plexus of the lateral ventricles. CSFflows caudally from each lateral ventricle intothe third ventricle through the paired foraminaof Monro (88), small channels that connectthe two lateral ventricles with the single,midline third ventricle. CSF continues itscaudal journey by flowing from the thirdventricle through the tiny aqueduct of Sylviuswithin the midbrain into the small fourthventricle at the level of the midpons andcerebellum (89). CSF then exits the brainthrough the medial foramen of Magendie andthe lateral foramina of Luschka into thecisterna magna at the base of the cerebellum.From this point CSF flows caudally around thespinal cord and eventually turns rostrally intothe subarachnoid space over the cerebralhemispheres, where the majority of CSF isabsorbed into systemic circula tion via theconnections between arachnoid (Pacchionian)granulations and dural sinuses. Minor amountsof CSF are absorbed into the venous circu -lation via the CSF-containing perivascular(Virchow–Robin) spaces.

CHAPTER 4 Cerebrospinal fluid 61

88

88Axial FLAIR MRI showing normal appearingforamina of Monro (arrows).

89

89 Normal, sagittal T1-weighted MRI showingthe cerebral aqueduct (arrow), fourth ventricle(circle), and cisterna magna (arrowhead).

90 91

L4

L5

90 Sagittal, T1-weighted MRI showing a Chiaritype 1 malformation (arrow). The cerebellartonsil extends below the foramen magnum(line).

91A normal sagittal spine MRI showing L4–L5interspace, a potential location of a lumbarpuncture (arrow).

92A diagram showing the ideal position of thechild for performing a lumbar puncture.


The infant, child, or adolescent is placed inthe lateral recumbent position (92); carefulpositioning greatly enhances the success rates oflumbar puncture. Young or anxious childrenmay require sedation, and all will benefit fromplacement of a topical anesthetic, such asEMLA® cream (a mixture of lidocaine andprilocaine), at least 30 minutes before thelumbar puncture is performed.

Sterile procedures are used to minimize therisks to the patient and the person performingthe procedure. The skin of the lower back isexposed, cleansed with an iodinated substanceand alcohol, and covered with a sterile,disposable drape. The landmarks of the iliaccrest and spinous processes are identified toreconfirm the proper site for the lumbarpuncture (92). The skin and subcutaneoustissues overlying the L3–L4 or L4–L5 interspaceare anesthesized using an injectable, localanesthetic, such as lidocaine. After sufficienttime has passed for the anesthetic to be effective,a sterile spinal needle, oriented bevel up andwith stylet in place, is introduced, angled towardthe umbilicus and slowly advanced a fewmillimeters. After each advance, the stylet iswithdrawn to determine if the subarachnoidspace has been reached. Often, a subtle butdistinct ‘pop’ is felt when the spinal duralmembrane is punctured. Needles without styletsshould not be used, since using such needles caninduce dermoid tumors of the lumbar space.

When CSF begins to flow, the openingpressure can be measured by attaching a threeway stopcock and manometer. The child oradolescent should be encouraged to extendhis/her legs and to relax as much as possible.When the patient fights, ‘bears down’, or

performs the Valsalva maneuver, the CSFpressure rises. Samples of CSF are collected intosterile tubes; a minimum of three tubes, eachcontaining at least 1 ml should be collected(tube 1: Gram stain and bacterial or viral studies;tube 2: chemistries [protein and glucose]; tube3: cell count [leukocytes and erythrocytes]).Some authorities suggest that tube 1 be sent forchemistries and tube 2 for microbiologicalstudies. Additional tubes will be necessary forCSF cytology or specialized studies, such asassays of CSF neurotransmitters, amino acids, ororganic acids or studies for multiple sclerosis(MS). When in doubt, consult the referencelaboratory for the appropriate tubes andrequired volumes. In general, 3–6 ml of CSF isobtained routinely from infants and children.Up to 15 ml can be obtained safely fromadolescents.

After removing the spinal needle, gentlepressure should be placed over the insertion siteto minimize local hemorrhage. Potentialcomplications of lumbar puncture includeheadache, local pain, infection, hemorrhage,nerve root irritation, tonsillar herniation, andspinal coning (clinical deterioration after lumbarpuncture in patients with spinal cord neoplasmand CSF block). Postlumbar puncture head -ache, the most common complication, usuallyoccurs in adolescent girls or young adults andconsists of a throbbing headache that beginswithin 72 hours of the lumbar puncture andis exacerbated by sitting, standing, coughing, orsneezing. Migraine-like features, includingnausea, vomiting, and photophobia, can bepresent. The headache often remits spon -taneously, but when severe, may require a bloodpatch performed by an anesthesiologist.

92


CSF content

Normal CSF is a watery liquid with a specificgravity of approximately 1.005. CSF differsfrom pure water by the presence of minuteamounts of protein, glucose, and minerals.Substances that can be identified in theCSF also include lactate, neurotransmitters,steroids, amino acids, organic acids, albumin/immunoglobulins, and complement factors.During certain conditions, bacteria, viralnucleic acids, leukocytes, erythrocytes, andtumor cells can also be detected.

ColorNormally, CSF is clear and colorless. Xantho -chromia (literally, yellow color) reflects thepresence of heme pigment in the CSF and mayindicate subacute subarachnoid hemor rhageand red cell lysis. Xanthochromia appearswithin 2–4 hours of subarachnoid hemorrhageand can persist for as long as 2 weeks afterthe hemorrhage. Xanthochromia can also beobserved when the serum bilirubin exceeds15 mg/dl (256.5 μmol/l) and in infants orchildren with hypercarotenemia.

ProteinCSF protein content arises in large part fromserum albumin; however, some CSF proteinsresult from intrinsic synthesis within the CNS.The lumbar CSF protein content variessomewhat with age. The content tends behighest in neonates, when the amount can be ashigh as 150 mg/dl (1500 mg/l) in healthyinfants, and lowest in young children andadolescents, when values of 15–45 mg/dl(150–450 mg/l) are considered normal. TheCSF protein content rises in many disorders ofthe CNS, including infections, leuko -dystrophies, neoplasms, and demyelinatingdisorders, both central (leukodystrophies) andperipheral (e.g. Guillain–Barré syndrome, GBS).Values of >500 mg/dl (>5000 mg/l) can beobserved during bacterial meningitis, spinaltumors, or spinal subarachnoid space obstruc -tion. When blood contaminates the CSF, theprotein rises 1 mg/dl (10 mg/l) for every750–1000 red blood cells/mm3.

GlucoseGlucose enters the CSF from the blood viafacilitated transport. The CSF glucose leveltypically averages two-thirds of the bloodglucose; equilibration from blood to CSFrequires 1–3 hours. The CSF glucose content isgenerally considered low when the value is<40% of the serum glucose or the absolutevalue falls below 40 mg/dl (2.22 mmol/l) inchildren and adolescents and 20 mg/dl (1.11mmol/l) in neonates. Low CSF glucose levels(hypoglycorrachia) can been observed inbacterial or fungal meningitis, CNS neoplasms,inflammatory disorders, occasional cases of viralencephalitis, and glucose transport deficiency (adisorder due primarily to mutations in the geneencoding the facilitated glucose transporterprotein GLUT1). A CSF/serum glucose ratio<0.4 supports the latter condition. Hypogly -corrachia in bacterial meningitis reflectsimpaired glucose transport into the CSF and,to a lesser degree, utilization of CSF glucoseby bacterial and leukocytes. Elevated CSFglucose levels have no diagnostic importanceother than to suggest a previously elevatedserum glucose level.

CellsNormal CSF contains no erythrocytes andvery few leukocytes. Modest numbers oferythro cytes can be seen during mildlytraumatic lumbar punctures, the consequenceof nicking capillaries or venules duringthe introduction of the spinal needle;occasionally the CSF is grossly bloody due tothe lumbar puncture alone. Waiting forthe CSF to clear and collecting an extratube of clearer CSF can improve thesensitivity and specificity of cell counts aftera traumatic lumbar puncture. Clarifyinga sample of bloody CSF by centrifugationcan help distinguish a bloody tap from asubarachnoid hemorrhage; xantho chromiawill be observed in the latter. Detectingbloody CSF can indicate subarachnoidhemorr hage secondary to nonaccidentaltrauma, rupture of a CNS aneurysm,hemorrhagic neoplasm of the spine or brain,or certain infections, such as herpes simplexvirus (HSV) encephalitis.

The normal CSF leukocyte count variessomewhat with age. Neonates up to 4 weeksof age commonly have increased numbers ofCSF leukocytes, as many as 20 white bloodcells (WBCs)/mm3. By contrast, CSFleukocyte counts should be below 5/mm3 inchildren or adolescents; however, leukocytecounts of 5–10/mm3 may be normal andmust be viewed with caution. When thelumbar puncture has been traumatic,approximately 1 leukocyte is present for every700–1000 erythrocytes/mm3. The numberand type of leukocytes in a CSF sample canprovide useful information regardingbacterial, viral, or fungal infections of the CNS(textbox). Cytological examination of the CSFis useful in many malignancies affectingchildren and adolescents.

CSF in CNS infections• Viral infections are suggested by normal

glucose, normal or modestly elevatedprotein, and lymphocytic pleocytosis. Amixed pleocytosis can be detected in theearly stages of viral disease.

• Bacterial infections are suggested by lowglucose, elevated protein, and neutrophilicpleocytosis.

• Tuberculous meningitis is suggested bylow glucose, elevated protein, andlymphocytic pleocytosis.

Specialized diagnostictesting of CSF samples

Infectious diseasesThe diagnosis of meningitis or encephalitisrequires examination of the CSF. Whenincreased intracranial pressure accompaniesthese infections in older children or adolescents,the lumbar puncture is sometimes deferredinitially and the patient treated empirically withantibiotics based on historical or laboratoryclues. Some experts suggest that mannitol (0.25g/kg) be given to obtunded subjects withsuspected bacterial meningitis approximately 30minutes before attempting the lumbarpuncture. Head CT should be obtained inobtunded patients, but antibiotic therapy mustnot be delayed while awaiting the scan. Inpatients with brain abscess, CSF examination bylumbar puncture is avoided, given that adverseoutcomes in such patients commonly correlatewith performance of the lumbar puncture; themicrobiological diagnosis is best made byneurosurgical aspiration or biopsy of the abscess.

When bacterial CNS infection is suspected,the clinician should obtain routine studies of theCSF (protein, glucose, and cell count) as well asa Gram stain and bacterial culture. Thesensitivity of the Gram stain in bacterialinfections is approximately 70%; either Gram-negative or Gram-positive bacteria can bedetected (93, 94). Culture is considered the


93

93 CSF sample showing leukocytes andgram-positive bacteria (Streptococcus species).

94

94 CSF sample showing leukocytes andgram-negative bacteria (Haemophilus influenzae).

‘gold standard’; however, the polymerase chainreaction (PCR) has promise as a rapid, sensitive,and specific means to detect bacterial pathogenswithin the CSF. When viral infection issuspected, the above studies should also beobtained, given the overlap in clinical featuresbetween bacterial and viral diseases. Studiesspecific for viral CNS infections include PCR,culture and assays of serum, and/or CSFantibodies (Table 11).

Multiple sclerosisAlthough brain MRI has generally supplantedthe need for CSF examination in typical cases ofMS, lumbar puncture can be useful in atypicalcases or suspected cases with normal orequivocal radiographic studies (textbox).

Clinical features of pediatric MS• Optic neuritis.• Unexplained fatigue.• Vertigo, gait disturbance.• Bladder dysfunction.• Weakness or sensory changes.


Table 11 Diagnosis of selected CNS viral infections

Virus Microbiological diagnosis

Herpes viruses Herpes simplex virus types 1 and 2 CSF PCR; serum or lesion fluid PCR in neonatesEpstein–Barr virus Serology; CSF PCRVaricella zoster virus CSF antibody; CSF PCRCytomegalovirus Urine PCR; CSF PCR; urine cultureHuman herpesvirus-6 Serology; CSF PCRHuman herpesvirus-7 Serology; CSF PCR

EnterovirusesNonpolio enteroviruses CSF RT-PCR; serum RT-PCR; stool culturePolioviruses CSF RT-PCR; stool, CSF, saliva culture

Arthropod-borne virusesWest Nile virus CSF IgM antibody; serologyLaCrosse virus CSF IgM antibody; serologyJapanese encephalitis virus CSF IgM antibody; serologySt. Louis encephalitis CSF IgM antibody; serologyTick borne encephalitis viruses CSF IgM antibody; serology

Human immunodeficiency virus Saliva or serum antibody; serum DNA/RNA PCR

Rabies CSF RT-PCR; saliva or serum antibodies

PCR: polymerase chain reactionRT-PCR: reverse transcription polymerase chain reaction

Most reference laboratories offer a CSF MSpanel consisting of CSF immunoglobulin G(IgG) synthesis rate, CSF IgG/albumin ratio,and assays for oligoclonal IgG bands and myelinbasic protein. These assays typically require 3–5 ml of CSF. To enable these calculations,the patient’s serum is assayed concurrently. MScan be suggested by detection of oligoclonalbands, elevated CSF IgG synthesis rate, orelevated CSF IgG/albumin ratio.

Metabolic disordersAnalysis of the CSF can provide usefuldiagnostic information regarding severalmetabolic disorders, including disorders ofneurotransmitters, amino acids, organic acidsynthesis, or mitochondrial function. Childrenor adolescents with mitochondrial disorders mayhave elevated CSF lactate; lactate elevations canalso be observed in bacterial meningitis but suchpatients also have leukocytosis and, usually,hypoglycoracchia, features not observed inpatients with mitochondrial disorders.

Cerebral folate deficiency, a rare disorderassociated with irritability, slow head growth,psychomotor retardation, ataxia, dyskinesias,and seizures, is supported by low CSF levels of5-methyltetrahydrofolate. Neurological symp -toms and signs in infants or children withthis disorder can resolve with folinic acidsupplementation. CSF amino acid analysisprovides the definitive diagnosis in infantswith nonketotic hyperglycinemia (glycineencephalopathy), a life-threatening, autosomalrecessive disorder associated with apnea,neonatal myoclonus, neonatal seizures,hypotonia, and hiccups. Infants with thisdisorder have elevated CSF to plasma glycineratios.

Assay of CSF neurotransmitters providesdiagnostic clues regarding several rare disorders,including GTP cyclohydrolase deficiency (dopa-responsive dystonia; Segawa disease),tyrosine hydroxylase deficiency, aromatic L-amino acid dehydrogenase deficiency, and succinate semialdehyde dehydrogenasedeficiency (textbox).

Clinical features of selected pediatricneurotransmitter disorders• GTP cyclohydrolase deficiency (Segawa

disease): fluctuating dystonia, tremor,postural dystonia, and oculogyric crisis;onset in childhood.

• Tyrosine hydroxylase deficiency: oculogyriccrisis, parkinsonism, tremor, andalterations of tone; onset in infancy orearly childhood.

• Aromatic L-amino acid dehydrogenasedeficiency: hypotonia, torticollis, dystonia,tremor, and dyshydrosis; onset in infancy.

• Succinate semialdehyde dehydrogenasedeficiency: hypotonia, seizures, ataxia,developmental delay, mental retardation,autism, aggression, and anxiety; onset ininfancy or early childhood.

Seizures, developmental delay, chorea,dystonia, autism, ptosis, oculogyric crisis andtremor are among the potential manifestationsof these rare but likely under-recognizeddisorders. Patients with Segawa disease canimprove dramatically with L-dopa therapy.

Miscellaneous conditionsExamining the CSF has an important role inestablishing the diagnosis of several otherconditions, including GBS, pseudotumorcerebri, and CNS leukemia. Within approx -imately 2 weeks of onset of their symptoms,the majority of children or adolescents withGBS have elevated CSF protein levels,sometimes as high as 1000 mg/dl (10 g/l).The CSF in GBS typically has no cells, afinding known as the albuminocytologicdissociation. Persons with pseudotumorcerebri, also known as idiopathic intracranialhypertension, have normal CSF parameters,but elevated CSF opening pressures. Finally,performing a cytopathological examination ofthe CSF can be diagnostic in children withCNS leukemia or carcinomatous meningitis.


CHAPTER 567

Genetic evaluation

Main Points• Genetic and syndromic disorders represent major causes of

neurological disorders of infants, children, and adolescents.

• Web-based clinical and laboratory resources, especiallywww.genetests.org, provide essential information for clinicians.

• Clinicians should understand the implications of autosomaldominant, autosomal recessive, X-linked, and mitochondrial modesof inheritance.

• Genetic studies available to clinicians include karyotype, FISH,DNA methylation, comparative genomic hybridization, and genesequencing.

www.genetests.org


Introduction

Understanding the genetic cause of a neurolog-ical disease provides both families and clinicianswith powerful information. First, families findconsiderable comfort in knowing the name ofthe condition that affects their child. Second,certain disorders have specific treatments thatcan be used only if the disease is diagnosed. Thenumber of unique therapies, such as enzymereplacement therapy in lysosomal storagediseases, grows daily. Third, when the diagnosisis known, clinicians can provide accurateanticipatory guidance and avoid unnecessarytesting. Making the diagnosis of Rett syndrome,for example, enables clinicians to give familiesspecific, detailed information regarding thenatural history of the disorder. Fourth, manyconditions affecting the nervous system areinherited, and knowing whether a condition isrecessive or dominant enables families to plan fortheir and their children’s futures. Finally,knowing the outcome of a disease, whether it isdeath within a few years or a life with minimalhandicaps, provides immense comfort to manyfamilies and children.

Several web-based, user-friendly resourcesprovide useful and accurate information forgeneralists, subspecialists, families, and patients.The most convenient site is GeneTests(www.genetests.org). Information at GeneTests,searchable by disease name, includes currentinformation regarding clinical manifestations,treatment, outcome, the genetic etiology(when known), and a list of laboratories thatperform the diagnostic testing. Anotherpowerful search engine, PubMed, links usersto the entire database of the USA NationalLibrary of Medicine. Families and patientsaccess considerable information on the web,and clinicians can assist in their search.Disease-specific foundations, such as theTuberous Sclerosis Alliance and many others,represent essential resources for families(textbox).

Resources for genetic disorders andgenetic testingGeneTests: http://www.genetests.org/National Human Genome Research Institute:http://www.genome.gov/MedLine Plus: http://www.nlm.nih.gov/medlineplus/genetictesting.htmlNational Office of Public Health Genomics:http://www.cdc.gov/genomics/UK Genetic Testing Network:http://www.ukgtn.nhs.uk/gtn/HomeOMIM: http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim

The entire field of genetic testing isadvancing rapidly; for example, whole genomecomparative hybridization has only beenused clinically for the past 5 years. As genesequencing techniques improve in efficiencyand the costs decrease, screening for the causesof diseases, either at the level of entire genesor of whole genomes, will become a reality.Advances in the technology not only offertremendous advantages for early and accuratediagnosis, but also create new challenges forcounseling and ethics.

To treat neurological diseases of thedeveloping nervous system effectively, cliniciansmust possess a basic understanding of humangenetics. Because families will ask probingquestions about their child’s disease, cliniciansmust be prepared. This chapter provides anoverview of human genetics and the methodsused to detect genetic disorders.

http://www.genetests.org/

http://www.genome.gov/

http://www.nlm.nih.gov/medlineplus/genetictesting.html

http://www.nlm.nih.gov/medlineplus/genetictesting.html

http://www.cdc.gov/genomics/

http://www.ukgtn.nhs.uk/gtn/Home

http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim


www.genetests.org

Human genetics: a primer

Humans have 23 pairs of chromosomes(22 autosomal pairs and 2 sex chromosomesfor 46 total chromosomes); each parentcontributes one set of chromosomes (95).Each chromosome is comprised of deoxyribo-nucleic acid (DNA). The information, writtenin a specific nucleotide code on the sense (5’ to3’) DNA strand, provides instructions how tobuild and operate the body. There are threebasic types of DNA sequences: coding DNA,which contains the coded sequence for aminoacids enabling cells to make proteins; regulatoryDNA, which contains essential informationfor cells to recognize when to make proteins,how much to make, and in which cells to makeit; and other DNA. The other DNA used to beconsidered dismissively as ‘junk’ DNA, butwe now understand that much of the so-called

junk DNA is necessary for subtle cellularfunctions, including gene regulation.

Human DNA is not neatly laid out likevegetable displays in a grocery store, but ismixed together like a tossed salad. A single gene,responsible for making one protein, may bechopped up and spread out over a large segmentof DNA. Regulatory and other DNA, or evenother genes, may lie in between. To organizethis information, each chromosome possesses anumber (1 through 22, X and Y), and each genehas a name. Each segment of the chromosomealso receives a number based on a pattern ofbands that has historically been identified usingspecial dyes. The location of a gene can be onthe short (p: for petite) or long (q: follows p inthe alphabet) arm of the chromosome. Finally,sequencing of the entire human genomeallowed scientists to assign a number to eachindividual base pair of the DNA.

CHAPTER 5 Genetic evaluation 69

95

95A normal female karyogram.

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 X Y


97

97A karyogram showing trisomy 21 (circle).

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 Y X

Wild type

Amino Acids

Nonsense

Amino Acids

Missense

Amino Acids

Deletion

Amino Acids

Insertion

Amino Acids

GTT GCA CCA AGC GAACAA CGT GGT TCG CTTGlu Arg Gly Ser Leu

GTT GCA CCA ATC GAACAA CGT GGT TAG CTTGlu Arg Gly Stop

GTT GCA GCA AGC GAACAA CGT CGT TCG CTTGlu Arg GlU Ser Leu

GTT GCA AGC GAAGAA CGT TCG CTTGlu Arg Ser Leu

GTT GCA GCC AAG CGA ACAA CGT CGG TTC GCT TGlu Arg Arg Phen Ala

96

96 Summary of the types of common DNA mutations.

CCA

In genetics anything that can go wrong doesgo wrong, at least on occasion (96). Trisomy 21(Down syndrome) occurs, for example, becausea child inherits an entire extra chromosome 21(97) or at least extra portions of critical generegions of chromosome 21. Velocardiofacialsyndrome (deletion 22q11), also known asShprintzen/DiGeorge syndrome (98), ariseswhen an essential piece of chromosome 22 isdeleted. Pelizaeus–Merzbacher disease, a raredisorder of white matter (leukodystrophy) canbe caused by a mutation (base substitution) inthe sequence of the DNA that makes theproteolipid protein (PLP22).

A few surprises make genetics and geneticdiagnosis more complicated. Potential sourcesof confusion are genetic polymorphisms,changes in DNA that may or may not be causallyrelated to a child’s condition. For example, a girlmay have autistic features that seem like Rettsyndrome, but sequencing of her MECP2 genemay show only a single base pair change thatmay not change the encoded protein or does soonly a little. So, is the mutation meaningful?Only by comparing the girl’s DNA sequence toher family members, other girls with Rettsyndrome, or a large normal population can it bedetermined whether the genetic polymorphismis significant.

Another confusing problem is mitochondrialgenetics. Mitochondria, the power plants of

human cells, have their own DNA inherited onlyfrom the mother. Some proteins of themitochondria are encoded by the mitochondrialDNA, but additional mitochondrial proteins areencoded by the nuclear or regular DNA.Mitochondrial disorders can result frommutations in either nuclear or mitochondrialDNA or from mutations in both. Nuclear DNAmutations account for most mitochondrialdisorders in childhood.

Consequently, a child may have clinicalfeatures compatible with Leigh disease, aprogres sive neurodegenerative disorder asso -ciated with mitochondrial dysfunction, butdetermining the responsible mitochondrial ornuclear gene can be very challenging.

A final twist to genetics is the observationthat one disease can have different genes thatcause it (genetic heterogeneity) or mutationsin a single gene can cause different diseases(phenotypic heterogeneity). Vanishing whitematter disease, for example, a leukodystrophywith progressive neurological decline, can becaused by a mutation in any one of at least five different genes encoding a eukaryoticinitiation factor. Mutations in the PLP genecan cause Pelizaeus–Merzbacher disease, adisabling leukodystrophy that causes severedevelopmental delay with onset in infancy, or X-linked spastic paraparesis, a slowly progres-sive disorder of adolescence or adulthood


9898The typical facial appearance of DiGeorgesyndrome (22q11 deletion) showing a longnose, epicanthal folds, posteriorly rotated ears,and underdeveloped philtrum.

associated with stiffness and weakness of the legs.

Understanding inheritance enables cliniciansto provide basic genetic counseling to familiesincluding a the discussion of recurrence risk.A recessive disorder means that both copiesof a mutated gene (one copy from each parent)are necessary for a child to have the disease.Many lysosomal storage diseases, such as TaySachs disease or metachromatic leukodystrophy,are inherited in this fashion. Because thecondition is recessive, both parents are well,even though they each carry one mutated copyof the gene. Each offspring of parents carryinga recessively-inherited disorder has a 25% chanceof being affected; 50% of the offspring arecarriers. The remaining 25% inherit both copiesof the normal gene and are neither affected norcarriers.

Dominant conditions require a singlemutated gene for the disorder to be apparent.In this instance, an affected parent passes thecondition to an affected child. For a disorderwith dominant inheritance, such as Hunting -ton’s disease, the risk of the disease in a childis 50%. There are no carriers in dominantlyinherited conditions, only affected or unaf -fected individuals. However, some dominantconditions can be modified by other genes orenvironmental factors, leading to variations inhow the disorder becomes expressed in anindividual (called variable penetrance).

Finally, X-linked disorders are inherited bymutations in genes on the X chromosome.Because males have only one X chromosome,50% of the male offspring of a woman carryingan X-linked mutation are affected, and 50% areunaffected. Examples of X-linked disorders areDuchenne muscular dystrophy (DMD) andfragile X syndrome. The situation for thefemale offspring of carriers of X-linkeddisorders can be complex. In general, 50%of the daughters are carriers and 50%lack any risk of passing the disorderto their offspring, either female or male.Girls or women who carry X-linked disorders,however, sometimes manifest a milder pheno -type. Female carriers of dystrophin muta tions,for example, can have cardiomyopathy, aserious complication of DMD in affected boysand men.

Diagnostic tools

Chromosome studies

KARYOTYPEA karyotype (95, 96), the most basic chromo-some study, reveals large chromosomal deletions,duplications, or rearrangements as well asdisorders of chromosome number (e.g. Downsyndrome [trisomy 21] or Turner syndrome[XO]). In this test the cytogenetic laboratoryharvests mononuclear leukocytes from thepatient’s blood. The leukocytes (monocytes andlymphocytes) are stimulated to proliferate for 3–4 days to enrich the sample with activelydividing cells. The laboratory then treats the cellswith a chemical to arrest the cells at metaphase.The cells are stained with a Giemsa stain toenable microscopic visualization of chromo somalbanding patterns. The chromosomes are paired,photographed, and analyzed. When ordering akaryotype, the clinician should request a high-resolution chromosome karyo type. The higherresolution means that the staining can detectsmaller areas of abnormality than the standardkaryotype resolution.

FLUORESCENT IN SITUHYBRIDIZATION (FISH)FISH can detect chromosomal deletions orduplications that are too small to visualize usingstandard or high-resolution karyotype (99).Each FISH is designed to probe a single regionof the chromosome and therefore detects only a single genetic disorder or mutation. A fluorescently-labeled FISH probe (composedof DNA) hybridizes (anneals) to its comple-mentary sequence on the chromosome. Sincehumans possess two pairs of genes andchromosomes, FISH shows two fluorescentsignals when both are present; samples from a child with a deletion syndrome show only asingle fluorescent signal. In cri du chatsyndrome, for example, FISH detects a singlefluorescent signal (100), indicating deletion of a region of chromosome 5p.

COMPARATIVE GENOMICHYBRIDIZATION (CGH)CGH enables genetic laboratories to screensamples for large numbers of mutations


simultaneously. Developed initially to measureDNA copy number in cancer cells, the methodallows mass screening for many different genedeletions, insertions, or duplications. Themethod employs slide-based microarrays thatcontain DNA regions of interest. The laboratoryextracts DNA from a patient’s leukocytes, mixesit with control DNA, and hybridizes minutequantities of this mixture to the slide.Fluorescent probes are added to the slide, andthe results are computer-generated andanalyzed. This method can simultaneouslydetermine, for example, if a child has Angelmansyndrome or a different gene deletion disorder.

Gene studies

POLYMERASE CHAIN REACTION (PCR)PCR is a rapid, sensitive method that targets an individual gene or chromosome region. PCRexploits the fundamental principle of DNAreplication. In this test the laboratory usesspecific primers (short pieces of DNA) thatspecifically anneal to DNA sequences that flankthe region or gene of interest. The laboratorythen amplifies the region between primers byheating and cooling the sample repeatedly in thepresence of a DNA polymerase. The segment ofDNA of interest is amplified exponentially. ThePCR product can be analyzed qualitatively (thepresence or absence of a PCR product) orquantitatively (the base pair size of the product).For example, PCR in fragile X syndrome, theresult of an expansion of CGG triplet repeats,detects a product that is larger than normal. Inthis instance, >200 repeats indicate fragileX syndrome; <50 are considered normal,whereas 55–200 are considered a ‘premutation’.

SEQUENCINGSequencing analyzes the actual base pair(nucleotide) sequence of a specific gene orregion of the genome. Sequencing is necessaryto detect the different single nucleotidemutations that can render a protein nonfunc -tional and therefore cause the disease. In thismethod, the laboratory extracts a patient’sDNA and then recreates a nucleotide sequencemap of the entire gene. For example, most casesof Rett syndrome result from one of eight mutations (four missense mutations –

a single or point mutation that codes for the wrong amino acid, and four nonsensemutations – a point mutation that results ina premature stop in protein synthesis), but>200 individual mutations in the methylCpG binding protein 2 (MECP2) gene havebeen associated with the disorder. Limitationsof sequencing include the length of timenecessary to produce results and the presenceof polymorphisms that may not be specific for the genetic condition in question.Sequencing can miss gene duplications.


100

100Abnormal FISH showing one green signal,indicating cri du chat syndrome (5p-).

99

99 Normal FISH showing two signals (green)for the short arm of chromosome 5.

Mitochondrial studiesTesting for mitochondrial DNA mutation canbe done by any of the methods discussedabove. Mitochondrial testing is renderedcomplex by heteroplasmy, the mixture ofmitochondria, and mitochondrial DNA,inherited from the child’s mother. Mutationsin mitochondrial genes may be present, butmay not lead to disease. Testing for mito -chondrial disorders therefore relies heavily onfunctional assays that measure the aggregateactivity of mitochondrial enzyme complexes inhuman tissues, usually muscle or skinfibroblasts. Mitochondrial disorders can beinherited as the result of mutations in thenuclear DNA, mitochondrial DNA, or the interplay of both mitochondrial andnuclear DNA.

Obtaining testingTesting can be hospital or institution specific,and depends upon the relationships orcontracting that exists between hospitals andreference laboratories. Many universities and large clinics support laboratories thatperform basic cytogenetic analysis andspecialized testing, such as FISH, on site.Highly specialized testing, such as geneanalysis by sequencing or CGH array, istypically performed by a regional or nationalreference laboratory. Tests for rare disordersmay be performed only at one or two locationsin the world (e.g. the gene test for vanishingwhite matter disease is currently available onlyat a laboratory in the Netherlands). Finally,certain tests are not available on a clinicalbasis; unless you find a researcher interested inyour patient’s disease, you will be unable toobtain testing. If a child possesses the clinicalcriteria for a disease, but the testing has beennegative, don’t hesitate to consult with apediatric neurologist or medical geneticist.

Future directions

Three major issues in the future of genetictesting in pediatric neurology loom on thehorizon. One is the rapid advance in medicalknowledge. Biomedical science has uncoveredmany the genetic causes of neurological disease(e.g. Rett syndrome, hereditary spasticparaplegia), but cost currently limits diagnostictesting. This phenomenon can limit our abilityto provide families with specific geneticdiagnoses, despite the scientific potential to doso. Within the next 20 years affordable, rapidsequencing of entire genomes may be available,but in the meantime, clinicians may be restrictedin what can be offered to patients and theirfamilies.

A second challenge to the clinician is thewealth of information in the medical literatureand lay press. Motivated patients and familiesread material about medical conditions on theinternet and ask clinicians questions aboutspecific disorders. While one of the authors wasdiscussing the differential diagnosis of a newlydiagnosed leukodystrophy, the grandmother ofthe child politely interrupted him and asked“Doctor, why isn’t this vanishing white matterdisease?” As you might guess, the grandmotherwas correct; the child had vanishing whitematter disease. Clinicians must be prepared andaccept the fact that parents and grandparentsmay possess more current information than theclinician. Viewing the care of children withneurological conditions as a partnershipbetween clinicians and families can greatlyenhance the experience for all.

A final area of uncertainty surroundscomplex neurological traits such as autism,epilepsy, ADHD, tics, Tourette syndrome, andmany more. Although some may dependlargely on genetic contributions, the relation -ships between environmental factors and thegenes causing these disorders have not beenfully defined. Moreover, these disorders mayresult from complex multigenic effects or gene–environment interactions. At present, geneticlinkage studies reported in the lay and scientificliterature may impart a false sense that specific,meaningful testing is already available.


CHAPTER 675

Newborn screeningand metabolictesting

Main Points• Newborn screening allows detection of treatable metabolic

disorders prior to the onset of neurologic damage.

• Abnormal newborn screening results require prompt consultationwith knowledgeable consultants.

• Inborn errors of metabolism can cause encephalopathy, seizures,and failure to thrive in infants and young children.

• Older children with encephalopathy, seizures, or cognitive declinesmay have a metabolic disorder.

indicate disease, since frequent false positivesoccur. Whenever there is clinical suspicion for aninborn error, regardless of whether newbornscreening has been obtained, additionaldiagnostic testing is indicated.

Abnormal results on anewborn screen

An abnormal newborn screen result oftenrequires immediate or emergent action by thepractitioner, including evaluation of the patientand initiation of potentially life-saving treatmentas described on the ACTion (ACT) algo -rithms (textbox). Prompt consultation with ametabolic geneticist is always indicated.Pediatricians and family physicians shouldprospectively identify a metabolic expert (e.g. ametabolic geneticist) and keep updated contactinformation readily available for current andfuture reference. (An excellent review is: New -born screening expands: recommenda tions forpediatricians and medical homes– implicationsfor the system. Pediatrics 2007;121;192–218.)

In most regions of the USA, an abnormalresult is referred to the primary care provideridentified on the newborn screening paperwork.

The ACT algorithms can be obtained throughthe American Academy of Pediatrics(www.medicalhomeinfo.org/screening/newborn.html) and the American College ofMedical Genetics (http://www.acmg.net/AM/Template.cfm?Section=ACT_Sheets_and_Confirmatory_Algorithms&Template=/CM/HTMLDisplay.cfm&ContentID=5661).

Inborn errors ofmetabolism

This section describes the clinical aspects ofinborn errors of metabolism as they present ininfants and children. Clinicians must be able torecognize the initial signs and symptoms ofthese disorders, initiate therapy, and refer suchchildren promptly to a pediatric neurologist ormetabolic geneticist to establish a diagnosis andcontinue treatment. Early treatment can preventpermanent neurological damage from many ofthese disorders.

Newborn screening

The goal of newborn screening is to identifyinfants with potentially morbid, but treatablemetabolic disorders prior to the onset ofsymptoms. Newborn screening is mandatoryor recommended in many regions of theworld; however, parents may opt out forreligious or other reasons, depending onthe locale. In the USA the majority of statesrequire expanded newborn screening for galactosemia, amino acidopathies, organicacidemias, biotinidase deficiency, congenitalhypothyroidism, congenital adrenal hypoplasia,disorders of fatty acid oxidation, cystic fibrosis,and hemoglobinopathies.

The first newborn screening test is obtainedin the first 2 days of life, before the infant leavesthe hospital, by performing a lateral heel stick.The drops of blood are collected onto a specialfilter paper card (the PKU or Guthrie card),allowed to dry, and mailed to the healthdepartment or reference laboratory forprocessing. Some regions require a secondscreen at the 2-week well-child check or withinthe first 4 weeks of life. Abnormal results arereferred to the primary care provider or,occasionally, the hospital, and recommendationsfor further testing are provided. The primarycare provider assumes responsibility forcontacting the patient’s family, evaluating theinfant, discussing the results, prescribing initialmanagement, and determining if the childrequires immediate hospitalization.

There are pitfalls in newborn screening. Forinstance, the collection paper cannot becontaminated with food, lotion, hand cleansersand so on, and must be transported to the testingfacility within 24 hours. Excessive heat can alsointerfere with the test, especially when screeningfor galactosemia; prior blood transfusion canalter results for disorders such as hemoglobin -opathies, and hyperalimentation can alter resultsas well. Some disorders, such as galactosemia,only appear when the child has been exposed tothe substance that cannot be metabolized (e.g.galactose); thus, the child may be asymptomaticas well as lack metabolic derangement early inlife. Like most screening evaluations, a normalnewborn screen does not eliminate thepossibility of disease. Some conditions, such asurea cycle abnormalities, are not detected bycurrent newborn screening methods. Similarly,an abnormal result on newborn screen may not


www.medicalhomeinfo.org/screening/newborn.html

www.medicalhomeinfo.org/screening/newborn.html

http://www.acmg.net/AM/Template.cfm?Section=ACT_Sheets_and_Confirmatory_Algorithms&Template=/CM/HTMLDisplay.cfm&ContentID=5661




CHAPTER 6 Newborn screening and metabolic testing 77

Inborn errors innewborns

Metabolic disorders affecting the term orpreterm newborn commonly present withseizures and encephalopathy. Infants with thesesymptoms and signs require urgent evalua -tion for infection, electrolyte derangement,hypoglycemia, and other common causes ofseizures. If such a cause is not readily apparent,clinicians should consider an inborn error ofmetabolism and begin an evaluation for this.Historical clues suggesting the possibility of ametabolic disorder include the onset ofencephalopathy or seizures 2–7 days after birth,as toxic metabolites accumulate. Clinical cluessuggestive of an inborn error of metabolism arecharacteristic odors of the infant’s sweat, urine,or other body fluids (such as ‘musty feet’, ‘maple

syrup’ or ‘cat urine’). If the newborn is clinicallyill and an inborn error is considered a possibility,a metabolic geneticist should be contactedimmediately. The clinician should anticipateshock and hypoglycemia, features common inmetabolic conditions; infants should receiveintravenous fluids containing glucose. Someinborn errors of metabolism are exacerbated bydietary intake of amino acids or proteins, andthese nutrients should be avoided until theunderlying disorder is identified.

Laboratory screening

Inborn errors cause abnormalities in multiplemetabolic tests (Table 12); urea cycle disorders,for example, cause elevated plasma ammonialevels but also cause characteristic patterns of the

Table 12 Initial laboratory studies to evaluate inborn errors of metabolism

Test Class of disorder Example Abnormal results Additional testing

Plasma amino Amino acidopathies; Maple syrup Elevated branched chain Varies, depending acids, urine organic acidopathies urine disease amino acids: leucine, upon disorderorganic acids isoleucine, valine;

low alanineAmmonia Urea cycle disorder Ornithine Elevated ammonia Check for elevated

transcarbamylase urine orotic acid to (OTC) deficiency confirm the

diagnosisLactate Mitochondrial disorder MELAS Elevated lactate Recheck lactate and

pyruvate to determine the ratio (normal lactate:pyruvate is 20:1)

Very long chain Peroxisomal disorder; Zellweger spectrum Abnormal plasma Check pipecolic acid, fatty acids leukodystrophy disorder; neonatal very long chain fatty phytanic acid, and

adrenal acid analysis plasmalogen synthesis to leukodystrophy differentiate between

peroxisomal disordersAcylcarnitine Disorders of fatty acid Medium chain acyl Abnormal profile of Genetic mutation profile; oxidation; metabolic CoA dehydrogenase plasma acylcarnitines; analysis of chromosome; carnitine levels myopathy; mitochondrial deficiency abnormal pattern of region 1p31

disorders serum or plasma carnitine

MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke syndrome.

serum or plasma amino acids. For this reason,the initial evaluation should include severalmetabolic tests, even if only one subtype of aninborn error is clinically suggested. These testscan include plasma amino acids, urine organicacids, serum acylcarnitine profile, serumcarnitine levels, plasma very long chain fattyacids, serum lactate, and serum ammonia.Routine urinalysis prior to administration ofglucose may also aid in diagnosis, butintravenous glucose should not be withheldfrom ill infants or children simply to obtaintesting.

Additional testing may be necessary based onthe infant or child’s presentation (Table 13). Ifclinical suspicion is high, it is not necessary towait for the results of initial testing to sendfurther testing or to initiate therapy. This isespecially important when managing anddiagnosing disorders that require urgent medicalintervention, such as ornithine transcarbamylasedeficiency, a urea cycle disorder.

Imaging

Brain MRI should be considered in theevaluation of infants or children with suspectedinborn errors of metabolism. Glutaric acidemiaor Zellweger spectrum disorder, for example,has characteristic imaging features (101).Consultation with a pediatric radiologist orneuroradiologist prior to imaging the childcan assist with the identifying the necessaryimaging sequences or whether contrast shouldbe administered. MRS can also be helpfulfor diagnosis of certain inborn errors ofmetabolism, such as nonketotic hyperglycinemiaor creatine deficiency (102), a disorder than canmimic cerebral palsy.


Table 13 Additional testing for metabolic disorders based on clinical features

Clinical feature Disorder(s) to consider Additional testingIntractable seizures Sulfite oxidase deficiency; molybdenum Urine sulfocysteine level

cofactor deficiencyIntractable seizures Pyridoxine deficiency; pyridoxine Trial of pyridoxine 50–100 mg

dependency per day; mutation analysis of the antiquitin gene

Intractable seizures Cerebral folate deficiency CSF level of 5-methyltetrahydrofolateCerebellar hypoplasia Congenital disorder of glycosylation Carbohydrate deficient transferrin

levelsAlopecia, eczema, seizures Biotinidase deficiency Serum biotinidase level‘Hiccups’ or seizures in utero Nonketotic hyperglycinemia CSF glycine levelExcessive startle Tay–Sachs disease, Sandhoff disease; Leukocyte lysosomal enzyme analysis

Krabbe disease (103); pyridoxine dependency

CSF: cerebrospinal fluid

CHAPTER 6 Newborn screening and metabolic testing 79

101A T2-weighted MRI showing middle fossafluid collections characteristic of glutaricacidemia type 1.

101

102102 MRS showing markedly diminished creatinepeak (arrow) in creatine deficiency due toguanidinoacetate methyltransferase deficiency.1, choline; 2, NAA.

103103A young infant withKrabbe diseasedemonstrating irritabilityand spastic quadriparesis.

1

2


104

104 ‘Bullseye’ maculopathy (arrow) in a childwith late infantile neuronal ceroid lipofuscinosis.

105

105 Macular cherry red spot (arrow) inTay–Sachs disease.

106

106Autopsy specimen showing pale, balloonedneurons in Tay–Sachs disease (H&E).

Later clinicalpresentations

After the newborn period, inborn errors ofmetabolism may vary in their presentation.A previously healthy infant who developsperiodic encephalopathy, new seizures, or failureto thrive may have an inborn error. Keyelements to review when taking the history arewhether the symptoms began after changingfrom breastfeeding to formula or after theintroduction of new foods, or if symptomsoccur after fasting or with fever. For example,medium chain acyl-coA dehydrogenase(MCAD) deficiency, an autosomal recessivedisorder of fatty acid oxidation, causes hypo -glycemia and hyperammonemia after fasting;these symptoms can appear as the infant beginsto sleep through the night and does not receivefrequent feedings. Some cases of sudden infantdeath syndrome (SIDS) may be due topreviously undiagnosed metabolic disorders,including MCAD. A family history of SIDS orother unexplained childhood death shouldheighten suspicion for an underlying inbornerror of metabolism.

Older children or adolescents with inbornerrors may present with progressive cogni -tive decline, seizures, myoclonus, or visualdeterioration. Clinicians should recognize visualdeterioration and cognitive decline, sometimesmanifesting as declining school performance, asthe initial symptoms of rare disorders suchas neuronal ceroid lipofuscinosis (NCL)(104), juvenile onset Tay–Sachs disease, orNiemann–Pick Type C. Ophthalmologicalfeatures, such as impaired vertical gaze inNiemann–Pick Type C or a cherry red spot inTay–Sachs disease (105), may be the initialclue to a specific diagnosis. Referral to anexperienced pediatric ophthalmologist shouldbe considered in all cases of suspected neurode -generative or metabolic disorders. Figure 106shows characteristic neuropathological abnor -malities of Tay–Sachs disease.

81

Chapter 7Disorders of development

Chapter 8Disorders of behavior and cognition

Chapter 9Disorders of language and hearing

Chapter 10Disorders of head size and shape

Chapter 11Disorders of cranial nerves

Chapter 12Disorders of peripheral nerves

Chapter 13Disorders of gait and balance

Chapter 14Disorders of sleep

SECTION 2

A PROBLEM-BASEDAPPROACH TOPEDIATRICNEUROLOGICALDISORDERS

Chapter 15Disorders of the newborn

Chapter 16Acute focal deficits

Chapter 17The dysmorphic child

Chapter 18Headaches

Chapter 19Hypotonia and weakness

Chapter 20Infections of the nervous system

Chapter 21Movement disorders

Chapter 22Seizures and paroxysmal disorders

Chapter 23Pediatric neurological emergencies

82

CHAPTER 783

Disorders ofdevelopment

Main Points• Clinicians should determine whether one or more developmental

categories are involved.

• When the delay is global, MRI and genetic studies are indicated.

• Clinicians must define whether the clinical course is static orregressive.

• Cases of developmental regression should be referred forevaluation promptly.

• Supportive therapies should be initiated as soon as developmentaldelay is suspected.

Introduction

As many as 15–20% of infants and children havedelays in one or more areas of development. Theclinician’s role in evaluating children withsuspected developmental delay is to recog-nize significant delays, assess for associatedneurological and non-neurological comorbidi-ties, and refer children appropriately for furtherevaluation, as needed. The initial clinicalevaluation should determine if the child hasdelays in single or multiple developmentalcategories and establish if the child’s develop-ment is static, progressing, or regressing. Devel-opmental regression not due to intercurrentillness or other comorbidity merits a promptreferral to a developmental specialist or childneurologist. This chapter reviews the pres-entation and common causes of isolatedcategories of delay and global developmentaldelay and closes with a discussion of devel-opmental regression. Treatment of the child withdevelopmental delay will eventually be tailoredto fit the underlying diagnosis. In all cases,however, the clinician should refer the childpromptly to appropriate therapists, includingspeech, occupational, and physical even beforethe diagnosis is established.

Motor delay

DIAGNOSIS AND CLINICAL FEATURESInfants and young children achieve gross motormilestones at predictable rates (textbox).

Timing of major motor milestones(World Health Organization)

Milestone AgeSitting without support 4–9 monthsStanding with assistance 5–11 monthsWalking with assistance 6–14 monthsStanding alone 7–16 monthsWalking alone 8–18 months

Delay in attaining motor milestones can bediagnosed when the skill level is less than twostandard deviations below the level expected forage. There are many causes of isolated gross

motor delay, some benign and others due tounderlying structural, genetic, or metabolicdisorders affecting the brain, spinal cord, nerves,or muscles. A specific, etiologic diagnosis ismade in <50% of the children with gross motordelays. Nonetheless, establishing a diagnosishelps the clinician, child, and family understandthe implications for the child and family.

Based on the history and physical exam, theclinician should categorize the patient’s grossmotor delay according to the followingdomains:• Temporal profile: static vs. regressive.• Muscle tone: hypotonic vs. hypertonic.• Distribution: hemiplegic, diplegic, or

quadriplegic.

These domains help determine the urgencyof referral, the probability of establishing adiagnosis, and the initial steps of evaluation.Motor regression, discussed at the end of thischapter, requires prompt referral. Intercurrentmedical illness, such as failure to thrive,substantial weight loss, symptomatic cardiacdisease, or psychological stress, can causetransient regression and may require distinctinterventions.

A common scenario encountered by theclinician is the child with a static motor delay.The motor deficit is rarely evident at birth, but as the infant matures, the deficit becomesapparent. An example of this is hemiparesis dueto perinatal stroke. At birth the infant moves allfour extremities smoothly and equally, but by6 months of age hemiparesis and abnormaltone, often manifesting as a fisted (cortical)thumb (107), become apparent. Such an infantmay acquire hand dominance long before thisskill is developmentally appropriate. Acquiringhandedness before the age of 12 months isconsidered potentially abnormal, but somenormal children do not display hand preferenceuntil the age of 18 months. Although theinfant’s motor deficit is static, the deficit maybecome more noticeable as the child grows andattempts to acquire new skills. Evaluation of thechild with a static motor delay is not urgent. Ofgreater importance is the early referral forphysical or occupational therapy to enhance useof the affected limb.

The clinician should characterize the distri-bution of motor deficit (Table 14). Hemiparesis

SECTION 2 A problem-based approach to pediatric neurological disorders84

CHAPTER 7 Disorders of development 85

107

107 Cortical thumb indicating upper motorneuron dysfunction.

Table 14 Selected causes of gross motor delay and associated clinical findings

Condition Associated featuresPerinatalHypoxic–ischemic encephalopathy Complicated delivery; quadriparesis (108)PVL/IVH Prematurity; spastic diplegiaArterial ischemic stroke Neonatal seizures; hemiparesisKernicterus Neonatal hyperbilirubinemia

Congenital/geneticPrader–Willi syndrome High forehead; narrow bitemporal diameter; retrognathia; hypotonia;

neonatal failure to thriveCerebral malformations Microcephaly; macrocephaly; abnormal MRIMyelodysplasia Spastic/hypotonic paraparesis/paraplegiaSpinal muscular atrophy Frog-leg posture; areflexia; tongue fasciculationsCongenital myotonic dystrophy Mother with myotonic dystrophy; neonatal bulbar dysfunction and/or

respiratory failureDuchenne muscular dystrophy Progressive weakness in childhood; male sex; Gower sign

IVH: intraventricular hemorrhageMRI: magnetic resonance imagingPVL: periventricular leukomalacia

108 Scissoring (crossing) of the legs in a childwith cerebral palsy and spastic quadriparesis.

108

refers to weakness of one side of the body, i.e.right hemiparesis refers to weakness of the armand leg on the right side. Weakness tends to begreatest in the arm, followed by the leg, andsometimes the face (109). The presence ofhemiparesis implies a contralateral cerebrallesion, such as a cortical dysplasia or perinatalstroke (110). Diplegia refers to weakness orparalysis of both lower extremities; this typicallyoccurs as a consequence of periventricularleukomalacia (PVL) in which the descendingmotor fibers to the legs are disrupted bydemyelination and axonal damage (111).Similar findings can also be found after bilateralintraventricular hemorrhage (IVH) withperiventricular infarction. In the absence of anappropriate history or brain MRI findings ofPVL, a lesion of the spinal cord should beconsidered.

Quadriparesis, or weakness of all four limbs,should be categorized according to the under-lying tone abnormality. Quadriparesis withincreased tone or spasticity is often the resultof brain injury due to perinatal or prenatalfactors, such as hypoxic–ischemic injury (108).Some congenital muscular dystrophies maycause weakness with rigidity or contractures thatcan mimic spastic quadriparesis. By contrast,quadriparesis with hypotonia, as in ‘floppy baby’syndrome, suggests a neuromuscular cause,such as spinal muscular atrophy.

The diagnosis of cerebral palsy (CP) can bemade when an infant or young child hashemiparesis, quadriparesis, or diplegic para-paresis of prenatal or perinatal origin. CP affectsapproximately 1 of every 500 newborns,resulting from hypoxic–ischemic injury,intrauterine infection, or perinatal stroke. CP isa descriptive diagnosis, and every child with thisdiagnosis should be evaluated for an underlyingcause. Most are the result of prenatal events.Children with CP generally face life-longdisability, although this can range from mild to severe. Although CP denotes motor impair-ment, children with CP often have comor-bidities, such as epilepsy, cognitive impairment,poor growth, gastrointestinal ailments, andorthopedic abnormalities, including progressivescoliosis. Despite advances in obstetric andneonatal care, rates of CP have not changedsubstantially over the past several decades. CP


can develop in both term and preterm infants,although rates are much higher in prematureinfants.

The brain injury causing CP does notprogress, but the clinical manifestations, espe-cially muscle tone and orthopedic compli-cations, may change as the child grows anddevelops. Early on, the infant with incipient CPmay appear weak and hypotonic, but over timespasticity appears in most instances. Infants withsuspected CP should be referred early forservices, including physical and developmentaltherapies. Children with CP are best managedby a multidisciplinary team that includespediatricians, child neurologists, neurodevel-opmental pediatricians, orthopedists, andtherapists. Depending upon the severity of theCP, children with this condition may requireorthotics, walkers, wheelchairs, and assistedcommunication devices.

Isolated gross motor delay often simplyrepresents the extreme end of the normal, bell-shaped curve of development. Dissociation ofmotor maturation, characterized by delays insitting or walking but with otherwise normaldevelopment, is most often a benign condition.Affected children may walk as late as 2 years ofage without any long-term motor impairments.As infants, they may appear to ‘sit on air’ whenheld in vertical suspension; the family historymay suggest other late walkers. Congenitalhypotonia without cause is another benigncondition presenting with hypotonia anddelayed motor milestones. Such children mayroll, sit, and walk late, but appear completelynormal by late childhood. Both conditionsrequire close monitoring to confirm theirbenign clinical course.


110

109The asymmetrically outstretched hand in achild with a right hemiparesis.

110T2-weighted MRI showing a large area ofporencephaly (circle) in a child with hemipareticcerebral palsy due to an in utero stroke.

111

111 FLAIR MRI showing cystic PVL (circle) in achild with hemiparetic cerebral palsy.

109

Global developmentaldelay

The term global developmental delay describesan infant or child with significant delays in twoor more developmental categories; most often,these are in the motor and language domains.Unlike isolated motor delay, global devel -opmental delay does not typically have a benignetiology or complete resolution of symptoms orsigns. Thus, clinicians must recognize thissituation early and initiate evaluation andsupportive treatment to maximize the child’smotor, social, and cognitive outcomes. A causecan be found in up to 50–60% of such cases.Common causes of global developmental delayare listed in Table 15. Again, the clinician’s roleis to determine the temporal profile of thechild’s condition and the distribution of the child’s deficits; in this instance, however, theclinician should determine whether the deficitsare in the gross motor, language, social, and/orfine motor areas. The clinician must againinitiate appropriate supportive treatment andrefer the child, as needed, for further evaluation.Standardized developmental assessment tools,such as the PEDS: Developmental Milestones,allow rapid and reasonably accurate screening ofdevelopment in the primary care setting.

Developmentalregression

Developmental regression usually suggestsserious underlying neurological disease(Table 16). The clinician’s role is to recognizeregression promptly in any of the developmentaldomains, differentiate this from transientregression due to intercurrent disease orpsychosocial stress, and initiate appropriatereferral for services as well as diagnostic evalu-ation. Gross motor regression can be noted asearly as the first few months of life; languageregression is usually identified much later, oncelanguage has been acquired. Language regres-sion is discussed extensively in Chapter 9Disorders of Language and Hearing.

Management ofdevelopmental delay

Developmental assessment is a cornerstone ofwell-child evaluations. Isolated gross motordelay and isolated language delay can be referredon a nonurgent basis while supportive therapies(physical, occupational, language, or devel-opmental) are being initiated. When an infant orchild has global developmental delay without an


Table 15 Selected causes of global developmentaldelay

Condition Associated featuresHypoxic–ischemic Complicated delivery, encephalopathy quadriparesisCongenital infection Microcephaly, intracranial

calcificationsFetal alcohol syndrome Microcephaly, dysmorphic

featuresChromosomal Dysmorphic features, brain anomalies anomaliesSyndromic disorders Dysmorphic features, brain

anomaliesAutism spectrum Impaired language skills, poor disorders social reciprocity, stereotypic

behaviors

Table 16 Selected causes of developmentalregression

Age Condition Features3–6 months Tay Sachs Seizures, excessive

disease startles, cherry-red spot

1–3 years Rett syndrome Loss of language and purposeful hand skills (113)

1–3 years Autism Loss of language and social skills

3–8 years Landau–Kleffner Loss of expressive syndrome and receptive

language (acquiredepileptic aphasia); abnormal behavior

apparent, underlying systemic cause, cliniciansshould utilize algorithms, such as the AmericanAcademy of Neurology Practice Guidelines for Evaluation of the Child with GlobalDevelopmental Delay, to guide their initialevaluation (112). According to this approach,brain MRI and genetic testing have the highestdiagnostic yield. MRS, a useful adjunct tostandard brain MRI, provides essentialdiagnostic information for certain conditions,such as mitochondrial disorders or creatinedeficiency. When these studies are unrevealing,the patient can be referred for subspecialtyevaluation coincident with starting physical,occupational, or speech therapy, as needed. Lossof previously acquired motor or language skills,i.e. developmental regression, always meritsprompt evaluation.

Representative clinicalscenarios

CASE 1An otherwise healthy 16-month-old boy hasgross motor delay. He rolled at 7 months, and satwithout support at 10 months. He has justbegun to pull to stand and will now ‘walk’supported along furniture. He has five individualwords and interacts appropriately with theexaminer. He has no dysmorphic features; hisneurological examination shows normal musclestrength and mild diffuse hypotonia. He is anonly child; no family members have neurologicalor neuromuscular disorders.

This child likely has the syndrome ofdissociated motor maturation. A normal serumcreatine kinase (CK) level, free T4, and thyroidstimulating hormone (TSH) will eliminate


112

Obtain detailed family and perinatal history

Review newborn screening results; repeat tests asneeded

Consider thyroid studies; consider lead level, as needed

(If the diagnosis is evident, refer for services)

Does the child appear dysmorphic or does the historysuggest a genetic or metabolic cause?

Refer for genetic/metabolic evaluation

Consider genetic testing (comparativegenomic hybridization or condition-specificstudies)

Obtain brain MRI

Consider ophthalmology consultation If seizures, obtain EEG

If the MRI is normal, consider geneticconsultation or testing, beginning withcomparative genomic hybridization

Yes No

112 Diagnostic algorithm for children with global developmental delay.

Duchenne muscular dystrophy (DMD) andhypothyroidism. Management consists ofcontinued observation, although referral fordevelopmental services could be considered.

CASE 2An 18-month-old girl has no words and doesnot understand simple instructions; she canpull to stand, but does not take steps inde-pendently. Examination shows a social childwith an occipital frontal circumference (OFC)<3rd percentile; she has wide-spaced teeth,brachycephaly, angular jaw, and diffusehypotonia.

This child likely has Angelman syndrome.This can be confirmed by DNA methylationstudies for 15q11.2-13 deletion/uniparentaldisomy/imprinting and in some, analysis forUBE3A gene mutation. As many as 10% ofchildren with Angelman phenotypes havenormal genetic studies. The child requiresreferral for genetic counseling and devel-opmental services.

CASE 3A previously healthy 3-year-old boy is referredfor evaluation of frequent falls and inability tokeep up with his peers. He walked at 1 year ofage and seemed normal until approximately 6 months ago. Examination shows a waddlinggait and a Gower sign.

This child likely has DMD. A serum CKvalue of several thousand units/L supports thisdiagnosis; DMD can be confirmed by mutationanalysis of the dystrophin gene. He should bereferred to a center with expertise in themanagement of neuromuscular disorders.

CASE 4The development of a previously healthy 11-month-old girl plateaus. During the subse-quent 3 months, she stops saying “mama” or“dada” and shows less interest in playing withher toys. Examination shows a nondysmorphicchild who does not reach for objects. She hasmild diffuse hypotonia and diminished musclestretch reflexes. Her head circumference, onceat the 25th percentile, now plots at the 10th

percentile.This child likely has Rett syndrome, the most

frequently identified cause of developmentalregression in young girls. Common featuresinclude developmental regression, acquiredmicrocephaly, and a characteristic movementdisorder consisting of repetitive hand-to-mouthor hand-wringing movements (113). Thedisorder can be confirmed in >90% of cases byidentifying mutations in the methyl CpGbinding protein-2 (MeCP2) gene.


113

113The hand wringing movementscharacteristic of Rett syndrome.

CHAPTER 891

Disorders ofbehavior andcognition

Main Points• Disorders of attention occur commonly in children with:

– Epilepsy, especially when intractable.

– Learning disabilities or cognitive impairments.

– Acute or chronic encephalopathies.

– Sleep disorders.

• Several anticonvulsant medications affect behavior and cognition:

– Phenobarbital causes hyperactivity and impairs short-term memory.

– Topiramate commonly causes reversible cognitive impairment.

– Divalproex sodium or valproic acid can cause reversible dementia.

– Levetiracetam may cause oppositional disorders, especially inadolescents.

• Children with disorders of cognition may require:

– MRI with or without MRS.

– Genetic evaluation including directed FISH for specific conditions orcomparative genomic hybridization.

• In autism spectrum disorders (ASD):

– Children commonly have disorders of language and behavior.

– The diagnostic yield of MRI is low.

– Specific neurological conditions, such as epileptic aphasia(Landau–Kleffner syndrome), can present similarly to ASD.

• Organic brain syndromes can present with acute, subacute, orchronic disorders of behavior and cognition.

Introduction

Disorders of behavior and cognition, oftencalled neurobehavioral disorders, occurcommonly in children. Moreover, many neuro -logical disorders, such as epilepsy, develop -mental delay, tic disorders, acute or chronicencephalopathies, and traumatic brain injury(TBI), can be accompanied by neuro-behavioral dysfunction that can exceed themorbidity of the neurological disorder per se.Not surprisingly, these situations produceconsiderable parental distress and familydiscord. This chapter describes selecteddisorders and emphasizes that children andparents benefit from a multidisciplinaryapproach to managing these conditions.

Disorders of attention

Approximately 5–10% of boys and a nearly equalnumber of girls living in the USA and othercountries may fit criteria for attention deficithyperactivity disorder (ADHD). The majorityof these children do not have other identifiablefunctional or structural neurological impair -ments. The principal features of ADHD arehyperactivity and difficulties with attention andimpulse control. The disorder can be catego -rized into subtypes (hyperactive–impulsive,inattentive, or combined), depending upon thepredominant symptoms or signs. The diagnosisof ADHD relies upon the observations ofparents and teachers and the utilization ofquestionnaires, such as the Vanderbilt ADHDDiagnostic Parent and Teacher Rating Scales,that score key behaviors present in children withADHD.

Management of ADHD requires a com -bination of behavioral approaches and medica -tions, such as the stimulants methylphenidate,amphetamine, and dextroamphetamine, and anorepinephrine reuptake inhibitor, atom -oxetine. Side-effects of stimulants includedecreased appetite, poor growth, insomnia, andtics. Children or adolescents with ADHD mayhave coexisting disorders, including learningdisability, oppositional defiant disorder, anxietyand depression, emphasizing that individualswith ADHD often need a multidisciplinary

therapeutic team consisting of primary careclinicians, psychologists, and child or adolescentpsychiatrists.

Children with neurological disorders affect -ing the function of the cerebrum and associatedwith so-called ‘static encephalopathies’ or‘organic brain syndromes’ have high rates ofimpairments of attention (Table 17). Somestudies suggest that the latter children are lesslikely to respond to stimulant medication thanchildren with ADHD alone, although thisconclusion is controversial.

Management of the underlying neurologicaldisorder must often be accompanied bythorough evaluation and management by a childpsychologist, behavioral therapist, and/or childpsychiatrist. Clinicians must understand thechild’s cognitive abilities and neuropsychologicalprofile to manage a child’s condition well. Suchinformation guides an optimal educational plan,allows families and educators to set appropriateexpectations and, as the child approaches adultage, allows for identification and recruitment ofavailable community resources and transitionservices. Preparation for the transition toadulthood is too often overlooked; the child andfamily are best served by providing anticipatoryguidance several years in advance of the youngadult’s needs.

Neurobehavioral toxicityof antiepileptic drugs

The majority of the antiepileptic drugs (AEDs)have ‘neurotoxic’ side-effects. In general, drugsthat enhance GABAergic tone (e.g. barbi-turates, benzodiazepines, tiagabine) are morelikely to produce unacceptable cognitive andbehavioral side-effects than others (Table 18).Most of these effects are dose dependent andincreased by polypharmacy. The practitionermust query the patient and family regardingmedication side-effects at every visit. It is alsouseful to warn the family regarding thesepotential side-effects and to engage in a pactwith parents ahead of time that AED treatmentwill be altered or adjusted in the event of suchtoxicity. This approach will foster a greaterdegree of trust between the family and thephysician.


CHAPTER 8 Disorders of behavior and cognition

Table 18 Neurobehavioral effects of commonly used anticonvulsant medications

AED Effect*Carbamazepine/oxcarbazepine Aggressiveness (uncommon)Clobazam SomnolenceEthosuximide Somnolence, sleep disturbances, psychosisFelbamate Insomnia, anxietyLamotrigine SedationLevetiracetam Oppositional/defiant behavior (especially in adolescents)Phenobarbital Hyperactivity, impaired short-term memory, sedationTiagabine SomnolenceTopiramate Cognitive/memory and language impairment, sedation, hyperactivity

(especially in younger children)Valproic acid/divalproex sodium Asthenia, sedation, dementia (rare)Vigabatrin Somnolence

*Some anticonvulsants may increase the risk of suicidal thoughts or behaviours.

93

Table 17 Selected conditions causing acute and subacute onset of organic brain syndrome in children andadolescents

Condition Typical age of onset Cardinal feature(s)

Opsoclonus–myoclonus syndrome Infancy to 5 years Neuroblastoma; acute cerebellar ataxia; (OMS) of age opsoclonus

Lennox–Gastaut syndrome (LGS) 2 years to early Astatic, atypical absence and generalizedchildhood convulsive seizures; generalized spike-wave

discharges on EEG ≤2.5 cps)

Myoclonic–astatic epilepsy of 2 years to early Astatic and atypical absence seizures; generalizedDoose (MAE) childhood spike-wave discharges on EEG ≤2.5 cps)

Systemic lupus erythematosus (and/or Older than 5 years Rash; splinter hemorrhages; acute encephalopathy anticardiolipin antibody syndrome) +/– stroke-like symptoms or chorea

Accidental or purposeful intoxication Any age Variable degrees of obtundation, (drugs, products, natural substances) disorientation, agitation

Medication side-effects Any age Variable degrees of obtundation, disorientation, (corticosteroids, chemotherapeutic agitationagents, OTC agents, etc.)

Meningeal malignancy (leukemia, Any age Headache; agitation; confusion; seizureslymphoma, primitive neuroectodermal tumor [PNET])

Acute disseminated Any age Acute/subacute encephalopathy; optic neuritis; encephalomyelitis (ADEM) seizures; long tract signs

Posterior reversible encephalopathy Any age Evidence of hypertension; visual impairment; syndrome (PRES) headache; agitation; confusion; seizures

Gliomatosis cerebri Second decade Behavioral decline; disinhibition; confusion; agitation; seizures

Disorders of cognition

Disorders of cognitive processing, relativelycommon in childhood, cause considerablesadness and frustration for parents. This difficultsituation is compounded by the absence of aspecific etiologic diagnosis for the majority ofchildren with mild intellectual retardation(intellectual quotient [IQ] 50–70) or learningdisabilities (LDs); parents may be distraught that‘nobody can tell them what is going on’.Included in this category are disorders of globalcognitive impairment (mental or intellectualretardation) and more restricted disorders ofcognition, known as LDs, in which academicachievement in one or more selective areas isimpaired more than expected relative to thechild’s overall intellectual potential. Childrenwith severe LDs and language impairment mayfunction less well than children with mildintellectual retardation. Individuals withcognitive disorders often have associateddifficulties with social judgment, problemsolving, impulse control, self-esteem, andemotional stability.

DEFINITIONSMental retardation (intellectual impairment orintellectual retardation), a neurological con -dition associated with global intellectualdifficulty, is defined by the combination of twofeatures: 1) IQ less than 70 (normal = 100 witha standard deviation of 15) (textbox), and 2)associated functional impairments in age-appropriate activities and expectations. Thelatter, a vague concept, is difficult to measure.

IQ Mental retardation70–79 Borderline50–69 Mild35–49 Moderate20–34 Severe<20 Profound

LDs are more difficult to define becausethere is no established consensus. Oper -ationally, these are defined as cognitiveimpairments in which a significant discrepancyexists between academic achievement andoverall intellectual potential. In the UK and

other European countries, the term ‘learningdisability’ has been used nearly synonymouslywith the USA term ‘mental retardation’.

DIAGNOSIS AND CLINICAL FEATURESEvaluation of suspected intellectual retardationrelies on standardized tests of cognitive ability(IQ tests) administered by a qualified psy -chologist (textbox).

Standardized tests of intellectualfunction

StandardStanford Binet (2.5 yr to young adult)Weschler Preschool and Primary Scale ofIntelligence (WPPSI) (2.5–7 yr of age)Weschler Intelligence Scale for Children(WISC) (6–16 yr of age)Weschler Adult Intelligence Scale (WAIS)(16–89 yr of age)

NonverbalLeiter (2–20 yr of age)Universal Nonverbal Intelligence Test (UNIT)(5–17 yr of age)Test of Nonverbal Intelligence (TONI) (6–89 yr of age)

This evaluation can be affected by socio-economic, cultural, or linguistic backgroundsand complicated in children with autism,deafness, language disorders, and emotional orpsychiatric conditions. The diagnosis of mentalretardation cannot be made confidently inchildren under 2 years of age. However, adevelopmental quotient (DQ) generated bystandardized instruments, such as the GessellDevelopmental Schedules, does correlate wellwith future measures of IQ.

Based on standardized IQ measurements andassociated population based studies, approx-imately 2% of the population has an IQ <70 andis considered intellectually impaired. Themajority of persons with an IQ of 50–70 lackidentifiable syndromic or structural brain abnor-malities that explain their cognitive impairment.Nevertheless, some individuals within thisgroup do possess brain malformations, congen-ital syndromes, or identifiable, familial condi-


tions. Thus, evaluation for such entities shouldbe considered. Among individuals with IQ <50,the majority are associated with other medicalor neurological disorders, including congen -ital syndromes and cerebral palsy. Medicalhistory, e.g. history of perinatal encephalopathyor encephalitis, and examination, e.g. phys -ical features suggesting a specific syndromicdisorder, guide the diagnostic assessment.

All children with cognitive disorders requirecareful physical and neurological evaluation andthorough psychoeducational testing. Thediagnostic evaluation beyond IQ testing iswarranted when a child has a history of globaldevelopmental delay before the age of 2 years,evidence of dysmorphism, or a family historyconsistent with an identifiable condition suchas fragile X syndrome, X-linked hydrocephalus,myotonic dystrophy, and others. Publishedpractice parameters regarding children withglobal developmental delay suggest that brainimaging (MRI) followed by genetic testingoffers the highest yield. In some cases, MRSmay add to the diagnostic yield, especially inchildren with suspected mitochondrial disor-ders or creatine deficiency (guanidinoacetatemethyltransferase deficiency). Studies for inbornerrors of metabolism (metabolic disorders)have very low yields in the absence of suggestivefeatures (e.g. children with homocystinuriadisplay neurological deterioration, arachno-dactyly, myopia, and ectopia lentis).

Given the rapid technical advances in the fieldof genetics, the ‘best’ approach to genetic testingconstantly changes. Current options include: a) early referral to a medical geneticist; b) targeted genetic testing using FISH for asuspected genetic defect (e.g. 7q11.23 deletionin Williams syndrome); or c) comparativegenomic hybridization (CGH) which may havehigher yield if no specific entity is suspected. Thelatter study, however, can miss larger chromo -somal anomalies such as balanced translocations,indicating that routine high resolution karyo -typing is still useful. Many experts recommendmolecular studies for fragile X mutation in anyboy with unexplained mental retardation;restricting such testing to boys with typicalclinical features or with a suggestive familyhistory may be more cost effective.

MANAGEMENTThe inability to provide effective medicaltherapies for the vast majority of children withintellectual retardation causes considerablepessimism among pediatricians and childneurologists. Families often resort to alternativeor complementary medical interventions foundon the internet or in the lay literature.Nootropic agents, such as piracetam, are notwidely used in the USA.

By contrast, thoughtful anticipatory guid-ance, as well as early recruitment of optimalmultidisciplinary resources, is invaluable. Thepediatrician or child neurologist can helpfamilies identify proper professional, educa-tional, and community resources. Associateddisorders of mood and attention may requirespecific pharmacotherapy with stimulants orantidepressants. Behavioral and family therapymay provide considerable benefits to the childand family. Attention to future transitionservices and to community programs andservices available once the child is older than 18is essential. These vary across communities;practitioners should create a comprehensive listof such resources that can be provided toparents.

CHAPTER 8 Disorders of behavior and cognition 95

Learning disability

DIAGNOSIS AND CLINICAL FEATURESLDs consist of heterogeneous disorders ofcognitive processing in which academicachievement in one or more cognitive domainsis worse than expected based on the individual’soverall intellectual potential. Approximately 5%of children in the USA receive special education,but an even higher percentage is likely to haveLDs (textbox).

Common subtypes of learning disability• Dyslexia: impairment of reading despite

normal intellect.• Nonverbal LD: difficulties with visuospatial

processing, spatial organization,nonverbal problem solving and nonverbalsocial skills.

• Mathematical disability: impairment ofarithmetical and mathematical ability.

• Writing disability: impairment of writtenlanguage.

• Disorders of executive function:impairment of organization and regulationof behavior and abilities.

The prototype and most prevalent of these isdyslexia. Dyslexia refers to significant impair-ment in reading ability despite normal intelli-gence; however, the term is often used toencompass various deficits of languageprocessing and learning in which difficulties inreading are prominent.

LD should be considered in children withschool difficulties and strongly suspected whenformal psychometric testing identifies a discrep-ancy between academic achievement and IQ.The definition and implications of LD varywidely among authorities and educationalsystems. Identification of children with LD isfurther complicated by that fact that suchdiscrepancies may also result from numerous,noncognitive confounders such as socioculturaland linguistic background, emotional andpsychiatric disorders, stress and anxiety, educa-tional neglect, and sleep disorders. Especiallychallenging are the children with borderline IQsand deficits in specific cognitive areas. Suchchildren do not qualify as mentally or intel-lectually retarded and may not demonstrate

discrepancies of sufficient magnitude to belabeled LD, yet may have academic abilitiessubstantially more disabling than those ofchildren with mild mental retardation.

Most children with LD do not haveidentifiable neurological or medical conditionsthat explain their disorders. However, studiessuggest a strong genetic influence on LD,emphasizing the importance of a thoroughreview of the family history. The simple question“who in the family is your child most like?”often provides important insights for bothclinicians and parents. Recent studies usingfMRI and diffusion tensor imaging suggest aneuroanatomical basis for certain conditions.Subtle cortical dysgenesis in the sylvian andposterior temporoparietal regions of the lefthemisphere has been identified in persons withLD. The usual asymmetry of the planumtemporal (the posterior–superior portion of thetemporal lobe that encompasses language and isnormally larger on the left side of the brain) maybe absent or reversed in persons with dyslexia.LDs can also be associated with numerousmedical, syndromic, and neurological disorders(textbox).

Selected conditions associated withlearning disability• Diabetes mellitus.• Epilepsy.• HIV/AIDS.• Low birth weight/prematurity.• Neurofibromatosis type 1.• Velo-cardio-facial (Shprintzen–DiGeorge)

syndrome.• Turner syndrome.• Fragile X carrier state.• Tourette syndrome.

MANAGEMENTThe management of children with LD mustinvolve parents, educators, and clinicians. Nospecific pharmacotherapy exists, althoughpsychostimulants have roles in children withdisorders of attention. Certain nations, such asthe USA, mandate services for children with LD.Generalists and specialists, e.g. child neurol-ogists, should function as advocates for childrenwith LD and assist families in identifying andimplementing the appropriate resources for their


children. Children with LD place an enormousemotional burden on many families, oftennecessitating psychological and psychiatricservices for the child and family. Although thesedisorders affect children lifelong, many childrenwill improve or adapt, particularly when theappropriate psychoeducational interventionshave been identified.

Autism spectrumdisorders (ASD) andrelated conditions

DIAGNOSIS AND CLINICAL FEATURESImpaired social interaction represents the corefeature of childhood conditions subsumedunder the rubric of the ‘pervasive devel-opmental disorders’ or ASD. At their extreme,these relatively common conditions causesome of the most disabling impairments ofneurological functioning among children,adolescents, and adults. The pathogenesis andoptimum management of these disordersremain poorly defined. We focus here onneurological issues specifically related to thepervasive developmental disorders.

The DSM-IV defines autism according to achecklist of criteria in three domains: a) recip-rocal social interactions; b) communication; andc) restricted and repetitive patterns of behavior orinterests, with an onset in the first 3 years of life.If a child meets an adequate number of criteria,the diagnosis of childhood autism is made; iffewer criteria are applicable, the child is identifiedas having pervasive developmental disorder nototherwise specified, PDD-NOS. Establishedstandardized instruments have been utilized forthe more formal diagnosis of autism (textbox).

Autism spectrum disorder diagnosticchecklists• DISCO ( Diagnostic Interview for Social

and Communication Disorders).• ADI (Autism Diagnostic Interview).• ADOS (Autism Diagnostic Observational

Schedule).• CHAT (Checklist of Autism in Toddlers).• STAT (Screening Tool for Autism in

Two-year-olds).• SCQ (Social Communication

Questionnaire).

Frequently, the cardinal clinical features areevident from a careful history and observationalclinical examination. In milder or atypical cases,formal evaluation may be necessary to confirmone’s diagnostic impression. Depending on thecommunity, the services desired, and theeducational program, definitive diagnosis byone of the instruments listed may be required.


Consensus documents regarding the medicaland neurological evaluation and management ofchildren with autism indicate that neurodi-agnostic studies are of limited value. In ASDwithout associated neurological or dysmor-phological features, the yield of brain imaging(MRI) is very low; most abnormal findings areincidental. EEG to identify continuous spike-wave of slow wave sleep should be considered in children with language regression. Genetictesting is indicated if the child has dysmorphicfeatures or a family history suggesting a geneticetiology. Only 2–5% of children with autismhave a recognizable disorder, such as tuberoussclerosis or fragile X syndrome; CGH maydetect unsuspected genetic mutations in a smallnumber of children with ASD.

Childhood disintegrativedisorderThis enigmatic condition is often thought of as‘late-onset autism’. These are children whoacquire core features of autism after the age of 3 years. Fortunately, this tragic condition is rare.Children presenting in this fashion deservethorough and complete neurological evaluation;the differential diagnosis overlaps considerablywith that of childhood onset organic braindisorders discussed below. Landau–Kleffnersyndrome (also known as acquired epilepticaphasia) deserves consideration in youngchildren with language regression (textbox; seeChapter 9 Disorders of Language and Hearing).

Features of Landau–Kleffner syndrome• Onset between 3 and 7 years of age.• Loss of the ability to understand spoken

language (so-called auditory agnosia).• Loss of spoken language.• Abnormal EEG showing epileptiform

features, often lateralizing.• Behavioral abnormalities, such as

hyperactivity, aggression, or depression.


Organic brain disordersof childhood

The term ‘organic brain disorder’ or ‘organicbrain syndrome’ refers to a heterogeneousgroup of conditions in which changes inbehavior and higher cortical function representthe core manifestations of a medical rather thana psychiatric disorder. Although rare, theseconditions present considerable challenges forphysicians and families. In general, conditionspresenting acutely (less than 1–2 days) or in asubacute fashion (days to weeks) are caused byunrecognized or established systemic diseases ortheir treatment (Table 17). Those presentingwith slow deterioration in function may be dueto such conditions as well, but may alsorepresent uncommon familial or hereditarymetabolic or neurodegenerative diseases(Table 19). Separation from psychiatric disordersremains extremely challenging and relies onrecognition of historical or examination cluesand on targeted diagnostic testing.

Conversion disorders

Previously referred to as hysteria, conversiondisorders encompass a group of conditions inwhich demonstrable or putative psychogenicfactors lead to clinical signs and symptoms that mimic ‘organic’ neurological disease.According to this formulation, suppressed or unconscious psychological conflict isconverted into outward physical manifestations.Distinguishing conversion from malingering(conscious, wilful mimicking of organic diseasewith intent to deceive) can be challenging, sothe two are considered together here.

Many parents and some physicians areunaware that conversion disorder occurscommonly in children; the condition is acommon source of diagnostic challenges andtreatment failures. The adage that conversiondisorder is a diagnosis of exclusion is prob -ably overstated as there can be specific clinicalfeatures that can allow for confident diag -nosis and management. When conversion is


Table 19 Conditions causing chronic or slowly progressive organic brain syndrome in children oradolescents

Condition Typical age of onset Inheritance Cardinal featuresSubacute sclerosing Childhood Acquired (nonfamilial) History of measles; behavior panencephalitis (SSPE) change; myoclonus; dysarthria;

dysphagia; blindnessAdrenoleukodystrophy 2–10 years or later X-linked ADHD-like disorder; behavioral

decline; long track signs; skin hyperpigmentation

Metachromatic leukodystrophy Adolescent or older Recessive Psychosis; later long track signsGM2 gangliosidosis Older child or adolescent Recessive Psychosis; mania; cognitive

declineWilson disease After first decade Recessive Behavioral disturbance;

dementia; dystonia; trismus; Kayser–Fleischer (K-F) rings

Neuronal ceroid lipofuscinoses Various types Recessive Cognitive decline; seizures; (NCL) visual decline; ataxia and

myoclonusPantothenate Late first decade Recessive Cognitive decline; dystonia; kinase-associated dysarthria; iron depositionneurodegeneration

suspected, clinicians should consult anexperienced child or adolescent psychiatrist(textbox).

Clinical features suggesting conversionin children or adolescents• Nonepileptic paroxysmal events.• Gait disorders (astasia-abasia).• Paralysis of one or more limbs.• Blindness.• Amnesia.

Psychogenic nonepilepticparoxysmal eventsChildren 8 years of age or older may presentwith paroxysmal events resembling seizures.The events are often frequent or recurrent andtypically occur in the presence of others. Theydo not occur in sleep (although parents andcaretakers may mistakenly come to this


conclusion) and rarely occur when the childor adolescent is alone. Up to 10% or moreof children with psychogenic nonepilepticevents also have epileptic seizures, a featurethat compounds diagnosis and management.These may resemble nearly any seizure type,including absence, generalized convulsion, andcomplex–partial. Sometimes, the child has seenindividuals with seizures, enabling the child tomimic the event. Certain clinical features arecharacteristic of psychogenic nonepilepticseizures allowing for a high index of suspicionand guided diagnostic evaluation (textbox).

As soon as the disorder is suspected,parents should be informed of the differentialdiagnosis and video-EEG monitoring shouldbe obtained. Prompt diagnosis will reducehospital stay and morbidity and enable moreeffective and appropriate intervention;medication-related deaths or severe allergicreactions have occurred in children withpsychogenic nonepileptic events! Despiteaccurate diagnosis, the therapy ofpsychogenic nonepileptic events remainschallenging.

Features suggesting psychogenic nonepileptic events• Occurrence primarily when caretakers/medical personnel are nearby.• Cognitive response to intervention during apparent generalized convulsion.• Ability of medical personnel to influence event by coaxing or cajoling.• Crying or screaming during an event.• Eye closure during the event and resistance to eye opening.• Lateral, to-and-fro neck or head movements.• Pelvic thrusting.• Asynchronous limb movements.• Absence of a postictal state after >1 minute convulsion.• Duration >5 minutes without systemic compromise.

CHAPTER 9101

Disorders oflanguage andhearing

Main Points• Disorders of language affect as many as 3% of all children.

• Permanent hearing loss affects 1 of every 750 children.

• Clinicians should screen for language and hearing deficits at everyopportunity.

• Stuttering appears between the ages of 2 and 5 years and typicallyresolves. Persistent stuttering affects 1% of the population.

• Autism spectrum disorders, a common cause of impaired language,are associated with varying impairment of communication andsocial reciprocity.

• Angelman syndrome should be suspected in a boy or girl withglobal developmental delay and little or no language.

• Genetic disorders account for 50% or more of permanent deafness.

• Connexin 26 mutation, GJB2/DFNB1, is the most common genedisorder associated with sensorineural hearing loss.

• Congenital cytomegalovirus infection is the most commonnongenetic cause of permanent deafness.


Introduction

The human capacity for language, a unique andprecious ability, causes distress when absent orimpaired. When a child does not learn tocommunicate, many concerns and diagnosesmust be considered. Language, the mostsensitive marker of early cognitive development,enables social and emotional development toproceed normally. Language delay and/orimpairment affect approximately 2–5% of 3-year-old children. Closely linked to the developmentof language is the facility of hearing. In theabsence of normal hearing, language develop -ment is impaired. Bilateral, permanent hearingimpairment of moderate or greater severityoccurs in 1 of 750 children; 80% of permanenthearing loss is present at birth.

Language disorders

Broadly speaking, impairments in language canbe acquired or congenital. An acquired languagedisorder implies that a child had a normal periodof language development and then experienceda decline in ability. By contrast, congenitallanguage impairment indicates deficits inlanguage ability that have been persistent sincebirth and often preclude normal languagedevelopment.

Normal languagedevelopmentThe development of language, a fascinating,shared human trait demonstrated acrosscultures, follows relatively stereotyped patterns.Even deaf children who acquire sign languageand not spoken language display a similarsequence of language development; deaf infants‘babble’ using their hands. Importantly, a delayin language ability not only implies languageimpairment, but raises concerns regarding otherpotential medical, neurological, or geneticdisorders.

Several instruments allow clinical assessment oflanguage milestones. For example, the Denver II(Denver Developmental Screening Tool II), awidely used screening tool for developmentaldisorders, screens over 30 different languagemilestones. Of these, four or five key milestonescan alert the clinician to the possibility of aproblem in language acquisition (Table 20).Although most children achieve given milestonesby a certain age, a range exists. Since referral andevaluation of children by language specialists oftentakes several weeks or months, the clinician shouldrefer early, rather than late, when concern aboutlanguage delay appears. The milestones listed inTable 20 are ‘late’ milestones, i.e. most childrenwill have achieved the milestone several monthsbefore, so that any child who has not achieved themilestone falls well outside two standarddeviations from the norm (textbox).

Table 20 ‘Late’ language milestones

Age MilestoneBefore age 12 months Infants should respond to sounds and voice, and should be making vocalizationsBy age 15 months Child should be using one word to specifically indicate something; it is acceptable that the

one word is not entirely correct (1 word at 1 year; easy to remember)By age 2 years Child should be combining words, and should have a vocabulary of over 200 words (2 word phrases

by 2 years)By age 3 years Child should be able to name a body part and a color, and be constructing phrases longer than

three words (3 word phrases by 3 years)

CHAPTER 9 Disorders of language and hearing 103

Concern exists regarding languagedevelopment when the child cannot:• Use one word specifically by age

15 months.• Combine two words by age 2 years.• Use a three word phrase by age 3 years.

Certain conditions, such as prematurity, abilingual home, serious chronic medicalconditions (for example, congenital heart diseaserequiring multiple hospitalizations), can delaythe early achievement of language development.However, between 2 and 3 years of age themajority of children with such factors should becatching up with their peers. Receptive language,the ability to understand, is usually moreadvanced than expressive language. Parentscan be reassured, in most cases, if a child hasmildly delayed expressive language, but normalreceptive language.

A confusing aspect of understandinglanguage disorders are the many terms usedin the literature and by language specialists.Definitions are listed below for some of themore commonly used terms and phrases.

Language: language refers to the ability tocommunicate. Language is broader than theability of speech, as it includes sign and spokenlanguage, as well as the subtler aspects ofcommunication such as prosody (the flow ofspeech) or accompanying facial expressions.

Speech: speech is the vocal output oflanguage. Speech impairments or difficulty canreflect an underlying language impairment.However, speech impairment can also resultfrom a biomechanical problem; for example, thechild with a tracheostomy tube which impairsvocal cord movement.

Aphasia: aphasia, a disorder of language, canbe expressive or receptive and complete orpartial, but may not be related to overallintelligence.

Expressive language: expressive language is theoutput of language. It can be in any form(speech or sign).

Receptive language: receptive language is theability of a person to understand language. Thiscan be tested by asking parents if their childcomprehends commands (for example, “Go getyour teddy bear”). The clinician should usequestions to assess receptive ability but must

avoid nonverbal clues (for example, cliniciansshouldn’t ask “Where is your nose?” while theypoint to their own nose).

Mixed impairment: a mixed language impair -ment refers to the presence of both expressiveand receptive language impairments. Theexpressive and receptive impairments may beequal in their severity or mismatched.

Specific language impairment: specificlanguage impairment is a deficit in languageability in the absence of other developmentaldelays. This contrasts with global developmentaldelay in which the child exhibits delays in two ormore developmental areas (e.g. both languageand gross motor skills). A child who cannot saya word by age 2 years has specific languageimpairment, whereas a 2-year-old child whodoes not speak nor walk has global develop -mental delay.

Apraxia: apraxia describes the inability toperform a skilled action, despite having themotor, cognitive, and sensory abilities toperform the action. Apraxia of speech refers to achild who appears to have normal cognition andunderstanding of expressive language, but hasdifficulty constructing or programming theirspeech (i.e. the child has trouble saying whatthey want to say).

Dysarthria: dysathria refers to an articulationdisorder producing speech that is slurred ordifficult to understand.

TestingThe assessment of a child’s language abilitiesbegins with the parental report of a child’sprogress. In addition, clinicians can include afew simple questions to ensure that a child ismeeting broadly defined developmentalmilestones for language. Early screening forlanguage delay and prompt treatment mayreduce the requirements for later specialeducation (textbox).

Key steps in recognizing and treatingchildren with language delays• Assess developmental milestones during

well-child visits and heed parentalconcerns regarding their child’s languageability.

• In the child with language delay, perform ahearing screen and determine if aneurological or genetic cause is apparent.

• Refer the child for speech and languagetherapy.

• Refer to a child neurologist when the childhas global developmental delay.


Neuroanatomy oflanguageLanguage depends on a complex, intercon -nected set of brain structures. Three criticalregions are especially important: Broca’s area,Wernicke’s area, and the arcuate fasciculus(114). The concept of three regions respon -sible for language is, however, a gross over-simplification of the neural circuitry thatgenerates language; several other brain areas(including the basal ganglia and cerebellum)have important roles. The major languageareas are located in the left cerebral hemispherein the majority of right-handed individuals(about 90–95%) and left-handed individuals(about 75%).

Broca’s area, located in the inferior lateralfrontal lobe, controls the production or motoraspects of language. By contrast, Wernicke’sarea, located in the superior posterior temporallobe adjacent to the auditory cortex (Heschl’sgyrus), controls the understanding or sensoryaspects of language. Broca’s and Wernicke’sareas are connected by the arcuate fasciculus.

114

114The lateral surface of the brain showingareas (Broca [1] and Wernicke [2]) andpathways (arcuate fasciculus [3]) involved inlanguage. 4, Heschl’s gyrus.

3

214

Epileptic causes

Landau–Kleffnersyndrome (LKS)LKS, a rare disorder, is marked by a relativelyabrupt regression or loss of language skills, usuallyin young school-aged children between 5 and 8years of age. Clinicians should consider LKS whena school age child begins to show auditoryagnosia, the inability to understand spoken words.

The child with LKS begins to have troubleunderstanding or responding to words spoken tothem (a verbal agnosia). In approximately 70%of cases the loss of language is associated withseizures, but in the remaining cases no clinicallyapparent seizures herald the onset of LKS. EEGrecordings reveal epileptiform discharges duringsleep; eventually >70–80% of the EEG duringsleep is filled with spike and wave discharges(electrical status epilepticus of sleep [ESES]).

Some authorities suspect that LKS is part of acontinuum of disorders that includes autismspectrum disorders (ASDs). Children with LKShave impaired language and often exhibitbehavioral abnormalities that include impairedsocialization skills. Unlike autism, children withLKS may respond to treatment with corticos -teroids or intravenous immunoglobulin. Thiscondition should be considered in a child over2 years of age with language regression. Despitetemporary responses to treatment, the prog -nosis is poor; only 18% recover fully, and 63%have persistent developmental delay/intellectualimpairment.

Electrical status epilep -ticus of sleep (ESES)/continous spike-wave ofslow wave sleep (CSWS)ESES, a poorly understood disorder of languageand behavior known also as continuous spike-wave of slow wave sleep (CSWS), is defined by aspecific electro graphic pattern during sleep. Asleep EEG shows spike and wave dischargesoccupying >75–80% of sleep (81). This conditiondiffers from LKS in the younger age of onset(typically less than 5 years of age) and the failureof language to progress. ESES should be consid -ered in the child with a pre-existing history ofseizures who fails to achieve normal languagemilestones. Obtaining an EEG is key for

diagnosis. Treatment and long-term prognosisfor ESES are not well understood, although thereappear to be permanent effects on learning forchildren who have had ESES.

Other causes

StrokeStroke, the prototype of neurological conditionsthat lead to loss of language, can affect children,as well as adults. Broca’s aphasia results from astroke in the frontal cortex, leading to aninability to speak; comprehension generallyremains intact. By contrast, a Wernicke’s aphasiaaffects the temporal lobe and causes impairedcomprehension (114). However, a stroke’seffects on language may not conform preciselyinto a pure Broca’s or Wernicke’s aphasia.

The effect of stroke on language varies widelyin children depending upon the age at which thestroke occurs. In general, the later a child has astroke, the more likely the effects on languagewill mimic those of adult stroke. Conversely, theearlier a child has a stroke, the less likelylanguage will be affected, at least to as great anextent. Stroke after the age of 10 years of agegenerally affects language in a child as it wouldin an adult. Prenatally and in early childhood,language areas are less fixed, and hence thedegree of recovery of language ability isconsiderably greater. However, large strokes cancause language impairment and cognitivedisability even in young infants. Because of thedisruptions in the normal circuitry of the brain,strokes of any size can impair normal languagedevelopment. A child who had a perinatal strokeaffecting Broca’s area may learn to talk normally,but may display permanent deficits that areevident during psychoeducational testing.



Autism/autism spectrumdisorders/pervasivedevelopmental delayLanguage impairment is a sine qua non for thepervasive developmental disorders, includingautism. Although these disorders overlapsubstantially in their clinical characteristics, theirunderlying pathophysiology is poorly under -stood. Autism is defined as the triad of impairedcommunication, impaired social interactions,and restricted and/or repetitive behaviors.Language deficits range from a complete lack oflanguage to near normal ability. Autism is aclinical diagnosis, but is not an etiologicdiagnosis. For example, children with fragile Xsyndrome (115) or tuberous sclerosis may beautistic. Recent studies have revealed that autismcan arise from very subtle genetic changes, suchas deletion or duplication of a particular regionon chromosome 16q.

NeoplasmsThe effects of cancer on language fall into twocategories. First, there can be direct effects fromthe cancer itself. A brain tumor can compress orinvade the normal language areas of the brain,causing delay or loss of language development.Brain tumors as a group are the second mostcommon childhood malignancy, comprising22% of all childhood malignancies. Thesymptoms or signs of brain tumors can be subtleinitially, consisting of changes in personality orlanguage ability, but more ominous features,such as headache, lethargy, ataxia, or cranialnerve abnormalities, eventually appear.

The other main effect of cancer is the delayedeffects on language from the surgeries, chemo -therapy, and radiation therapy that encompasstreatment. First, language impair ment can resultdirectly from surgery necessary to removetumors growing in areas involved in languageproduction. Second, chemotherapy andradiation therapy can have long-term effects onneurocognitive development. For chemo -therapy alone, processing speed and verbalmemory are affected. Cranial radiation therapyis avoided, whenever possible, before the age of3–4 years given the potentially severe effects onlanguage and cognitive development.

A unique entity, cerebellar mutism syndrome,occurs within 1–2 days postoperatively in asmany as 25% of children who undergo resectionof tumors in the posterior fossa, especiallymedulloblastoma. The children have markedlydiminished speech, often progressing to mutism,emotional lability, hypotonia, and ataxia. Themutism resolves in a majority of cases, often overa prolonged time period of months, but most children have a degree of permanentneurological impairment, including speechimpairment.

115A young boy with fragile X syndromeshows large, prominent ears, a cardinal featureof the disorder.

115

Genetic causesLanguage impairments commonly affectfamilies, and monozygotic twins are more oftenaffected than dizygotic twins. Despite theseobservations, the progress on identifyinggenetic causes of language impairment has beenremarkably slow. To date, there are nocommercial tests available to examine for causesof isolated language delay (termed specificlanguage impairment, SLI), and only one genecontrolling language has been identified.

The identification of FOXP2, a gene thatcauses a failure of language development whenmutated, marked a new era in the understandinglanguage development. Children with muta -tions in FOXP2 have fairly severe difficulties intalking, moderately impaired grammatical andcomprehension abilities, and some degree oforomotor apraxia. Thus far, FOXP2 is believedto be responsible for only a small minority(probably <1%) of all children with impairedlanguage development. However, genesdownstream of FOXP2, such as CNTNAP2,may participate in a greater proportion ofpediatric language disorders.

Several other genetic causes of languageimpairment should be considered in theappropriate clinical context. Children withAngelman syndrome have near completeabsence of language; the ability to speak morethan five single words or combine words intosentences nearly always makes a diagnosis ofAngelman syndrome unlikely. Children withAngelman syndrome also have markeddevelopmental delay, gait and/or limb ataxia,seizures, and a happy demeanor (sometimestermed ‘happy puppet’) (116). Anglemansyndrome, a contiguous gene deletionsyndrome, is caused by loss of the maternalchromosome 15q11.2-q13 region. Loss of thepaternally-inherited copy of this same regioncauses Prader–Willi syndrome.

Girls with Rett syndrome, caused by amutation in the MeCP2 gene on the Xchromosome, have normal early development,but between the ages of 6 and 18 months,development plateaus, and developmental skills,including language, regress. Characteristics ofgirls with Rett syndrome include midline hand-wringing movements (113), autistic behaviors,seizures, breathing abnormalities, unsteady gait,tremors, and deceleration of head growthleading in some to microcephaly. Boys can be

severely affected and usually die in infancy oryoung childhood.

Fragile X syndrome, a disorder of boys andmen, presents with developmental delay,seizures, and difficulty with behavior andlanguage; IQ is often <70 and approximatelyone-fifth have autism. The gene causing fragile Xsyndrome is a triplet, CGG repeat expansion ofthe FMR1 gene on the X chromosome. Normalindividuals possess <50 CGG repeats in thisregion; individuals with fragile X syndrome have200 or more (the full mutation). Persons with55–200 are considered premutation carriers.Classic physical exam findings include a largehead, long face, protruding ears (115), and largetestes (after the onset of puberty). Girls orwomen with the full mutation can also beaffected, occasionally, but have a less severephenotype. Adult premutation carriers, moreoften men, can display intention tremor, ataxia,dementia, parkinsonism and autonomic dysfunc -tion, a condition that has been named fragile X-associated tremor and ataxia syndrome (FXTAS).Women premutation carriers experience fragileX-related ovarian failure.


116

116An adolescent with Angelman syndromeshowing typical features of microbrachycephalyand happy disposition.


Children with Williams syndrome haverelatively preserved language skills in the face ofrelatively low IQ. Children with Williamssyndrome are very gregarious and oftenmaintain a chatter of conversation (‘cocktailparty’ personality). The mutation causingWilliams syndrome is a contiguous gene deletionat the 7q11.23 region of chromosome 7. Otherimportant clinical features of children withWilliams syndrome include hypercalcemia,cardiovascular disease (especially aortic orpulmonary stenosis), hypotonia and feedingdifficulties in infancy, endocrine and growthabnormalities in later childhood, and a

distinctive ‘elfin’ facial appearance, consisting ofa small upturned nose, long philtrum, widemouth, and full lips (117, 118).

In the absence of an identifiable syndromeonly modest advice can be offered currently tothe parents of a child with an inherited deficit inlanguage without obvious cause. The risk ofrecurrence may be as low as 6% (for a sporadictrait) to as high as 25% (assuming a recessivemode of inheritance). Because the same geneticdefect may display phenotypic heterogeneity,one child might have a very profound difficultyin learning to speak, while another child mightbe only mildly affected.

117 118

117A child with Williams syndromedemonstrating characteristic ‘elfin’ features,including a wide mouth with full lips and abroad forehead.

118An older child with Williams syndrome.


StutteringStuttering, a disorder of speech, not language,consists of disruptions in the normal flow ofspeech with prolongations and/or repetitionsof words or parts of words. It can be a life-longdisorder, although symptoms are usually attheir worst during the peak age of onsetbetween 2 and 5 years of age. Stuttering hasbeen linked to mutations in GNPTAB, a geneon chromosome 12 that participates in cellrecycling.

Persistent developmental stuttering affectsapproximately 1% of the population, but affectsup to 5% of children. Boys and girls are equallyaffected, but more girls recover than boys, soover a lifetime, boys and men have a higherprevalence rate. The spontaneous recovery rateis approximately 80%. The likelihood ofspontaneous recovery is lowest in boys withonset in primary school or later, and less likelyif they have concurrent language impairment.

Meningitis andencephalitisMeningitis or encephalitis can damage areas ofthe brain necessary for language; meningitis canalso produce hearing loss. Thus, assessments ofhearing and language should be performed inall children who experience encephalitis orbacterial meningitis. Approximately 15% ofchildren who survive bacterial meningitis havepersistent language difficulties through child -hood. As many as 50% of children who surviveherpes simplex virus (HSV) encephalitis haveperma nent deficits of language and memory. Ingeneral, meningitis or encephalitis in theneonatal period tends to be associated withmore severe neurodevelopmental sequelae.

Head traumaChildren who experience traumatic brain injury(TBI) commonly experience post-traumaticdisorders of language. Many children recoverslowly; cognitive recovery occurs over 1–3 years, but after this time period there islittle additional improvement. The number ofintracranial lesions and the initial GlasgowComa Score are the clinical factors mostpredictive of final language outcomes. Age atwhich the injury occurred does not correlatewith eventual outcome. For children withinflicted TBI (child abuse, nonaccidentaltrauma) approximately two-thirds havepermanent speech and language difficulties.MRI, especially T2-weighted FLAIR images,can establish the extent and severity of braininjury.

ManagementTreatment for language impairment can beeffective, depending on the severity of impair -ment and the cause. Because early treatment isassociated with improved outcome, andbecause referral and evaluation can take severalmonths, clinicians should refer childrenpromptly. Meta-reviews of treatment show thatchildren with expressive language difficultyrespond well to treatment. By contrast, childrenwith receptive language impairment respondless well. Therapy often consists of a mixture ofdidactic (direct teaching) and less structured(responsive) modes. Therapy longer than >8 weeks is associated with an improvedoutcome. The clinician should identify a teamof therapists who can work with languageimpaired children. In the USA, early interven -tion refer rals can be made for children <3 yearsof age; school-based programs are available forolder children.

Stuttering ceases within 1 year of the onsetin approximately 40% of children who stutter.For children with persistent stuttering, a varietyof speech therapist and/or parent-directedapproaches are available. Medications have noproven benefit for stuttering. Because of thepotential emotional and social effects ofpersistent stuttering, counseling is indicated forolder children.


Hearing disorders

Permanent hearing loss, especially sensorineuralhearing loss (SNHL), has been linked to long-term deficits in cognitive outcome. The severityof the disability is correlated with the degree ofhearing loss and the age at which hearing lossoccurs. In addition, the presence of othermedical conditions (either causative, associated,or in addition to the hearing loss) such aslearning difficulties or cerebral palsy, also affectthe long-term prognosis. Historically, thetypical student with SNHL graduated fromsecondary school with the language andacademic achievement level of a 10-year-oldchild.

Congenital bilateral permanent hearingloss affects 112 of every 100,000 live bornchildren (about 0.1%). Because of the adverseoutcomes associated with congenital hearingloss, universal newborn hearing screening hasbeen instituted in the USA during the past15 years. Prior to universal newborn screening,hearing loss was detected at an average ageof 2–3 years. Multiple studies have shown thatearly treatment of those with hearingimpairments leads to improved language skillsand better IQ test results. Besides thetreatment, the other major factor associatedwith improved outcomes was the degree offamily involvement.

Neuroanatomy ofhearingSound enters the human ear as vibrations. Thevibrations are converted by the cochlea to nerveimpulses that are carried by the cochlear(auditory) nerve (CN8) to the hearing centersof the cerebral cortex. Unilateral hearing losscan occur from damage to the middle ear,cochlea, or CN8. After arriving in thebrainstem, signals are sent ipsilaterally andcontralaterally through the medial geniculateganglia of the thalamus and eventually reach theprimary auditory cortex (Heschl’s gyrus; 114).Bilateral hearing loss indicates damage to bothcochlea or implies a more widespread problem,since the nerves that carry information aboutsound transmit their information to both sidesof the nervous system immediately afterentering the brainstem. The auditory cortex,where sound is ‘heard’, is responsible fordecoding sound into meaningful pieces ofinformation. People with very small lesions ofthe auditory cortex can have pure worddeafness, being unable to understand spokenlanguage, despite having normal hearing,reading, and writing ability.

SNHL is diagnosed based on reducedhearing acuity by auditory testing. Hearing ismeasured in decibels (dB), where 0 dB isdefined as a tone burst at a given frequency inwhich young adults can perceive the sound 50%of the time. Hearing loss can be categorized asmild, moderate, severe, or profound. Mildhearing loss (25–40 dB threshold) leads to lossof some consonant sounds; moderate (40–70dB), the inability to hear much of conversa -tional speech; severe (70–90 dB), the inabilityto hear even one’s own vocalizations; andprofound (>95 dB), absence of all hearing.

TestingHearing screening of infants employs testing ofotoacoustic emissions (OAE) or the automatedauditory brainstem response (AABR or ABR).OAE measures the response of cochlear haircells to an acoustic stimulus using a probe andmicrophone placed in the ear canal. AABRmeasures the brain’s response to a 35 dBstimulus delivered to the infant using smallearphones. Infants can fail OAE because ofhearing loss or disorders of the middle ear; bothscreening tests identify infants who shouldundergo more sensitive and specific evaluationusing the AABR (ABR).

ABR records the brain’s electrophysiologicalresponse to sound stimuli delivered at severalintensities and frequencies. The response to

sounds delivered via headphones is recorded viaelectrodes placed on the infant’s forehead andover the mastoid bones. The test can identifysensorineural or conductive hearing loss. Afterthe age of 3 years, the hearing of most childrencan be assessed using behavioral audiometry.The latter can consist of play audiometry, inwhich correct identification of sounds isrewarded by engaging activities, or observa -tional audiometry, in which the audiologistassesses hearing by observing the child’sresponse to sounds. Neuroimaging, especiallytemporal bone MRI, should be considered in allchildren with sensorineural hearing loss(SNHL). MRI accurately detects many of theacquired or congenital disorders of the cochleaassociated with deafness (Table 21).


Table 21 Disorders of cochlear anatomyassociated with deafness in childhood

Condition DefinitionMondini dysplasia Congenital defect of the cochlea

associated with a reduced number of cochlear turns, hearing loss, and endolymphatic–perilymphatic fistula

Enlarged vestibular Congenital or acquired aqueducts enlargement of fluid-filled

canals within the temporal bone; can be a feature of Pendred and Waardenburg syndromes (119)

Cochlear hypoplasia Various forms of hypoplasia can be observed in children with brachio-otorenal syndrome

119A child with Waardenburg syndromedemonstrating hypertelorism and acharacteristic eye appearance.

119


Conditions associatedwith hearing loss

Genetic disordersApproximately 50% of deafness is genetic.Genetic disorders can be divided into nonsyn-dromic causes, largely due to mutations in thegenes encoding the gap junction proteinconnexin 26 (GJB2/DFNB1), and thoseassociated with syndromic disorders. Approxi -mately 50% of genetic hearing loss resultsfrom mutations in GJB2/DFNB1. More than400 syndromes are associated with deafness(Table 22).

Infectious disordersCongenital infections and bacterial meningitisremain major causes of congenital and acquiredhearing loss, respectively, in infants and youngchildren. Congenital cytomegalovirus (CMV)infection accounts for up to 20% of SNHL inchildren; 50% of the infants with symptomaticcongenital CMV infections (CMV disease) and7% of those with asymptomatic infections havehearing loss. Ganciclovir therapy of infants withCMV disease appears to reduce the frequencyand severity of hearing loss. Sensorineuraldeafness can also complicate congenital infec -tions with rubella, Toxoplasma gondii, andTreponema pallidum.

Table 22 Selected syndromes associated with deafness

Syndrome Features

Autosomal dominantWaardenburg (119) Sensorineural deafness; white forelock; heterochromia iridis (120)Branchio-otorenal Sensorineural, conductive, or mixed hearing loss; renal anomalies; preauricular pitsStickler Sensorineural deafness; cleft palate; osteoarthritis

Autosomal recessiveUsher Sensorineural deafness; retinitis pigmentosaPendred Sensorineural deafness; euthyroid goiter

X-linked recessiveAlport Sensorineural deafness; progressive glomerulonephritis

120 Heterochromia iridis in Waardenburg syndrome.

120

SNHL develops in 3–30% of infants,children, and adolescents with bacterial menin -gitis. The likelihood of deafness correlates withthe severity of meningitis and the length ofillness prior to antibiotic therapy. Althoughsome controversy persists regarding the role ofcorticosteroids, most authorities recommendearly dexamethasone treatment in children withbacterial meningitis, especially H. influenzaemeningitis.

Otitis mediaChildren with otitis media commonly havetransient conductive hearing loss. Approximately50% of children with persistent otitis media witheffusion (OME) have mild hearing loss, while5–10% have moderate hearing loss. This can leadto a transient impairment of speech andlanguage; however, there are limited data linkingOME to permanent impairments in languageability.

Auditory processingdisorderNot strictly a disorder of hearing, auditoryprocessing disorder, also known as centralauditory processing disorder, reflects the brain’sability to discriminate words or sounds; formalhearing testing and intelligence are normal. Theclinician should suspect a disorder of auditoryprocessing in children who have poor listeningskills, difficulty with multistep problems, orcannot acquire vocabulary. Disorders ofauditory processing may coexist with dyslexia,ADHD, ASD, or developmental delay. Manage -ment includes the use of auditory trainers,training in auditory memory enhance ment, andmodifications of the educational environment.

Management

HEARING AIDSA hearing aid, consisting of a tiny microphone,amplifier, and speaker, can assist the child withSNHL. An aid amplifies vibrations by convertingsound to electrical pulses (analog technology) orto binary signals (digital technology). ‘Behindthe ear’ hearing aids contain an ear mold thattransmits sounds and an electronic case that isworn behind the ear. ‘In the ear’ aids place allelements of the aid within the ear. Cliniciansshould consult audiologists to ensure that thechild receives the proper hearing aid.

COCHLEAR IMPLANTSA cochlear implant is an electronic device thatcan improve the recognition of sounds bychildren or adults with sensorineural deafness. Itconsists currently of external (microphone,sound processor, and transmitter) and internal(receiver and electrodes) components (121).The device ‘hears’ environmental sounds andsends electrical currents to the auditory nerve.Thus, a cochlear implant can bypass thedefective portions of the middle or inner ear.Approximately 4 weeks after implantation, thecochlear implant is turned on, and over the nextseveral months the amplitude is graduallyadjusted so that the recipient adapts to the newsounds. Currently, the USA Food and DrugAdministration has approved implantation inchildren as young as 12 months.


121The external appearance of a cochlearimplant in a young woman with profounddeafness.

121

CHAPTER 10115

Disorders of headsize and shape

Main Points• Occipital-frontal circumference (OFC) provides essential

information regarding intracranial volume, brain size, and growth.

• The majority (80%) of postnatal brain growth occurs in the first2 years of life.

• Macrocrania (large head) can be caused by megalencephaly,hydrocephalus, extra-axial fluid collections, or a thickenedcalvarium.

• Microcephaly (small head) can be the result of congenital, acquired,genetic, hereditary, syndromic, or environmental disorders.

• Megalencephaly (large brain) is the result of familial, syndromic, orstorage disorders.

• Skull growth occurs in the plane perpendicular to the suture.

• A misshapen head often reflects positional plagiocephaly.

• Craniosynostosis can be acquired, syndromic, or genetic. Sagittalsynostosis, causing dolichocephaly (scaphocephaly or long head), isthe most common form of craniosynostosis.


ment of brain growth. The occipital-frontalcircumference (OFC) is proportional to theintracranial volume: 80% brain; 10% blood; and10% CSF. Since the brain contributes themajority of the volume, the OFC largely reflectsthe growth of the brain. Head circumferencegrowth charts, standardized for the normalpopulation from birth to 18 years of age (122),define normal as within 2 standard deviations(SD) of the mean (textbox).

Estimating OFC in normal infants andchildren• The rule of ‘3s and 9s’: after an average

OFC of 35 cm at birth, 5 cm incrementsoccur at 3 months (40 cm), 9 months (45 cm), 3 years (50 cm), and 9 years (55 cm).

• The expected OFC ± 1 cm for a given infant<12 months of age can be estimated bythe formula: [length (cm)/2] + 10 cm. For example, a newborn infant who is 50 cm long (20 inches) should have anOFC of 35 cm.

Introduction

Just as periodic assessments of height andweight represent important parameters ofsomatic growth in childhood, measuring thehead circumference enables clinicians to assessthe growth of the brain. The human brain growsfrom 400 g at birth to approximately 1400 g atadulthood (brain size is smaller in women andlarger in men). Early childhood is a dynamictime as 80% of the postnatal brain growth occursduring the first 2 years of life. Whereas fetalbrain growth is determined primarily byneuronal proliferation, postnatal growth occursprincipally because of myelination and increasedneuronal cell and neuropil volume. Geneticprogramming and disorders affecting braingrowth have dramatic effects on the brainduring this period of rapid growth. Thischapter focuses on the diagnostic evaluation ofchildren with macrocephaly, microcephaly, andmisshapen heads caused by positional deforma -tion or craniosynostosis.

TestingMeasuring the head circumference duringchildhood provides an indirect clinical assess -

122A head size chart for young girls.

Months Years1 2 3 4 5 6 7 8 9 10 11 12 15 18 2 3 4 5 6 7 8 9 10 12 14 16 18

CM

62

60

58

56

54

52

50

48

46

44

42

40

38

36

34

32

30

2SD (98%)

Mean (50%)

-2SD (2%)

122

CHAPTER 10 Disorders of head size and shape 117

An OFC greater than 2 SD is macrocrania(also called macrocephaly), while an OFC lessthan 2 SD is microcrania (also called micro -cephaly). In using 2 SD for such definitions, 2%of the normal population will be eithermacrocephalic or microcephalic. If one uses 3SD as the cut-off, nearly all individuals in thesegroups have pathological disorders of the brain.

To obtain an accurate OFC the clinicianshould use a flexible but nonstretching meas -uring tape. The head should be measured at itsgreatest circumference, typically at the level ofthe frontal and occipital prominences (123),and verified by the reproducibility of themeasurement (obtaining the same value for 2 of3 measurements). Serial OFC measurements aremore valuable than a single measurement asthey indicate growth velocity (124). Headgrowth that follows percentile lines has differentimplications than acceleration or deceleration of

123

123 How to measure the occiptal-frontalcircumference (OFC).

124

124A head size chart showing patterns in (A) hydrocephalus,(B) familial macrocrania, (C) acquired microcephaly, as in Rettor Angelman syndrome, and (D) congenital microcephaly.

Months Years1 2 3 4 5 6 7 8 9 10 11 12 15 18 2 3 4 5 6 7 8 9 10 12 14 16 18

CM

62

60

58

56

54

52

50

48

46

44

42

40

38

36

34

32

30

2SD (98%)

Mean (50%)

-2SD (2%)

A

B

CD

head growth. Acceleration across percentile linesindicates an excessive increase in the intracranialvolume, as seen in hydrocephalus, subduralhematomas, metabolic megalencephaly, andfamilial macrocephaly, whereas decelerationindicates a disease process that has destroyedbrain tissue or severely affected neuronal growthor myelination. Patterns that show consistentlysmall or large OFCs since birth usually indicatethat the process is congenital, having occurredduring fetal brain development.

The clinical assessment of the head alsoincludes inspection of the skull for shape andpalpation of the fontanels and the sutures(textbox).

Fontanels• A large posterior fontanel may suggest

hypothyroidism or a syndromic disorderaffecting bone growth.

• The anterior fontanel closes between10 and 20 months of age; the fontanelis closed in approximately 40% of normal12-month-old infants.

The posterior fontanel is open at birth, but by6 weeks it is usually nonpalpable. The anteriorfontanel, approximately 3 × 3 cm at birth,progressively closes as the infant grows. By 6months the anterior fontanel can be quite small(1 × 1 cm) in normal infants, but the fontaneldoes not close completely until 10–20 months ofage. The anterior fontanel should be flat orslightly concave with the quiet infant in thesitting position. A tense, bulging fontanel canindicate increased intracranial volume; increasedvolume can also lead to ‘splitting’ or widening ofthe cranial sutures to accommodate an increasein volume that has occurred too rapidly forbone growth. When there is deficient braingrowth, the sutures may be overriding. This canbe confused with suture synostosis, but the headshape remains normal, albeit small, reflectingimpaired brain growth rather than cran -iosynostosis. If the head is normal in size, butmisshapen, a positional deformation orcraniosynostosis should be suspected.

Macrocephaly

By definition, macrocephaly means that thehead circumference is greater than 2 SD abovethe mean. Causes of macrocephaly include alarge brain (megalencephaly), obstruction ofCSF pathways and absorption (hydrocephalus),compartmentalization of blood or CSF (e.g.subdural collections), or a thickened skull orscalp (Table 23).

The evaluation of the child with macro -cephaly begins with measuring the head circum -ference and documenting whether the large headis congenital or acquired. Family history andmeasurements of parental and sibling head sizesare essential. A thorough developmental historycan identify associated brain dysfunction. Theexamination should include: comparison of headsize to height and noting somatic overgrowth ordwarfism; identification of dysmorphic features;careful skin inspection for signs of neurocuta -neous disorders; palpation for visceromegaly;and a complete neurological examination todetect neurological deficits. Most children withmacrocephaly require neuroimaging, partic -ularly MRI. MRI provides the most sensitiveimaging of the brain parenchyma and detectsmost malformations. Genetic and/or metabolicevaluation may be necessary, depending uponthe history, physical, and imaging results.



Table 23 Selected causes of macrocephaly

MegalencephalyAnatomic

Benign familialSymptomatic familialWith somatic overgrowth:

SotosSimpson–Golabi–BehmelWeaver

With dwarfism:Achondroplasia

Neurocutaneous syndromes:NeurofibromatosisBannayan

MetabolicLeukodystrophy:

CanavanAlexander

Lysosomal storage disease:Tay SachsMucopolysaccharidoses (Hurler, Hunter, Sanfilipposyndromes)

HydrocephalusAqueductal stenosisDandy–Walker cystChairi II malformationObstruction from tumor, cysts, infection, hemorrhage

Subdural fluidHematomaHygromaBenign extra-axial fluid collection of infancy

Thickened skull or scalpSevere anemiaCraniometaphyseal dysplasiaCraniosketetal dysplasiaProteus syndromeOsteogenesis imperfecta

Megalencephaly, part of a constellation offindings that may indicate a particular disorder,occurs in >100 syndromes. All children withmegalencephaly should be examined closely forcutaneous stigmata of neurocutaneousdisorders, especially neurofibromatosis type 1(Table 23). Making a syndromic diagnosisrequires identi fying the child’s abnormalfindings and matching the features with knownsyndromes. Thickened skull or scalp, perhapsthe least common cause of macrocephaly,occurs in certain bone diseases and syndromes.Classic examples of storage megalencephalyare Tay Sachs disease (105, 106) and themucopolysaccharidoses (258).

MegalencephalyThe causes of megalencephaly (large brain) havetraditionally been divided into anatomical versusstorage. The anatomical enlargement of thebrain, the most common type of megalen -cephaly, can be caused by excessive proliferationof neurons, increased size of the neurons, orcombination of both with no known metabolicetiology. Included in this category are familialcauses, with or without neurological deficits.Because familial megalencephaly (124, line B)without neurological deficits is most commonlyan autosomal dominant feature, the clinicianmust obtain the head measurements of parentsand siblings. Megalencephaly can also be seen insomatic overgrowth syndromes and some typesof dwarfism.

HydrocephalusChildren with hydrocephalus, an important,treatable cause of macrocephaly, have OFCpatterns that show acceleration of headgrowth velocity (124, line A). The infant withhydrocephalus typically has suture separation(diastasis) and a bulging fontanel. The childtypically has signs and symptoms of increasedintracranial pressure and a cranial vault that islarge in proportion to the face (125). Commoncauses of congenital hydrocephalus includeaqueductal stenosis (CSF obstruction at thecerebral aqueduct), Dandy–Walker malforma -tion (obstruction of the outlet of the 4th

ventricle with cerebellar hypoplasia; 126), andChiari II (small posterior fossa with cerebellartonsils and medulla well below the foremanmagnum and associated with myelomeningo -cele). Chiari III is associated with occipitalencephalocele (127). Acquired hydrocephaluscan result from any disease process thatobstructs the CSF pathways including tumor,meningitis, and subarachnoid hemorrhage.

Subdural collectionMacrocephaly due to subdural collection ofblood or CSF is potentially treatable andtherefore important to identify. Subduralhematomas (66) with head enlargement andsigns of increased intracranial pressure can be oneof the presentations of nonaccidental trauma.Benign extra-axial fluid collections of infancy(128), a common condition associated withmacrocrania, can sometimes be confused withchronic subdural hematomas or hygromas. Thiscondition should be suspected in infants withaccelerated head growth that crosses percentilesbut eventually stabilizes above the 98th per-centile. This condition is thought to reflectdisproportional skull growth relative to braingrowth, causing increased subarachnoid spacebetween the two structures. During the secondyear of life the brain growth catches up and theCSF space diminishes. Benign extra-axial CSFcollections can be distinguished from subduralcollections by identifying cortical veins traversingthe space, normal sized or slightly enlargedlateral ventricles, absence of mass effect, and CSFdensity of the extra-axial fluid. Such infants canbe managed conservatively, although some mayhave mild developmental delays.


125

125The large cranium of a child with hydrocephalus.


128

127127An infant with a large occipitalencephalocele.

128 Noncontrast CT showing benign extra-axial fluid collections of infancy (arrows).

126126 Sagittal T1-weighted MRI showing thecharacteristic features of Dandy–Walkermalformation. The arrow denotes the large,retrocerebellar CSF collection (cyst). This childalso has agenesis of the corpus callosum.


Microcephaly

Microcephaly indicates that the brain is small,more than 2 SD below the mean for age.Although mildly microcephalic individuals canhave normal intelligence, mental retardationand neurological deficits are usually propor -tional to the degree of microcephaly. The childwith microcephaly has craniofacial dispropor -tion with the cranial vault small relative to theface (129). For normal infants, the midline ofthe oval formed by the face and the cranialvault should be at the eyebrow level. Inmicrocephalic infants the forehead slopesbackward and the face below the eyebrowscomprises more of the oval volume thannormal (130). A useful method for estimatingmicrocephaly for infants less then 6 months ofage is to compare the head circumference withthe chest circumference. In microcephalicinfants, the OFC will be smaller than the chestcircumference, whereas the OFC should equalthe chest circumference in normal infants.

129

129A child with microcephaly showing arelatively small forehead and cranium inproportion to the face.

Microcephaly can result from a lack ofnormal neuronal proliferation, diminishedneuronal growth and myelination, orencephaloclastic processes with loss of braintissue. An approach to classifying microcephalyis to consider the onset as congenital (prenatal)or acquired (postnatal). Within these categoriesare both genetic and environmental causes(Table 24). The genetic etiologies involveabnormal brain growth or proliferation with orwithout associ ated malformations. Theenvironmental etiolo gies usually limit braingrowth or involve loss of brain parenchyma.

Congenital microcephaly (124, line D)without any other associated malformations canbe autosomal dominant, recessive, or X-linked.Other genetic causes of microcephaly includetrisomy, ring, and deletion chromosomesyndromes. Microcephaly with other brain andsomatic malformations is associated with >450syndromes listed in McKusick’s Catalog ofMendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim).




130

130An infant with microcephaly showing asmall, backward sloping forehead and cranium.

Table 24 Selected causes of microcephaly

CongenitalGenetic

Familial: AD, AR, XLRSyndromic: Smith–Lemli–Opitz, Cornelia deLange, Rubinstein–Taybi, Dubowitz, WilliamsAssociated with other brain malformationsChromosome abnormalities: trisomy, deletions

EnvironmentalCongenital infection:

CytomegalovirusRubella virusLymphocytic choriomeningitis virus

Drugs or toxins:AlcoholAntiepilepticsCocaineHeroin

Maternal PKURadiation exposureIschemic vascular events

AcquiredEnvironmental

Hypoxia/ischemiaInfection: meningitis, encephalitisTrauma: nonaccidentalEndocrine:

HypothyroidHypopituitarism

Metabolic:HypoglycemiaAminoaciduriasOrganic acidurias

MalnutritionGenetic

Rett syndromeAngelman syndrome

AD: autosomal dominant; AR: autosomal recessive; PKU: phenylketonuria; XLR: X-linked recessive

A syndromic diagnosis can be established byidentifying the complete constellation of brainand somatic malformations and matching thefindings with known syndromes using searchtools such as OMIM, Genetests (http://www.genetests.org/) or Smith’s RecognizablePatterns of Human Malformation (2006,Elsevier Saunders, Philadelphia) (Table 25).

Congenital infections, important, potentialcauses of microcephaly, often produce intra -cranial calcification, as well as choriore tinitis,cataracts, or SNHL. Rubella virus (Germanmeasles) and CMV are congenital infectionsassociated with microcephaly. Lymphocyticchoriomeningitis (LCM) virus, a rodent-bornearenavirus, should be considered in infants whohave negative studies for CMV or Toxoplasmagondii. In utero drug and alcohol exposure canaffect the developing brain as can maternalradiation exposure, diabetes mellitus, oruncontrolled maternal phenylketonuria (PKU).Ischemic vascular events and placental insuffi -ciency can also affect the developing brain andcause microcephaly.

Perinatal asphyxia is a potential cause ofacquired microcephaly. In order for micro -cephaly to be ascribed to asphyxia, however,infants must have neonatal histories compatiblewith hypoxic ischemia encephalopathy.Postnatal meningitis and encephalitis as well asnonaccidental trauma can also cause micro -cephaly. Inborn errors of metabolism commonlyaffect the growth of the brain and are a consider -ation in the diagnostic evaluation. Untreatedcongenital hypothyroidism can cause micro -cephaly as can hypoglycemia and hypopitu -itarism. Although not common in developedcountries, extreme malnutrition can also affectbrain growth. Finally, Rett and Angelmansyndromes are among the disorders that shouldbe considered in children with acquiredmicrocephaly. Rett syndrome is a major cause ofacquired microcephaly in girls (124, line C).However, not all girls with Rett syndrome willbe microcephalic despite the postnatal deceler -ation in head growth.

The diagnostic evaluation of infants orchildren with microcephaly begins with an accu -rate measurement of the head circumferenceand a careful search for dysmorphic features andother organ involvement that might suggest aspecific syndrome. A complete history should beobtained with attention to pregnancy-associated


Table 25 Selected syndromes associated withmicrocephaly

Syndrome FeaturesAngelman Microcephaly and brachycephaly, syndrome fewer than 5 single words, wide

mouth, prognathism, widely-spaced teeth, jerky/ataxic gait; pleasant personality

Rett syndrome Postnatal microcephaly in many, developmental regression, loss of language and purposeful hand movements, characteristic movement disorder

Cri du chat Microcephaly, low birth weight, short syndrome stature; meowing cry as infants (131)Trisomy 18 Microcephaly, rocker-bottom feet,

congenital heart defects, cleft lip and palate (132)

Trisomy 13 Microcephaly, midface hypoplasia fingers over-lapping the thumbs, polydactyly, holoprosencephaly (133)

Wolf–Hirschhorn Microcephaly, seizures, cleft lip, syndrome ‘fish-like’ mouth, hypotoniaMiller Dieker Microcephaly, lissencephaly, seizures, syndrome characteristic faciesSmith–Lemli– Microcephaly, hypotonia, polydactyly, Opitz syndrome syndactyly, characteristic facies,

hypospadias in boys

risk factors, including prenatal infections ordrug and alcohol use, and to the infant’sperinatal period. Infants with microcephalyrequire neuroimaging. Brain MRI accuratelyidentifies most brain malformations, but headCT is more likely to identify calcifications thatmay suggest congenital infections (134).Genetic evaluation involves the identification ofpossible syndromes. High resolutionchromosomes, fluorescent in situ hybridization(FISH), methylation studies, and comparativegenomic hybridization should be considered,depending upon the child’s features. Metabolicstudies to consider include free T4, TSH,serum lactate, serum amino acids, and urineorganic acids.




131 132

131A child with cri du chat (5p-) syndromedemonstrating microcephaly and acharacteristic facial appearance.

132A child with trisomy 18 showingcharacteristic hand position.

133133A child with trisomy 13showing cleft lip, midfacehypoplasia, omphalocele, and abnormal toes.

134134A noncontrast CT showing intracranialcalcifications in congenital CMV disease.

Misshapen heads

Abnormal head shape is described as:• Dolichocephaly (scaphocephaly): long

head, front-to-back.• Brachycephaly: short head, front-to-back.• Plagiocephaly: parallelogram or trapezoidal

head.• Trigonocephaly: triangular head (pointed

forehead).• Turricephaly: tall head, shaped like a tower.• Oxycephaly: cone-shaped head.

The skull (calvarium) grows to accommodatethe growth of the brain, leading to a calvariumthat is oval or round in shape and symmetrical.The skull can grow because of the sutures (135,136), open spaces between each of the skull’seight bones. The sutures function as growthplates for the skull bones, and growth occursperpendicular to the suture. If a suture prema -turely closes (synostosis), compensatory growth


135

135A helical CT showing the locations of thecranial sutures in superior view. 1: Lambdoidsutures; 2: sagittal suture; 3: coronal sutures;4: anterior fontanel.

1

3

4

2

occurs from the remaining open sutures. Thenet effect of compensatory growth is that theskull now grows maximally in the directionparallel to the closed suture. If sagittal suturesynostosis occurs, compensatory growthperpendicular to the coronal and lambdoidsutures produces elongation of the head ordolichocephaly/scaphocephaly. In synostosis ofthe coronal sutures, compensatory growthperpendicular to the sagittal suture leads tobrachycephaly, a short head front-to-back, witha broad forehead. Similarly, metopic suturesynostosis causes trigonocephaly (137), atriangle-shaped head from compensatorygrowth perpendicular to the coronal sutures.With synostosis of one of the two lambdoidsutures, compensatory growth perpendicular tothe open lambdoid suture results in posteriorplagiocephaly. Finally, synostosis of multiplesutures at the skull base leads to turricephaly, atall head shaped similar to a castle tower, oroxycephaly, a cone-shaped skull.


136

137

136A helical CT showing the locations of the cranial suturesin lateral view. 1: Coronal; 2: squamosal; 3: lambdoid; 4: sagittal.

137A child with trigonocephaly showingpointed forehead and suture ridging due tometopic suture craniosynostosis.

4

31

2

Positional ordeformationalplagiocephalyThe most common cause of a misshapen head isnot craniosynostosis but positional ordeformational plagiocephaly. Because of the‘back to sleep’ recommendation for the infants’sleep position, 5–48% of otherwise healthynewborns exhibit some degree of positionalplagiocephaly. Torticollis can also contribute toplagiocephaly. The characteristic shape of thehead in positional plagiocephaly is a‘parallelogram’ with flattening of one side of theocciput and forward advancement of theipsilateral forehead and ear. The parallelogramdeformation can best be appreciated by lookingdown at the top of the baby’s head so thatcomparison can be made of the position of theears and the prominence of the forehead andface on the ipsilateral face.

Positional plagiocephaly can often bedistinguished from the much rarer lambdoidsynostosis by the head shape (138). Whereaspositional plagiocephaly will have theparallelogram appearance, the head in plagio -cephaly due to craniosynostosis has a trapezoidal

shape with compensatory bossing of thecontralateral occipital–parietal area and posteriordisplacement of the ipsilateral ear. Helical CT ofthe skull may be needed to detect lambdoidsuture synostosis.

Treatment of positional plagiocephalyconsists of positioning the head of the supineinfant toward the side opposite to the flattening.This can include arranging the crib so theinfant turns toward the nonflattened side andincreasing supervised ‘tummy time’ when theinfant is awake. If these maneuvers fail and theskull deformity remains disfiguring, the infantmay benefit from a skull molding helmet. Iftorticollis is present, there should be regularstretching of the involved sternocleidomastoidmuscle. This can be accomplished by turningthe infant’s head and neck so that the chintouches one shoulder, holding this position for10 seconds, and then repeating the process tothe other shoulder. The parent should performthree repetitions at each diaper/nappy change.In addition, the trapezius muscles should bestretched by tilting the head so the ear toucheseach ipsilateral shoulder, held for 10 seconds,and then repeated three times for each shoulder.


138

138 Diagrams showing head shape in (A) positional plagiocephaly, and (B)lambdoidal craniosynostosis.

A B

Cranial synostosisSagittal suture synostosis, the most commontype of craniosynostosis, causes an elongatedhead, dolichocephaly or scaphocephaly, thelatter named for the keel-like ridge of the fusedsagittal suture. Sagittal fusion accounts for about50% of all cases of craniosynostosis. Bicoronalsynostosis, causing 25% of cases, results inbrachycephaly. Approximately 33% of childrenwith brachycephaly have a single genemutation as the cause of their disorder. Metopicsynostosis, accounting for 10% of cases ofcraniosynostosis, results in trigonocephaly.Because metopic craniosynostosis can beassociated with deletion syndromes, genetictesting, including karyotype and microarray,should be considered. Finally, lambdoidsynostosis, the least common form ofcraniosynostosis, accounting for only 2–4% ofcases, may be associated with intrauterineconstraint.

In order of frequency, the patterns ofcraniosynostosis are: sagittal (50–60%); coronal(20–30%); metopic (5–10%); lambdoid (2–4%);and multiple (uncommon).


139

139A child with Crouzon syndrome, showingthe shallow orbits and tall forehead.

More than 180 syndromes are associatedwith craniosynostosis (textbox).

Selected syndromes associated withcraniosynostosis• Crouzon (139).• Antley–Bixler.• Apert.• Pfeiffer.• Saethre–Chotzen.

Many of the more common syndromicforms of craniosynostosis are autosomaldominant with variable expressivity and involvemutations of the fibroblast growth factorreceptors (FGFRs) or related genes. FGFRs areimportant signaling molecules that regulate cellprolifer ation, differentiation, and migrationthrough complex pathways.

DIAGNOSISEvaluation of patients with craniosynostosis firstinvolves documenting the involved suture(s)and identifying associated craniofacial and brainmalformations. Brain malformations are bestdetected by MRI, while 3D (helical) CT allowsfor 3-dimensional reconstruction of the bonyanatomy of the skull and face (140, 141). Thechild should be examined for dysmorphicfeatures and any associated skeletal or otherorgan involvement. Because disorders ofhearing and vision can accompany coronalsynostosis, such children should have thoroughophthalmological and audiological evaluations.Clinicians should be aware that increasedintracranial pressure can complicate multiplesuture synostoses and search for worryingsigns or symptoms, such as headaches, diplopia,or papilledema. Developmental screening,psychoeducational testing, and genetic screensfor single gene mutations may be appro -priate for children with syndromic causes ofcraniosynostosis.

MANAGEMENTManagement and comprehensive evaluation ofchildren with craniosynostosis are best accom -plished at a craniofacial center which has amultidisciplinary team of specialists for thesurgical and medical management for thesechildren. Because growth of the skull allowsmaximum benefit from corrective surgery,clinicians should refer children with suspectedcraniosynostosis as early as possible.


140

140A helical CT showing doliococephaly andabsence of the sagittal suture indicative ofsagittal synostosis.

141

141A helical CT showing trigonocephaly andmetopic suture craniosynostosis.

CHAPTER 11131

Disorders of cranial nerves

Main Points• Isolated disorders of the cranial nerves, i.e. cranial neuropathies,

are uncommon in childhood.

• With the exception of cranial nerves 1 and 2 which originate fromcerebral neurons, the cranial nerves arise from neurons located inthe brainstem, extending from the midbrain rostrally to themedulla caudally.

• Bell’s palsy, the most common cranial neuropathy, causes weaknessof the upper and lower portions of the face.

• Papilledema, an abnormality of the optic nerve (CN2), usuallysignifies increased intracranial pressure.

• Horizontal diplopia suggests disorders of CNs 3 and 6, whereasvertical diplopia indicates a disorder of CNs 3 or 4.

• Möbius syndrome, a rare disorder, consists of agenesis of the motornuclei for CNs 6 and 7.

• Crossed signs, consisting of paralysis of a cranial nerve on one sideand paralysis of the arm and/or leg on the opposite side, indicate abrainstem lesion at the level of the cranial neuropathy.

• Inflammatory conditions (i.e. neuritis) can affect CNs 2, 3, 4, 6, 7, 8,and 12. Some of these improve with corticosteroid treatment.

75%. Brain MRI in persons with Kallmansyndrome may show absence or hypoplasia ofthe olfactory bulb and tracts or absence of theolfactory sulci and may be associated withagenesis of the corpus callosum. Managementconsists of replacement of sex steroids andtreatment with human chorionic gonadotropinand gonadotropin releasing hormone.

Anosmia affects 10% or fewer individualswith mild TBI, but 50% or more of persons withsevere TBI. In general, the likelihood of post-traumatic anosmia varies inversely with thepatient’s lowest Glasgow Coma Scale score.Anosmia after head injury can result fromcerebral contusion to the olfactory centers,injury of the olfactory nerve, usually at the levelof the cribiform plate, and trauma to the noseand sinuses. Unfortunately, the majority ofpersons with post-traumatic anosmia havepermanent loss of smell; only a small percentagerecovers normal smell completely. Olfac-tory nerve dysfunction can also be the conse-quence of acute rhinitis, medication use,smoking, holoprosencephaly, cystic fibrosis, andCHARGE (coloboma of the eye, heart anomaly,choanal atresia, retardation, and ear anomalies)syndrome.

Introduction

With the possible exception of Bell’s palsy, theacute paralysis of the 7th or facial cranial nerve,disorders of cranial nerves (CNs) 1–12 are infre -quently encountered by the typical pediatricpractitioner. This chapter, organized sequen -tially by cranial nerve, describes the clinicalmanifestations of several disorders of the cranialnerves and provides clinicians with informationfor their effective management. Please refer toChapter 1 The Pediatric Neurological Exam -ination for additional details regarding theclinical examination of each cranial nerve.

Cranial nerve 1 (olfactory nerve)

Congenital or acquired disorders affecting smellare extremely uncommon; consequently, fewpediatric or adult neurologists assess smellduring the routine neurological examination.Anosmia, the loss of smell, can be difficult todetect in young children who lack thedevelopmental ability to describe smells orrespond to neurological testing of smell; olderchildren can provide reliable informationregarding smell. Congenital anosmia is a featureof Kallman syndrome, a disorder characterizedprincipally by hypothalamic hypogonadism.Kallmann syndrome affects 1 in 10,000–86,000persons. Additional features of Kallmansyndrome include brachydactyly, cleft lip orpalate, color blindness, and SNHL. Thedisorder exists in several forms: 1) an X-linkedcondition (KAL1) due to mutations in KAL;and 2) autosomal dominant conditions (KAL2,KAL3, and KAL4) due to mutations in FGFR1,PROKR2, and PROK2, respectively. Thesegene abnormalities account for approximately25% of cases of Kallman syndrome; theremainder are of uncertain genetic origin.

Kallman syndrome can be suspected bydetecting incomplete sexual maturation orarrested puberty and low or normal levels ofleuteinizing and follicle stimulating hormonesin the presence of low levels of sex hormones.The function of hypothalamic–pituitaryhormones is otherwise normal. Testing by FISHor gene sequence analysis can confirm thegenetic etiology of Kallman syndrome, but genetesting will be unrevealing in approximately


disorders, such as septo-optic dysplasia. Clini-cians should examine the fundus routinely andbecome comfortable with the appearance of theoptic nerve (142).

Drugs or toxins associated with opticneuropathy include: methanol, carbonmonoxide, ethylene glycol, vincristine, lead,isoniazid, ethambutol, and quinine.

Cranial nerve 2 (optic nerve)

Because disorders of CN2 affect vision, suchconditions are often recognized readily bychildren or their parents. Potential causes ofoptic nerve or visual dysfunction include toxic neuropathies (textbox), optic neuritis,migraine, neoplasms, trauma, metabolic disor-ders, vascular disorders, vitamin deficiencies,leukemia, infections of the CNS, and congenital

CHAPTER 11 Disorders of cranial nerves 133

142

142An enlarged, but otherwise normal appearing optic nerve.


Optic neuritisOptic neuritis, inflammation of the optic nerve,occurs most frequently in young adultsbetween the ages of 20 and 45 years, thusoverlapping with the age of greatest risk for MS. Only 5% or so of cases of optic neuritisinvolve children or adolescents, but, like adults,there is a female predominance. In contrast to adults, children frequently have bilateraloptic neuritis and infrequently have MS.Symptoms associated with optic neuritis,consisting of vision loss or blurring, headache,and pain during eye movement, can beginabruptly within 24 hours or insidiously over1–2 weeks. Neuro-ophthalmological findingsinclude decreased visual acuity, especially forred–green colors, optic disk swelling (‘papil-litis’, either unilateral or bilateral) (143), retinalhemorrhages and, when optic neuritis is unilat-eral, an afferent pupillary defect. The latter canbe detected using the swinging flashlight test.

Children with suspected optic neuritis shouldbe studied by MRI with and without gadoliniumusing fat-suppressed STIR (short T1-inversionrecovery) sequences (144). Optic nerves, as wellas brain and spinal cord, should be studied, giventhe potential associations of optic neuritis with MS, Devic’s disease, or acute dissem-inated encephalomyelitis (ADEM) (145). Themajority of cases of optic neuritis in children canbe linked to recent infectious illnesses, includingEpstein–Barr virus (146) or immunization; MSdeserves consideration when optic neuritisoccurs in adolescents or when the brain MRIshows features suggestive of MS.

Children with optic neuritis should betreated with corticosteroids, using modifica -tions of the adult optic neuritis treatmentprotocol (textbox).

Optic neuritis treatment protocol• Methylprednisolone 15 mg/kg/day

(maximum 1000 mg/day) IV in equallydivided doses every 6 hr for 3 days,followed by

• Prednisone 1 mg/kg/day (maximum 60 mg/day) PO for 11 days, followed by

• Prednisone 0.5 mg/kg/day (maximum 60 mg/day) PO QOD for 3 days.

Most children recover completely, althoughsome will later have neurological featuressuggesting MS or spinal cord disease compat -ible with neuromyelitis optica (Devic’s disease).The latter can be associated with circulatingIgG (neuromyelitis optica [NMO] antibodies)to aquaporin-4, the brain’s most abundantwater channel.


145

145A T2-weighted MRI showing characteristicmultifocal hyperintensities (arrow) consistentwith ADEM.

144

144 A T2-weighted, fat suppressed MRIshowing an enlarged nerve (arrow) with signalhyperintensity compatible with optic neuritis.

146

146A FLAIR MRI in EBV-induced optic neuritisshowing signal hyperintensity in the opticchiasm (arrow) compatible with inflammation.

143

143 Papillitis (optic neuritis) with optic nerveswelling and hemorrhage (arrow).


Optic nerve hypoplasiaWhen clinicians encounter optic nerve hypo -plasia, they should consider congenital disordersof the CNS, including septo-optic dysplasia,lissencephaly, schizencephaly, hydran encephaly,hydrocephalus, fetal alcohol syndrome,anencephaly, and intrauterine infec-tions (cyto -megalovirus, Toxoplasma gondii, lymphocyticchoriomeningitis virus, rubella, syphilis).

Septo-optic dysplasia (DeMosier syndrome)is a heterogeneous condition associated withoptic nerve hypoplasia, absence of the septumpellucidum, brain anomalies, and endocrino-logic dysfunction. Ophthalmological featuresmay consist of nystagmus and impairments ofvisual fixation and pursuit. The imaging hallmarkof this condition is an absent septum pellucidum,detectable either by CT or MRI (147–149).Sagittal T1 MRI can reveal pituitary ectopia, afinding that has a strong association withhypothalamic–pituitary axis dysfunction anddisorders of TSH, growth hormone, and/oradrenocorticotropic hormone (ACTH). Septo-optic dysplasia has been linked to mutations inseveral genes involved in neural development,including HESX1, a homeobox gene, and SOX2and SOX3, genes encoding transcription factors.Management of septo-optic dysplasia consists ofhormone replacement, vision therapy, andtreatment of associated features, such as seizures.Long-term prognosis for children with septo-

147

147A normal coronal FLAIR MRI showing anintact septum pellucidum (arrow).

148

148A coronal T2-weighted MRI in septo-opticdysplasia showing absence of the septumpellucidum.

149

149A T2-weighted coronal MRI showing absentseptum pellucidum and small optic nerves(arrows) in a child with septo-optic dysplasia.

optic dysplasia varies according to the severity ofassociated brain anomalies; many havepermanent neurode velopmental disabilities.


Optic nerve atrophyAcquired optic nerve atrophy (150) results fromhydrocephalus, CNS tumors, metabolic disor-ders, demyelinating disorders, or genetic condi-tions. Optic atrophy commonly accompanieschiasmal or optic nerve gliomas in patients withneurofibromatosis type 1 (NF-1) (151), aneurocutaneous disorder that should besuspected when children have axillary freckling(152) and multiple café au lait spots. Opticnerve gliomas appear in approximately 10–20%of patients with NF-1; conversely, one-third ormore of children with optic gliomas have NF-1.Most optic nerve gliomas in children with NF-1 can be followed clinically without inter-vention; treatment can be required whentumors grow aggressively and cause vision lossor hydrocephalus.

Acquired optic nerve atrophy can be a mani-festation of Leber’s hereditary optic neuropathy(LHON), a mitochondrial disorder that resultsfrom mutations in the genes encodingnicotinamide adenine dinucleotide hydride(NADH) dehydrogenase in complex I of theelectron transport chain. Persons with thisdisorder experience the fairly abrupt onset ofpainless visual loss that can progress to completeblindness within several months; most affectedpatients are adults, but onset during childhoodis reported. Rarely, patients with LHON can have ataxia, tremor, or prolonged QTsyndrome. The diagnosis of LHON can besupported by electrophysiological studies(showing abnormal VEPs) or ophthalmologicalexamination (showing microangiopathy or diskedema) and confirmed by detecting thecharacteristic point mutations in mitochondrialDNA. No effective therapy exists.

150

150A fundus photograph showing a pale opticnerve consistent with optic nerve atrophy.

151A T2-weighted, fat-suppressed axial MRIshowing a markedly enlarged optic nerve(arrow) in a patient with NF-1 and optic glioma.

152Axillary freckling consistent with NF-1.

151

152


PapilledemaPapilledema, swelling of the optic nerve, oftenindicates increased intracranial pressure due to intracranial mass lesions or idiopathicintracranial hypertension (pseudotumor cerebri)(153–155). Features include edema of the optic nerve, blurring of the disk margins, retinalhemorrhages, loss of venous pulsations, andenlargement of the physiological blind spot.However, papilledema can also be seen inchildren with hydrocephalus, encephalitis,venous sinus thrombosis, and lead intoxication.Optic nerve swelling, considered papillitis, is acommon feature of optic neuritis. Papilledemashould be differentiated from pseudopa -pilledema (Drusen), a condition that results fromprogressive calcification of proteins and poly -saccharides that accumulate within the opticnerve and elevate the nerve (156). Druseninfrequently appears before the age of 12 yearsand rarely produces visual symptoms.

153 Papilledema in a child with increasedintracranial pressure.

153

Post-traumatic blindnessPost-concussive blindness, although not due tooptic nerve dysfunction, is a disorder that clini -cians will encounter. Post-concussive blindnesscan occur after relatively minor head injury inyoung children. The disorder does not resultfrom direct trauma to the optic nerves, butreflects cortical visual impairment. Blindnessbegins immediately after head trauma andpersists for minutes to hours. When thedisorder occurs as a migraine variant, transientblindness can be accompanied by headache,nausea, vomiting, confusion, or agitation. Theneurological examination reveals intactpupillary responses to light and normalappearing optic nerves. EEG may revealmedium to high amplitude posterior slowing,whereas imaging studies, either CT or MRI, areusually normal. Less commonly, acute corticalblindness can be a manifestation of posteriorreversible encephalopathy syndrome (PRES) ormitochondrial disorders, such as MELAS.


154 Papilledema and retinal hemorrhage(arrow) in a child with increased intracranialpressure.

155 High-grade papilledema with retinalhemorrhage.

156 Optic nerve drusen. Note enlargement ofthe optic nerve and blurring of the disk margins.

154

155

156

Cranial nerve 3(oculomotor nerve)

The oculomotor nerve innervates the medial,superior, and inferior rectus muscles, thelevator muscle of the upper eye lid, theconstrictor of the pupil, and the ciliary body.

Consequently, lesions of the oculomotor nervecause varying combinations of ptosis, pupillaryabnormalities, and abnormal extraocularmovements. Complete paralysis results inptosis, mydriasis, absent pupillary responses,and downward/outward deviation of the eye(157–159).


158The child shown in 157 2 weeks later withmilder ptosis and residual strabismus. Note thelateral deviation of the right eye.

158

159The child shown in 157, 158 with recurrenceof mild right ptosis without strabismus orpupillary involvement 3 months later.

159

157A-3-year old child with an acute rightoculomotor nerve (CN3) palsy with ptosisand ophthalmoplegia.

157

Abnormalities ofpupil sizePupillary size reflects the relative balance ofparasympathetic and sympathetic pupillary toneas well as the intensity of the ambient light andthe integrity of the optic nerve or retina(160–162). Parasympathetic stimulation of thecircular muscle of the pupil causes pupillaryconstriction, whereas sympathetic stimulation ofthe radial muscle causes pupillary dilation (alsocalled dilatation). Pupillary dilation (mydriasis)can result from increased sympathetic tone ordecreased parasympathetic tone; conversely,pupillary constriction (miosis) results increasedparasympathetic tone or from lesions that affectsympathetic innervation of the pupil (textbox).

Pupillary abnormalities• Adie pupil: a dilated pupil, usually unilateral,

that does not react to light or convergence.• Argyll Robertson pupils: small pupils that

constrict during accommodation but donot constrict in response to bright light.

• Marcus Gunn pupil: another name for arelative afferent pupillary defect; a pupilthat dilates paradoxically to bright light(the ‘swinging flashlight test’).

Mydriasis can be observed in angry orexcited persons or in children or adolescentsexperiencing absence seizures. Unilateralmydriasis can indicate an oculomotor nervepalsy, and because the parasympathetic fiberstravel in the outer bands of the nerve,unilateral pupillary dilatation in an obtundedor comatose child or adolescent suggestsherniation of the uncus of the temporal lobe.Horner syndrome (163), a condition asso -ciated with unilateral miosis, ptosis, andipsilateral reduction of facial sweating, can becongenital or acquired. The pupils may appearequal in the light and pupillary asymmetry(anisocoria) becomes apparent in a darkened ordimly-lit room. Acquired Horner syndromecan be the result of birth trauma to the brachialplexus, tumor, carotid artery dissection,migraine or, in a toddler-aged child, aneuroblastoma affecting the sympathetic fibersfrom the spinal roots of C8, T1, T2, or T3 orsympathetic neurons in the superior cervicalganglion. MRI, including intravenous contrast


160

160 Normal sized pupils.

162

162 Miotic pupils in a healthy child.

163

163A child with Horner syndrome. Note theptosis and miosis of the left eye.

161

161 Mydriatic pupils in a healthy child.


and fat-suppressed techniques, should encom-pass anatomy from the hypothalamus supe-riorly through T3 inferiorly in children withHorner syndrome.

Congenital third nerve palsyParalysis of the oculomotor nerve, nearly alwaysunilateral, can be present at birth, occasionallyas the consequence of birth trauma, but morecommonly as a cryptogenic process. Congenitaloculomotor paralysis, often unrecognized in thenewborn period, can also be associated withsepto-optic dysplasia or congenital brainstemhypoplasia. Consequently, infants with featuressuggesting congenital oculomotor palsy shouldundergo MRI. Uncommon causes of oculo-motor paralysis in childhood include aneurysmsof the posterior cerebral artery, stroke, tumor,carotid artery–cavernous sinus fistula, andcavernous sinus thrombosis. Amblyopia is acommon complication of congenital oculo-motor paralysis. Cyclic oculomotor palsy, a rarecongenital disorder of the oculomotor nerveknown also as oculomotor palsy with cyclicspasms, produces rhythmic or cyclic mydriasisand ptosis.

OphthalmoplegicmigraineOphthalmoplegic migraine, an uncommonmigraine variant, typically affects the oculo-motor nerve, causing ptosis, exotropia, diplopia,and mydriasis. Headache and vomiting, otherpotential signs and symptoms compatible withmigraine, may or may not accompany the oculo-motor paralysis; headache can precede the onsetof paralysis by several days. The paralysis can lastfrom hours to several days or more. MRI mayshow inflammation or gadolinium enhancementof the oculomotor nerve, suggesting that thepathogenesis of transient ophthalmoplegia ofchildhood represents acute inflammation andreversible demyelination (164). Occasionalchildren have recurrent attacks of oculomotorparalysis. Because the majority of affectedchildren recover completely, the treatmentconsists primarily of managing pain.

Myasthenia gravisPtosis and diplopia, features suggesting partialCN3 palsy, can be relatively common mani-festations of juvenile myasthenia gravis. Incontrast to true lesions of CN3, includingophthalmoplegic ‘migraine’, myasthenia gravisspares the pupils and rarely causes pain. Thediagnosis of myasthenia gravis is supported byresolution of ptosis and diplopia afteradministration of edrophonium chloride (the‘tensilon test’) or neostigmine.

164

164 Gadolinium enhanced sagittal T1-weightedMRI showing an enhancing CN3 (arrow) in achild with ophthalmoplegic ‘migraine’.


Cranial nerve 4(trochlear nerve)

Isolated lesions of CN4 or trochlear nerve areextremely uncommon. Children with CN4palsies, whether congenital or acquired, exhibithead tilt or diplopia in the vertical plane.Difficulty descending stairs in the presence ofnormal balance and muscle strength can be animportant clue that a child or adolescent hastrochlear nerve dysfunction. Like congenitaloculomotor palsy, congenital CN4 palsy maynot be identified until early childhood. AcquiredCN4 palsies can be the result of head trauma,demyelination (as might occur in MS) orincreased intracranial pressure. Children withacquired trochlear palsies usually improvespontaneously. Persistent deficits and congenitaltrochlear palsies may require strabismus surgeryor prism therapy.

Cranial nerve 5(trigeminal nerve)

The trigeminal nerve (CN5) innervates themuscles of mastication and subserves sensation tothe face via the ophthalmic, maxillary, andmandibular branches (165). Isolated lesions of the trigeminal nerve are exceedingly uncom -mon. Rarely, tumors of the trigeminal nerve, suchas schwannomas or meningiomas, can producemotor or sensory dysfunction of the trigeminalnerve and, if large or infiltrating, the tumors mayalso affect the function of the cerebellum or otherCNs. Wallenburg or lateral medullary syndrome,an important stroke syn drome in adults, causes‘crossed’ sensory signs consisting of impairedfacial sensation on the side ipsilateral to the strokeand loss of pain and temperature in theextremities on the side opposite the stroke.Trigeminal nerve dysfunction can alsoaccompany cavernous sinus thrombosis.

Trigeminal neuralgia or tic douloureux, anuncommon disorder in childhood, causesintense, lancinating pain in the distribution of thetrigeminal nerve. The disorder has beendescribed in children as young as 13 months.Children with trigeminal neuralgia shouldundergo MRI studies of the brainstem to excludetumors or other lesions of the trigeminal nerve orbrainstem; the disorder has been associated withlipoma, schwannoma, and an infiltrating rhado -myosarcoma. Management should begin withmedications, such as gabapentin, carba mazepine,or oxcarbazepine, which ameliorate neurogenicpain. Microvascular decompression has been usedsuccessfully to treat children who did not respondto medication management.

165 Schematic showing the distribution of thesensory branches of the 5th cranial nerve.

165

Ophthalmicbranch

Maxillarybranch

Mandibularbranch

168 Duane syndrome. In the left panel the child is looking straight ahead;there is mild strabismus with the left eye adducted. In the right panel, thechild is attempting to look to the left, but cannot fully abduct the left eye.

Cranial nerve 6(abducens nerve)

Because of the long intracranial course of theabducens nerve, paralysis of this nerve,characterized by deviation of the eye medially,weakness of abduction and diplopia (166, 167),occurs frequently in children or adolescents withincreased intracranial pressure. This paralysis,considered a ‘false localizing sign’, can be theresult of intracranial tumors, infections, oridiopathic intracranial hypertension (pseudo-tumor cerebri). Gradenigo syndrome, caused byinflammation of the abducens nerve, cancomplicate otitis media or mastoditis andproduces pain as a result of concomitantinflammation of the trigeminal nerve. Möbiussyndrome, a rare, congenital disorder associ-ated with aplasia of the motor neurons of CNs6 and 7, causes facial diplegia and absent ocularabduction.

Duane syndromeDuane syndrome or Duane’s retractionsyndrome, a disorder that can mimic abducenspalsy, results from aberrant innervations of thelateral and medial recti muscles that controlabduction and adduction, respectively. Thelateral rectus muscle is commonly fibrosed,usually unilaterally, producing restriction ofabduction (168). The disorder has been linkedto a mutation in the gene encoding alpha2-chimaerin, a signaling protein involved in thepathfinding of corticospinal axons. Children oradolescents with this disorder do not experiencediplopia and can be managed conservativelywith prism therapy.


166 Left abducens(CN6) palsy. In theleft panel, the child islooking forward; inthe right panel thechild is attempting tolook left.The left eyefails to abduct.

166

167 Mild leftabducens palsyshowing that the childcannot fully abductthe left eye (arrow).

167

168

Cranial nerve 7 (facial nerve)

Bell’s palsyBell’s palsy, by far the most common cranialneuropathy, affects 1 in 7,500 children or adultsannually in the USA. The disorder often beginswith pain behind the ear; paralysis of the faceappears shortly thereafter. In contrast to upper

motor neuron lesions, such as stroke, thatproduce weakness of the lower portion of theface, Bell’s palsy causes weakness of both theupper and lower portions of the face. Thus, achild or adolescent with Bell’s palsy displays anasymmetric smile (169) and weakness of eyeclosure (170). Because CN7 subserves taste andinnervates the stapedius muscle, persons withBell’s palsy may experience altered taste, tinnitus,or hypersensitivity to sounds (hyperacusis).


169

169 Left Bell’s palsy, at rest.The smile isasymmetric.

170 Left Bell’s palsy, when attempting to closethe eyes tightly.The entire left side of the face is weak.

170

with simple nonsteroidal anti-inflammatoryagents, such as ibuprofen or acetaminophen.Surgical decompression of the nerve, onceconsidered an important therapeutic adjunct, israrely considered currently. The majority ofpediatric patients with Bell’s palsy recovercompletely, although occasional individuals haveresidual disorders of taste, hearing, or facialmovement. Bell’s palsy recurs in 5–10% ofchildren; contrast-enhanced MRI of thetemporal bones should be considered inrecurrent or persistent Bell’s palsy to excludelesions of CN7 or skull base.

Progressive facial hemiatrophy, also known asParry–Romberg syndrome, is associated withslowly progressive atrophy of fat andsubcutaneous tissues on one side of the face,more often the left. The disorder of unknowncause typically begins in children or adolescentsbetween the ages of 5 and 15 years. Children oradolescents with Parry–Romberg syndrome canexperience seizures or trigeminal neuralgia. Thedisorder cannot be cured, although surgicalprocedures, including fat implantation, canminimize the disfigurement associated with thedisorder.

The disorder, usually unilateral, can be bilateral(171, 172) when it accompanies conditionssuch as GBS or Lyme disease. Acute facialparalysis in children and adolescents can be seenin children with hypertension, otitis media,leukemia, varicella-zoster infection (RamsayHunt syndrome), cat scratch disease, or tumorsinvolving the facial nerve.

The weakness associated with idiopathicBell’s palsy usually reaches its peak within 2 days,but recovery can take weeks or months. Becausevirus-induced inflammation, possibly due toherpes simplex virus (HSV) type 1, is believed tobe an inciting factor in Bell’s palsy, many author -ities recommend treatment with aciclovir (orvalaciclovir) and prednisone orally. Children or adolescents with Lyme disease-induced Bell’s palsy require antibiotic therapy, usuallywith amoxicillin. The authors suggest pred-nisone 1–2 mg/kg/day orally (maximum of 60 mg/day) for 7–10 days in children oradolescents with Bell’s palsy and an absence ofsigns suggesting Lyme disease, hypertension,leukemia, or varicella-zoster virus infection. Acomplete blood cell count should be consideredto exclude acute leukemia. Pain can be managed


171A child with facial diplegia at rest. 172The child in 171 when attempting to closehis eyes tightly. He cannot bury his eye lashes.

171 172

Cranial nerve 8 (acoustic nerve)

Disorders of hearing, sometimes the result oflesions of the cochlear division of the acousticnerve are discussed in Chapter 9 Disorders ofLanguage and Hearing. Disorders of thevestibular division, the portion of the nerve thatreceives efferent impulses from the threesemicircular canals, produce vertigo, ofteninterpreted by children or adolescents as‘dizziness’. Inflammation of the vestibular nerve(vestibular neuritis) can accompany severalinfections, especially those of the upperrespiratory tract. Children or adolescents withvestibular neuritis experience the relativelyabrupt onset of intense vertigo, nausea andvomiting, and nystagmus, the cardinal sign ofvestibular dysfunction. Symptoms areexacerbated by movement, so most individualswith vestibular neuritis prefer sedentary activitiesuntil the acute phase subsides. Signs orsymptoms of cochlear nerve dysfunction, suchas tinnitus or hearing loss, are absent.

Children with acute vestibular neuritisshould undergo brain MRI to exclude othercauses of vestibular dysfunction, such asintracranial tumors, MS, or ADEM, and mayrequire neurophysiological studies, such aselectronystagmography. Evaluation in a hearingand balance center can provide usefulinformation. Although the acute symptomsassociated with viral neuritis begin to resolve inseveral days, movement-induced vertigo canpersist for several months. Some authoritiessuggest a brief course of oral corticosteroids,similar to that used in Bell’s palsy, in personswith vestibular neuritis. Other disorders cancause acute or episodic vestibular dysfunction inchildren and adolescents (textbox).

Miscellaneous disorders of childhoodassociated with acute or episodicvestibular dysfunction• Waardenburg syndrome.• Migraine, especially variants such as

benign paroxysmal vertigo.• Multiple sclerosis.• Benign paroxysmal positional vertigo.• Complex partial epilepsy.• Ménière disease (rare in childhood).• Postconcussion syndrome.

Labyrinthitis, acquired infection or inflam-mation of the bony labyrinth, producesvestibular and cochlear dysfunction. Thus,persons with this disorder have tinnitus andhearing loss, in addition to vertigo. Labyrinthitiscan be viral or bacterial and associated withmastoiditis and purulent or aseptic meningitis.Bacterial disease requires aggressive antibiotictherapy. Mondini dysplasia, a congenitalanomaly of the cochlea and semicircular canals,can be associated with deafness, vestibulardysfunction, and a risk of recurrent bacterialmeningitis due to the presence of anendolymphatic–perilymphatic fistula. Temporalbone MRI is useful in the evaluation of themembranous labyrinth.



Cranial nerves 9 and 10(glossopharyngeal andvagus nerves)

CN9 and CN10 are often considered togetherbecause isolated disorders of the glossopha-ryngeal nerve, such as a schwannoma or aplasiaof the motor nuclei, are rarely encountered. Bycontrast, bilateral dysfunction of CN9 and 10can be a prominent feature of cerebral palsy orCNS trauma. Cerebral palsy can be associatedwith pseudobulbar palsy, an upper motorneuron disorder associated with abnormalitiesof swallowing and speech. Bilateral bulbardysfunction can also be the result of bilat-eral perisylvian polymicrogyria, a congenitaldisorder also known as the syndrome ofFoix–Chavany–Marie (173), or after HSVencephalitis-associated damage to the insularcortices bilaterally (174).

Because the muscles of the larynx areinnervated by branches of the vagus nerve,lesions of the vagus nerve produce vocal corddysfunction manifesting as hoarseness of voice.Unilateral vocal cord dysfunction can be theresult of TBI, surgical damage to the recurrentlaryngeal nerve, or congenital aplasia. Bilateralvocal cord dysfunction, incompatible with lifeunless managed by tracheostomy, can beassociated with Chiari II malformation anddysplasia of the brainstem nuclei.

173Axial FLAIR MRI showing a thickenedinsular cortex (arrows) compatible withpolymicrogyria in Foix–Chavany–Mariesyndrome.

173

174 Coronal T2-weighted MRI showingatrophy of the insular cortices bilaterally(arrows) in a child who survived HSVencephalitis but could not move his facenormally or swallow.

174


Cranial nerve 11 (spinal accessory nerve)

Isolated lesions of the spinal accessory nerve,extremely uncommon in children, can be post-traumatic or iatrogenic after neck surgery.Tumors of the nerve, although described, areexceptionally rare. The signs and symptoms ofspinal accessory nerve dysfunction consist oftrapezius atrophy, limitation of shoulderelevation (shrugging), shoulder pain, andshoulder weakness. The majority of personswith spinal accessory nerve palsies recover withphysical therapy and conser vative management.

Cranial nerve 12(hypoglossal nerve)

Lesions of the hypoglossal nerve, usuallyunilateral, produce ipsilateral weakness, atrophy,and fasciculations of the tongue (175).Hypoglossal neuropathy can be idiopathic,postinfectious (e.g. after infectious mononu -cleosis), post-traumatic, postsurgical, orassociated with tumors of the nerve or vascularanomalies that impinge upon the nerve as it exitsthe medulla. Children or adolescents withidiopathic hypoglossal neuropathy may have afavorable outcome with recovery of tonguefunction. Children or adolescents withneck–tongue syndrome, an uncommondisorder, experience transient, intense neck painand altered sensa tion of half of the tonguefollowing sudden neck rotation. The disorderhas been attributed to compression of the C2nerve root containing afferent nerve fibers fromthe tongue. Finally, tongue fasciculations are acommon feature in infants with spinal muscularatrophy.

175Atrophy of the right side of the tongueand deviation of the tongue to the right in aright hypoglossal nerve (CN12) palsy ofuncertain origin.

175

CHAPTER 12151

Disorders ofperipheral nerves

Main Points• Disorders of the peripheral nervous system are much less common

in children than disorders of the central nervous system.

• Brachial plexus injuries often occur with prolonged second stage oflabor and in infants with birth weight >4500 g or shoulder dystocia.

• Guillain–Barré syndrome, acute inflammatory demyelinatingpolyneuropathy, can manifest with autonomic dysfunction andweakness of facial, bulbar, respiratory, and extremity muscles.

• Complex regional pain syndrome should be suspected whenchildren or adolescents display pain and weakness that seemsdisproportional to the extent and severity of the inciting injury.

• Ankle or lower leg weakness, frequent ankle sprains, and pes cavusshould suggest the possibility of Charcot–Marie–Tooth disease, aheterogeneous neuromuscular disorder linked to several genemutations.

Neonatal brachialplexopathy

DIAGNOSIS AND CLINICAL FEATURESNeonatal brachial plexopathy, a condition thataffects approximately 2 of every 1000 live-born(0.2%) infants, usually results from stretchinjuries to the plexus during an infant’s delivery.Risk factors for brachial plexus injuries includelarge size, especially birth weight >4.5 kg,prolonged second stage of labor, and shoulderdystocia. The brachial plexus, formed by nerveroots C5–T1 (176), innervates the muscles ofthe arm and also contains sympathetic fiberstravelling in T1. Consequently, the newbornwith brachial plexopathy displays varying

Introduction

In contrast to disorders of the CNS, which arevery common, disorders of the peripheralnervous system are relatively uncommon ininfants, children, and adolescents. Despite this,most generalists will encounter at least twoconditions, neonatal brachial plexopathy andGuillian–Barré syndrome (GBS), more thanonce during their practice careers. Otherpediatric disorders of peripheral nerves, such assacral neuropathy, porphyria, complex regionalpain syndrome, and others, will likely beencountered only by child or adult neurologists.This chapter describes selected disorders,focusing on the clinical manifestations andmanagement of these conditions.


176 Brachial plexus.

Cords Division Trunks Roots

Dorsal scapular nerve

Suprascapular nerve

Later

alco

rd

cord

cordPoste

rior

Medial

Nerve to subclavius

Lateral pectoral nerve

C5

Long thoracic nerve

C6

C7

T1

Axillary nerve

Mediannerve

Medial cutaneous nerve of the forearm

Medial cutaneous nerve of the arm

Lower subscapular nerve

Upper subscapular nerve

Medial pectoral nerve

Thoracodorsal nerve

Ulnarnerve

Musculocutaneousnerve

Radialnerve

C8

176

degrees of arm weakness, and when T1 isinvolved due to injuries to the entire plexus orthe lower trunk, the infant has a Hornersyndrome (163).

Neonatal brachial plexus injuries have beentraditionally categorized as Erb’s palsy, the mostcommon manifestation, reflecting injury toC5–C7, and Klumpke palsy, denoting injury toC8–T1. Erb’s palsy produces weakness of theshoulder muscles and flexion/supination of theforearm. Hand function is preserved. Bycontrast, Klumpke palsy produces weakness ofthe flexors of the wrist and intrinsic muscles ofthe hand but preservation of the upper arm.Consequently, the infant with an Erb’s palsymaintains the arm extended, internally rotated

CHAPTER 12 Disorders of peripheral nerves 153

178

178 Klumpke palsy.

177

177 Erb’s palsy.

at the shoulder, and flexed at the wrist (177),whereas the infant with a Klumpke palsy has aclaw-like hand with preserved upper armfunction (178). Muscle stretch reflexes areabsent in both forms. Neonatal brachialplexopathy can be associated with clavicularfracture, facial paralysis, or diaphragmaticparalysis due to involvement of the phrenicnerve which arises from the C3–C5 roots.

MANAGEMENTThe infant with neonatal brachial plexopathyshould be managed conservatively for the firstweek, unless avulsion of the nerve roots, anuncommon situation, is suggested by thepresence of Horner syndrome and complete,

severe paralysis of all muscles subserved by theplexus. In this instance, the infant shouldundergo MRI of the cervical spine and plexus,and neurosurgical consultation should beobtained. If available, EMG and nerveconduction studies can define the extent ofthe injury and the potential for recovery,especially when obtained at 2–3 weeks of age.In infants with less severe plexus injuries,physical therapy should begin after 7 days.Many infants with brachial plexus injuriesimprove during the first few weeks, andapproximately two-thirds have recoveredsatisfactory use of the arm by 2 years of age.

The surgical management of infants withbrachial plexus injuries remains controversial.Surgical procedures include nerve grafting,usually with a segment of the sural nerve, andneurolysis, a process in which the nerve sheathis cut and adhesions removed to diminishtension on the nerve. Some authorities suggestthat neurosurgical consultation be obtained ifthe infant has no signs of biceps function at 3 months. Others suggest that surgicalintervention can be delayed until after 6 months without substantially affecting thelong-term outcome. Intense physical therapyremains a major component of rehabilitationregardless of decisions regarding surgicalmanagement. Orthopedic procedures, includingosteotomies and tendon transfers, may becomenecessary in older children who have limitedrecovery of motor function.

Brachial plexopathy ofchildren or adolescents

Brachial plexopathy can occasionally occur in children or adolescents as the result of trauma (especially sports injuries), infection,tumors, and reactions to immunizations. Insome instances, no cause can be identified.Brachial plexus neuritis, a postinfectious orimmunization-related disorder, producesintense shoulder pain, and weakness of themuscles innervated by the upper roots of theplexus appears after 5–7 days. With the excep-tion of the pain, the clinical features mimic thoseof Erb’s palsy. EMG 2 or more weeks after aninjury or the onset of pain in neuritis showsfeatures of denervation including positive wavesand fibrillations. MRI of the spine or plexusshould be normal in brachial plexus neuritis or reveal nonspecific bony changes. Manage-ment consists of physical therapy and painmanagement.

Lumbosacral plexopathy

The lumbosacral plexus, consisting of nerveroots L1–S4 (179), innervates the muscles ofthe lower extremities and subserves sensation to the buttocks, perineum, thighs, and legs.Conditions that affect the function of thelumbosacral plexus are much less frequent thanthose affecting the brachial plexus, and includetrauma, radiation, neoplasia, vascular lesions,and infection. Children or adolescents withlumbar plexopathies display varying degrees ofmotor and sensory dysfunction in the buttocksand leg. Iatrogenic lumbosacral plexopathy has been reported after pelvic surgery or childbirth; a certain number of cases are idiopathic.Definitive management and prognosis oflumbosacral plexopathies depend upon theetiology; most conditions require physicaltherapy.



179

179The lumbar plexus.

1st lumbar

From 12th thoracic

2nd lumbar

3rd lumbar

4th lumbar

5th lumbar

IlioinguinalIliohypogastric

Genitofemoral

Lat. femoral cutaneous

Lumbosacral trunk

Accessory obturator

Obturator

Femoral

To psoas and iliacus

Sacral neuropathy

Sacral neuropathy, an uncommon neurologicalcondition in childhood, can be secondary totrauma, inflammation, hemorrhage, or tumorand can occur in children or adolescents afterprolonged surgical procedures, such as livertransplantation, as a consequence of reversiblenerve compression. The sciatic nerve provides

both motor and sensory function to the leg.Persons with sciatic neuropathy display weak-ness of knee flexion and weakness of dorsi-flexion, plantar flexion, eversion, and inversionof the foot. Sensory loss occurs in the posteriorportion of the leg from the buttocks to the foot,the medial surface of the leg below the knee,and the dorsal as well as plantar surfaces of thefoot.


Hereditary neuropathywith liability to pressurepalsy

Hereditary neuropathy with liability topressure palsy (HNPP), an autosomal domi-nant disorder secondary to mutations in thegene encoding peripheral myelin protein 22(PMP22 located at 17q11.2), usually presentsin adults who experience sensory loss orweakness as the result of mild trauma,repetitive motion, or nerve compression. The

disorder affects approximately 3 per 100,000persons, and reflects damage to, and slowrepair of, peripheral myelin. Persons withHNPP often have carpal tunnel syndrome, adisorder causing weakness, sensory loss, andparesthesias in the distribution of the distalmedian nerve (180). Carpal tunnel syndrome,an uncommon disorder in childhood oradolescents, can be seen in persons withhypothyroidism or diabetes mellitus, pregnantwomen, men or women with work-relatedrepetitive motion injuries, and persons with

180

180The sensory nerves of the arm and their distribution.

Medial brachialcutaneous and

intercostobrachialnerves

Medialantebrachial

cutaneous nerve

Ulnar nerve

Upper lateral brachialcutaneous nerve

Posterior brachialcutaneous and lower

lateral brachialcutaneous nerve

Posterior antebrachialcutaneous nerve

Lateralantebrachial

cutaneous nerve

Radial nerve

Mediannerve

Medial brachialcutaneous andintercostobrachialnerves

Medial antebrachialcutaneous nerve

Ulnar nerve


181181Anadolescent withpes cavus(arrow) due toFriedreichataxia.

182

182 Diagram of the arch in pes cavus.

Arch in pes cavus

Normal arch

mucopolysaccharidoses due to accumulationof glycosaminoglycans.

HNPP should be suspected in adolescentswho have carpal tunnel syndrome or recur-rent and prolonged paresthesias or weaknessassociated with trivial nerve compression(such as after crossing the legs for extendedperiods or falling asleep with an arm restingon a chair, so-called ‘Saturday Night Palsy’).Onset in early childhood has been described.The sensory and motor abnormalities areusually transient, but in adulthood, mild

disability can occur as the result of prolongedor permanent motor dysfunction. The neuro-logical examination may show reducedmuscle stretch reflexes, especially at the anklesand, occasionally, pes cavus (181, 182). Thediagnosis can be supported by findingprolonged distal latencies on electro -diagnostic studies and confirmed by identi -fying deletions in PMP22 using FISH or genesequencing. Management consists currentlyof providing education and anticipatoryguidance regarding provocative factors.

Guillain–Barré syndrome

DIAGNOSIS AND CLINICAL FEATURESGBS, also known as acute inflammatorydemyelinating polyneuropathy (AIDP), affectsapproximately one in 100,000 persons annually.The disorder can affect children or adolescents,and is an immune-mediated condition asso-ciated with macrophage-induced damage ofmyelin and blockage of nerve transmission.Infection, immunization, and surgery can act astriggers for the disorder. Infectious agents arethe most commonly identified triggers asso-ciated with GBS, including Epstein–Barr virus,CMV, Campylobacter jejuni, rubella virus,dengue virus, influenza viruses, Mycoplasmapneumoniae, and several other agents, bothviruses and bacteria, that produce respiratory orgastrointestinal illnesses.

GBS can begin insidiously over 1–3 weeks orabruptly in 24 hours or less. Painful paresthesiasor distal weakness are the usual initial symptomsin children or adolescents. Weakness, the moreserious aspect of GBS, often begins in the legsand ascends to involve the arms, the face, andthe muscles of respiration. Less frequently, themotor cranial nerves controlling swallowing oreye movement can be involved. Papilledema canbe observed occasionally. Variations in thepattern and severity of weakness occur; somechildren or adolescents have severe weaknessthat progresses rapidly to complete quadriplegiaand ventilator dependence. Autonomic nervoussystem dysfunction, consisting of hypertension,tachycardia, or bradycardia, can be a prominentfeature and, along with respiratory muscleinvolvement, be life-threatening.

GBS should be suspected in previously-healthy children or adolescents who experiencerapidly evolving lower extremity weaknessassociated with subjective sensory complaintsor autonomic instability. Painful paresthesiascan be a prominent and, occasionally, the firstsymptom. The presence of facial diplegia (171,172), as well as absence of a sensory level,distinguishes GBS from transverse myelopathy,another postinfectious disorder that causesextremity weakness. The diagnosis can beconfirmed by electrophysiological studies thatdemonstrate slowed nerve conduction veloc -ities, motor conduction block, or absence orprolongation of F waves or H responses,measures of the integrity and function of the

spinal efferent and afferent loop. Spinal MRImay show nerve root enhancement (219).Examination of the CSF characteristically showsan albuminocytologic dissociation (elevatedprotein in the absence of cells), especially1–2 weeks after the onset of symptoms.

MANAGEMENTTreatment consists of meticulous monitoring ofpulmonary function and institution of eitherplasmapheresis or intravenous immunoglobulin(IVIG). Most pediatric neurologists favor thelatter, given the ease of administration and theapparent therapeutic equivalency of IVIG andplasmapheresis in adults. There are, as yet, norandomized controlled trials comparing thesemodalities in children or adolescents, however.The standard regimen of IVIG is 2 g/kg givenin equally divided doses over 2–5 days; there areno data to favor shorter or longer courses.Corticosteroids, either orally or intravenously,have no role in the acute management of GBS.The respiratory effort (via bedside measurementof the negative inspiratory force [NIF] and theforced vital capacity [FVC]) and swallowing(gag reflex) of nonventilated children oradolescents must be monitored at least every 6 hours during the initial phases of the disorder.The treating physician must also attend carefullyto the vital signs for evidence of autonomicinstability, especially hypertension or cardiacdysrhythmias, which may require medicationmanagement. Rehabilitation services should beinstituted early. Although as many as 30% ofadults with GBS have motor sequelae despitetreatment, approximately 90% of children oradolescents with GBS recover completely; rarely,relapses can occur.

RELATED DISORDERSThe Miller Fisher variant of GBS, a notuncommon condition in children, producesataxia, ophthalmoplegia, and arreflexia. Likeconventional GBS, triggers include infectionand immunization. This variant of GBS has beenassociated with antibodies against GQ1b, aganglioside present in peripheral myelin, in asmany as 90% of cases. Management consists ofadministering IVIG in doses using a regimenidentical to that of GBS.

Chronic inflammatory demyelinating poly -neuropathy (CIDP), considered a relateddisorder distinct from AIDP (GBS), consists of


neurogenic pain and prolonged or relapsingbouts of weakness, especially of the legs.Children or adolescents with this disorder haveelectrodiagnostic results similar to those withGBS and, like those with GBS, respond toIVIG. In contrast to those with GBS, however,children or adolescents with CIDP improvewith modest doses of corticosteroids (e.g.prednisone) given orally for days to weeks afterIVIG. Some persons with CIDP occasionallyrequire therapy with other immunomodulatingdrugs.

In the USA and Europe the ‘axonal variant’of GBS (referred to as acute axonal polyneu-ropathy) is rare, but this variant is much morecommon in Asia, particularly in Japan. In thisform, weakness and atrophy are more profound,and EMG and nerve conduction studiesdemonstrate axonopathy and denervation. Therate of recovery is much slower than in GBS,and the likelihood of full recovery is less. Nopreferred treatment exists.

Complex regional painsyndrome

Complex regional pain syndrome (CPS),known previously as reflex neurovasculardystrophy or reflex sympathetic dystrophy, is animportant but relatively infrequent cause ofextremity pain and weakness in children andadolescents. The disorder has been divided intotwo categories, CPS I, a disorder triggered bytissue injury, and CPS II, a condition associatedwith nerve injury. Both cause chronic, oftendisabling pain in children or adults. Thedisorder begins after relatively minor injury toan extremity and progresses over the ensuingdays or weeks to a chronic pain syndrome thateventually leads to disuse, weakness, trophicskin changes, joint stiffness, and muscleatrophy. Children or adolescents with thisdisorder exhibit changes in skin temperature ofthe affected extremity and burning, dysestheticpain that is disproportional to the incitinginjury. Although the pathogenesis of CPSremains poorly defined, current theories invokethe role of neurotransmitters and immunologicresponses. The diagnosis remains largelyclinical.

Management consists of physical therapyand treatment with medications effectiveagainst neurogenic pain, such as gabapentin,pregabalin, carbamazepine, or amitriptyline.Because emotional stress seems to participatein the pathogenesis or persistence of pain,psychological therapies appear to have a rolein the management of children or adolescentswith CPS.


Inherited peripheralneuropathy

Several inherited disorders of peripheral nervescan appear in children or adolescents. The mostcommon of these, Charcot–Marie–Toothdisease (CMT), affects approximately 1 in 2500persons. CMT represents a clinically andgenetically heterogeneous autosomal dominantor recessive disorder caused by mutations atmore than 20 different gene loci. Type 1A, forexample, results from duplication of the PMP22gene, which causes protein overproduction,Schwann cell dysfunction, and demyelination.The disorder begins in late childhood oradolescence with difficulty walking, especiallyon rough surfaces, being an early symptom.Affected persons commonly experience recur -rent ankle sprains and often come to diagnosisthrough the astute observations of experiencedorthopedists or pediatricians. Persons withCMT exhibit pes cavus (181, 182), loss ofmuscle stretch reflexes, and weakness of ankledorsiflexion and eversion, causing foot drop anda steppage gait, and muscle wasting, causing astork leg appearance. Over time, weakness ofhand and forearm muscles appears, and manypersons with CMT have neurogenic pain of thehands and feet. The disorder cannot be cured,but the disorder progresses slowly and does notaffect life span. Management consists of physicaltherapy, pain management, orthotic use, andcareful orthopedic intervention.

Critical illnesspolyneuropathy/myopathy

Critical illness polyneuropathy/myopathy, anuncommon disorder, produces diffuse weaknessor flaccid quadriplegia in children (and adults)who experience sepsis and/or multiorgansystem dysfunction and require extendedmechanical ventilation. Factors associated withthis disorder include administration of corti-costeroids and prolonged hospitalization inintensive care units. Electrodiagnostic studiesmay show axonal neuropathy; serum CK levelsmay be markedly elevated. Children with criticalillness neuropathy/myopathy recover sponta -neously, although recovery can be gradual andincomplete. Affected individuals may requireextensive neurorehabilitation.

Miscellaneous causes ofperipheral neuropathy

Other causes of peripheral neuropathy inchildren and adolescents include:• Acute intermittent porphyria.• Mitochondrial disorders.• Fabry disease.• Familial dysautonomia.• Neurofibromatosis type 1.• Nerve tumors (schwannoma,

neurofibroma, sarcoma).• Systemic lupus erythematosus.• Chemotherapy-related peripheral

neuropathy (especially vincristine).• Heavy metal intoxication.


CHAPTER 13161

Disorders of gaitand balance

Main Points• Many childhood neurological problems present as impairment of

gait or balance.

• The clinician should assess disorders of gait along three axes:

– Temporal profile: acute, subacute, chronic.

– Distribution: symmetric vs. asymmetric; ascending vs. descending;proximal vs. distal.

– Diagnostic category: orthopedic, inflammatory/rheumatologic,neurological, psychogenic.

• The more acute the onset the greater the need for promptevaluation; optimal outcome may depend on expeditious diagnosisand treatment.

– Bowel and bladder dysfunction implies spinal cord involvement andthe need for timely MRI.

• Common neurological disorders resulting in acute symmetricimpairment of gait and balance include: Guillain–Barré syndrome;syndromes of spinal cord compression; transverse myelitis; acutecerebellar ataxia; intoxications; multiple sclerosis.

• Common neurological disorders resulting in subacute symmetricimpairment of gait and balance include: Guillain–Barré syndrome;polymyositis/dermatomyositis; midline tumors of the posteriorfossa; other inflammatory and neoplastic conditions.

• Neurological disorders resulting in chronic slowly progressive gaitand balance impairments usually result from neoplastic orhereditary degenerative conditions.


Introduction

Numerous pediatric neurological disorderspresent as impairments of gait or balance andcomprise a very broad and diverse group ofneurological conditions. Often, these disordersrepresent serious neurological conditions inwhich prompt evaluation and management maydramatically alter outcome. In other circum -stances, accurate diagnosis avoids unnecessarydiagnostic testing and provides early peace ofmind for families; alternatively, correct diseaseidentification may at least allow for propercounseling and prognostication. Most of thesedisorders require evaluation by a specialist, butthe clinician should recognize when urgentevaluation is critical.

Evaluation

In evaluating disorders of gait the clinician mustconsider a broad differential diagnostic catego -rization early on, since many gait disordersrepresent specific orthopedic or rheumatologicdisorders (Table 26). Specific neurologicaldisorders often display a specific temporal profile(Table 27). The rate of onset and distribution ofimpairment provide useful clues to thedifferential diagnosis (Tables 28 and 29, pages164, 165).

As a rule of thumb, orthopedic andrheumatologic causes of gait impairmentpresent in a subacute fashion (aside obviouslyfrom traumatic disorders) and display asubstantial degree of asymmetry.

Table 26 Orthopedic and rheumatologic conditions presenting as gait disorders

Age of Location Symmetry Clinical Temporal profile/ Laboratory/onset features other features imaging

findingsDiskitis 2–7 yr Spine: lower Yes Refusal to walk/ Acute Abnormal uptake

thoracic–lumbar stand; increased onset; intervertebral disk (BS);intervertebral disk lumbar lordosis mild fever narrowed intervertebral

space and end-plateedema (MRI)

Toxic 3–6 yr Hip No Antalgic gait; Subacute; Increased acetabulum–synovitis hip, thigh, or mild fever femoral head

knee pain distance (PF);joint effusion (US)

Septic Any age Variable Rarely Antalgic gait; Acute/subacute; Elevated ESR,arthritis monoarticular signs fever/systemic CRP, WBC;

‘pseudoparalysis’/ signs tissue and jointdiminished space effusion,range of motion swelling (PF)

Legg– 4–8 yr; Hip Rarely Antalgic gait; mild Subacute/chronic Varies with Calve– M>>F groin, hip, thigh stage of Perthes or knee pain; stiffness; disease (PF)disease thigh atrophySlipped F: Hip Rarely Antalgic gait; pain Acute/subacute; Medialcapital 11–13 yr; (hip, thigh, or knee); no fever displacement offemoral M: tenderness; decreased epiphysis (PF)epiphysis 13–15 yr range of motion;

spasm; leg shortening

BS: bone scan; MRI: magnetic resonance imaging; PF: plain radiograph; US: ultrasound; ESR: erythrocyte sedimentationrate; CRP: C-reactive protein; WBC: white blood cell count

CHAPTER 13 Disorders of gait and balance 163

Table 27 Localization of gait disorders along the neuraxis

Neuraxis level Clinical features Specific examplesNeocortical Impaired higher cortical Cerebral infarction; lysosomal storage

functions; encephalopathy diseases; peroxisomal disorders

Basal ganglia Dystonia; rigidity/bradykinesia; Idiopathic torsion dystonia;other movement disorders extrapyramidal syndromes

Brainstem Cranial nerve deficits; crossed Infarction; tumor/abscess;sensory deficit1; crossed motor signs2 hemorrhage

Cerebellum Ataxia/coordination Acute cerebellar ataxia; pilocytic astrocytoma;impairment/tremor; hypotonia; medulloblastoma (183); opsoclonus–myoclonus pendular reflexes3; syndrome; ataxia-telangiectasia; Friedreich ataxia;rebound phenomenon4 congenital disorders of glycoslyation (184)

Spinal cord Sensory level; mixed UMN + LMN Transverse myelitis; mass lesion;signs; bowel + bladder dysfunction infarct/hemorrhage; Friedreich ataxia

Alpha motor neuron Weakness; atrophy (early); hypotonia; Spinal muscular atrophy; poliomyelitisareflexia; fasciculations syndromes; anterior spinal artery syndrome

Peripheral nerve Weakness; atrophy (varies); hypotonia; AIDP; CIDP; other peripheralhypo- or areflexia; +/– sensory loss neuropathies; compression/traumatic

Muscle Muscle pain/tenderness; weakness Poly/dermatomyositis; (proximal > distal); normo- or muscular dystrophieshypoactive reflexes; pseudohypertrophy(DMD); atrophy (late)

AIDP: acute inflammatory demyelinating polyneuropathy; CIDP: chronic inflammatory demyelinating polyneuropathy;DMD: Duchenne/Becker muscular dystrophy; LMN: lower motor neuron; UMN: upper motor neuron1Facial sensory loss opposite to body sensory loss. 2Unilateral lesion in brainstem above the level of pyramidal decussation (lower medulla) may cause facial, tongue, or bulbar weakness on one side and extremity weakness on the other. 3Response to ‘knee-jerk’ reflex results in several to-and-fro oscillations of the distal lower extremity.4Failure to check and adjust spontaneously to sudden, unexpected imposed movements of the limbs or trunk.

183 184183Axial FLAIR MRIshowing characteristicappearance of amedulloblastomafilling the 4th ventricle(arrow).

184 Coronal, T2-weighted MRI showingpancerebellar atrophy(arrows) in a childwith a congenitaldisorder ofglycosylation(CDG1a).

Table 28 Specific causes of gait/balance disorders classified by rate of onset

ADEM: acute disseminated encephalomyelitis; AIDP: acute inflammatory demyelinating polyneuropathy; OMS:opsoclonus–myoclonus syndrome


AcuteCerebral/cerebellar/brainstem infarctionDrug intoxication:

Phenytoin, ethanol, sedative hypnoticsAnterior spinal artery syndromeSpinal epidural hemorrhageTransverse myelitisTrauma (usually obvious)Guillain–Barré syndrome (AIDP)Psychogenic (astasia/abasia)

SubacuteADEMIdiopathic torsion dystoniaAcute cerebellar ataxiaOMS (idiopathic or paraneoplastic)Vitamin B12 deficiencyVitamin E deficiencyAIDPPolymyositis/dermatomyositis

ChronicLysosomal storage diseases:

Krabbe disease, metachromatic leukodystrophy, Fabry disease

Peroxisomal diseases:Adrenoleukodystrophy, adrenomyeloneuropathy

Other metabolic disorders:Congenital disorders of glycosylation(especially CDG1a; 184)Mevalonic aciduriaSome disorders of fatty acid oxidation

Other leukodystrophies:Vanishing white matter disease (185, 186)

Neoplastic disorders:Mass lesion, lymphoma, leukemia

Spinal muscular atrophy (type III particularly)Genetic disorders:

Ataxia telangiectasiaFriedreich ataxiaOther spinocerebellar degenerative disorders

Muscular dystrophyMyotonic dystrophyDuchenne/Becker muscular dystrophy

185 185 Axial T2-weighted MRI showing increasedsignal intensity diffusely throughout the whitematter in a child with vanishing white matterdisease.

Table 29 Specific disorders classified by distribution of impairment

ADEM: acute disseminated encephalomyelitis; AIDP: acute inflammatory demyelinating polyneuropathy


SymmetricADEMNeurodegenerativeMidline tumors (posterior fossa)Acute cerebellar ataxiaTransverse myelitisAIDPPolymyositis/dermatomyositisMuscular dystrophy

AsymmetricADEMInfarctionSome spinal cord massesCompression neuropathies

AscendingAIDPPeripheral neuropathiesMyotonic dystrophy

DescendingCervical cord tumorsSyrinx

ProximalPolymyositis/dermatomyositisMuscular dystrophies (most)

DistalCerebral infarctionAnterior horn cell disease(spinal muscular atrophy)Peripheral neuropathiesAIDPMyotonic dystrophy

186186Axial T1-weighted MRI showing diffuse lossand cystic changes of white matter in a childwith vanishing white matter disease.The childalso has a cavum vergae (arrow).


Pain, swelling, and deformity of limbs orjoints are often present. The child, reluctant tobear weight, manifests an antalgic or painfulgait. Muscle bulk, strength, tone, and reflexpatterns usually remain intact. In somefulminant cases of idiopathic juvenile arthritis,however, striking muscle atrophy and weaknessmay be present and be accompanied by signsand symptoms of arthritis, including swelling,tenderness, rubor/calor, and early morningjoint stiffness that may improve as the dayprogresses. Likewise, thigh muscle atrophy maybe present with chronic Legg–Calve–Perthesdisease (aseptic necrosis of the femoral head).The rheumatologic exception to the above rulesis polymyositis/dermatomyositis, but here weinclude this as a neurological disorder giveninvolvement of muscle as the cause of gaitimpairment.

DISTRIBUTION WITHIN THE NERVOUS SYSTEMOnce the above analysis has been carried out,one should consider what level of the nervoussystem is affected (textbox).

Upper motor neuron lesions are typicallyassociated with increased tone (spasticity),hyper-reflexia, preservation of muscle bulk,and Babinski signs.

Lower motor neuron lesions are typicallyassociated with decreased tone (hypotonia),hyporeflexia, and early loss of muscle bulk.

This enables clinicians to establish the correctdiagnosis and direct evaluation and manage -ment. Key points regarding level of involvementalong the neuraxis are noted in Table 27.Clinicians must recognized that in acutedisorders of the CNS (cerebral hemisphere,brainstem, and spinal cord) the ‘typical’ uppermotor neuron (UMN) findings of hypertonicity(spasticity) and hyper-reflexia may be replacedtemporarily by profound hypotonia (orflaccidity) and hypo- or areflexia. Babinskiresponses to plantar stimulation may also beabsent (silent plantar response) makingidentification of an early UMN processchallenging.

Patterns of presentation

Acute/subacute‘ascending’ paraparesisThe prototypic disorder causing an ascendingparaparesis is Guillain–Barré syndrome (GBS).The typical patient with GBS presents withrelatively symmetric lower extremity weakness,sometimes accompanied by hyperpathia andhyperalgesia, that progresses rapidly in hoursto a few days. Weakness progresses in a distal toproximal, lower extremity to upper extremityfashion. A substantial proportion of childrenand adolescents also have various degrees offacial nerve weakness (165, 171, 172), espe -cially bilateral paralysis, and some haveabducens palsies and/or papilledema. Motorinvolvement is usually far more prominent thansensory symptomatology, although the lattermay appear as severe neuropathic pain.Autonomic dysfunction in the form oftachycardia or hypertension may be prominentfeatures, and bladder dysfunction can alsooccur. Prominent bowel or bladder dysfunc -tion, however, should suggest spinalcord pathology. The differential diagnosisincludes transverse myelitis, other spinalcord syndromes, poliomyelitis syndromes,meningeal leukemia, or lymphoma. GBSshould be considered in children or adoles centswith acute or subacute paraparesis, especiallywhen accompanied by prominent paresthesias.

Acute paraparesis withsensory level and boweland bladder dysfunctionThis pattern, the classic spinal cord syndrome,of abrupt onset of paraparesis, sensory level, andbladder or bowel dysfunction is a neurologicalemergency and requires urgent MRI imaging ofthe spinal cord. Children usually present withthe abrupt onset of lower extremity paralysisevolving over a period of several hours. This isassociated with back pain, anesthesia, and/orhypalgesia below a certain spinal level andimpairments of bowel or bladder functionpresenting as urinary retention and diminisheddefecation often associated with stool leakage.This constellation of features and its potentiallygrave implications must be considered aneurosurgical emergency. Hence, MRI with and


without contrast of the entire spinal cord mustbe performed as soon as feasible even in theabsence of trauma or suspected infection. Urgentneurosurgical consultation should follow if amass lesion (187) or traumatic spinal cord injuryis identified. Lumbar puncture must not beperformed before the MRI.

In the absence of a mass lesion, the diagnosisis usually acute transverse myelitis (also calledidiopathic or acute myelitis; 188). Whenassociated with optic neuritis, the condition isknown as neuromyelitis optica (NMO or Devic’sdisease, potentially associated with antiaqua porinantibodies). In either case, the condition isgenerally considered to be a postinfectious orparainfectious, immune-mediated disorder; ahistory of a prodromal infectious illness is oftenelicited. The CSF may be normal or show a mildto moderate lympho cytic pleocytosis with mildto moderate protein elevation. Nerveconduction studies should be normal initially,but if anterior horn cells are affected directly,signs of denervation emerge later.

MANAGEMENTTreatment of acute paraparesis in padiatricpatients involves supportive care, attention toairway protection (especially in rapidlyprogressive GBS), physical therapy, andadministration of IVIG or corticosteroids.Children with GBS improve with administrationof IVIG, given as a total dose of 2 g/kg over2–5 days. Plasmapheresis also provides benefitin GBS, but ease of IVIG administration,especally in young children, and the morefavorable side-effect profile of IVIG favor thistherapy over plasmapheresis in pediatricpatients. Most authorities recommend adminis -tration of high-dose corticosteroids, usingmethylprednisolone or equivalent inter -vaneously, in acute myelitis, and some advocateIVIG, but the relative efficacy of these therapiesis currently unknown. The prognosis for GBS isquite favorable in children, with 80% or morerecovering completely. By contrast, theprognosis for acute transverse myelitis is not asfavorable. Approximately one-third of pediatricpatients with myelitis have an excellent outcomewith full or nearly full recovery, one-thirdimprove sufficiently to walk independently buthave neurological sequelae, and the final thridhave limted recovery and remain nonambu -latory with severe para- or quadriparesis.

187

188

188 T2-weighted spine MRI showing areas ofsignal hyperintensity in the cervical regioncompatible with transverse myelitis (arrow).

187 T1-weighted, gadolinium-enhanced spineMRI showing an intramedullary tumor that wasfound at surgery to be an ependymoma(arrows).


Acute/subacuteasymmetric impairmentof gaitThis pattern of gait abnormality has a muchbroader differential diagnosis with many casesbeing due to non-neurological disorders(Table 26). Other causes include cerebral,brainstem, or spinal cord infarction orhemorr hage, traumatic or compressiveneuropathies or neuropraxias, vasculitis andother putative immune-mediated neuro -logical disorders, and idiopathic torsiondystonia presenting with unilateral lowerextremity dystonia. Careful attention to the

Table 30 Selected causes of acute ataxia in childhood

ADEM: acute disseminated encephalomyelitis; GBS: Guillain–Barré syndrome; OMS: opsoclonus–myoclonus syndrome

• Intoxication:– Sedatives, anticonvulsants, alcohol, antihistamines• Infection:– Meningitis, encephalitis, especially of the brainstem– Labrynthitis, vestibular neuronitis• Mass lesions:– Cerebellar astrocytoma– Medulloblastoma, ependymoma– Hydrocephalus• Immunologic:– Postinfectious cerebellitis (varicella, nonpolio

enteroviruses)– ADEM– OMS:

paraneoplastic (occult neuroblastoma),postinfectious, idiopathic

– Miller Fisher variant of GBS

• Seizure• Vascular:– Brainstem or cerebellar infarction:

vertebral artery dissection– Cerebellar hemorrhage– Vascular malformation or ruptured aneurysm• Traumatic brain injury, including concussion• Familial ataxias (e.g. acetazolamide responsive)• Psychogenic disorders (e.g. conversion)• Metabolic disorders:– Urea cycle abnormalities– Hartnup disease– Mitochondrial disorders

presence of pain, swelling, local signs ofinflammation, local trauma or pressure, or ofan antalgic gait assists in establishing thecorrect diagnosis. In absence of clues,directed neuroimaging is necessary to clarifythe underlying disorder.

Subacute symmetricmuscle weaknessThis is the classic pattern of polymyositis/dermatomyositis. These condi tions aredescribed in Chapter 19 Hypotonia andWeakness.


Acute/subacute ataxiaMost cases of acute cerebellar ataxia representpostinfectious or parainfectious disorderspreceded by a mild infection (Table 30). In thepast, varicella was recognized as a commonprodromal illness; cases have occasionally beenobserved after varicella vaccination. Childrenwith acute ataxia, often of toddler age, refuse towalk or display truncal and gait instability thatappears over hours to a few days. The child oftenotherwise appears well, although some haveheadache and persistent vomiting.

Given the broad differential diagnosis,urgent neuroimaging is required in all cases.This can consist of an unenhanced head CTinitially to exclude a posterior fossa tumor,hemorrhage, or infarction. If these are absent,and there is no evidence of intoxication, then apresumptive diagnosis of acute postinfectiouscerebellar ataxia is usually made. MRI should beobtained to exclude subtle infarction,encephalitis, or ADEM (189). CSF analysis maybe considered (particularly if meningitis is arealistic consideration), but the results rarelyhelp clarify the diagnosis. Therapy consists ofsupportive care, and resolution is anticipated ina period of weeks or less. Corticosteroids can beindicated if MRI demonstrates features ofADEM.

Careful follow-up is needed to recognizeother disorders associated with acute ataxia,particularly OMS. This condition may initiallypresent in a fashion identical to acute cerebellarataxia with later appearance of opsoclonus(‘dancing eyes’) and myoclonus (‘dancinghands and feet’) as well as of an encephalopathycharacterized by intense irritability, disinhi -bition, sleep disruption, and randomly aggres -sive behavior. Opsoclonus can be recognized asabrupt, random, rapid, or shimmering bursts ofconjugate eye move ments occurring in alldirections of gaze. These are often gaze-evokedand may be associated with synchronous eyelidtwitching movements (myoclonus). Thisneuro-ophthalmologic manifestation can beextremely subtle, and sustained observation ofthe child’s eye movements is often necessary todetect it. Abrupt, rapid, ‘random’ twitching oflimbs, face, or trunk (myoclonus) may also beevident, but this also can be very subtle.

At least fifty percent of the time OMS is aparaneoplastic neurological disorder associatedwith occult neuroblastoma, usually low-grade,

189

in the abdomen, chest, pelvis, or neck. Theevaluation of such children requires a carefulabdominal and rectal examination, urine forhomovanillic (HVA) and vanillylmandelic(VMA) acids, as well imaging of the neck,chest, abdomen, and pelvis. Imaging mayinclude combinations of CT, MRI, and iodine-131-meta-iodobenzylguanidine (MIBG) scin -tiscan. Children with opsoclonus/myoclonusand negative initial studies for occultneuroblastoma should undergo periodicrescreening, as above, for at least 6–12 months.Resection of the neurob lastoma, if found, maynot result in clinical improvement. Treatmentconsists of high-dose ACTH plus monthlyIVIG for months; various other immunomod -ulatory therapies have been used, includingrituximab, cyclophosphamide, and 6-mercap -topurine. The course is usually protracted andthe outcome poor, with most children sustain -ing long-term neurobehavioral sequelae.

189White matter lesions compatible withADEM (arrows) on a coronal FLAIR MRI.


Chronic, slowlyprogressive gaitimpairment withspasticityDisorders resulting in this pattern of gaitimpairment are generally heredo-familialgenetic disorders of various types, although rarecases in children of neoplastic, paraneoplastic,and infectious disorders may present in thisfashion (e.g. acquired immunodeficiencysyndrome [AIDS]-related myelopathy orchronic myelopathy secondary to radiation andhigh-dose methotrexate). MRI of brain andspinal cord may be helpful in guiding thediagnostic evaluation. Based on the clinicalpattern and neuroimaging results, specificgenetic testing or CSF analysis may be helpful.

Slowly progressive gaitimpairment with lowerextremity atrophy andareflexiaThese conditions represent the spectrum ofhereditary motor and sensory neuropathies ofwhich CMT is the prototype. However, CMThas now been subdivided into a large numberof unique, specific genetic conditions. Thesetoo are heredo-familial genetic disorders ofvarious types and some represent variant formsof the conditions above.

Slowly progressive gaitimpairment withproximal muscleweaknessThis pattern generally indicates an underlyingmuscular dystrophy of which Duchenne/Becker muscular dystrophy (DMD) is theprototype. This is discussed in detail in Chapter19 Hypotonia and Weakness.

Chronic or slowlyprogressive ataxiasNumerous rare heredo-familial genetic disor -ders present with slowly progressive ataxia.These heterogeneous genetic disorders shareonly the commonality of truncal +/– appen -dicular ataxia. Inheritance is often autosomaldominant with variable penetrance andanticipation. Ataxia telangiectasia (AT), a rare,

autosomal recessive neurodegenerative disorderaffecting approxi mately 1 in 50,000 personsworldwide, results from mutations in the ATMgene, a gene encoding a protein that promotesDNA repair. Young children with this disorderdisplay oculomotor apraxia, dysarthria, chorea,myoclonus, and progressive ataxia that usuallybegins after the child starts to walk but beforeage 5 years. Ocular telangiectasias (190),considered a hallmark feature of AT, are usuallypresent by 5–7 years of age. Children with ATtypically live into middle adulthood, but have a40% risk of malignancy, especially leukemia andlymphoma. MRI shows progressive pancere -bellar atrophy.

Friedreich ataxia, an autosomal recessivedisorder affecting approximately 1 in 50,000persons, usually begins in late childhood orearly adolescence. The disorder results fromexcessive triple nucleotide repeats (GAA) in thegene (FXN) encoding frataxin, a protein thatparticipates in protecting cells, especially thecell’s mitochondria, from oxidative stress.Persons with this disorder have progressiveataxia, foot deformities, including pes cavus(181, 182), optic atrophy, deafness, scoliosis,heart disease (hypertrophic cardiomy opathyand conduction defects), progressive loss ofvibratory and position sense, and an increasedrisk of diabetes mellitus. The diagnosis ofFriedreich ataxia, supported by detectingabnormal ECG, EMG, and nerve conductionstudies, is confirmed by genetic testing. Thedisorder has a variable prognosis, withcardiomyopathy or cardiac conduction abnor -malities being a cause of premature death inmany patients with Friedreich ataxia. Therapywith idebenone, an antioxidant similar tocoenzyme Q10, may be beneficial.

Psychogenic gaitdisorders, includingastasia/abasiaInability to walk and severe unsteadiness inwalking can be manifestations of conversiondisorder. Many children of age 8–18 willpresent to the emergency department or lesscommonly to their primary care physician withsevere gait impairment. Recognizing childrenwith a conversion (non-neurological) orfactitious disorder often requires consultationwith a child neurologist.


190

190 Sclera in a child with ataxia telangiectasia showingtelangiectatic blood vessels.

CHAPTER 14173

Disorders of sleep

Main Points• Benign sleep myoclonus occurs in as many as two-thirds of healthy

children. When the disorder affects infants, the clinical featuresmust be distinguished from neonatal seizures.

• Night terrors, a common parasomnia, usually begin between theages of 2 and 4 years.

• Nightmares, frightening dreams, usually appear between the agesof 3 and 5 years.

• Sleep walking begins between the ages of 4 and 8 years and affectsas many as 15% of children.

• Restless leg syndrome causes night time leg discomfort in 1% ofchildren and adolescents.

• Delayed sleep-phase syndrome represents a common sleep disorderof adolescents.

• Enuresis, which behaves as an autosomal dominant trait, occurs in10% of 6-year-olds and in 1% of 15-year-olds.

• Narcolepsy, an uncommon disorder with onset in adolescence,consists of cataplexy (abrupt loss of muscle tone), hypnagogichallucinations, sleep paralysis, and excessive day time somnolence.

Introduction

Disorders of sleep represent some of the mostcommon neurological conditions affectingchildren and adolescents. Although most arebenign and many remit over time, childhooddisorders of sleep account for many lost hours ofsleep for parents and numerous referrals toprimary care physicians and specialists. Thegeneral absence of randomized controlled trialsin pediatric sleep disorders greatly limits theclinician’s ability to manage these conditionsscientifically. This chapter describes theontogeny of sleep in children and focuses oncommon childhood disorders of sleep,including the restless leg syndrome and theparasomnias.

Normal sleep of infants,children and adolescents

Much like the motor and cognitive develop -ment of infants and young children, sleepundergoes orderly stages of maturation thatbegin in utero and continue into adulthood.Fetuses, as expectant mothers can readilyconfirm, have cyclic patterns compatible withsleep and wakefulness as early as 28–30 weeks ofgestation. At birth infants spend approximately66% of each 24 hour period asleep, charac -teristically in blocks of 3–4 hours after which thehealthy infant awakens for feedings. Much of theinfant’s sleep time is spent in rapid eyemovement (REM) or active sleep (textbox).


REM: rapid eye movement or ‘active’ sleep,the first stage of sleep in infants. During thisstage, muscle twitches, smiles, grimaces, andnystagmoid eye movements can be observed,especially in young infants.

Non-REM: nonrapid eye movement or ‘quiet’sleep, the first stage of sleep in children,adolescents, and adults. During this stage,little eye or muscle activity is observed.

By 1 year of age, children spend approxi -mately 12 hours each day in sleep, and most ofthis time is spent in quiet sleep. The amount oftime devoted to sleep and also to REM sleepcontinues to decline gradually throughoutchildhood and adolescence, achieving adultpatterns by mid- to late-adolescence. Inadolescents, delayed sleep-phase patterns,characterized by late bed times and difficultmorning arousals, often appear. By age 20 thesleep pattern is characterized by 8–9 hours ofsleep per night with approximately 25% of thistime spent in REM sleep.

Non-REM sleep stages are graded 1–4.Stage 1 sleep follows drowsiness and the EEG atthis time shows sharp waves (‘transients’) in themidline at the top of the head (‘vertex’) withoutsleep spindles (191, 192).

Stage 2 sleep, a state of deeper sleep, followsstage 1; the EEG at this stage shows sleepspindles (rapid [12–14 Hz], crescendo–decrescendo, low to medium amplitude wavesthat appear over the vertex [193]) and Kcomplexes (spontaneous or stimulated sharpwaves and high amplitude slow waves that arealso observed best over the vertex).

CHAPTER 14 Disorders of sleep 175

191191 Normal awake EEG ina 6-year-old child showingrhythmic posteriordominant activity (alphawaves; circled) in alongitudinal bipolar(‘double banana’) montage.

193193 EEG showing sleepspindles (circled) in stage 2sleep (coronal montage).

192192 EEG showing vertextransients (circled) in stage 1sleep (coronal montage).

195 Sagittal T1-weighted MRI annotated to show the pathways of the reticular activatingsystem (1).

194 EEG showing slow waves(circled) of stage 3–4 sleep(coronal montage).

Stages 3 and 4, the deepest stages of sleep,are considered slow wave sleep (194); the EEGat this time shows medium to high amplitudeslow waves of approximately 2–3 Hz. Overall,stages 1–4 occupy approximately 5%, 50%, 5%,and 15% of sleep, respectively, in adolescents andadults; the remainder consists of REM sleep.

Sleep reflects complex interactions betweenthe cerebral cortex and brainstem. The reticularactivating system, a vague neural network thatinvolves numerous cells of the pons, medulla,thalamus, and hypothalamus (195), plays themajor role in determining sleep–wake cycles.Several neurotransmitters, including serotonin,norepinephrine, and acetylcholine, participate


195

in this process. REM sleep appears to arise fromthe locus caeruleus, whereas the median raphenucleus and thalamus contribute to non-REMsleep.

A sleep study or polysomnogram consists ofsimultaneous monitoring of several physio -logical components (87). These includerecordings of muscle activity (EMG) of the chinand extremities (usually the tibialis anteriormuscle), heart rate (ECG), breathing (includ -ing nasal/oral airflow and oxygen saturation),limited leads of the EEG, eye movements, andboth video and audio recordings of the child’sactivity in sleep. Depending upon the child’ssymptoms, the sleep study may also include amultiple sleep latency test (MSLT), a test thatassesses the child’s ability to fall asleep. Thetypical MSLT consists of five opportunities tonap, beginning 1–3 hours after usual awaken -ing, and records sleep onset and REM latency.Short sleep latencies may suggest conditions,such as narcolepsy, that produce excessivesomnolence.

1

194

been achieved, can suggest urinary tractinfection, abuse, or other psychological issues.

MANAGEMENTManagement should begin with a thoroughhistory regarding onset, associated features, andfamily history. Most children with enuresis havefamily members or second degree relatives whohad enuresis, and this information can be usedto reassure parents that enuresis is nearly always‘outgrown’. Behavioral strategies, such as daytime bladder training, limiting fluids after theevening meal, and routine bladder emptyingbefore bedtime, can be effective initialapproaches. For those children who do notrespond to such therapies, desmopressin(DDAVP) can be used at bedtime. Imipramine,a tricyclic antidepressant, has been used, as well,but this drug has many side-effects includingconstipation, sedation, and the potential for fataloverdoses.

Common sleep disorders

Snoring and obstructivesleep apneaApproximately 2–10% of children snore.Snoring, the sound of the oropharyngealstructures vibrating during sleep, occurs inchildren with adenotonsillar hypertrophy,asthma, and second-hand exposure to tobaccosmoke. Some children who snore also haveobstructive sleep apnea, a relatively commondisorder that can produce hypoxemia,hypercapnia, and frequent night time arousals.Snorers, and those with obstructive sleep apnea,can exhibit excessive day time somnolence,hyperactivity, or impaired school performance.Management begins with a polysomnogram;children with obstructive sleep apnea maybenefit from adenectomy or weight loss if obese.If severe, night-time continuous positive airwaypressure (CPAP) or bilevel positive airwaypressure (BIPAP) may be necessary.

Nocturnal enuresisEnuresis remains one of the most troublingproblems encountered by primary carephysicians. The condition is common because itreflects the continuum of the normal evolutionof gaining nocturnal urinary continence. At theage of 3 years, as many as one-third of otherwisehealthy children are enuretic, and by 6 years ofage, the proportion has declined to 10% or less.The condition continues to disappear, but asmany as 1% of 15-year-olds still have enuresis.Enuresis behaves as an autosomal dominant traitwith variable expressivity. Before the age of10 years, boys are affected by enuresis more thangirls; after this age, boy and girls are affectedequally.

Enuresis can occur throughout the night,independent of sleep stage or depth of sleep.Children with enuresis are more likely to haveparasomnias, such as sleep walking, sleep starts,or night terrors, but otherwise appear normal.Although genetic factors are the majordeterminants of the risk of enuresis, certainother conditions, such as chronic urinary tractinfection, anatomical or neurological abnormal -ities, account for as many as 10% of cases ofchildhood enuresis. Secondary enuresis, nighttime wetting that appears after continence has


Restless leg syndromeRestless leg syndrome, affecting as many as 10%of adults, also occurs commonly in children,affecting as many as 2% of children andadolescents. Features that suggest restless legsyndrome include the urge to move the legs,usually associated with painful sensations,during periods of inactivity or sleep, and painfulsensations in the legs that are relieved by walkingor standing. Children with restless leg syndromecommonly have a parent or close relative withthe disorder. Although some children withrestless leg syndrome also have ‘growing pains’,not all children with growing pains meet criteriafor restless leg syndrome (textbox).

Criteria for restless leg syndrome inchildren• An urge to move the legs, usually

accompanied by uncomfortablesensations.

• Movement relieves the uncomfortablesensations or the urge to move the legs.

• A description from the child of legdiscomfort.

• A family history of the disorder issupportive.

Adopted from an USA National Institutes of HealthWorkshop on Restless Leg Syndrome.

Management strategies for children are notyet well defined; however, studies for irondeficiency (ferritin, serum iron, iron bindingcapacity) should be considered, and any irondeficiency should be treated with oral ironsupplementation. Serum hemoglobin levelsalone have low sensitivity for detecting irondeficiency.

Parasomnias

As a group, parasomnias in one form or another,are remarkably common in children, affectingnearly all children at some point during thematuration of their sleep patterns (textbox).Some, such as sleep starts, teeth grinding(bruxism), or nocturnal myoclonus, are minorphenomena that require reassurance only,whereas others, such as sleep walking (som -nambulism) or nocturnal head banging (jactatiocapitis nocturna), may require intensivebehavioral and medication therapy.

Selected parasomnias affectingchildren and adolescents• Sleep walking: affects as many 15% of

children and adolescents.• Bruxism (teeth grinding): affects as many

as 30% of children and often remits byage 5 years.

• Nocturnal myoclonus (‘sleep starts’): asleep–wake transition phenomenon,begins in infancy and affects up to two-thirds of all children.

• Sleep talking: a very benign parasomnia,affects the majority of children.

• Head banging and body rocking: can becommon in young children; serious injury,such as subdural hematoma, has beenreported.

• Night terrors: a disorder of slow wavesleep, start abruptly and have dramaticbehavioral and autonomic features(mydriasis, tachycardia, diaphoresis).

Nightmares and nightterrorsNightmares and night (or sleep) terrors affect asmany as 40–50% of children, usually betweenthe ages of 3 and 5 years. Distinguished fromnight terrors by their milder nature andoccurrence in late sleep, nightmares typicallyoccur during REM sleep. The child awakens,frightened but oriented, and describes aterrifying dream. By contrast, the child withnight terrors, often slightly younger than onewith nightmares, awakens abruptly, often duringthe first few hours after sleep onset, screaming,disorientated with amnesia, and has dramatic


autonomic features with papillary dilation,tachycardia, and diaphoresis. Night terrors arisefrom stage 3 or 4 sleep. The child withnightmares can be consoled by parents, whereasthe child with night terrors is often inconsolableand may run from the parents in fear.

MANAGEMENTManagement of both nightmares and nightterrors begins with comprehensive parentaleducation and behavioral approaches. Potentialtriggering factors, such as late night television,computer games just before bed, or liquids inthe evening, should be eliminated; parentsshould be reassured that their children areotherwise normal. Modest amounts of diazepam(1–2 mg depending upon the child’s age orweight), or melatonin (1–3 mg) at bedtime maybe necessary in severe cases of night terrors.

EEG should be considered in severe cases toexclude nocturnal epilepsies, such as nocturnalfrontal lobe epilepsy, a disorder that can producescreaming, stiffening, thrashing, kicking, andother dramatic motor phenomena. Occasion -ally, rolandic epilepsy (benign childhoodepilepsy with centrotemporal spikes) producesmotor or behavioral phenomena that can beconfused with a sleep disorder.

Sleep walkingSleep walking, a dramatic parasomnia thataffects up to 10% of the pediatric population,usually begins between the ages of 4–8 years.Clinical manifestations vary from sitting up inbed with or without motor automatisms towalking about performing complex tasks, suchas urinating, eating, or exiting the house.Polysomnography in the child with somnam -bulism shows an arousal from deep sleep,stages 3 or 4. Management includes behavioralstrategies, such as door alarms or locks that arechild proof, and avoidance of factors thatinfluence arousal or sleep stage, such asmedications or fluids before bed time.

Neonatal sleepmyoclonus

Neonatal sleep myoclonus, an almost universalphenomenon in young infants, begins as early asthe first few days of life and peaks in the first2 months of life. The infant with myoclonus hasjerking or twitching of the arms and legs thatcharacteristically occurs in sleep. A variation ofthis condition consists of side-to-side headmovements that occur as the nursing childbecomes drowsy and drifts into light sleep. Themyoclonic movements, especially those of thelegs, can be quite dramatic, at times, and raiseconcern to parents and providers regarding thepossibility of seizures. Neonatal sleep myoclonuscan usually be distinguished from seizures by itsconsistent occurrence only in sleep. Reviewingvideos obtained by the parents can be veryuseful, but in some instances an overnightvideo–EEG is necessary to exclude the diagnosisof epileptic seizures. Older children with sleepmyoclonus, a benign disorder, experience thesensation of abruptly falling, followed bymyoclonus and arousal.


Narcolepsy

Narcolepsy, an uncommon disorder charac -terized principally by excessive somnolence, canbegin during puberty. The prevalence ofnarcolepsy in the adult population is estimatedto be approximately 1 per 2000 persons; theprevalence in adolescence is likely lower, on theorder of 1 per 6000. Narcolepsy consists ofseveral elements: abrupt loss of muscle tone andmovement (cataplexy); excessive day timesomnolence (narcolepsy); vivid auditory orvisual hallucinations at the end or beginning ofsleep (hypnagogic hallucinations); and sleepparalysis (a sense of immobility, usually at sleeponset). The pathogenesis of narcolepsy seemslinked to abnormalities in hypocretin in thelateral hypothalamus.

The diagnosis of narcolepsy is established byhistory, polysomnography, and MSLT. MSLTshows a shortened sleep latency, often less than5 minutes, and early onset REM sleep. Thesefindings, coupled with the presence of otherfeatures, such as cataplexy, usually establish thediagnosis of narcolepsy. Management consists ofbehavioral and environmental modifications andmedications, such as modafinil, sodium oxybate,and methylphenidate.

Delayed sleep-phasesyndrome

Many adolescents have sleep patternscompatible with delayed sleep-phase syndrome.This disorder, characterized by the late onset ofsleep and late arousals the next morning, oftenbegins when adolescents reach junior or seniorhigh school. Affected adolescents stay up late,reading, doing homework, playing video games,or watching television, and have difficultyarising for school the next morning. Weekendspose fewer issues since adolescents can usuallysleep later. These changes reflect environmentalfactors, such as the demands of homework andschool attendance, but may also indicatephysiological differences unique to adolescence.Management consists of restoration of morenormal sleep/wake cycles through improved‘sleep hygiene’. Encouraging physical activity(walking or jogging) in the afternoon sun (lighttherapy) and limiting the amount of time spentwatching television after 9 pm can be useful


therapeutic strategies. Melatonin in doses of3–5 mg 1 hour before the desired sleep time hasalso been beneficial. Parental reassurance iswarranted when the adolescent is makingappropriate academic and social progress.

Advanced sleep-phasesyndrome

Advanced sleep-phase syndrome, much lesscommon than delayed sleep-phase syndrome, isassociated with early morning arousals and theinability to stay awake in the evening (textbox).The disorder does not usually cause academicdifficulties, given that affected children oradolescents do not have excessive day timesomnolence, but advanced sleep-phase syn -drome can affect social function. Manage mentconsists of light therapy in the evening, tosustain wakefulness, and melatonin in the earlymorning, to restore sleep.

Delayed sleep-phase syndrome isassociated with late sleep onset and latearousals.

Advanced sleep-phase syndrome isassociated with early sleep onset and earlyarousals.

CHAPTER 15181

Disorders of thenewborn

Main Points• Extremely premature infants have high risks of permanent

neurodevelopmental disorders including cerebral palsy,developmental delay, and epilepsy.

• Refinements in MRI technology make this the preferred imagingmodality for infants with neurological disorders.

• Neonatal encephalopathy due to hypoxia and ischemia remains acommon condition with considerable long-term consequences.

• Stroke largely affects term infants, causing seizures and disability.

• Diagnosing brain death in newborn infants remains challenging.However, clinicians can gain valuable information by assessingcortical and brainstem responses.

• Premature infants with grade 3 and 4 intraventricular hemorrhageshave high rates of disability.


Introduction

The intrauterine and neonatal periods areassociated with dramatic changes in CNSdevelopment. Certain disease entities, affectingterm or preterm infants, present only during thistime. With technological advances in neonatalmedicine in the developed world, more than85% of the infants weighing less than 1500 g atbirth currently survive. Extremely prematureand low birth weight infants who survive theneonatal period have substantial risks ofpermanent neurological disabilities, and 20% ormore of the surviving infants have cerebral palsy(CP), defined as a nonprogressive or staticdisorder affecting motor function. Many moreare at risk for learning disabilities, ADHD,autism, developmental delay, and mentalretardation. This chapter provides a briefoverview of conditions unique to this criticalperiod of life.

Assessing the neonate

When evaluating newborn infants, cliniciansmust consider several factors. First, the clinicianmust seek historical information that helpsclarify the clinical situation. Historical informa -tion relevant to the care of newborns arises fromthe prenatal, perinatal, or immediately postnatalperiods (Table 31). Second, clinicians must usepowers of observation to identify clinicalfeatures in the neonate that provide importantdiagnostic clues. Such information can includeintrauterine growth retardation, hepato spleno-megaly, orthopedic anomalies, abnormalities ofhead size such as microcephaly (129,130) ormacrocephaly (125) and dysmorphic orcutaneous features that suggest specificdisorders. Clinicians must also recognize thatmedication therapy with benzodiazepines,opiates, or barbiturates, even in modest doses,can adversely affect an infant’s alertness, tone,respiratory effort, and motor activity.

Often, however, the history and examin -ation yield few specific clues, and an infant mayappear much worse neurologically than canreadily be explained. In these cases, a step-wiseapproach should be utilized. Some form ofCNS imaging should be considered strongly.Although the available imaging modalities havedifferent advantages and disadvantages, a brainMRI should be obtained if an infant has anabnormal neurological examination. An EEGshould be obtained if a child is encephalopathicor has abnormal movements that might suggestseizures. Hypotonic infants may require EMGand nerve conduction studies, although thesestudies are challenging to perform and interpretin young infants.

CHAPTER 15 Disorders of the newborn 183

Table 31 Historical factors to consider in the evaluation of neonates

PrenatalFamilial conditionsHistory of late fetal miscarriageMaternal health and prenatal care:

folate intake/stores; diabetes; other maternal conditionsMaternal substance use or abuse (ethanol, other drugs)Maternal ageIntrauterine growth restriction (IUGR)Trauma (physical/psychological)Premature laborOligo- or polyhydramniosFetal movement pattern (decrease or increase [e.g. hiccups or seizures in utero])Fetal ultrasoundAmniocentesis

PerinatalPrematurityPlacental issues (previa, abruption, insufficiency)Prolonged rupture of membranes (PROM)Maternal feverMaternal infection status (HIV, HSV, group B streptococci)Loss of fetal movement

PostnatalGestational ageBody size (large for gestational age [LGA], small for gestational age [SGA])Birth asphyxiaNeonatal seizuresInfection/meningitisSystemic disease

Neuroimaging of thenewborn

Several modalities can be used to image thebrain of a newborn infant (textbox).

Comparison of modalities for imagingthe newborn brain• Head ultrasound:– Rapid, portable.– Low resolution and user dependent.• Computed tomography:– Rapid.– Exposure to ionizing radiation; usually

requires transport of the infant.• Magnetic resonance imaging:– Sensitive, high resolution.– Longer scan times and requires transport

of the infant.

Cranial or head ultrasound (US) has beenused clinically for more than 30 years. Head UScan be performed relatively quickly at thebedside, a useful characteristic when evaluatingcritically ill infants. However, US studies of thebrain are limited by overall resolution, the skillof the technician acquiring the images, and theability of the physician who interprets theimages. Sensitivity is highest for midline orsupratentorial processes and those producingstriking changes in tissue density, and is lowestfor processes involving the cortex of the brainand posterior fossa. Overall, the detection ofabnormalities and prediction of outcomes byhead US is frequently constrained by modestsensitivity and lower specificity.

Computed tomography (CT), an X-raybased technology, exposes young infants toionizing radiation. In most hospitals infantsmust be moved from the newborn intensive careunit (NICU) to the radiology department;however, scan time is short (typically 5–10 minutes, or less), so unstable infants canbe returned quickly to the NICU. CT reliablydetects acute intracranial bleeding, intracranialcalcifications, and major developmental braindefects, and accurately assesses ventricular size.When combined with contrast administration,CT visualizes major cerebral veins and sinuseswell. Enhanced CT or CT angiography can be

useful in infants with stroke or suspectedsinovenous thrombosis.

Magnetic resonance imaging (MRI) of thebrain, the preferred modality for assessing mostCNS conditions affecting the neonate,accurately and sensitively detects subtleabnormalities of brain tissue integrity includingcongenital malformations, cortical migrationdefects, tissue ischemia, inflammation orhemorrhage, infection, trauma, and others. Themajor drawbacks of MRI include the length oftime required to acquire a complete scan,typically 30 minutes, and the reality that infantsmust be transported to the scanner. Specificsequences permit the prompt identification ofacute neuronal damage as in stroke (diffusion-weighted imaging [DWI] along with calculationand mapping of the apparent diffusioncoefficient [ADC]), visualization of major axontracts (diffusion tensor imaging, DTI) andvisualization of venous and arterial structures(magnetic resonance venography [MRV] andangiography [MRA], respectively).

MR spectroscopy (MRS) provides additionalinformation regarding tissue metabolism andwell-being, offering the ability to identifyelevations in lactate (as in acute ischemia; 196),decrements in N-acetylaspartate (NAA; as inneuronal loss from prior injury) or absence ofthe creatine peak (the principle clue toguanidinoacetate methyltransferase (GAMT)deficiency) (102). As the application of thesetechniques becomes more widespread in theneonatal period, MRI combined with MRS may offer additional prognostic informationwhich would otherwise be inaccessible.



196

196 MRS showing reduced N-acetylaspartate (NAA) peak(arrow) and a prominent lactate peak (arrowhead) inhypoxic-ischemic injury.

EEG in the newborn

The patterns of the neonatal EEG dependgreatly on the gestational age of the infant. TheEEG patterns of 28 weeks gestation infants, forexample, differ dramatically from those of37 weeks gestation or near-term infants. EEGpatterns in the newborn can occasionally bediagnostic, but are often frustratingly vague.Nonetheless, EEG can provide importantprognostic information when obtained seriallyin infants with neonatal encephalopathy due tohypoxic-ischemic encephalopathy (HIE). EEGpatterns are discussed in greater detail inChapter 3 (Electrophysiological Evaluation ofInfants, Children, and Adolescents).

Burst suppression (197), a severely abnormalEEG finding, often portends a serious,sometimes grim, prognosis, especially in full-term infants. The pattern, indicating globalbrain dysfunction, can be observed in infantswith severe congenital brain malformations,severe HIE, or specific inborn errors ofmetabolism (e.g. nonketotic hyperglycinemia),but can also be encountered in neonates whoare unexplicably encephalopathic. When theneonatal burst suppression pattern isencountered, clinicians should consider severalconditions, including HIE.

EMG in the newborn

Electromyography (EMG) and nerve con -duction velocity (NCV) testing of newbornsposes several problems, including variablesensitivity and specificity and the frequent needto sedate fragile infants. Despite theselimitations, EMG and NCV often enableclinicians to distinguish neuromusculardisorders (e.g. spinal muscular atrophy orcongenital hypomyelinating neuropathy, agenetic condition due to mutations in severalgenes involved in myelin formation) from otherconditions producing neonatal hypotonia, suchas Prader–Willi syndrome and other geneticdisorders.


197

197A burst suppression EEG compatible with severe, diffusebrain injury.

Specific conditions

Neonatalencephalopathy and HIEThe major cause of neonatal encephalopathy(abnormal brain function in the newborn) ishypoxic–ischemic injury, a consequence of ‘birth asphyxia’. Birth asphyxia is often definedas an Apgar score below 7 at 5 minutes (Table 32).

Although birth asphyxia and HIE are oftenused interchangeably with neonatal encepha -lopathy, many infants with the latter conditionlack obvious evidence for asphyxia orhypoxia–ischemia. Severe HIE affects approx -imately 3 of every 1000 live-born infants.Infants with HIE often have nonepilepticmyoclonus or seizures in the first 12–24 hoursof life.

The Sarnat staging system, used to grade theseverity of an infant’s HIE, combines clinicalfindings, as summarized in Table 33, and EEGpatterns to help predict the outcomes of infantswho survive HIE. Several studies suggest thatEEG patterns, especially when combined withMRI features, have reasonable predictive value.Asphyxiated infants with normal or non -epileptiform EEGs, for example, have betteroutcomes than infants whose EEGs showabnormally slow background activity. Infantswith neonatal MRIs showing diffuse white orgray matter abnormalities also are more likely tohave adverse neurodevelopmental outcomesafter HIE. Therapy currently consists ofsupportive care. Head cooling (hypothermia),the standard approach to management at manycenters, appears to reduce long-termneurological morbidity.


Table 32 Components of the Apgar score (worst score = 0; best score = 10)

ScoreElement 0 1 2Skin color Completely cyanotic Acrocyanosis No cyanosisHeart rate Asystolic <100 bpm >100 bpmReflex irritability No response to stimuli Grimace/weak cry Strong cry/withdrawalMuscle tone Flaccid Some tone Active movementsRespiratory activity None Irregular/weak Robust effort

Table 33 Sarnat staging system of HIE

Sarnat stage Mental status Ventilator Feeding Tone Seizures Probability of difficulty severe handicap

or death1 (mild) Hyperalert No Mild Jittery No <1%2 (moderate) Lethargy No Moderate High Yes 25%3 (severe) Coma Yes Severe Flaccid Yes up to 75%


PeriventricularleukomalaciaPeriventricular leukomalacia (PVL), one of themost common injuries to the CNS of prematureinfants, is technically a neuropathologicaldiagnosis determined at autopsy. However,MRI and head US findings can accuratelypredict the presence of PVL in many instances.PVL, caused by ischemia in the periventricularregion at the border zone between differentarterial supplies, consists of damage to the whitematter tracts that lie adjacent to the lateral edgesof the ventricles (198–201). Because of thelocation of the injury, PVL affects thecorticospinal tracts, axons projecting from the neurons that control body movement (109, 202). PVL leads to CP, especially spasticdiplegia, but all four limbs can be affected, acondition known as spastic quadriparesis,especially when PVL leads to extensive axonalloss (203). Besides having spasticity (108, 204),infants with PVL have increased rates ofepilepsy, suggesting neuronal as well as axonalinjury.

198

199 200

198 Cranial sonography showingperiventricular hyperechogenicity compatiblewith edema and tissue infarction (arrow).

199 Sagittal cranial sonography showingperiventricular hyperechogenicity (arrow)compatible with PVL.

200Axial FLAIR MRI showing PVL and gliosis(arrows).


201

201 Coronal gradient recall echo (GRE) MRIshowing PVL (1) and hemosiderin indicatinggerminal matrix hemorrhage (arrow).

11

202

203

202A gadolinium-enhanced sagittal T1-weighted MRI showing cystic PVL (arrow)in a child with hemiparetic cerebral palsy.

203An axial T2-weighted MRI showingmarked white matter volume loss as aconsequence of severe PVL.

204

204 Bilateral cortical thumbs and flexion posture ofthe arms in spastic quadriparesis.


KernicterusKernicterus, bilirubin encephalopathy, canoccur in premature or full-term infants withelevated serum levels of unconjugated bilirubin.Risk factors in full-term infants include earlyonset jaundice (first 24 hours of life), unrecog -nized disorders (e.g. ABO incom patibility) thatpredispose to hemolysis, glucose-6-phosphatedehydrogenase deficiency, cephalohematoma,infection (sepsis), and dehydration. Early clinicalfeatures of kernicterus consist of lethargy,alterations of muscle tone (hypo- or hyper -tonia), high-pitched cry, and opisthotonus.Subsequent neurological abnormalities includedeafness, ophthalmoplegia (especially limitationof vertical gaze), staining of the deciduous teeth,and athetoid CP. Kernicterus and the per manentneurological disability associated with thisdisorder can be prevented by strict adherence topublished algorithms for manag ing hyper -bilirubinemia in neonates.

StrokeNeonatal stroke, defined as a stroke occurring inthe first 28 days of postnatal life, has aprevalence of 1 in every 4000 births. Strokemore often affects term infants and accounts forapproximately 10% of the seizures that occuramong such infants during the first week of life.However, many infants with strokes thatoccurred perinatally or prenatally do not presentwith neurological signs until 4–6 months of agewhen they exhibit asymmetric leg or armmovement. Neonatal strokes can be arterial(205–207) or venous, and associated withcongenital heart disease, infection, orthrombophilic disorders. Many infants lack areadily identifiable cause. Although the risk forstroke recurrence is quite low (<5%), infantswith stroke should undergo a comprehensiveevaluation for thrombophilic disorders(textbox), especially when venous thrombosis isdetected.

Thrombophilic or hemorrhagicdisorders associated with neonatalstroke• Factor V Leiden mutation.• Prothrombin G20210A mutation.• Deficiencies of protein C, protein S, or

antithrombin.• von Willebrand disease.

Treatment consists of supportive care andanticonvulsant medications, as needed. Infantswith stroke are at risk for epilepsy andpermanent disabilities affecting motor andcognitive function.


205 206

207

205 Noncontrast head CT in neonate showinga hypodense area in the left frontal region(arrow) compatible with a cerebral infarction.

206A diffusion-weighted MRI in a newbornshowing cytoxic edema in the left hemispherecompatible with cerebral infarction (arrow).

207 MRA showing decreased flow in the leftmiddle cerebral artery (arrow).


Brain death in theneonateBecause of the factors that impair our ability toassess the mental status of term or prematureinfants, the neonatal brain death examinationmust be approached with considerable caution.Metabolic disturbances and drug effects must beexcluded to ensure that the clinical examinationis not affected by these confounding factors.The brain death examination begins byexcluding reversible conditions. The infantshould have normal temperature and bloodpressure and be unresponsive to all stimuli. Theclinician must document the absence of corticaland brainstem functions (textbox), includingflaccid tone, absent spontaneous or inducedmovements (other than spinal reflex move -ment), unreactive midposition or dilated pupils,absent oculocephalic (doll’s eyes) and oculo -vestibular (caloric) responses, absent gag, absentprimitive reflexes (suck, root, gag), and absenceof respiratory effort in response to a rising CO2.

Intracranial sinovenousthrombosisThrombosis of intracranial venous sinuses andveins can be precipitated by several factors,including dehydration, meningitis, orhypercoagulable states such as factor V Leidenand prothrombin G20210A mutations anddisseminated intravascular coagulation. Clini -cians must maintain a high index of suspicionbecause infants with sinovenous thrombosisoften have nonspecific signs or symptoms,including lethargy, poor feeding, seizures, orautonomic instability. When severe, sinovenousthrombosis can lead to infarction and intra -cranial hemorrhage. Sinovenous thrombo sis isbest detected and monitored by MRI and MRV(208), although Doppler US or CT venogramscan also be used. Management consists ofintravenous hydration and treatment of seizures.Anticoagulation with unfractionated heparinshould be considered for infants with extensiveclots and little or no intracranial hemorrhage.Head CT should be obtained 24–48 hours afterthe initiation of heparin to confirm the absenceof intracranial hemorrhage.

208

208An MRV with absent flow in the righttransverse sinus compatible with an intracranialvenous sinus thrombosis.

SeizuresSeizures are reliable but nonspecific indicatorsof neurological dysfunction in infants, and affectapproximately 1 in every 200–1000 live-bornneonates. Causes of neonatal seizures includeinfection, stroke, HIE, metabolic or geneticdisorders, structural brain abnormalities, drugwithdrawal, and intracranial hemorrhage.Neonatal seizures usually do not consist ofgeneralized tonic–clonic seizures, even when theunderlying abnormal electrical activity isgeneralized. Rather, neonatal seizures tend to befocal or multifocal, often with repetitivemovements that can be mistaken for normalbaby activity. Complicating the evaluation ofneonates with suspected seizures are the factsthat electro graphic seizures can be observed onan EEG without clinical correlates and thatabnormal movements similar to seizures canoccur without EEG abnormalities.

Phenobarbital remains the most commonlyused medication to treat neonates with seizures(Table 34). The drug can be given as anintravenous loading dose of 10–20 mg/kg; anoral or intravenous maintenance dose of 3–5 mg/kg/day divided into two equal dosescan be initiated 12 hours after the load. Usefuladjuncts include lorazepam, 0.05–0.1 mg/kgintravenously, and phenytoin, given as afosphenytoin loading dose of 15–20 mg/kgintravenously and an intravenous or oralmaintenance dose of 3–7 mg/kg/day dividedinto two equal doses starting 12 hours after theload. However, therapeutic phenytoin levels aredifficult to maintain with oral dosing.Levetiracetam appears to have some promise asa safe, effective anticonvulsant for neonatalseizures.


Features of the brain deathexamination• Cortical: coma, absence of response to all

stimuli, absent muscle stretch reflexes,flaccid paralysis.

• Brainstem: absence of pupillary responses,gag, respiratory effort, primitive reflexes,oculocephalic, and caloric responses.

Determining cerebral blood flow byradionuclide imaging can be used to confirmbrain death, but cerebral blood flow can bepreserved in some infants in the acute stage ofclinical brain death. The absence of cerebralblood flow in brain death appears to be due to acombination of low cerebral perfusion pressurecoupled with the presence of vasoconstrictorsreleased in the brain parenchyma. Other imagingstudies, including MRI, have limited utility in theassessment of brain death in neonates.

The current criteria to establish brain deathin term infants more than 7 days of age are aminimum of two detailed neurological examina -tions, separated by 48 hours, confirming absentcortical and brainstem activity as above, and twoEEGs showing isoelectric tracings (70), alsoseparated by a minimum of 48 hours. The EEGsmust be performed in a precise fashion, asspecified by the American Electroencephalo -graphic Society. Criteria for brain death inpreterm infants or infants less than 7 days of agedo not exist. The absence of criteria in preterminfants reflects the immaturity of the CNS; forexample, the pupillary light responses do notappear until 29 or 30 weeks gestation, and theoculocephalic reflex is not present until about32 weeks gestation.

Table 34 Anticonvulsants for neonatal seizures

Medication Loading dose Maintenance dose LevelsPhenobarbital 10–20 mg/kg IV 3–5 mg/kg/day 15–40 μg/mlLorazepam 0.05–0.1 mg/kg IV N/A N/APhenytoin 10–20 mg/kg IV 3–7 mg/kg/day 10–20 μg/mlLevetiracetam 20 mg/kg IV 10–60 mg/kg/day N/A

N/A = not applicable

Infants with pyridoxine-dependent seizures,a unique and extremely rare entity, oftenpresent in the first days of life with intractableseizures that are resistant to multidrug therapy.Treatment consists of intravenous pyridoxine(50–100 mg) as a bolus, given while the infantundergoes an EEG and close monitoring forapnea, a potential complication of intravenouspyridoxine administration. In classic casesthe EEG normalizes and the seizures stopwithin minutes of pyridoxine administration.However, administration of pyridoxine(vitamin B6) orally for 2 weeks thereaftermay be necessary to exclude this conditionreliably, especially in older infants or atypicalcases. The disorder results, in most classiccases, from mutations in the ALDH7A1 genewhich encodes antiquitin, a member of thealdehyde dehydrogenase superfamily. Elevatedurinary levels of alpha-amino adipic semi -aldehyde (α-AASA) can be identified in infantswith pyridoxine-dependent seizures. Folinicacid-responsive seizures, another cause ofneonatal seizures, also appears to result frommutations in the ALDH7A1 gene.

Neuromuscular disordersThe newborn infant with low tone, feedingdifficulties, contractures, or respiratory insuffi -ciency may have a neuromuscular disorder. Theapproach to neonatal hypotonia is discussed indetail in the chapter regarding hypotonia andweakness. The clinician should inspect hypo -tonic or weak infants for contractures andshould assess the position of the legs and armsat rest, the spontaneous movements of the limbsand face, including eye opening, the tone, andthe character of muscle stretch reflexes. Whilethe absence of reflexes can be indicative of lowermotor neuron conditions in children or adults,the character of the muscle stretch reflexes ininfants is a less reliable sign. Arthrogryposis(209), consisting of congenital contractions andimmobility of one or more limbs, can be due toseveral disorders affecting the CNS or peripheralnervous system (textbox).

Causes of arthrogryposis• Congenital muscular dystrophy.• Intrauterine viral infection.• Spinal muscular atrophy.• Maternal myasthenia gravis.• CNS anomalies.• Spinal cord defects.• ARC (arthrogryposis, renal dysfunction,

cholestasis) syndrome.• 22q11 (velocardiofacial) syndrome.• Nemaline myopathy.• Oligohydramnios.


209 209An infant with arthrogryposis, fixedabnormal posture of the feet.

Intraventricularhemorrhage (IVH)Neonatal IVH usually results from hemorrhagein the periventricular germinal matrix(210–213), a highly vascular zone of cellproliferation from which neurons and glia arisein the developing brain (Table 35, overleaf). Thegerminal matrix is especially vulnerable to the

effects of perinatal hypoxia and birth asphyxia.The risk for IVH correlates inversely withgestational age: IVH affects 20–40% of infants<28 weeks gestation but almost no infants after34 weeks gestation. Because of the improvedsurvival of extremely premature, small infants,the rates of IVH and its complications haveincreased. The occurrence of IVH after birth


210 211

210An axial FLAIR MRI showing bilateralgerminal matrix infarctions (arrows).

211 Postmortem gross specimen in fatalneonatal intraventricular hemorrhage in apremature infant.

212

212 Coronal section of another infant withintraventricular hemorrhage shows clots fillingboth lateral ventricles (arrows).

213

213 Histological specimen showing germinalmatrix hemorrhage (H&E).

214 Sagittal cranial sonography showingneonatal grade 1 IVH (arrow indicates blood).


can be marked by severe or subtle clinical signsincluding seizures, autonomic disturbances, ora full fontanel; more often, it is clinically silent.The major complications of IVH include death,CP, cognitive delay, and posthemorrhagichydro cephalus that sometimes necessitatesneurosurgical intervention and/or the place -ment of a shunt. IVH can be graded reliably bythe head US findings (214–217).

Hydrocephalus following IVH, acomplication of grade 3 or 4 IVH, results fromobstruction to CSF flow at the aqueduct ofSylvius, posterior fossa, or pacchionian granula -tions from the blood clots and inflammatoryresponses. Posthemorrhagic hydrocephalus

must be managed in concert with the NICUteam and neurosurgeon. A combination oflumbar punctures and external ventricular draincan be used for initial manage ment; infants oryoung children requiring chronic treatmentrequire placement of a permanent ventriculo -peritoneal shunt. Unfor tunately, severe IVH canbe an ominous complication of prematurity. Asmany as 20–30% of infants with grade 3 or 4IVH die, and 50% of the survivors requireventricular drainage. Many have CP as aconsequence of concomitant PVL. By contrast,the outcomes of premature infants with grade 1or 2 IVH do not differ from premature infantswithout IVH.

Table 35 Grading of neonatal intraventricular hemorrhage

Grade FeaturesGrade 1 Germinal matrix hemorrhage onlyGrade 2 Germinal matrix hemorrhage and some intraventricular bloodGrade 3 Germinal matrix hemorrhage and intraventricular blood that distends one or both ventriculesGrade 4 Germinal matrix hemorrhage, intraventricular hemorrhage with ventricular distention (hydrocephalus)

and intraparenchymal hemorrhage

214


215215 Sagittal cranial sonography showingneonatal grade 2 IVH (arrow indicates blood).

216

217

216 Sagittal cranial sonography showingneonatal grade 3 IVH (arrow shows blood fillingand distending the lateral ventricle).

217Axial cranial sonography in neonatal grade 4 IVH showing ventriculomegaly andperiventricular infarction (arrow).

CHAPTER 16 199

Acute focal deficits

Main Points• Acute focal neurological deficits require urgent evaluation, often in

an emergency department.

• Acute visual loss or double vision requires urgent evaluation in anemergency department or by an ophthalmologist.


Acute bilateral legweaknessThe most common neurological processescausing acute weakness in both legs involve thespinal cord or the peripheral nerves. Thedifferential diagnosis of acute spinal cord lesionsin children includes trauma, spinal tumors,transverse myelitis, acute disseminatedencephalomyelitis (ADEM) or multiple sclerosis(MS) (218), and vascular events such as ruptureof an arteriovenous malformation (AVM) orspinal cord ischemia. Acute bilateral leg weak -ness, usually the result of trauma or inflam -mation, requires urgent neuroimaging of thespine to exclude lesions, such as tumors orhemorrhages, compressing the spinal cord andrequiring emergent neurosurgical intervention.

The history should focus on symptomspotentially associated with these conditions,including preceding illnesses, fever, neck or backpain, recent trauma, urinary retention orincontinence, constipation, and family history.The most common acute process involving theperipheral nerves in children is Guillain–Barrésyndrome (GBS); other, much less commoncauses of acute or subacute peripheralneuropathy include heavy metal poisoning,nutritional deficiencies, metabolic disorders, andchemotherapeutic agents (Table 36). Thehistory should focus on the common symptomsassociated with GBS, such as preceding illness,surgery or immunization, numbness or tinglingin the feet or legs, (common early features inchildren or adolescents with GBS), as well assymptoms or signs that suggest vasculitis ortoxin exposure.

The first priority in examining the child withacute bilateral leg weakness is to determine ifthe child has upper motor neuron (UMN) orlower motor neuron (LMN) signs. UMN signsinclude hyper-reflexia and Babinski signs; spinalcord lesions usually induce a sensory level ordecreased rectal tone. LMN signs includehyporeflexia/areflexia and absent Babinskisigns; peripheral neuropathies affecting bothmotor and sensory nerves have sensory loss inradicular or peripheral nerve distributions. Afterdetermining whether the process involves theUMNs (brain and spinal cord) or LMNs(peripheral nerve, neuromuscular junction, ormuscle), the clinician can formulate adifferential diagnosis and create a diagnostic ortherapeutic plan.

Introduction

This chapter focuses on the evaluation andneurological causes of an acute focal deficit ininfants, children, and adolescents. Non-neurological causes of acute deficits, such asorthopedic, rheumatologic, or infectiousdisorders are not discussed. This materialemphasizes the key historical and examinationfindings, as well as the differential diagnosis forfocal deficits due to neurological disorders.

Acute arm or legweakness

When assessing acute limb weakness, theclinician must obtain a detailed history andperform a focused neurological examination.The history should focus on the eventsimmediately preceding the onset of theweakness, and clinical progression which can be‘maximal at onset and then static’, ‘worsening’,‘improving’ or ‘fluctuating’. The goal of theneurological examination is to localize thelesion and to deduce whether the problem isin the brain, the spinal cord, the peripheralnerves, the neuromuscular junction, or muscle.Defining the temporal profile and localizingthe process enable the clinician to generate acomprehensive differential diagnosis. Forexample, acute ascending weakness of both legsimplies a process involving the spinal cord orperipheral nerves, whereas acute weakness of aleg, arm, and one side of the face implies a lesionof the brain or brainstem.

CHAPTER 16 Acute focal deficits 201

Table 36 Peripheral causes of bilateralleg weakness

Predominantly motor nervesGuillain–Barré syndromeHexane inhalation or ‘huffing’Lead toxicity

Motor and sensory nervesVasculitis (systemic lupus erythematosus,Sjögren’s syndrome, HIV)Arsenic and other heavy metal toxicity

MANAGEMENTInitial management of acute bilateral legweakness should include immobilization of theentire spine if there is a history of trauma. Inevery case, recent injury or not, the patientrequires urgent evaluation in an emergencydepartment. MRI of the cervical, thoracic, andlumbar spine, with and without contrast, is thebest imaging modality to evaluate an acutespinal cord process. Even if the neurologicalexamination localizes the lesion to onesegment of the spinal cord, the entire cordshould be imaged to detect subclinicalinvolvement at other levels of the spinal cord.When GBS is being considered, L-spine MRIwith and without intravenous gadoliniumsupports the diagnosis of GBS when enhancingnerve roots are found (219). A CSF profileshowing an elevated protein with normal whiteblood cell count is another supportive finding.However, lumbar puncture should not beperformed until an intraspinal mass lesion isexcluded by a spine MRI.

218

218A sagittal FLAIR MRI in an adolescentshowing areas of signal hyperintensitycompatible with MS (circle = Dawson finger).

219

219A gadolinium-enhanced, T1-weighted spineMRI showing nerve root enhancement in GBS(arrow).


Unilateral leg weaknessUnilateral leg weakness is often due a non-neurological process such as a joint or otherorthopedic problem, often secondary to trauma.However, the same neurological processes thatcause acute bilateral leg weakness can causeacute unilateral leg weakness, including spinalcord tumor, transverse myelitis, or early GBS.Poliomyelitis and polio-like conditions causedby the nonpolio enteroviruses (e.g. EV71)occasionally deserve consideration. A frontallobe brain lesion, such as a tumor or abscess,can also cause unilateral leg weakness. If arheumatologic or orthopedic cause is notevident, the history and examination shouldfocus on the spinal cord and peripheralnerve causes of weakness. Brain and spineMRIs with and without intravenous contrastshould be considered.

Bilateral arm weaknessBilateral arm weakness, a rare presentation ofacute weakness in children, indicates a processinvolving the cervical spinal cord, such as spinalcord syringohydromyelia (syrinx) (220) ortransverse myelitis (221), or an acute vascularevent such as hemorrhage or infarction. Theclassic presentation of a cervical syrinx isthe gradual onset of sensory loss in a cape-likedistribution. Later, as the syrinx expands,the motor fibers exiting the anterior hornsare affected, and weakness appears, often firstin the intrinsic muscles of the hands. Thenaratrophy can be detected by having the childproduce a tight fist or palpating the belly ofthe first dorsal interosseus muscle (222).Transverse myelitis, usually preceded by a viral illness, may present with neck or backpain. Acute spinal cord infarction or spinalcord vascular malformation with an acutehemorrhage could cause acute painlessweakness of both arms. A rare cause of bilateralarm weakness in children is bilateral brachialplexitis. This can be due to viral infection suchas cytomegalovirus (CMV) or varicella-zostervirus (VZV) and presents with deep, boringshoulder pain in addition to arm weaknessand hyporeflexia.

Unilateral arm weaknessAs with unilateral leg weakness, isolated armweakness is an unusual neurological presen -tation. However if the initial evaluation does notidentify a rheumatologic or orthopedic cause,the neurological entities causing bilateral armweakness should be considered. Stroke cancause acute unilateral arm weakness, sometimesaccompanied by subtle weakness of the leg orface that is not noticed by the patient. Brachialplexus neuritis, an uncommon condition, canalso cause acute, unilateral arm weakness.

Hemiparesis/hemiplegiaHemiparesis refers to weakness (paresis)involving one side of the body (right or left),whereas hemiplegia refers to complete paralysisof one side. In most cases the correct descriptionfor a deficit is hemiparesis, but the words areoften used interchangeably. Acute hemiparesis,the most common presentation of stroke inchildren, requires urgent evaluation in thenearest emergency department. Other disorderscausing acute hemiparesis include migraine,brain tumor, abscess, intracranial hemorrhage,and metabolic disorders such as mitochondrialdisorders or hypoglycemia. Complicatedmigraine is discussed in Chapter 18 Headaches,and post-ictal (Todd’s) paralysis is discussed inChapter 22 Seizures and Other ParoxysmalDisorders.

Noncontrast brain CT, the fastest initial brainimaging, accurately detects intracranial hemorr -hage and most mass lesions. The typicaltemporal profile for most causes of acutehemiparesis is maximal deficit at onset and staticcourse (e.g. ischemic stroke) or improvementover hours (e.g. complicated migraine or post-ictal Todd’s paresis). However, some ischemicstrokes can have a fluctuating course; thus,episodes of acute hemiparesis need completeevaluation for underlying cause, even if theyhave resolved. The most sensitive imagingmodality for detecting acute ischemia, infarc -tion, or tumor (223) is MRI of the brain.


220

220A T2-weighted spine MRI showing Chiarimalformation (upper arrow) and a cervicalsyrinx (lower arrow).

221A T2-weighted spine MRI showing an areaof signal hyperintensity compatible withtransverse myelitis.

222 Palpating for atrophy of the first dorsalinterosseus muscle.

221

222 223

223Axial T2-weighted MRI showing a largetumor (arrow) causing shift of the midline andventricular enlargement.


Acute facial weakness

Acute unilateral facial (hemifacial) weakness in achild is usually due to Bell’s palsy, a conditionthat can occur from the neonatal periodthrough old age. The examination (textbox)reveals facial asymmetry that may be inapparentat rest and only evident upon facial movement,such as smiling or eye closure (169, 170).Prominent signs include asymmetric foreheadwrinkling, elicited by encouraging a child tolook upwards while holding their head still,unilateral weakness of eye closure, and droopingof the corner of the mouth. The affected sideoften appears ‘fuller’, due to asymmetricflattening of the nasolabial fold. By definition,Bell’s palsy is an idiopathic process affectingCN7. If other CNs are affected, the child needsevaluation for an evolving brainstem process.Bell’s palsy improves dramatically and oftenresolves in the first 4 weeks after onset, withfurther recovery possibly occurring over thenext 6 months. Recurrence occurs in up to 10%of cases and may prompt evaluation, such as acontrast-enhanced MRI of the brainstemand temporal bone, for other causes of CN7palsy.

Key elements of the neurologicalexamination in facial weakness• Bell’s palsy or lesions of the CN7 or its

pontine nucleus– Forehead and lower face are weak.– Facial sensation is normal.– Associated symptoms can include

heightened sensitivity to sound(hyperacusis) and altered taste.

• Cerebral stroke– Forehead movement is normal; eye and

mouth closures are weak.– Facial sensation may be affected.– Associated symptoms can include arm

or leg weakness.

Acute hemifacial weakness that spares theforehead is the result of stroke until provenotherwise. The child with this finding should beevaluated immediately in an emergencydepartment with special attention towardsunderlying, treatable causes of stroke such asarterial dissection or unsuspected congenital

heart defects. Other CNS causes of acutehemifacial weakness include brain tumor, brainabscess, and demyelinating diseases, such asADEM or MS.

Congenital hemifacial weakness is occa -sionally noticed suddenly rather than having atruly acute onset. Inspecting old photographs

224

224An infant with asymmetric crying facesyndrome at rest.

225

225An infant with asymmetric crying facesyndrome when crying. Note that eye closureis normal.


226226 Diagram toshow visualfields andlesions of thevisual pathway.

Left Right

Optic chiasmOptic nerve

Optictract

Lateralgeniculatebody

Opticradiation

Defects in visual field of

Left eye Right eye

12

3

4

5

6

1

2

3

4

5

6

Acute visual loss

Acute visual loss can be separated into twocategories: monocular and binocular (textbox).The following material discusses the keyelements of the history and neurologicalexamination and the differential diagnosis forboth conditions. Acute visual loss requiresurgent evaluation in an emergency departmentor by an ophthalmologist, even if the symptomsare resolving. Lesion location and thecorresponding visual field deficit are depicted inFigure 226.

Key elements of the eye examination inacute visual loss • Determine if the loss is monocular or

binocular.• If binocular, determine if there is a

homonymous hemianopsia.• If monocular, determine if there is optic

disk swelling suggesting optic neuritis. • Document visual acuity.• Determine if this is primarily an

ophthalmological disorder and if so, referurgently to an ophthalmologist, otherwiserefer to the emergency department.

can help differentiate congenital from acutecauses. Congenital causes of facial asymmetryinclude asymmetric crying face syndrome (224, 225), due to hypoplasia of the depressoranguli oris muscle that causes asymmetry of thelower portion of the face when crying, andMöbius syndrome, congenital aplasia ofbrainstem nuclei for CN6 and 7 and,occasionally, other motor CNs.

Acute bilateral facial weakness is uncommonin children, but may be due to GBS, bilateralBell’s palsy and botulism in infants. Infantilebotulism presents with poor feeding,constipation, weakness of the eyelids and faceand later, weakness of the extremities andmuscles of respiration. The acute onset ofbilateral ptosis and facial diplegia can bemistaken for lethargy, suggesting infection orencephalopathy, but infants remain alert, oftenwith robust arm and leg movements, at leastinitially. Pupils can be large or midposition andsluggishly reactive to bright light. The diagnosiscan be confirmed by identifying toxin in theinfant’s stool or by detecting an incrementalresponse during repetitive nerve stimulationduring EMG.


Acute monocularvisual lossMonocular visual loss, a visual deficit confinedto one eye only, is typically due to a processanterior to the optic chiasm affecting the opticnerve, the retina, or the globe. Neurologicalcauses of monocular visual loss include opticneuritis or optic neuropathy; less commonly,embolic stroke or vasospasm due to vasculitis(both rare in children) can cause occlusion ofthe retinal arteries with transient or permanentretinal ischemia. The initial examination shoulddocument visual acuity, pupillary response,visual fields, the appearance of the optic nerve,and a neurological examination to localize thelesion. Vision in the unaffected eye is normal inall respects, including preservation of fields ofgaze. The child should be evaluated with urgentimaging and referral to an emergency depart -ment. If a primary ophthalmological processsuch as acute glaucoma is suspected, the patientshould be examined by an ophthalmologist.

Acute binocularvisual lossBinocular visual loss presents with loss of visionthat persists when either eye is closed. This istypically due to a lesion posterior to the opticchiasm, i.e. a process involving the fibers of thevisual pathway, but can also occur in acute,bilateral, optic neuritis. Sudden hypotension, asin syncope, can cause symmetrically decreasedperfusion of the occipital lobe and bilateralvisual loss, but this is a rare cause of bilateralvision loss in childhood. Migraine can causetransient visual scotomata (blind spots in thevisual field) that may be perceived with one orboth eyes open.

Referral to an emergency department forcomprehensive evaluation is appropriate forthis presentation, especially if there areunexplained syncopal symptoms. If there is aquadrantanopsia or hemianopsia, the mostsensitive imaging modality is MRI of the brain,including the orbits, optic nerve, and opticpathways; gadolinium enhancement should beconsidered when there is concern for demyeli -nating disease, tumor, or abscess.

Acute double vision(diplopia)

As in acute visual loss, the initial evaluationmust determine whether the problem is in theeye or the brain (textbox). The examinershould ask the patient to cover one eye. Ifdouble vision persists, then the disorder mayinvolve the cornea or the globe or benonphysiological. If the double vision resolveswith covering one eye, however, double visionis due to eye misalignment. This is most oftendue to a disorder of CN3, 4, or 6 or anintraocular or retrobulbar process preventingfull movement of the globe. The latter canoccur with ocular muscle hypertrophy, as inthyroid eye disease, or with an intraorbital mass,such as a lymphoma.

Key elements of the eye examination inacute double vision• Determine if the double vision is

monocular or binocular.• If monocular, inspect for cataract, corneal

scarring, or dryness, or an intraorbitalmass. Most cases require urgent referralto an ophthalmologist.

• If binocular, examine the eye movements,looking for ocular misalignment. Considerurgent referral to an ophthalmologist.

• Determine if the double images are side-by-side or up-and-down.

• Side-by-side images suggest CN3 orCN6 palsy.

• Up-and-down images suggest CN3 orCN4 palsy.


Eye misalignmentFirst, inspect the eye for proptosis; if present,this suggests a mass preventing full eyemovement. If there is no proptosis,determine whether a CN is involved byassessing the position of the eyes whenlooking forward and when attempting to lookup, down, left, and right. A child with a newpalsy requires urgent imaging, especially

palsies of CN6. Such palsies can be seen withany cause of increased intracranial pressure,even if the nerve itself is not directly involved.Table 37 shows typical abnormalities in eyeposition and eye movement in CN palsies ofthe right eye; findings in left-sided palsieswill be the opposite. See Chapter 11 foradditional information regarding cranialnerve palsies.

Table 37 Typical abnormalities in eye position and eye movement in CN palsies affecting the right eye

GAZE CN3 (R) CN4 (R) CN6 (R)Forward Right eye down and out Right eye is higher Slight adduction of

the right eyeLeft Impaired adduction of Impaired adduction of Full adduction

the right eye the right eyeRight Full abduction Full abduction Impaired abduction of

the right eyeUp Impaired right eye Impaired right eye NormalDown Impaired right eye Impaired right eye NormalOther features Ptosis and dilated pupil Right head tilt Slight head turn to right

right eye

Main Points• Isolated dysmorphic features are common and generally

insignificant.

• In hypotonic infants, consider Prader–Willi, Down, orSmith–Lemli–Opitz syndrome and congenital myotonic dystrophy orspinal muscular atrophy.

• In the child with seizures and dysmorphic features, consider Aicardi(girls only), Angelman, Wolf–Hirschhorn, or velocardiofacial (22q11)syndrome.

• Homocystinuria, Down syndrome, neurofibromatosis type 1 (NF-1),Fabry disease, mitochondrial encephalopathy lactic acid strokesyndrome (MELAS), and cerebral autosomal dominant arteriopathywith subcortical infarcts and leukoencephalopathy (CADASIL) cancause strokes in pediatric patients.

• Mucopolysaccharidoses, fragile X syndrome and fetal alcoholsyndrome should be considered in children with globaldevelopmental delays.

• NF-1 should be considered when the child has multiple café au laitspots, and tuberous sclerosis complex should be considered ininfants or children with multiple hypopigmented macules.

The dysmorphicchild

209CHAPTER 17

227

227 Mild clinodactyly.

There are many different ways to cate gorizedysmorphic features, and consultation with aclinical geneticist or dysmorphologist should beconsidered strongly for the child with subtle orunusual physical features. Several excellentresources exist for evaluating children with asingle or multiple dysmorphic features, includingSmith’s Recognizable Patterns of Human Malfor -mation (2006, Elsevier Saunders, Philadelphia)or Medical Genetics, and on-line resources, suchas OMIM (On-line Mendelian Inheritancein Man) (www.ncbi.nlm.nih.gov/sites/entrez?db=omim) and GeneTests (www.genetests.org).

Here, we have grouped dysmorphic featuresaccording to their clinically-associated featuresas a clinician might encounter them in practice.This chapter is not intended to be anencyclopedic review of genetic syndromesand dysmorphology, but focuses on neuro -logically-relevant disorders with physicalfeatures that provide critical diagnostic clues.

SECTION 2 A problem-based approach to pediatric neurological disorders

Introduction

Dysmorphic means an abnormal shape, andwhen applied to humans, refers to a bodyfeature that differs from the normal appearance.Certain isolated, minor dysmorphic features,such as clinodactyly (incurving of the little (fifth)finger; 227) or syndactyly (fusion or webbing)of the second and third toes (228, 229), arevery common and usually have little diagnosticsignificance. In a child with neurological issuessuch as developmental delay, seizures, or stroke,however, a dysmorphic feature (230) or apattern of dysmorphic features can be a majorclue to a specific diagnosis. Dysmorphic features(birth defects), such as microbrachycephaly orprognathism in Angelman syndrome (116), asan example, may be the herald signs of theunderlying disorder. Moreover, children withthree or more minor birth defects have a highprobability of having a major birth defect and,often, an identifiable syndromic or geneticdisorder.

210

www.ncbi.nlm.nih.gov/sites/entrez?db=omim

www.ncbi.nlm.nih.gov/sites/entrez?db=omim

www.genetests.org

228228 Syndactyly of thesecond and third toesin an infant.

229 Syndactyly of thesecond and third toesof a young child.

229

230 Long taperingfingers characteristicof 22q11 deletionsyndrome.

230

211CHAPTER 17 The dysmorphic child

231The characteristic facial appearance ofPrader–Willi syndrome.

231

232 The face of an infant with trisomy 21(Down syndrome) showing midface hypoplasia,epicanthal folds, and posteriorly rotated ears.

232

Down syndromeDown syndrome, caused by trisomy of all orcritical regions of chromosome 21 (97),remains the most commonly recognizeddysmorphic syndrome, affecting approximately1 in 1000 newborns. Infants with Downsyndrome have hypotonia and characteristicdysmorphic features including epicanthal folds,flat nasal bridge, midface hypoplasia (232,233), short hands and fingers, a single,transverse palmar crease (234), and Brushfieldspots (235). A substantial number of infantshave congenital heart lesions, especially of theatrioventricular canal, and disorders of thegastrointestinal tract, including duodenalstenosis and Hirschsprung disease. Olderchildren and adults with Down syndrome havedevelopmental delay/intellectual retardationand high rates of hypothyroidism and leukemia.


The hypotonic infant

Prader-Willi syndromeInfants with Prader–Willi syndrome, the resultof uniparental disomy at 15.q11.2, have strikinghypotonia, weak cry, feeding difficulties,hypoplastic genitalia, and modest intrauterinegrowth retardation. Their facial appearancecan be characteristic showing high forehead,narrow bifrontal diameter, micrognathia, andabnormal external ears. Children and adultswith Prader–Willi syndrome have prominenthyperphagia, obesity, almond-shaped eyes, finehair, small hands or feet, emotional lability, anddevelopmental delay (231).

212

233A child withtrisomy 21 (Downsyndrome) showingfacial featurescharacteristic of thedisorder.

233

234A transversepalmar crease(arrow).

234

235235 Brushfield spots(arrow).


236

236 Myotonic dystrophy in an adult womanwith a myopathic face (slight tenting of theupper lip, ptosis, and flat nasolabial folds).


Smith–Lemli–OpitzsyndromeInfants with Smith–Lemli–Opitz syndrome, anautosomal recessive disorder mapping to11q12-q13, have hypotonia, microcephaly,ambiguous genitalia in males, and characteristicfacial appearance consisting of micrognathia, V-shaped upper lip, microglossia, short nose,and anteverted nostrils. The disorder resultsfrom deficiency of 7-dehydrocholesterol reduc -tase; infants with Smith–Lemli–Opitz syndromecan be diagnosed by detecting elevated serumlevels of 7-dehydrocholesterol.

Myotonic dystrophyMyotonic dystrophy, an autosomal dominantdisorder due to an expanded CTG triplet repeatin the gene encoding dystrophia myotonicaprotein kinase (DMPK), can present in theneonatal period, particularly when the infant’smother is the affected parent. Neonates withmyotonic dystrophy, in addition to beingmarkedly hypotonic, have marked weakness offacial and bulbar muscles, leading to respiratoryfailure and poor feeding. The infants mayhave foot deformities (talipes) but lack thedysmorphic features typical of adults (cataracts,thin face, male pattern baldness). The mothermust be examined for signs of myotonicdystrophy (236) when considering this disorder.

Congenital spinalmuscular atrophy(Werdnig Hoffmandisease)Infants with the congenital form of spinalmuscular atrophy, Werdnig Hoffman disease,can present in the neonatal period withprofound hypotonia. Such infants can haveareflexia and arthrogryposis (multiple contrac -tures; 209) because of intrauterine inactivity.The disorder can be confirmed by analysis of thesurvival motor neuron-1 gene, present onchromosome 5.

214

237 Pili torti inMenkes disease.

237

238 Sagittal reconstruction of a CT angiogramshowing tortuous blood vessels in Menkesdisease.

238

239

239Wormian bones in Menkes disease.


The neonate withencephalopathy orseizures

Menkes diseaseMenkes disease, an X-linked disorder due to amutation in the copper transporting ATPasegene (ATP7A) causes neonatal hypothermia,failure to thrive, developmental delay, hypo -tonia, and seizures. Infants have sparse, brittle,and twisted (kinky) hair, although this pheno -type may not be recognizable until the infantsare a few months old. The diagnosis can besuspected by detecting pili torti (twisted hair;237) or low levels of serum copper andceruloplasmin (the copper carrying protein),and confirmed by sequence analysis of ATP7A,the gene responsible for the disorder. MRIshows abnormalities of white matter andprogressive cortical atrophy, MRA showstortuous blood vessels (238), and skullradiographs show wormian bones (239).Treatment with subcutaneous injections ofcopper histidine or copper chloride begin ningbefore 10 days of age may improve theoutcome of infants with classic Menkesdisease.

240

240Thalamic calcifications in pseudoTORCHsyndrome.

241 Posterior lissencephaly in a child with LIS1gene mutation.

241


Lissencephaly andholoprosencephalysyndromes Major malformations of the brain, such asholoprosencephaly or lissencephaly, are oftenassociated with abnormal facial features. Infantswith Miller–Dieker syndrome, a lissencephaly(‘smooth brain’) syndrome (241) caused by acontiguous deletion of the LIS1 gene onchromosome 17, have seizures and charac -teristic facial features (prominent fore head,brow furrowing, bitemporal hollowing, flatmidface, thick upper lip). The spectrum offeatures depends on the size of the contiguousgene deletion and involvement of other genes inthe same region.

Holoprosencephaly, a spectrum of disordersin which the cerebrum fails to cleave, consists ofalobar (the most severe with no separation andsingle ventricle), semilobar, and lobar (the leastsevere with fusion in the frontal lobes only)(243–245). Dr. William DeMyer observed inthe 1960s that the appearance of the face of the

Aicardi–GoutièressyndromeAicardi–Goutières syndrome (pseudoTORCHsyndrome) is the result of a mutation in theTREX1 gene at chromosome 3p21. Infantspresent in the first days or months of lifewith encephalopathy, seizures, impaired headgrowth, sterile pyrexias, and abnormalities oftone, spasticity, and/or dystonic posturing.These infants resemble those with congenitalinfection by the presence of microcephaly,intracranial calcifications (240), leukody strophyand CSF pleocytosis. Infants withAicardi–Goutières syndrome have elevated CSFlevels of alpha-interferon. Up to 40% have puffyswelling of the fingers and toes.

216

242 Normal coronal T2-weighted MRI of thebrain.

242

243A coronal T2-weighted MRI showing fusionof the frontal lobes (circle) consistent withlobar holoprosencephaly.

243

244 An axial T2-weighted MRI showing thalamicfusion (circle) and a single ventricle compatiblewith semilobar holoprosencephaly.

244

245A head CT scan showing a fusion of thehemispheres and a large single ventricle inalobar holoprosencephaly.

245


child with holoprosencephaly often predicts thebrain malformation. Infants or children withholoprosencephaly display facial anomaliesranging from cyclopia and proboscis (single eyeand rudimentary nose) or cleft lip and palate tosubtle features such as single or widely spacedcentral incisors and normal facial appearance(246, 247). Microcephaly is an additional,common feature. Infants of diabetic mothers areat risk of holoprosencephaly; up to 50% resultfrom gene abnormalities, such as trisomy 13 or18, or deletions and duplications including 13q,del(18p), del(7)(q36), dup(3)(p24-pter),del(2)(p21), and del(21)(q22.3). Others appearto follow an autosomal dominant patternwith variable penetrance. Neurode velopmentaloutcome varies; those with severe defects (alobarholoprosencephaly) have poor outcomes.


246

247

246 Single, central megaincisor in a child withholoprosencephaly.

247 Wide spaced teeth in a child with lobarholoprosencephaly.

248An infant with Zellweger syndromeshowing characteristic facial appearance.

Zellweger spectrumdisorderZellweger spectrum disorder (also known ascerebrohepatorenal syndrome) is a group ofdisorders due to mutations in any of severalgenes encoding peroxisomal biogenesis. It canpresent in the neonatal period with seizures,encephalopathy, and hypotonia. Infants mayappear normal, or they may have a flattenedmidface, large anterior fontanel, high forehead(248), hepatomegaly, hypotonia, and bonystippling apparent on long bone radiographs.Infantile Refsum disease and neonataladrenoleukodystrophy are additional disordersin the Zellweger spectrum. The diagnosis canbe established by measuring plasma very longchain fatty acids or performing sequenceanalysis of peroxisomal (PEX) genes.

248

CHAPTER 17 The dysmorphic child 219

249

250

249 Lacunar retinopathy (arrow) of Aicardisyndrome.

250 Normal coronal T1-weighted MRI withintact corpus callosum (arrow).

251 Coronal T2-weighted MRI in Aicardisyndrome showing absent corpus callosum andcortical dysplasia of the left hemisphere.

252Anomalous vertebral bodies in a child withAicardi syndrome.

251

252

The child with seizures

Aicardi syndromeAicardi syndrome, an X-linked disorder distinctfrom Aicardi–Goutières syndrome, should beconsidered in infant girls with infantile spasms,chorioretinal lacunae (249), detected byophthalmological exam, agenesis of the corpuscallosum (250, 251), confirmed by CT orMRI, and vertebral anomalies that can bedetected on chest radiographs (252). Girls withAicardi syndrome have a characteristic facialappearance consisting of a prominent pre -maxilla, upturned nasal tip, decreased angle ofthe nasal bridge, and sparse lateral eyebrows.The disorder maps to Xp22, although a specificgene has not, as yet, been linked to the disorder.

22q11 (velocardiofacial)syndromeChildren with DiGeorge/Shprintzen (velocar -diofacial) syndrome, caused by a contiguousgene deletion in the 22q11.2 region, can haveseizures and developmental delay. Dependingupon the extent of the deletion they may havehypocalcemia as an infant, congenital heartdisease (tetralogy of Fallot, atrial septal defect,ventricular septal defect, truncus arteriosus, orpulmonic stenosis), immunodeficiency, anddysmorphic features (98, 253), including cleftlip or palate, elongated face (254), almond-shaped eyes, small ears, polydactyly, andasymmetric crying facies (224, 225). Lessfrequent features include microcephaly, mentalretardation, short stature, slender hands anddigits (255), and inguinal hernia. Children oradults with velocardiofacial syndrome maydisplay nasal speech, related to palatineinsufficiency or clefting, learning disabilities, orbehavioral disorders. Some have called thisCATCH 22 syndrome, an acronym derivedfrom cardiac anomalies, abnormal facies, thymichypoplasia, cleft palate, and hypocalcemia dueto abnor malities of chromosome 22.


253

253An infant with velocardiofacial(Shprintzen–DiGeorge) syndrome due to22q11 deletion.The child has midfacehypoplasia and characteristic appearance to the nose.

Wolf–HirschhornsyndromeWolf–Hirschhorn syndrome, caused by partialdeletion of the short arm of chromosome 4,presents in infancy with seizures (affecting morethan half of the patients), hypotonia,developmental delay, and congenital heartdisease. Infants have a ‘Greek warrior helmetappearance’ of the head, microcephaly, andmalformed ears with pits/tags, as well as fish-like mouth, small chin, short philtrum, cleft lipor palate, coloboma of the eye, and cardiacseptal defects.


255

254An adolescentwith hearing loss andcharacteristic facialfeatures (long nose) in22q11 deletionsyndrome.

255 Long, taperingfingers in 22q11deletion syndrome.

254

The child with languageimpairment

Angelman syndromeChildren with Angelman syndrome have adistinct phenotype that consists of devel -opmental delay, microbrachycephaly, widely-spaced teeth, and prominent mandible (116,256). Children with Angelman syndrome haveprofound language delays with minimal or nospeech; more than five individual words or useof two word phrases makes Angelman syndromeunlikely. Receptive language and nonverbal skillsare better than expressive skills. The child withAngelman syndrome has jerky, ataxic gait withraised arms (40) and a distinctive behavioralphenotype consisting of hyperactivity and ahappy, smiling demeanor (257). Seizures can bedifficult to control in some children. Angelmansyndrome results from loss or mutations of thematernally-derived UBE3A gene on chromosome15. Approximately 70% of cases result fromdeletion of the region (15q12) containing thisgene; 10% result from mutations in UBE3A.

Williams syndromeChildren with Williams syndrome, the result ofcontiguous gene deletions in the 7q11.23region, exhibit a gregarious, loquacious person -ality despite having mental retardation. Childrenwith this disorder have a distinctive, elfin facialappearance including a long brow, low nasalbridge, broad philtrum, and small widely spacedteeth (117, 118). Supravalvular aortic stenosisand infantile hypercalcemia are additional,important features of Williams syndrome.


256

257

256 Prognathism in a girl with Angelmansyndrome.

257 Stereotypic hand and arm posture in a childwith Angelman syndrome.

The child with globaldevelopmental delay

MucopolysaccharidosesThree mucopolysaccharide (MPS) disorders,Hurler, Hunter, and Sanfilippo syndromes,affect the CNS and cause global developmentaldelay, hepatosplenomegaly, and dysmorphicfeatures (258). Hurler syndrome or MPSIresults from deficiency of alpha-L iduronidase,and Hunter syndrome or MPSII results fromdeficiency of iduronate-2-sulfatase. Sanfilipposyndrome, MPSIII, has four subtypes (A–D)resulting from enzymes involved in themetabolism of the glycosaminoglycan, heparansulfate. Hurler and Sanfilippo syndromes areautosomal recessive, whereas Hunter syndromeis X-linked recessive.

Each of these disorders can produceprogressive neurological deterioration, althoughpersons with the Hurler–Scheie and theattenuated form of Hunter disease can havenormal intelligence. Seizures can be a compli -cation of Sanfilippo syndrome. Common to allmucopolysaccharidoses is the tissue accu -mulation of glycosaminoglycans that can lead tohepatosplenomegaly, short stature, macro -cephaly, macroglossia, conductive hearing loss,spinal stenosis, cardiac valvular disease, andcoarse facial features. The latter can be strikingin Hurler syndrome, the most severe of themucopolysaccharidoses, and mild to absent inchildren with Sanfilippo syndrome. MRI mayshow enlarged perivascular (Virchow–Robin)spaces (259) and dramatic cortical atrophyduring the advanced stages of the condition(260). Cardiorespiratory complications shortenthe life span of persons with mucopolysac cha-ridoses. Enzyme replacement therapy, oftencoupled with bone marrow transplantation, isemerging as a promising means to address thesystemic complications of some of thesedisorders.


258258The coarsefacialappearance andsynophrys ofSanfilipposyndrome.

259 ProminentVirchow–Robin(perivascular)spaces (arrow)as inmucopolysaccharidosis.

259

260

260 Marked cerebrocortical atrophy inthe later stages of Sanfilippo syndrome.

224 SECTION 2 A problem-based approach to pediatric neurological disorders

Noonan syndromeNoonan syndrome should be considered in achild with motor developmental delay, shortstature, congenital heart disease (especiallypulmonary valve stenosis or hypertrophiccardiomyopathy), and facial characteristics(262) including hypertelorism, low set and/orabnormally shaped ears, and vivid blue or blue-green irises.

Cornelia de LangesyndromeChildren with Cornelia de Lange syndromehave moderate to severe mental retardation,with distinctive facial features includingsynophrys (confluent eyebrows), archedeyebrows, long eyelashes, and microcephaly(263). Other clinical feature can include hearingloss, autism, cardiac septal defects, andhypoplastic genitalia. Inheritance is X-linked orautosomal dominant with two known genes.

Congenital disorders ofglycosylationThe congenital disorders of glycosylation(CDG) are a heterogeneous group of disorderswith multiorgan involvement; symptoms caninclude developmental delay, ataxia, neuropathy,and cardiac, liver, and gastrointestinal involve -ment. CDG1a, the most common with morethan 400 cases worldwide, causes invertednipples, abnormal accumulations of subcuta -neous fat, retinitis pigmentosa, and dysmorphicfacial appearance with almond-shaped eyes.MRI shows pancerebellar atrophy (184). Thediagnosis is suggested by finding elevatedserum carbohydrate deficient transferrins andconfirmed by enzyme analysis of fibroblasts.Specific treatment is currently available only forCDG1b.

Fragile X syndrome Boys and men with fragile X syndrome, due to atrinucleotide (CGG) repeat expansion in theFMR1 gene, have a distinctive facial appearancewith large ears, long, narrow face, midfacehypoplasia, large lips, and prominent jaw (261).Affected individuals exhibit moderate to severedevelopmental delay/mental retardation,macro-orchidism, and behavioral abnormalitieswith aggressiveness, hyperactivity, and autism.Fragile X syndrome accounts for 1–2% of boyswith autism. The diagnosis can be confirmed bymolecular analysis of the FMR1 gene. Affectedmales have >200 CGG repeats; persons with55–200 repeats have a ‘premutation’ and are atrisk for fragile X-associated tremor, ataxiasyndrome (FXTAS), a neurodegenerativedisorder that causes intention tremor, ataxia,and cognitive decline after the age of 50 years.

261

261A child with fragile X syndrome andprominent ears.


262

262The characteristic facial appearance ofNoonan syndrome.

263

263The facial appearance of Cornelia de Langesyndrome.

266

266Abnormal hand creases (arrow) in fetalalcohol syndrome.

265

265A child with fetal alcohol syndrome with apoorly developed philtrum, microcephaly, andthin vermillion border of the upper lip.

264

264 Facial appearance (thin vermillion borderof the upper lip) suggestive of fetal alcoholexposure.


Fetal alcohol syndromeChildren with fetal alcohol syndrome, also calledfetal alcohol spectrum disorder (FASD), canhave mild to severe symptoms and signsconsisting of developmental delay/intellectualretardation, hyperactivity, failure to thrive,micro cephaly, and cardiac defects. Dysmorphicfeatures of FASD include short palpebralfissures, short upturned nose, smooth, longphiltrum, thin vermillion border of the upperlip, and small fingers and finger nails (264–266).


The child with a stroke

Several genetic disorders are associated with anincreased risk of stroke during childhood oradolescence. These include homocystinuria,Down syndrome, neurofibromatosis type 1(NF-1), Fabry disease, mitochondrial encepha -lopathy with lactic acidosis and stroke(MELAS), and cerebral autosomal dominantarteriopathy with subcortical infarcts andleukoencephalopathy (CADASIL). The latterdisorder, which rarely presents in childhood, isthe result of mutations in NOTCH3, a geneencoding a transmembrane protein thatpromotes smooth muscle cell survival. Arterialor venous thrombosis can be observed ininfants, children, or adolescents with factor VLeiden or prothrombin 20210 gene mutations.

The child with deafness

Pendred syndromePendred syndrome, caused by a mutation in theSLC26A4 gene, represents the most commonsyndromic cause of hearing loss. Children withthis disorder have sensorineural hearing loss(SNHL) and goiter. Mutation in the SLC26A4gene has also been associated with the largevestibular aqueduct syndrome and hearing loss.

Alport syndromeAlport syndrome, another syndromic cause ofdeafness, results in SNHL and progressiveglomerulonephritis that can lead to end-stagerenal failure.

Usher syndromeUsher syndrome, the result of a mutation in thegene encoding myosin VIIA, causes retinitispigmentosa before puberty and severe congen -ital SNHL. Ataxia can also occur.

CongenitalcytomegalovirusinfectionCongenital cytomegalovirus (CMV) infectionrepresents the most common nongenetic causeof deafness in childhood. Infants with congen -ital CMV infection can be symptomatic at birth(congenital CMV disease), exhibiting micro -cephaly, jaundice, hepatosplenomegaly, andpetechial rash, or be silently affected and appearnormal at birth. Hearing loss affects approx -imately 50% of the infants with CMV diseaseand 8% of the infants who are silently infected.

267

267 Retinal angioma in tuberous sclerosis(arrow).

268

268 Hypopigmented skin lesion in a child with tuberoussclerosis (arrow).


Tuberous sclerosisTS or tuberous sclerosis complex (TSC), anautosomal dominant disorder due to mutationsat 9q34 (TSC1) or 16p13.3 (TSC2), is amultisystem condition producing epilepsy,learning difficulties, behavioral disorders(including autism), skin lesions, retinal lesions(267), renal angiomy olipomas, and cardiacrhabdomyomas. The skin lesions consist ofhypopigmented macules (268–271), raisedfleshy areas, shagreen patches (thickenedareas of skin, consisting of orange peel-like

The child withneurological signs orsymptoms and birthmarks

Common neurocutaneous disorders include:• NF-1: affects 1 in 3000–4000 children.• Tuberous sclerosis (TS): affects 1 in 6000

children; 50% are new mutations.• Sturge–Weber syndrome: 3 per 1000

children have facial hemangiomas; 10% orless of these have Sturge–Weber syndrome.

269

269 Hypopigmented skin lesion in another child with tuberous sclerosis.

270

270Truncal ash leaf spots characteristic of tuberous sclerosis (arrows).

271

271The same truncal ash leaf spots in 270 viewed with a Woods lamp(arrows).


272

272 Facial angiofibromas in tuberous sclerosis.

273

273 Facial angiofibromas in tuberous sclerosis(arrows).

274

274 Characteristic CT scan appearance intuberous sclerosis showing a calcified lesionnear the foramen of Monro (arrow).

275

275 Enhancing periventricular nodules intuberous sclerosis (arrows).


glial nodules, subependymal giant cell tumors,and subcortical tubers (274–278), aresufficiently characteristic to confirm thediagnosis. Pathological findings consist of firmsubcortical tubers and hard periventriculargliotic nodules (279, 280).

hamartomas, usually found in the low back),facial angiofibromas (272, 273) and subungualfibromas. The diagnosis can be suspected inchildren with epilepsy or developmental delayand >3 hypopigmented macules; neuroimagingfeatures, consisting of calcified periventricular

276

276 Gadolinium-enhanced axial FLAIR MRI intuberous sclerosis showing enhancing giant celltumors near the foramen of Monro (arrows).

277

277 Gadolinium-enhanced axial T1-weightedMRI showing a giant cell tumor (arrow)extending into the anterior horn of the lateralventricle and obstructing the foramen ofMonro.

278

278Axial T2-weighted MRI showing numerouscortical tubers (arrow) in tuberous sclerosis.

279 Pathological specimen showing theappearance of a cortical tuber (arrows) intuberous sclerosis.

280 Pathological specimen showingintraventricular gliotic nodules (arrows) intuberous sclerosis.

279

280


281

281An EEG showing hypsarrhythmiacharacteristic of infantile spasms, a commonfeature of tuberous sclerosis.

282Areas of T2 MRI signal hyperintensity(arrows) in the basal ganglia of a child with NF-1.

282

Neurofibromatosis type 1Children with NF-1, caused by mutations inthe neurofibromin gene 1 at chromosome17q11.2, may present to clinicians because ofmacro cephaly, hypertension, learning disability,vision loss, seizures, or developmental delay.MRI commonly shows areas of T2 prolon -gation in the basal ganglia, pons, andcerebellum (282, 283). The diagnosis issuggested by the presence of café au lait spots:>6 spots >5mm in size for a prepubertal childand >6 spots >15 mm in size for a postpubertalchild (284).

The diagnosis of NF-1 can be confirmed bythe presence of café au lait spots and one ormore of the following clinical criteria:• 2 or more neurofibromas of any type or 1

plexiform neurofibroma (285).• Freckling in the axillary or inguinal

regions (286).• Optic glioma (287).• 2 or more Lisch nodules

(iris hamartomas; 288).• A distinctive osseous lesion such as

sphenoid dysplasia or thinning of the longbone cortex with or withoutpseudarthrosis.

• A first degree relative (parent, sibling, oroffspring) with NF-1 by the above criteria.


Infants with TSC have increased rates ofinfantile spasms (281), an ominous epilepsysyndrome associated with developmental delayand intractable seizures. Most authorities in theUSA suggest adrenocorticotropic hormone(ACTH) initially; such therapy should beguided by a child neurologist. In many regionsof the world, as well as in the USA, vigabatrin isconsidered, but especially in infants who do notrespond to ACTH. Children with TSC requireperiodic ultrasound evaluation of the heart andkidneys. Cardiac rhabdomyomas typicallyregress with age, whereas renal lesions,including angiomyolipomas and cysts, usuallyappear and grow over time. Children with TSC,especially TSC2, are at risk of hypertension andrenal failure. Subependymal giant cell tumorscan obstruct the foramina of Monro (277) andcause hydrocephalus. Some authorities suggestannual or every other year MRIs in childrenwith TSC until 21 years of age and early resec -tion when subependymal giant cell tumors showcontrast enhancement or rapid interval growth.

283Axial T2-weighted MRI showing signalhyperintensities in the pons and cerebellum(arrows) in NF-1.

284 Café au lait spots in NF-1.

285 Orbital plexiform neurofibroma (arrow) in NF-1.

286Axillary freckling in NF-1.

287 Gadolinium-enhanced sagittal T1-weightedMRI showing a fusiform glioma (arrow) of theright optic nerve in NF-1.

288 Lisch nodules (arrow) of the iris in aperson with NF-1.

284

285

288287

286

283



Children with NF-1 have high rates of opticnerve gliomas, as well as other intracranialneoplasms, and require annual ophthalmo -logical examinations. Optic atrophy can be thefirst sign of an optic glioma. Some authoritiessuggest an MRI at the time of the diagnosis ofNF-1 to establish the extent of brain involve -ment. MRIs can be obtained thereafter based onthe appearance of new neurological signs orsymptoms, such as headaches, seizures, visionloss, or changes in personality or behavior.Neurocognitive testing can facilitate schoolplacement in children with academic difficultiesand suspected learning disabilities. Rarely,children with NF-1 can have hydrocephalus asthe result of aqueductal stenosis.

Neurofibromatosis type 2NF-2, a distinct disorder caused by mutation inthe gene encoding neurofibromin-2, also calledmerlin, located on chromosome 22q12.2,causes tumors of CN8 (usually bilateral acousticneuromas or schwannomas; 289), cerebralmeningiomas, and schwannomas of the dorsalspinal roots. Virtually all patients with NF-2 lackcutaneous or peripheral manifestations of NF-1,as described above. NF-2 rarely presents before14 years of age, but should be suspected inchildren or adolescents with deafness, especiallybilateral, or unexplained vestibular dysfunction.

Sturge–Weber syndromeChildren with Sturge–Weber syndrome (SWS)have facial port-wine hemangiomas (nevusflameus; 290), seizures, leptomeningealangiomatosis, hemiparesis, and glaucoma.Hemagiomas can occur in other body areas inchildren with SWS; the syndrome can overlapwith Kippel–Trenaunay–Weber syndrome, adisorder associated with extremity or truncalhemangiomas and extremity hypertrophy. Theprobability of intracranial leptomeningealangiomas in infants with facial hemangiomasdepends upon the extent of facial involvement;hemangiomas in the V1 (ophthalmic) divisionof the trigeminal nerve have the strongest association with intracranial angiomas. Rarely,SWS can occur without facial hemangioma.

Infants and children with SWS are at highrisk for glaucoma (291) and should be referredpromptly to an ophthalmologist when this issuspected. Buphthalmos (enlargement of theglobe) and glaucoma occur commonly. MRI inSWS shows progressive cerebral hemiatrophyrelated to the meningeal angioma; early on,infants with SWS show accelerated myelinationipsilateral to the intracranial angioma (292).CT shows leptomeningeal calcification overtime (293). Epilepsy in patients with SWSrequires aggressive management with anti -convulsants and early consideration of epilepsysurgery in children with SWS and intractableseizures. Laser treatments can reduce theappearance of the port-wine stain.

Von Hippel LindausyndromeVon Hippel Lindau syndrome, a disorder dueto mutations in the tumor suppressor geneVHL on chromosome 3, causes angiomas ofthe retina, hemangioblastomas of the cere -bellum or spinal cord, and increased rates ofcarcinoma of the kidney and pancreas.Headache can be a common presenting featurein an otherwise healthy-appearing child;headaches or unexplained posterior fossa orspinal hemorrhage should suggest thediagnosis. Pheochromocytomas frequentlyoccur and produce hypertension. The diagnosisis confirmed by ophthalmological examinationand neuroimaging, especially with MRI.

289

289 Gadolinium-enhanced axial T1-weightedMRI showing enhancing auditory canalschwannomas in NF-2 (arrows).

290The facial appearance of a child withSturge–Weber syndrome showing a port-winestain (facial hemangioma).

291 Congenital glaucoma of the left eye, as seenin Sturge–Weber syndrome.

291

290

292

292 Axial T1-weighted, gadolinium-enhancedMRI showing hemispheric atrophy andleptomeningeal enhancement in Sturge–Webersyndrome. Arrow indicates an angioma in thetrigone of the left lateral ventricle.

293

293 CT showing cortical calcifications inSturge–Weber syndrome.


294

294 Sagittal T1-weighted MRI showing ananomalous posterior fossa in an infant withPHACES syndrome (arrow = dysplasticcerebellum; 1 = retrocerebellar cyst).

1


PHACES syndromePHACES syndrome, a disorder that can beconfused with SWS because of facial port-winestaining, is an acronym for: posterior fossaabnormalities; hemangioma of the face; arterialcerebrovascular anomalies; cardiac defects,especially coarctation of the aorta; eyeanomalies; and sternal defects. The majority ofinfants with PHACES syndrome are female.Several ophthalmological abnormalities havebeen observed in these infants, includingchoroidal hemangiomas, coloboma, microph -thalmos, strabismus, and optic nerve hypoplasiaor atrophy. MRI facilitates the diagnosis becauseposterior fossa abnormalities are exceptionallyrare in SWS but fairly characteristic of PHACESsyndrome (294).

MiscellaneousneurocutaneoussyndromesProteus syndrome and Cowden syndrome areovergrowth syndromes (295) that can presentwith macrocrania in childhood. They areassociated with mutations in the phosphataseand tensin homolog (PTEN) gene, a tumorsuppressor gene. Persons with these disordersare at increased risk for tumors of the breast,prostate, uterus, and brain. A related disorder,Bannayan–Riley–Ruvalcaba syndrome, alsoassociated with PTEN mutations, causesmacrocephaly, motor developmental delay, andsubcutaneous lipomas. Incontinentia pigmenti,a rare neurocutaneous disorder caused bymutations in the gene NEMO (NF-kappaBessential modulator), can be associated withwaxy lesions of the skin (296), developmentaldelay, seizures, and microcephaly. Cataracts andanomalies of the teeth, e.g. peg-shaped teeth,can be additional features of incontinentiapigmenti. Epidermal nevi can be observedin several pediatric syndromes, includingepidermal nevus syndrome, hemimega len-cephaly (297) and Proteus syndrome.

296296 The waxy,hyperpigmented lesionsof incontinentia pigmenti.

297297 Hemimegalencephaly,as seen in the epidermalnevus syndrome. Arrowsindicate the cerebralcortical gray matter. Notethe thickened cortex onthe right, indicative ofcortical dysplasia.

295

295 Hemihypertrophy in Proteus syndrome.

R



MyelomeningoceleMMC (a bony defect of the spine containingboth meninges and neural elements) andmeningocele (a bony defect of the spinecontaining meninges only) reflect failure ofposterior neuropore closure. These disorders,along with related conditions lipomeningocele,lipomyelomeningocele, anterior meningocele,are considered manifestations of spinal bifidaor ‘open spine’. Myelomeningocele andmeningocele usually occur at the lumbar orlumbosacral levels (300, 301); however, thesedisorders can also affect the cervical or thoracicregions.

The manifestations and neurologicaloutcomes of these disorders depend upon thelevel and severity of the defect and the presenceof complications, such as hydrocephalus andinfection. A MMC at the L4 level or below or ameningocele at any level is usually associatedwith independent ambulation, whereas a MMCabove this level usually does not providesufficient motor control to allow independentambulation. Hydrocephalus, a common asso -ciated feature of MMC, results from a Chiari IImalformation (302) and requires placement of a ventriculoperitoneal shunt. Urologicaland orthopedic issues are also common,indicating that infants, children, or adultswith MMCs should be managed by anexperienced multidisciplinary team consisting of neuro surgeons, urologists, orthopedists, andrehabil itation specialists. Seizures can occur,necessitating neurological consultation, andvarying degrees of cognitive dysfunction may bepresent, especially in children with hydro -cephalus.

The infant with a neuraltube defect

The human CNS begins as a flat plate, theneural plate, on the dorsal surface of thedeveloping embryo. This plate then folds,becoming the neural groove, and the groovecloses dorsally to form the neural tube. Theneural tube briefly has openings at each end,rostrally, the anterior neuropore, and caudally,the posterior neuropore. These events evolverapidly during the first 4 weeks of gestation,typically before a woman recognizes that she ispregnant; the anterior neuropore closes by 26 days and the posterior neuropore closes by28 days. When the neural tube fails to close orcloses aberrantly, neural tube defects are theresult. Neural tube defects, consisting of opendefects such as anencephaly and myelomeningo -cele (MMC), and closed defects such as spinabifida occulta and tethered cord, affect approx -imately 1 in 1000 live-born infants in the USA.Although the precise etiology of most neuraltube defects remains uncertain, folic acidsupplementation (0.4–4.0 mg daily) reduces theincidence of MMC, suggesting that folatedeficiency or folate-associated factors haveimportant roles in the embryogenesis of thesedisorders.

AnencephalyAnencephaly, failure of anterior neuroporeclosure, represents the most dramatic and severeof the neural tube defects and is incompatiblewith life. Infants with this disorder, more oftenfemale, lack much of the scalp, skull, andcerebrum (298, 299), but may have residualportions of the brainstem. Consequently,newborn infants with anencephaly maytemporarily display rudimentary brainstemfunctions, such as breathing, sucking, andswallowing.

298

298 An infant with anencephaly (side view).

301300

300 Sagittal T2-weighted spine MRI showing amyelomeningocele. Neural elements (arrow)extend into the CSF-containingmyelomeningocele (1).

301A child with a repaired lumbar MMC(arrow). Note the hair patch adjacent to thedefect.

302 Chiari type II showing a dysplastic,elongated brainstem (arrows) and thecerebellum extending below the level of theforamen magnum (circle).

299

299 The infant in 298 shown posteriorly. Notethe absence of scalp, skull, and cerebral cortex.

302

1


Tethered cordTethered cord, a less severe manifestation ofneural tube defects, should be considered inyoung children with low back pain, scoliosis,accentuated lumbar lordosis, and unexplaineddelays in achieving urinary continence. Suchchildren often have cutaneous signs, such aslipomas, hemangiomas, or hairy patches in thelumbosacral region, or unilateral foot defor -mities. Tethered cord can be detected in the first

6 months of life by spinal ultrasound (53) orlater in life by spinal MRI (303). Tethered cordcan be associated with intraspinal lipoma (304),hydrosyringomyelia (220) or Chiari I mal -formation (220, 264), indicating that childrenwith suspected tethered cord usually requireimaging of the entire spine and brain.Management consists of neurosurgical release ofthe tethered spinal cord.


303

303T2-weighted sagittal spine MRI showing atethered spinal cord (arrow).

304

304T1-weighted sagittal spine MRI showing atethered spinal cord (arrow) and an intraspinallipoma (1).

[A] [P]

1

CHAPTER 18 241

HeadachesMain Points • Migraine affects 3% to 15% of children and adolescents.

• Rescue medications for pediatric migraine include nonsteroidal anti-inflammatory drugs and the triptans.

• Pediatric migraine can be prevented using cyproheptadine,topiramate, divalproex sodium, amitriptyline, β-blockers, and calciumchannel blockers.

• Major migraine variants include paroxysmal vertigo, paroxysmaltorticollis, cyclic vomiting, basilar migraine, hemiplegic migraine, theAlice-in-Wonderland syndrome, and acute confusional migraine.

• As many as 5% of the adolescent population, mostly female, havechronic daily headaches, a multifactorial disorder in which migraineand psychological factors have important roles.

• Headaches associated with intracranial tumors are chronic, mild, oftenoccipital in location and associated with other signs or symptoms,including unexplained emesis, diplopia, ataxia, or seizures.

• Pseudotumor cerebri (idiopathic intracranial hypertension) producesdaily headaches and visual changes, including diplopia and transientobscurations.

• Postconcussion syndrome, a common complication of mild traumaticbrain injury, causes daily headaches, memory loss, somnolence, anddizziness or vertigo.

Introduction

Headaches represent some of the most commonproblems encountered by primary care physiciansand child neurologists. As many as 50% ofadolescents report occasional headaches, and8–15% of adolescents, or more, have migraine.Moreover, 1 of every 100 children (1%) under 5years of age also has headaches, usually migraines.Headaches cause considerable concern forparents and physicians. Although brain tumorscertainly cause headaches, the vast majority of

headaches in childhood or adolescence are notthe result of tumors or other life-threateningconditions. However, tumors do occur, and thechallenge posed to clinicians is to differentiateheadaches due to tumors from headaches due toless serious conditions. This section focuses ontwo types of headaches, migraine, a commondisorder producing intermittent or occasionalheadaches, and chronic daily, a disorder thatcauses persistent headaches, and also describesother headache syndromes that can affectchildren and adolescents.

Migraine

DIAGNOSIS AND CLINICAL FEATURESMigraine reflects the complex interaction ofgenetic predilections to headaches andenvironmental factors that trigger migraines.Most neurologists and neuroscientists currentlyfavor the neurovascular pathogenesis whichstates that cortical spreading depression andneurochemically-induced vascular dilatationlead to the aura and headache, respectively.Several environmental factors, including certainfoods and activities, can initiate the cascade ofevents that lead to migraine headaches and theirassociated features.

The International Headache Society definesmigraine without aura, formerly known ascommon migraine, as intermittent headaches,unilateral or bilateral, that last 1–72 hours andproduce nausea or vomiting (textbox).

Migraine without aura (∼70% ofpediatric migraine)• At least five attacks.• Headache lasting 1–72 hours.• Unilateral or bilateral, pulsatile, intense, or

aggravated by activity (at least twofeatures).

• Nausea or vomiting, photophobia orphonophobia (at least one feature).

• No other cause (positive family history).

Migraines are often made worse by brightlights (photophobia) and loud sounds(phonophobia). Migraine headaches can beconstant, pulsatile, and worsen with movementor activity. Many children with migraine alsohave motion- or car-sickness, recurrent epistaxis,or allodynia (cutaneous pain, usually of thescalp).

Migraine with aura, formerly known as classicmigraine, includes these features, but ispreceded or accompanied by a fully reversibleaura that can consist of vertigo, ‘dizziness’,dysarthria, paresthesias, and visual phenomena,including flashes, sparkles, or a scintillatingscotoma with zig-zag margins (known as afortification spectrum) that can progress tocomplete hemianopsia (textbox).

Migraine with aura (∼30% of pediatricheadache)At least two attacks of headache with at leastthree of the following features:• Fully reversible aura.• Aura develops gradually over 4 minutes.• Aura lasts no more than 60 minutes.• Headache that follows the aura within

60 minutes or may begin before orsimultaneously with the aura.

The evaluation of children with suspectedmigraine should begin with a comprehensivemedical history and physical examination.Physicians should pay particular attention to thechild’s head circumference, blood pressure, andfunduscopic examination (305). A child withmigraine should have a normal neurologicalexamination and a positive family history of thedisorder before a clinician can assume that thechild’s headaches represent migraines.


305

305 Normal optic nerve.

MANAGEMENTTreating childhood migraine begins with athorough search for migraine triggers. Manyfoods or chemicals, including prepared meats,monosodium glutamate, cheeses, aspartame,caffeine and chocolate, provoke migraine.Dehydration, stress (both good and bad),altitude, lack of adequate sleep, and irregularroutines can also trigger migraines in manychildren. Thus, a peaceful night’s rest andadequately spaced meals of the appropriatefoods are the foundations of optimummanagement of migraine for all children.

Unfortunately, many children or theirparents cannot identify specific triggeringfactors that can be avoided. Thus, migrainemanagement in most children relies heavilyupon pharmacological and nonpharmaco-logical therapies. Specific strategies dependupon the frequency of the migraines and theeffects that the migraines have on schoolattendance and job or athletic performance.Infrequent migraines (less than four permonth) that last less than 24 hours and do notinterfere with school attendance or otheractivities can be treated with rescue or abortive medications (Table 38, overleaf). Lowcost, well-tolerated, over-the-counter prepar -ations, such as acetaminophen, ibuprofen, andnaproxen sodium, work effectively for manychildren and adolescents, especially whencoupled with rest and brief cessation of activity.

The available data suggest that certaintriptans (sumatriptan nasal spray andzolmitriptan nasal spray) have benefit inpediatric migraine and produce few side-effects.Some children will benefit with administrationof antinausea medications, such as meto -clopramide or hydroxyzine, concurrently. Wecurrently reserve triptans for the adolescent orthe occasional older child who does not respondto appropriate doses of the nonsteroidal anti-inflammatory drugs (NSAIDs). A rescue planbased on the child’s age and their response toabortive medications should be provided for allchildren with migraine (textbox).

CHAPTER 18 Headaches 243

Rescue plan for migraine in children<12 years of age or adolescents whodo not respond to triptans:• Ibuprofen or naproxen sodium (10 mg/kg)

at migraine onset. If nausea and vomitingaccompany the headaches, considermetoclopramide or hydroxyzine orally orpromethazine suppositories (the lattershould not be used in children <2 yr). Bealert for extrapyramidal side-effects.

• If the headache persists for 4 hours andthere is no vomiting, give naproxensodium 10 mg/kg.

• If the headache persists for 6 hours and the child cannot sleep, consider diphenhy dramine, 12.5–25 mg,depending upon weight and age, for sedation.

• If the headache persists for >12 hoursand the child cannot sleep, considerevaluation by a physician.

Rescue plan for migraine inadolescents (>12 years of age):• Ibuprofen or naproxen sodium orally at

migraine onset. Some adolescentsrespond favorably to aspirin-containingprepara tions. (Because of the risk of Reyesyndrome, aspirin-containing medicationsmust be avoided in adolescents withchicken pox or influenza). If the adolescentdoes not usually respond to NSAIDs,provide sumatriptan nasal spray (5–20 mg) or zolmitriptan nasal spray (5 mg). If nausea or vomiting occurconsider meto clopramide orally orpromethazine rectally.

• If the headache persists for 2 hours,repeat the triptan.

• If the headache persists for 4 hours, givenaproxen sodium, 10 mg/kg orally.

• If the headache persists for 6 hours andpromethazine has not been used, givediphenhydramine, 25 mg.

• If the headache persists for >12 hoursand the adolescent cannot sleep, considerevaluation by a physician.

• Ergotamine preparations (e.g.dihydroergotamine) cannot be given if theadolescent has received a triptan in thepreceding 24 hours.

When migraines exceed four per month andinterfere with school attendance andperformance or participation in activities,prevention should be considered (Table 39). Thechoice of medication depends on the child’s ageand weight, the side-effect profile of themedication, and the presence of comorbidfactors. Many commonly used medications,including cyproheptadine, divalproex sodium,imipramine, gabapentin, and amitriptyline, havenot been studied adequately in pediatricpopulations. Sedation and weight gain can limitthe satisfactory use of the above medications,especially in adolescents. After age 10 years therisk of valproate hepatotoxicity is negligiblewhen this drug is used as monotherapy. There isa 1–2% risk of spina bifida and fetal valproatesyndrome in the offspring of mothers who takevalproate during their pregnancies.

Currently, we suggest cyproheptadine inchildren of normal weight under age 10 years;topiramate in adolescents and overweightchildren, and amitriptyline in adolescents whoreport insomnia or depression. Topiramatetherapy can be associated with cognitivedysfunction, such as memory loss and word-finding problems, especially at higher doses,whereas amitriptyline and cyproheptadinetherapy can be associated with appetite stimula -tion, weight gain, and sedation. Alterna tive andcomplementary therapies, including massagetherapy, biofeedback, megavitamin therapy(especially ribo flavin), relaxation–distractionmethods, craniosacral therapy, and chiropracticmanipulation, have been used with variablesuccess, especially in adolescents who experiencefrequent, prolonged migraines.


Table 39 Medications for prevention of pediatric migraine

Drug Dose Side-effectsCyproheptadine 2–8 mg/day PO Sedation, weight gainAmitriptyline 10–50 mg/day PO Sedation, weight gainDivalproex sodium 10–15 mg/kg/day PO Weight gain, sedation, hair lossTopiramate 0.25–2 mg/kg/day PO Weight loss, sedation, cognitive dysfunction,

dyshydrosis causing over-heating, nephrolithiasis

Table 38 Medications for the acute treatment of pediatric migraine (rescue medications)

Drug Dose Side-effectsNonsteroidal AnalgesicsAcetaminophen 10 mg/kg PO GI upsetNaproxen sodium 10 mg/kg PO GI upsetIbuprofen 10 mg/kg PO GI upset

Combination medicationsAspirin–caffeine–acetaminophen1 1 or 2 tablets PO GI upsetIsometheptene–dichloralphenazone– 1 or 2 capsules PO Sedation, dizziness

acetaminophenAcetaminophen, butalbital, and caffeine2 1 tablet PO Sedation

Triptans Zolmitriptan 5 mg nasal spray Jaw tightness, weakness, anxietySumatriptan 5–20 mg nasal spray Bad taste, tingling, flushing, nausea

1Aspirin-containing preparations should be avoided when children or adolescents have chicken pox and influenza.2Given the potential for addiction, this should be used sparingly.

Migraine variants

Several transient neurological phenomena ofchildren and adolescents are consideredmigraine variants. Some, but not all, are asso -ciated with headache, indicating that a familyhistory of migraine has an important role inestablishing these diagnoses. These variantsinclude:• Paroxysmal vertigo: a disorder of young

children associated with recurrent episodesof abrupt and transient vertigo and often,emesis.

• Paroxysmal torticollis: a disorder of infantsand young children associated withrecurrent episodes of abrupt torticollislasting hours to a few days.

• Cyclic vomiting: a childhood disorder withrecurrent bouts of unexplained emesis thatoften begins in the early morning and lastsseveral hours.

• Ophthalmoplegic migraine: recurrentbouts of ophthalmoplegia, usually affectingthe oculomotor (CN3) nerve, oftenwithout headache. Many authorities believethat this condition is due to inflammationof the oculomotor nerve rather than amigraine variant. MRI with intravenouscontrast may show inflammation of thenerve near its exit from the midbrain(164).

• Hemiplegic migraine: a disorder ofchildren and adolescents associated withepisodes of acute and transient hemiparesis.

• Basilar migraine: a disorder of adolescentscharacterized by intermittent episodes ofvertigo, dysarthria, and ataxia, followed oraccompanied by headache; can beassociated with syncope.

• Acute confusional migraine: a disorder,usually occurring in adolescents, producingabrupt confusion, often associated withanxiety, fear, or combativeness.

Chronic daily headaches

DIAGNOSIS AND CLINICAL FEATURESAfter the age of 13 years chronic daily headachebecomes an extremely common headachesyndrome, accounting for as many as 40% ofheadaches and affecting as many as 5% ofadolescents (textbox).

Chronic daily headache• Occur at least 15 days per month.• Present for at least 3 months.• Last more than 4 hours per day.• No identifiable intracranial pathology.

Approximately 75% of adolescents withchronic daily headache are female. Chronic dailyheadache appears to be a multifactorial disorder,with a migraine predilection and female sexbeing major predisposing factors.

The components of chronic daily headachescan sometimes be organized according tovulnerabilities (e.g. female sex and a familyhistory of migraine); precipitants (e.g. acute orchronic illness, family discord); and main -tenance factors (e.g. depression, perfectionistpersonality type). Medication overuse (reboundheadaches) of NSAIDs, opiates, or triptans, canbe an additional maintenance factor that is oftenunder-recognized in children. The headaches ofchronic daily headache tend to be daily,holocranial, and moderate in severity. Manyadolescents with such headaches have alsofrequent, intercurrent migraine-like phenomenawith nausea, phonophobia, and photophobiathat impart an undulating or fluctuating courseto this headache syndrome. Neurologicalexamination is typically normal, as areneuroimaging results, routine laboratorystudies, and, if performed, CSF analysis.


Other headachesyndromes

Tension-type headachesTension-type, nonmigrainous headaches affectas many as 15–20% of adolescents. The clinicalfeatures consist of bilateral, nonpulsatileheadaches of mild to moderate intensity that last30 minutes to several days. Children oradolescents with tension-type headaches, oftendescribed as a tightening sensation, do not havenausea, vomiting, or exacerbations with activityand may respond to amitriptyline, biofeedback,or relaxation–distraction strategies.

Idiopathic intracranialhypertension(pseudotumor cerebri)Also known as pseudotumor cerebri, IIHrepresents an infrequent, but important cause ofheadaches in childhood and adolescence. Factorsassociated with IIH include medication use,especially minocycline, endocrinological dis -orders, such as hypothyroidism, and obesity. Theheadache can be holocranial, intermittent orconstant, and exacerbated by activity. Affectedpatients may complain of diplopia or transientvisual obscurations (episodes of blurred visionlasting less than 30 seconds); neurologicalexamination usually reveals papilledema (307,308) and sixth cranial nerve palsy (166, 167).Brain MRI and MRV should be obtained toexclude intracranial mass lesions and cerebralsinovenous thrombosis, potential causes ofincreased intracranial pressure. The diagnosis is confirmed by lumbar puncture that detects an elevated CSF opening pressure, usually >250 mm H2O. Therapy consists of repeatedlumbar punctures or administration of aceta -zolamide; rarely, optic nerve sheath fenestrationis necessary to preserve optic nerve function.


MANAGEMENTAdolescents with chronic daily headachesrequire a comprehensive neurological examina -tion, including funduscopy; most shouldundergo brain MRI to exclude intracranialabnormalities (e.g. Chiari malformation; 306).Thyroid studies, complete blood cell count,erythrocyte sedimentation rate, urinalysis, andcomprehensive metabolic panel should beconsidered, depending upon the associatedsymptoms. CSF examination is usually notindicated unless there are signs or symptomssuggestive of idiopathic intracranial hyper -tension (IIH; pseudotumor cerebri).

Because chronic daily headaches oftenrepresent transformed migraines, we suggestthat therapy begins with migraine preventivemedications such as topiramate or amitriptyline(textbox).

Treatment of chronic daily headaches• Eliminate medication (especially NSAIDs

and opiates) or caffeine overuse.• Consider amitriptyline or topiramate.• Manage comorbid conditions such as

depression and sleep disorders.• Consider complementary therapies,

including distraction–relaxation,biofeedback, chiropracty, riboflavin, andcraniosacral therapy.

Clinicians should search for comorbidfactors, including depression, family stressors,and sleep disorders, including restless legssyndrome. Headaches may not improve unlessthese comorbid factors are managedsatisfactorily. Therapies that may benefit selectedadolescents with chronic daily headachesinclude megavitamin therapy (especiallyriboflavin), craniosacral therapy, and chiropracty.With the passage of time, headaches usuallyimprove in adolescents who have chronic dailyheadaches precipitated by minor head trauma orinfections, such as infectious mononucleosis orMycoplasma pneumoniae.


307

307 Mild papilledema showing indistinct opticnerve margins and elevation of the nerve inidiopathic intracranial hypertension(pseudotumor cerebri).

308

308 High-grade papilledema showingobliteration of the disk margin, disk elevation,and hemorrhages.

306

306 Sagittal T1-weighted MRI showing a Chiari type 1malformation (arrow).


Intracranial neoplasmsHeadaches associated with intracranial masslesions result from increased intracranialpressure and traction on intracranial vascularstructures. Such headaches tend to be morenoticeable during the early morning hours orupon awakening and may remit as the dayprogresses. With time, other neurological signsand symptoms appear, such as ataxia, diplopia,personality change, seizures, or focal deficits.

Approximately two-thirds of pediatric braintumors involve structures of the posterior fossa(309–311), causing early cerebellar dysfunctionand signs or symptoms of increased intracranialpressure (312), including ataxia, diplopia,headache, vomiting, and papilledema (313).Signs and symptoms of supratentorial tumorsinclude headaches, seizures, and changes inpersonality or vision (314, 315) (Table 40, page250). The diagnosis of intracranial tumors isestablished best by brain MRI, typically withintravenous administration of gadolinium.

309

309 Unenhanced axial T2-weighted MRIshowing a tumor (arrow), compatible with amedulloblastoma, filling the 4th ventricle.

310 311

310 Sagittal T2-weighted MRI showinghydrocephalus and posterior displacement of the 4th ventricle by a brainstem glioma (arrow).

311Axial FLAIR MRI showing amedulloblastoma (arrow) within the 4th ventricle.


312 313

312Axial FLAIR MRI with transependymal flow(arrows) indicating increased intracranialpressure in a child with a neoplasm obstructingthe 4th ventricle.

313 Fundus photograph showing papilledema.

314 315

314 Contrast CT showing a large enhancingmass that was shown by biopsy to be asupratentorial primitive neuroectodermaltumor.

315Axial FLAIR MRI showing a diffuse,hemispheric lesion (arrows) that was shownby biopsy to be a glioblastoma multiforme.


Table 40 Childhood intracranial neoplasms and associated symptoms or signs

Neoplasm FeaturesSupratentorial Infratentorial

Glioblastoma multiforme MedulloblastomaSeizures, headaches, personality change (315) Headaches, vomiting, ataxia (309)

Oligodendroglioma Pilocytic astrocytomaSeizures, headaches Headaches, vomiting, ataxia

Optic pathway glioma EpendymomaVision changes, headaches Headaches, vomiting, ataxia

Primitive neuroectodermal tumor (PNET) Brainstem glioma (310, 317)Seizures, macrocephaly (314) Focal deficits (e.g. diplopia, facial weakness),

‘crossed signs’ (focal cranial neuropathy associated Hypothalamic tumors (gliomas, hamartoma) with contralateral hemiparesis)

Seizures, vision changes, endocrinopathies, diencephalic syndrome (elfin faces, growth failure)

Choroid plexus papilloma Hydrocephalus, headaches

Teratoma Seizures, headaches

Pituitary adenoma (uncommon in childhood) (316)Headaches, bitemporal hemianopsia

316

316A gadolinium-enhanced sagittalT1-weighted MRI shows a pituitary adenoma(arrow).

317

317Axial T2-weighted MRI in a child withheadache shows a brainstem tumor (arrow) andenlarged 3rd ventricle (arrowhead) indicatingaqueductal obstruction.

VasculitisHeadache is the presenting complaint in asmany as 40% of adolescents with systemic lupuserythematosus. The headaches can be intermit -tent, resembling migraine, or chronic,resembling chronic daily headaches of childhood and adolescence. Patients with vasculiticdisorders typically have elevated seruminflammatory markers, CSF pleocytosis andprotein elevations, and abnormal MRIs showinginflammation, stroke, or vascular abnormalities,such as stenosis, beading, or occlusion. CNSvasculitis and stroke can be a complication ofvaricella zoster virus infection in young childrenand resemble the adult disorder of herpes zosterophthalmicus and stroke.

PostconcussionsyndromeHeadache frequently accompanies the post -concussion syndrome, a condition that follows50% or more of cases of traumatic brain injury.The headaches consist of daily, dull, oftendisabling pain that disrupts concen tration,school performance, and other activities of dailyliving. The pathogenesis of the postconcussionsyndrome remains contro versial, and somebelieve that psychological factors, such asdepression or anxiety, may contribute topostconcussion syndrome. The diagnosis isestablished clinically, based upon the presence ofsymptoms, including headache, dizziness,fatigue, irritability, and sleep problems.Concentration and memory can also beaffected. The majority of children or adolescentswith the postconcussion syndrome recoverspontaneously, usually within 3–6 months.Amitriptyline, topiramate, and nonpharma -cological strategies can be used when headachesinterfere with daily activities.

Miscellaneous headachesyndromes• Exertional headaches: headaches provoked

by running, swimming, weight lifting, andother activities. May remit withindomethacin therapy.

• Ice cream headaches: brief headaches(<5 minute duration) provoked byingestion of cold food or drink. Commonin persons with migraine.

• Altitude headaches: holocranial, throbbingheadaches associated with travel to altitudeabove 2,348 metres (8,000 feet). Can betreated or prevented with acetazolamide ordexamethasone.

• Hypertensive encephalopathy: producessevere, throbbing, or constant headachesthat are present upon awakening. MRIsshow T2 prolongation affecting theoccipital and parietal cortices; also knownas posterior reversible encephalopathysyndrome (PRES).

• Intracranial hypotension: producesmigraine-like headaches that are typicallypositional in nature. The child oradolescent may be asymptomatic whensupine; headaches appear and intensifywhen the child is standing. Intracranialhypotension occurs iatrogenically afterlumbar puncture or neurosurgicalprocedures or spontaneously with duralleaks. Persons with Marfan orEhlers–Danlos syndromes are at increasedrisk for spontaneous dural leaks andintracranial hypotension. MRI may identifythe site of the leak; isotope cisternographycan be used to confirm CSF leakage.

• Paroxysmal hemicrania: produces frequentunilateral orbital or supraorbital pain thatcan occur several times per day and last2–30 minutes. Autonomic symptoms canbe prominent features. The headaches mayrespond to indomethacin.

• Jolts and jabs: considered by some to be avariation of migraine, this type of headachelasts seconds and can occur many times perday. Pain can be quite severe and mayrespond to indomethacin.


CHAPTER 19 253

Hypotonia andweakness

Main Points• Neonatal hypotonia (‘the floppy infant’) can result from disorders

of the brain, spinal cord, nerve, and muscle, as well as from genetic,hereditary, or systemic conditions.

• Spinal muscular atrophy, a degenerative disorder of anterior horncells, usually presents in the first year of life and causes progressiveweakness.

• Duchenne muscular dystrophy, the most common musculardystrophy, causes chronic, progressive, fatal weakness in boys.

• Myasthenia gravis, uncommon in young children, is suggested bybulbar dysfunction and fluctuating systemic weakness.

• Dermatomyositis, an uncommon cause of weakness in children oradolescents, is suggested by skin rash, especially over the knuckles,and diffuse muscle weakness and tenderness.

Introduction

Hypotonia and muscle weakness, relativelycommon symptoms and signs in youngchildren, result from many different conditions,including disorders of muscle, neuromuscularjunction, peripheral nerve, and the CNS.Specific diagnoses are influenced by age, sex, therate of progression, and the presence of other

signs and symptoms, features that may enablethe clinician to recognize specific diseasepatterns. This chapter describes importantcauses of hypotonia and weakness in infants,children, and adolescents, focusing onneonatal hypotonia, spinal muscular atrophy,Duchenne muscular dystrophy, congenitalmyopathies, dermato myositis, and myastheniagravis.

utilize a consistent battery of examinationtechniques that distinguish normal variations intone from the clearly abnormal. In addition, theclinician must take into account the infant’sstate; a sated infant who has just finishingnursing may seem weak and hypotonic whencompared to the crying, hungry infant.Components of the Dubowitz MaturityExamination provide a useful foundation forexamining tone in newborn infants (textbox).

Components of the DubowitzExamination for assessing an infant’s tone • Square window: flexion of the infant’s

wrist.• Scarf sign: adduction and flexion of the

infant’s arm across the chest.• Popliteal angle: flexion/extension of the

infant’s knee.• Heel to ear: flexion of the infant’s leg

and hip.

Assessment of tone should include movingthe extremities through their entire ranges ofmotion; especially important in young infantsare: flexion/extension at the elbow; flexion/extension at the wrist; flexion/adduction/abduction at the hips; flexion/extension at theknees; and flexion/extension at the ankles. Theresting posture of a full-term infant with normaltone consists of flexion/adduction of theshoulders and hips and flexion of the elbows andknees. By contrast, a hypotonic term infantassumes a ‘frog leg’ posture (320) consisting ofabduction and extension of the legs as well as thearms. Healthy preterm infants assume varyingdegrees of ‘frog leg’ postures, depending uponthe degree of prematurity.

The two remaining components of themotor examination, strength and reflexes, canprovide important insights to the etiology ofhypotonia in infants. Although difficult to testin a young infant, strength can be assessed bygauging the infant’s arm or leg withdrawal inresponse to a noxious stimulus applied distally,e.g. pressure to the finger or toe nail bed. Aninfant with normal strength withdraws vigor -ously, whereas the response in a weak infant willbe feeble. The infant’s response to noxiousstimuli depends not only on the infant’s

The hypotonic infant

DIAGNOSIS AND CLINICAL FEATURESAn infant’s muscle tone reflects the complexinteractions of the brain, spinal cord, peripheralnerve, neuromuscular junction, and muscle.Lesions at any of these levels can produceabnormally low muscle tone (hypotonia), withor without weakness (textbox).

Potential causes of hypotonia in infants• CNS: intracranial hemorrhage, neonatal

brain tumor, hydrocephalus,developmental brain abnormalities suchas lissencephaly or the Dandy–Walkermalformation.

• Neuromuscular: spinal muscular atrophy,congenital myopathy, congenitalhypomyelinating polyneuropathy,neonatal myasthenia gravis

• Syndromic: trisomy 21 (232–235),Prader–Willi syndrome (231), Turnersyndrome (318, 319), Zellweger spectrumdisorders (248), Angelman syndrome(257), Rett syndrome (113), Williamssyndrome (118), and others.

• Infectious: congenital (TORCH) infections,neonatal meningitis, herpes simplex virusencephalitis, sepsis, infant botulism.

• Metabolic: hypoglycemia, hypocalcemia,hyponatremia, hyperbilirubinemia,hypothyroidism, disorders of organic acidor amino acid metabolism, mitochondrialdisorders, glycogen storage disorders.

• Miscellaneous: benign congenitalhypotonia.

In addition, systemic conditions, such ascongenital or perinatal infections, metabolicderangements, such as hypoglycemia or hypocal -cemia, and genetic or hereditary diso rders, suchas Prader–Willi syndrome (231), representimportant, potential causes of hypotonia. Thus,the clinician must evaluate the hypotonic or‘floppy infant’ comprehensively and thought -fully, paying close attention to all physical andlaboratory clues.

Assessing tone requires considerable patienceand clinical practice. The clinician must createinternal norms through repeated examinationsof infants of various gestational ages and must


CHAPTER 19 Hypotonia and weakness 255

318

320

318 The facial appearance of a child with Turnersyndrome. Note the webbing on the right sideof the child’s neck.

320 Frog leg posture in an infant withWerdnig–Hoffman disease (spinal muscularatrophy).

319

319 Neck webbing (arrow) in Turnersyndrome.

strength, but also on his or her alertness. Asomnolent, obtunded, or comatose infant mayappear hypotonic and weak despite havingnormal neuromuscular function. Again,repeated prac tice is essential in creating internalnorms for examining an infant’s strength.

Muscle stretch reflexes, also known as deeptendon reflexes, are more easily assessed thanstrength, especially at the infant’s biceps, knees,and ankles. The examiner can apply the samescale used to grade the reflexes of older childrenor adults: 0: absent; 1: minimally present; 2: normally active; 3: hyperactive; and 4:clonus. In general terms, a hypotonic, weakinfant with absent or markedly diminishedmuscle stretch reflexes likely has a disorder ofthe anterior horn cells or peripheral nerves,whereas a hypotonic infant with easilyobtainable reflexes, whether weak or not, mayhave a systemic or CNS cause of hypotonia.

Selected disorders ininfants

Spinal muscular atrophySpinal muscular atrophy (SMA), a progressive,autosomal recessive condition, has an incidenceof 1 in 10,000 live births.

DIAGNOSIS AND CLINICAL FEATURESSMA has three distinct phenotypes with onset inchildhood (textbox).

Phenotypes of SMA• Type 1 (Werdnig–Hoffman disease): onset

in the first 6 months; infants never sit andusually die within 2 years.

• Type 2: onset between 7 and 18 months;infants sit but never walk; they may die inchildhood or live to adulthood.

• Type 3 (Kugelberg–Welander disease):onset after 18 months; children will walkand live to adulthood.

Infants with Werdnig–Hoffman disease, themost severe form, usually appear normal at birthand present with hypotonia in the first fewweeks of life. Occasionally, the disorder beginsin utero, causing an arthrogryposis syndromewith diminished fetal movements, weakness,and multiple contractures (209). Infants withWerdnig–Hoffman disease have symmetricweakness, proximal more than distal, tonguefasciculations and absent or markedly dimin -ished muscle stretch reflexes. The infant withthis disorder typically exhibits a frog leg posture(320). Because facial movements are normal,these infants appear bright and alert (321), buthead control and cry are noticeably weak. Theseinfants never sit and have progressive bulbar andrespiratory weakness. Without respiratory andnutritional support, such infants typically diewithin the first 2 years of life.

Type 2 and type 3 SMA affect toddlers andyoung children. Children with either type maybe seen because of motor developmental delayand slowly progressive weakness. Examinationshows hypotonia, symmetric, proximal > distalweakness and markedly diminished or absentmuscle stretch reflexes. Bulbar and respiratorydysfunction may be prominent in type 2 SMA,

but these complications are only a late or minorfeature in type 3 SMA. A fine tremor, mostnoticeable when the child reaches for objects,can be seen in both types 2 and 3. Intellect ispreserved in all types of SMA.

SMA results from mutations in thesurvival motor neuron (SMN) gene, located onchromosome 5q13. This mutation causesprogressive loss of anterior horn cells, dener -vation, and muscle cell death. The diagnosis ofSMA currently relies upon demon strating ahomozygous deletion affecting exon 7 ofSMN1. SMN1, the gene mutated in SMA, hasa nearly identical copy, known as SMN2, on thesame chromosome. The SMA phenotypereflects the interactions of the SMN1mutation(s) and the number of copies of SMN2possessed by the child. Children with type 1SMA have one or two copies of SMN2, whereasthose with type 2 or 3 tend to have three or more.

MANAGEMENTManagement of SMA requires a team approach,involving neuromuscular specialists, primary carephysicians, respiratory therapists, physicaltherapists, dieticians, and parents. The manage -ment must begin by providing parents withaccurate and candid information regarding the cause, therapy, and prognosis of SMA.Pulmonary disease remains the most commoncause of death in both types 1 and 2 SMA.Current guidelines favor noninvasive approachesto respiratory care, consisting of frequentsuctioning, chest physiotherapy, and noninvasiveventilation such as bilevel positive airway pres -sure (BiPAP). Gastrostomy can provide a safe,effective means for providing adequate fluids andcalories.


Prader–Willi syndromeHypotonia in the neonatal period is the mostcommon early feature of Prader–Willi syndrome,a genetic disorder due to an abnor mality onchromosome 15. In approximately 70% of casesPrader–Willi results from a deletion on thepaternal chromosome 15; in 25% the conditionis the result of maternal uniparental disomy, asituation in which the infant inherits twomaternal copies of chromosome 15, but nocopies from the father. Infants with Prader–Willisyndrome display hypotonia, small hands andfeet, almond-shaped eyes (322), and poor suckthat leads to early failure to thrive. In contrast toinfants with neuromuscular causes of hypotonia,infants with Prader–Willi syndrome have normal strength. Children with Prader–Willisyndrome usually have short stature, behavioral

problems (especially compul sions), cognitive/developmental delays, and hyperphagia thatleads to morbid obesity and obstructive sleepapnea. Growth hormone deficiency commonlyoccurs in children with Prader–Willi syndromeand may warrant replacement therapy. Thediagnosis can be established by DNA methy -lation studies, the most sensitive test, or FISHanalysis.

Absence or deletions of the maternalchromosome 15 causes Angelman syndrome, adisorder that also causes hypotonia in theneonatal period. The childhood phenotype ofAngelman syndrome, distinctly different fromthat of Prader–Willi syndrome, consists ofmicrobrachycephaly (116), severe develop-mental delay/mental retardation, and seizures.


321321 Paradoxicalrespirations and alertappearance in a child withWerdnig–Hoffman disease.

322322Almond-shaped eyesin Prader–Willi syndrome.

Neonatal myotonicdystrophyMyotonic dystrophy, an autosomal dominantdisorder affecting approximately 1 in 10,000persons, occasionally presents in the neonatalperiod. Such infants have diffuse hypotonia,symmetric weakness of the extremities, bulbardysfunction, facial diplegia, respiratory distressand, often, club feet. Infants display a character -istic ‘tented’ appearance of the upper lip (323).In nearly all instances of severe neonatalmyotonic dystrophy, the mother is the affected


323

324

323 Characteristic facial appearance(hypotonia, ptosis, tenting of the upper lip)in an infant with myotonic dystrophy.

324 Myotonic dystrophy in the mother andinfant.

parent (324). The diagnosis can be establishedby molecular genetic studies that demonstratemarkedly high numbers of trinucleotide (CTG)repeats (typically >2000 with normal <34) inthe dystrophia myotonica protein kinase(DMPK) gene. A substantial number of infantswith severe congenital myotonic dystrophy diein the neonatal period. Survivors improve, butare usually develop mentally delayed and subse -quently display the slowly progressivemyopathy typical of childhood- or adult-onsetforms.

Congenital myopathiesCongenital myopathies, a heterogeneous groupof conditions, have been divided historically intodisorders with an identified metabolic defect,such as the glycogen storage disorders, andgenetic or structural disorders of muscle, such asnemaline myopathy (textbox).

Selected congenital myopathies

‘Metabolic’• Glycogen storage disease type II (Pompe

disease): see text.• Carnitine deficiency: variable presentation

with myopathy, hepatomegaly,metabolic/encephalopathic crisis, or aSIDS-like presentation. It can be primary,due to a defect in the carnitine transporterprotein, or secondary, due to disorders offatty acid oxidation or organic acids.

• Mitochondrial disorders: many, variedpresentations.

‘Structural’• Nemaline myopathy: congenital,

childhood, and adult forms; variableclinical features; autosomal recessive andautosomal dominant inheritance; mayrespond to L-tyrosine.

• Central core disease: static weakness withonset in infancy or early childhood;autosomal dominant or sporadicinheritance.

• Myotubular myopathy: severe weakness,often with death in early childhood; X-linked recessive inheritance.

Most congenital myopathies have beenlinked to specific gene regions or geneticmutations. Infants with these conditions, as agroup, display hypotonia and systemic and/orbulbar weakness at birth or in the first few weeksof life, as well as certain systemic features,depending upon the disorder. Infants withglycogen storage disease type II, Pompe disease,for example, have hepatomegaly, failure tothrive, macroglossia, hearing loss, cardiomegaly,and characteristic ECG patterns consisting of ashortened PR interval with a broad, wide QRScomplex. Infants with Pompe disease and othercongenital myopathies may have nonspecific


elevations of serum CK. In the case of Pompedisease the diagnosis can be established bymeasuring acid alpha-glucosidase (GAA)enzyme activity in cultured skin fibroblasts.Enzyme replacement therapy withalglucosidase alfa (synthetic GAA) beginningbefore 6 months of age improves motorfunction and increases survival rates in infantswith Pompe disease; enzyme replacementtherapy may improve strength and respiratoryfunction in late-onset forms.

Infants with nemaline myopathy, inheritedas an autosomal dominant or recessive disorder,resemble those with SMA1 and manifest withneonatal hypotonia, weak suck, and respiratorydysfunction. In contrast to infants with SMA1,however, infants with nemaline myopathyslowly improve, although they continue toshow motor delays. The diagnosis is establishedby demonstrating red nemaline rods onGomori trichome stained muscle tissue.Mutations in the muscle proteins, α−actin ornebulin, can be identified in some children withnemaline myopathy. Therapy with L-tyrosineappears to improve bulbar function in infants orchildren with this disorder.

325 Ptosis in a young infant withbotulism.

326 Marked head lag in a 5-month-oldwith infant botulism.

327 Facilitation (bar) during repetitiveEMG stimulation in infant botulism.


Infant botulismInfant botulism appears in previously healthyinfants between the ages of 3 and 8 months.However, cases have been described with onsetas early as the first week of life or as late as12 months of age. Symptoms and signs of infantbotulism usually develop over several days,although infant botulism occasionally beginsabruptly and causes a sudden infant deathsyndrome (SIDS)-like disorder. The earliestsymptoms are poor suck, poor feeding, weak cryand a ‘lethargic’ appearance. The latter is theresult of prominent ptosis (325). As the disorderprogresses, respiratory distress, diffuse hypo -tonia, and weakness of the arms and legs appear,leading to a floppy, ‘frog leg’ posture. Consti -pation is a prominent early feature in nearly allcases. Examination of infants with botulismshows ptosis, head lag (326), absent or weakgag, diffuse hypotonia and weakness, mydriasis,weak suck, and cry. Muscle stretch reflexes maybe normal, hypoactive, or absent, dependingupon the stage and severity of the disorder.

325 326

327

In contrast to adult-type botulism, whichresults from ingestion of preformed toxin,infant botulism results from ingestion ofClostridium botulinum spores. C. botulinumspores can be found in soils and in certainfoods, such as raw honey. Because infants lacksufficient gastric acidity to kill C. botulinum, thespores multiply and produce toxin. The toxin,the most potent neurotoxin, enters the systemiccirculation and binds to cholinergic synapses,causing weakness and constipation. Thediagnosis of infant botulism is established bydetecting toxin in stool samples; EMGfacilitation of >15% on repetitive stimulation at20 or 50 Hz supports the diagnosis (327).Management currently consists of providingbotulism immune globulin (BabyBIG) whichshortens the duration of the disorder. Infantsrecover from infant botulism completely,although a small number of infants (~5%)experience relapses that are generally shorterand less severe than the initial episode of infantbotulism.


Weakness in children andadolescents

Performing the motor examination on toddlersrequires patience, skill, and creativity, but withsufficient time even the most fearful 2-year-oldcan cooperate. The motor exam can begin withthe child sitting on a parent’s lap. Washable toys,such as finger puppets or plastic animals, can beused to examine the child’s upper extremitystrength and dexterity. Most will reach for arubber duck or other toy eagerly, and theexperienced examiner can gauge the strength ofthe child’s grasp and resistance to pulling the toyaway. Toys can also facilitate the examination ofgait and lower extremity strength. The toy canbe tossed a short distance down a hallway, andmost young children (2 years of age and older)can be enticed to chase and recover the toy.Having the child arise from the floor (328, 329)provides a reasonable assessment of pelvic girdlestrength. The uncooperative child who kicks,hits, or cries unwittingly provides compre -hensive information regarding the strength andsymmetry of face, arm, and leg movements!

Assessing the strength of older children andadolescents can be a friendly competitionbetween the examiner and examinee. Each prac -titioner should devise a routine, so that no com -ponent of the motor examination is overlooked.Given the relevance of facial weakness to manyneuromuscular conditions, the exam shouldbegin with the face by inspecting for ptosis,

having the child smile, show their teeth, andclose his or her eyes tightly, ‘as if they have soapin them’ and then having the child looksurprised. The child with normal facial strengthshould be able to smile fully and ‘bury’ the eyelashes with tight eye closure, whereas a child withfacial weakness cannot (330). The examiner canthen move caudally down the body, firstexamining the muscles of the shoulder girdle andarms and ending with an examination of legstrength. Finally, watching the child walk (39)not only provides essential informationregarding distal leg strength, but also usefulinformation regarding the symmetry of move -ments and muscle tone.

Tone should be assessed formally by movingeach joint through a full range of motion.Proximal tone in the lower extremities of infantsand young children can be assessed byalternately adducting and abducting the hips,and distal tone can be assessed by gentledorsiflexion of the ankles. The ankles shoulddorsiflex above 90° without resistance. Musclestretch reflexes (‘jumpers’ for the toddler) canbe assessed using regular techniques and graded0–4, as outlined above. The symmetry andintensity of the biceps, brachioradialis, patellar,and Achilles tendon reflexes (31–33) providesufficiently compre hensive information. Hypo -reflexia suggests disorders of the lower motorneuron, whereas hyper-reflexia suggestsdisorders of the upper motor neuron.

328

328, 329Arising from the floor as a test of pelvic girdle musclestrength.

330 Inability to ‘bury’ the eyelashes in facial weakness(arrow).

329 330


Selected disorders inchildren and adolescents

Duchenne musculardystrophyDuchenne muscular dystrophy (DMD), aprogressive, X-linked disorder due to mutationsin the dystrophin gene, affects 1 of every 3300live-born males. The disorder typically beginsbetween the ages of 2 and 5 years. Parents notethat their young boys cannot keep up with theirpeers and do not walk or run normally. Exami -nation at this time demonstrates symmetric,proximal muscle weakness manifesting as awaddling gait and a Gower sign or maneuver inwhich the boy uses arm support to achieve thestanding position (331). The latter sign,although not specific for DMD, indicates pelvicgirdle weakness. Lumbar lordosis and pseudo -hypertrophy of the gastrocnemius muscles(332), secondary to replacement of muscletissue with fat and connective tissue, are alsousually noted over time.

All voluntary muscles, as well as the heart andmuscles of respiration, are eventually affected inboys with DMD. This leads to progres siveweakness, contractures, scoliosis, cardiomy -opathy, and respiratory insufficiency. Boys withDMD usually lose the ability to walk by thetime they are 12 or 13 years of age. Becausedystrophin is also expressed in brain, boys withDMD often have neurocognitive abnormalitiesaffecting verbal memory. Girls and women,carriers of the condition, are rarely mildlysymptomatic.

Boys with DMD have markedly elevated(several thousand times normal) serum levels ofCK and characteristic findings on muscle biopsyincluding variation in fiber size, proliferation ofcollagen, and replacement of muscle by adiposetissue (333, 334). Dystrophin gene analysisreveals mutations that lead to premature stopcodons in the vast majority of boys withDMD and complete absence of the dystrophinprotein. Dystrophin connects the intracellularcytoskeleton and the extracellular matrix,assisting with load bearing and cell signaling.Dystrophin gene mutation testing by PCR willdetect a deletion or other mutation in about70% of cases; in the remainder, muscle biopsywith immunostaining for dystrophin isnecessary.

Although there remains no cure, boys withDMD benefit from daily corticosteroid therapy,using prednisone 0.75 mg/kg/day. Prednisonetherapy prolongs the ability to ambulate which,in turn, delays the appearance and progressionof contractures, scoliosis, and respiratoryinsufficiency. Weight gain is a potential side-effect that can adversely affect muscle function.Survival into the mid-20s is not uncommon.Physical therapy, supportive care, and periodicassessment of cardiac function should be done.Novel genetic therapies that aim to increasedystrophin protein expression may hold promisefor some patients with certain frame shift orother dystrophin mutations.


331

332

331 The Gower sign indicating pelvic girdle muscle weakness.This is acommon early feature in boys with Duchenne muscular dystrophy.

332 Pseudohypertrophy of the calves inDuchenne muscular dystrophy.

333 334

333 Muscle biopsy in a 3-year-old boy withDuchenne muscular dystrophy shows markedvariation in the size of muscle fibers, necroticfibers, and mild endomysial fibrosis (H&E).

334 Muscle biopsy in the same child showingonly a single muscle fiber (arrow) staining fordystrophin. Normally, all muscle fibers shouldshow dystrophin staining.

Other musculardystrophiesOther forms of muscular dystrophy are muchless common than DMD (textbox). Beckerdystrophy, a dystrophinopathy with onset inadolescence or early adulthood, progresses moreslowly than DMD and can be associated with anear-normal life span. Pelvic girdle weakness andstriking calf hypertrophy are typical findings,and cardiomyopathy can be a prominentfeature. The latter complication necessitatesannual cardiac evaluation and echocardiography.Fascioscapulohumeral dystrophy, an autosomaldominant disorder caused by a deletion onchromosome 4, produces weakness of the face,shoulder, and pelvic girdle musculature.Symptoms usually appear by the age of 20 years,although a severe congenital form can present ininfancy with hypotonia, diffuse weakness, andsensorineural hearing loss. Myotonic dystrophycan present as severe disease in the neonatalperiod, as discussed elsewhere, or in adolescenceas a slowly progressive condition associated withmuscle weakness of the face (‘myopathic facies’),hands, and legs. After the age of 5 years,children or adolescents with this disorder havegrip or percussion myotonia (335, 336); askingthe patient to squeeze your fingers and ‘let gofast’ is a useful screening test for a myotonicgrip. Children with myotonic dystrophy willrelease your fingers very slowly. Adolescents andadults with myotonic dystrophy have amultisystem disorder with frontal balding,cataracts, learning disability/mental retardation,cardiac conduction abnor malities, diabetesmellitus, and abnormalities of gastrointestinalmotility. ‘Tenting’ or a ‘fish-mouth’ appearanceof the upper lip is an important sign (337).


Muscular dystrophies with onset ininfancy, childhood, or adolescence• Myotonic dystrophy: neonatal form with

bulbar dysfunction; childhood oradolescent form with facial diplegia, gripmyotonia, learning disability, andprogressive systemic weakness.

• Duchenne muscular dystrophy:dystrophinopathy with onset in earlychildhood, causing severe, progressivesystemic weakness.

• Becker muscular dystrophy:dystrophinopathy with onset inadolescence, causing calf hypertrophy,pelvic girdle weakness, andcardiomyopathy.

• Fascioscapulohumeral dystrophy: onset by age 20 years, causing facial and shoulder girdle muscle weakness; severeneonatal form with diffuse weakness andhearing loss.

• Limb girdle dystrophy: a heterogeneousgenetic disorder with variable onset andprogression causing lower extremityweakness.

• Congenital muscular dystrophy:a heterogeneous disorder with variablepatterns of inheritance; some involvemuscle, eye, and brain disorders such aspolymicrogyria or lissencephaly (e.g. Fukuyama muscular dystrophy due to a mutation in the gene encodingthe protein, fukutin).


335

337

336

335 Elicitingmyotonia bypercussion inmyotonic dystrophy.

336 Involuntaryadduction of thethumb, indicatingmyotonia, in responseto percussion of thethenar muscle inmyotonic dystrophy.

337An older childwith myotonicdystrophy showingmyopathic(‘expression-less’)facies with tenting ofthe upper lip.

Myasthenia gravisMyasthenia gravis (MG), an uncommonpediatric neuromuscular disorder, has severalforms in childhood: a transient neonatal formthat usually occurs in the offspring of womenwith MG; a neonatal form in infants whosemothers do not have MG; an ocular form withophthalmoparesis; and a juvenile form thatbegins in late childhood or adolescence andresembles the adult disorder. With the exceptionof congenital MG which has a genetic basis,other forms of MG result from circulatingantibodies that interfere with acetylcholinetransmission at the neuromuscular junction.Infants with neonatal MG display hypotonia,diffuse weakness, facial paresis, ptosis, andbulbar and respiratory dysfunction. Resolutionof ptosis, facial paresis, and hypotonia after theadministration of neostigmine, a longer-actingacetylcholinesterase inhibitor, confirms thediagnosis.

Children with the ocular form of MG haverecurrent or persistent ptosis (338) and ophthal -moparesis that may respond poorly to acetyl -cholinesterase inhibitors. The juvenile formbegins in late childhood or adolescencewith fluctuating systemic weakness, ptosis,diplopia, dysarthria, and dysphagia. Thediagnosis can be suspected by electrodiagnosticfindings of a decremental response to repetitivestimulation and confirmed by detection of MG-specific antibodies or resolution of weakness(e.g. ptosis) following administration of theacetylcholinesterase inhibitors, edrophoniumchloride (the Tensilon Test) (339, 340) orneostigmine. As many as 80% of childrenwith generalized MG have detectable serumantibodies to acetylcholine receptors, and asubstantial proportion of those withoutacetylcholine receptor antibodies have circu -lating antibodies to the muscle-specific tyrosinekinase (anti-MuSK antibodies). Management ofjuvenile forms involves administration of theacetylcholinesterase inhibitor pyridostigmine,immunomodulation using prednisone, azathio -prine, or intravenous immunoglob ulin, andthymectomy. Because children or adoles centswith MG occasionally have thymomas, acommon feature in adult MG, chest CT shouldbe obtained in all children and adolescentswith MG.


339

340

338

338 Unilateral ptosis compatible withmyasthenia gravis.

339 Ptosis and ophthalmoplegia in a child withmyasthenia gravis.

340 Improvement in ptosis but persistence ofophthalmoplegia after administration ofedrophonium chloride (Tensilon Test).


Dermatomyositis/polymyositisDermatomyositis, an uncommon inflammatorymyopathy of childhood, begins insidiously withsymmetric, proximal weakness affecting arm andleg muscles. Affected children fatigue easilywhen climbing stairs and may have bulbardysfunction that can resemble MG. Thedisorder can be distinguished from MG bythe lack of response to acetylcholinesteraseinhibitors and the presence of a skin rash thatcan appear before, during, or after the onset ofmuscle weakness. Muscle bulk is usually normalunless the disease has been present for months,but muscle tenderness and diffuse discomfortmay be evident. Skin findings that suggestdermatomyositis include periorbital heliotrope,a ‘butterfly’ rash reminiscent of systemic lupuserythematosus (341), or a scaly, erythematous,eczematoid rash over the knuckles of the fingersor toes (Gottron sign).

Markers of muscle inflammation, includingerythrocyte sedimentation rate or serum CK canbe normal or elevated; biopsy of affectedmuscles shows perifascicular muscle cell atrophyand inflammation (342). Other measures ofmuscle involvement (aldolase or serumcreatinine) can be elevated in the absence of anelevated CK. Treatment consists of physicaltherapy and long-term administration ofimmunomodulating agents including pred -nisone, intravenous immunoglobulin, andcyclophosphamide. High-dose oral corti -costeroids, prednisone 1–2 mg/kg day initiallywith change to alternate day steroids andgradual taper over weeks to months, remain themainstay of therapy. Various ‘steroid-sparing’strategies are also advocated including concur -rent use of cyclophosphamide, methotrexate,azathioprine, or cyclosporin, as well as ‘pulse’steroid strategies. The disease is protracted, butmost children ultimately go into remission andlong-term prognosis is generally favorable.Unlike adults, pediatric patients with dermato -myositis rarely have underlying or occultmalignancies.

In children with polymyositis progressiveproximal muscle weakness develops over aperiod of weeks. There may be associatedmuscle pain and tenderness but sensorydisturbances, as seen in acute inflammatorydemyelinating polyneuropathy (AIDP), ordermatologic features, as seen in dermato -

myositis, are absent. Pelvic girdle muscles aretypically affected leading to a waddling gait,increased lumbar lordosis, difficulty climbingstairs or walking uphill, and fatigability.Reaching for objects on shelves, combing one’shair, and similar actions become difficult due toproximal upper extremity weakness. Treatmentalso relies on immunomodulators, but thecourse of disease is generally shorter and morefavorable than in dermatomyositis.

342

342 Muscle biopsy in dermatomyositis showsvariation in fiber size and perifascicularinflammation (arrow) (×200).

341

341 Facial rash in dermatomyositis.

269CHAPTER 20

Infections of thenervous system

Main Points• Fever, behavior change, headache, and meningeal signs suggest

meningitis or encephalitis. Children with encephalitis have seizures,altered mental status, and/or focal deficits.

• Infants with suspected herpes simplex virus encephalitis requireurgent therapy with aciclovir, using 60 mg/kg/day.

• Acute disseminated encephalomyelitis (ADEM), a postinfectiousdisorder, accounts for approximately 10–15% of childhoodencephalitis.

• Congenital infection is suggested by hepatosplenomegaly, jaundice,rash, intrauterine growth retardation, microcephaly,hydrocephalus, and intracranial calcifications.

• Lyme disease, due to the spirochete, Borrelia burgdorferi, is a majorcause of Bell’s palsy among children living in endemic areas.

• Cat-scratch disease, due to Bartonella henselae, causes fever ofunknown origin and rarely, an encephalitis-like disorder.

• Neurocysticercosis, caused by the larvae of Taenia solium, is a majorcause of seizures and hydrocephalus among children in manyregions of the world.

Introduction

Several infectious disorders have becomeuncommon as a consequence of compul soryimmunization programs. Such disorders includepoliomyelitis, Haemophilus influenzae type bmeningitis, mumps meningoen cephalitis,measles encephalomyelitis, Japanese encepha -litis, congenital rubella embry opathy, andsubacute sclerosing panencephalitis. By contrast,many other infectious disorders, includingcongenital and postnatal disorders, cannot beprevented by immunization. These remainpotential causes of death and neuro -developmental disorders among childrenworldwide. This chapter describes selectedinfectious disorders of the CNS that may beencountered by primary care physicians andneurologists (textbox).

Infections of the CNS• Bacterial meningitis.• Viral (aseptic) meningitis.• Virus encephalitis.• Congenital infections.• Lyme disease.• Cat-scratch disease• Neurocysticercosis.• Cerebral malaria,• HIV/AIDS.

Bacterial meningitis

DIAGNOSIS AND CLINICAL FEATURESMany different bacteria, acquired throughmaternal transmission or environmentalcontact, cause meningitis in newborn infants(textbox).

Bacteria causing meningitis in infants:• Streptococcus agalactiae (group B

streptococcus).• Escherichia coli.• Staphylococcus species.• Listeria monocytogenes.• Pseudomonas aeruginosa.• Citrobacter species.

Bacteria causing meningitis in childrenand adolescents:• Haemophilus influenzae type b.• Streptococcus pneumoniae.• Neisseria meningitidis.• Mycobacterium tuberculosis.

After the age of 6 months, three organismscause the majority of cases of bacterialmeningitis in developed nations (textbox).However, meningitis due to H. influenzaetype b has nearly disappeared in populationswith compulsory H. influenzae type b (HIB)vaccination programs. In many regions of theworld Mycobacterium tuberculosis constitutes apotential cause of bacterial meningitis.

Risk factors for S. pneumoniae meningitisinclude sickle cell anemia, asplenia, humanimmunodeficiency virus/acquired immunedeficiency syndrome (HIV/AIDS), nephroticsyndrome, cochlear implantation, and cranio -cerebral trauma causing CSF leaks. Collegestudents or persons with inherited deficienciesof the complement system are at increased riskfor N. meningitidis infections. Risk factors for H. influenzae meningitis include sickle cellanemia, asplenia, and HIV/AIDS.

Chronic conditions, such as leukemia,lymphoma, or immunodeficiency states, maypredispose to infection with Pseudomonasaeruginosa or other gram-negative organisms.Recent ventricu loperitoneal shunt proceduresincrease the risk of meningitis or ventriculitis


due to Staphylococcus species or gram-negativeorgan isms, including Escherichia coli. Shunt-related CNS infections are most likely duringthe first 3 months after the operative procedure.Risk factors for tuberculous meningitis includecontact with persons at high-risk (drug addicts,prisoners) or residence in an endemic area.

In the newborn the early signs of bacterialmeningitis consist of poor feeding, vomiting,low-grade fever, or change in behavior. Seizuresand lethargy occur often. The physical signs ofmeningitis may be subtle in infancy, consistingonly of somnolence or irritability and a full orbulging fontanel. In the older child, symptomsand signs include somnolence, headache, stiffneck, vomiting, and fever. After 1 year of age,

signs of meningeal irritation can usually beelicited (textbox).

Signs of meningeal irritation in thesupine child or adolescent• Brudzinski sign: flexion of the legs evoked

by neck flexion.• Kernig sign: spasms of the hamstring

muscles evoked by knee extension.

Pneumonia can be present in children oradolescents with S. pneumoniae or H. influenzaemeningitis. Petechiae or purpura (343) shouldprompt physicians to suspect N. meningitidis.

CHAPTER 20 Infections of the nervous system 271

343

343 Petechial and purpuric rash in a child with meningococcemia.


Table 41 Cerebrospinal fluid findings in neurological infections

Infection Cell Count1 Protein2 Glucose Gram stainBacterial meningitis ↑↑ to ↑↑↑ (N) ↑↑↑ Low3 BacteriaAseptic meningitis ↑ to ↑↑↑(M/L) ↑↑ Normal No organismsTB meningitis ↑ to ↑↑↑ (L) ↑↑↑ Low No organismsVirus encephalitis N to ↑↑↑ (M/L) ↑↑ Normal No organisms

1Cell count↑ 10–100 leukocytes/μl↑↑ 100–1000 leukocytes/μl↑↑↑ >1000 leukocytes/μl2Protein↑↑ 50–200 mg/dl (500–2000 mg/l)↑↑↑ >200 mg/dl (>2000 mg/l)N = Neutrophilic; L = Lymphocytic; M = MixedThe pleocytosis associated with virus infections is often mixed (neutrophilic and lymphocytic) during the early phase ofinfection but typically becomes lymphocytic during the subsequent stages of infection.3Low = less than two-thirds of serum; can be as low as 0.

The diagnosis of bacterial meningitis isconfirmed by performing a lumbar punctureand examining the spinal fluid (Table 41). Mostbacteria can be detected by culture methodsand identified by automated techniques. Thepolymerase chain reaction (PCR) can be usedto detect Mycobacterium tuberculosis or bacteriain cases of pre- or partial antibiotic treatment.Imaging studies, such as CT or MRI, may showhydrocephalus (344) or meningeal enhance-ment (345). When hydrocephalus is presentearly in meningitis of children or adolescents,tuberculous meningitis deserves consideration.Infants with Citrobacter species meningitiscommonly have brain abscesses (346).

MANAGEMENTPrompt treatment of bacterial meningitis, usingempiric strategies, can diminish the potential fordeath or severe neurodevelopmental sequelae(Table 42).

Table 42 Empiric treatment of bacterialmeningitis in the pediatric age group

Drug DoseNeonates (infants up to 90 days of age)Ampicillin 150–300 mg/kg/d, divided

q 6–8 hours, ANDGentamicin 2.5–7.5 mg/kg/d, daily or divided

q 8 hours, ANDCefotaxime 150–300 mg/kg/d, divided

q 6–8 hours

Children and adolescentsVancomycin 60 mg/kg/d, divided q 6 hours, ANDCefotaxime 300 mg/kg/d, divided q 6–8 hours

ORVancomycin 60 mg/kg/d, divided q 6 hours, ANDCeftriaxone 100 mg/kg/d, divided q 12 hours


344

346

345

344 Hydrocephalus inHaemophilusinfluenzae meningitis.

345 Enhancement ofleptomeninges of thecisterna magna(arrow) in H.influenzae meningitis,compatible withbasilar inflammation.

346 Multiple brainabscesses in neonatalCitrobacter koseri(diversus) meningitis.


Upon confirmation of the bacterial speciesand antibiotic susceptibility profile, theantimicrobial regimen can be modified (Table43). Many authorities suggest that dexam -ethasone should be given empirically in childrenor adolescents with suspected menin gitis, using0.6 mg/kg/day in four divided doses for 2–4days, with the first dose given before the firstdose of antibiotics. Dexam ethasone therapy isassociated with improved outcomes, includinglower rates of hearing loss, especially in childrenwith H. influenzae meningitis.

Mortality rates for infants with bacterialmeningitis range from less than 10% for terminfants to more than 30% for infants weighingless than 1000 g. Approximately 40% of infantswho survive neonatal bacterial meningitis haveneurodevelopmental sequelae, such as cerebralpalsy, neurodevelopmental disorders, hydro -cephalus, or seizures. As many as 40% ofchildren or adolescents with pneumococcalmeningitis die. Up to 10% of the children oradolescents who survive bacterial meningitishave sensorineural hearing loss (SNHL); somesurvivors have hydrocephalus, cognitive impair -ment, or motor disabilities.

Table 43 Antimicrobial therapy in bacterial meningitis

Pathogen Antibiotic(s) Dose1

Streptococcus agalactiae Penicillin G 250,000–400,000 U/kg/dEscherichia coli Cefotaxime 150–300 mg/kg/dand other ANDgram-negative organisms Gentamicin 2.5–7.5 mg/kg/dListeria monocytogenes Ampicillin 150–300 mg/kg/d

ANDGentamicin 2.5–7.5 mg/kg/d

Staphylococcus aureus Vancomycin 60 mg/kg/dor ORStaphylococcus epidermidis Nafcillin 100–200 mg/kg/dStreptococcus pneumoniae

(penicillin sensitive) Penicillin G 250,000–400,000 U/kg/d (penicillin resistant) Vancomycin 60 mg/kg/d

ANDCefotaxime 300 mg/kg/dORCeftriaxone 100 mg/kg/d

Neisseria meningitidis Penicillin G 250,000–400,000 U/kg/dHaemophilus influenzae

type bβ-lactamase-negative Ampicillin 300–400 mg/kg/dβ-lactamase-positive Cefotaxime 300 mg/kg/d

ORCeftriaxone 100 mg/kg/d

Antibiotics are given intravenously in equally divided doses every 4–12 hours, depending upon the drug. The duration oftherapy ranges from 7–28 days, depending upon the organism, the age of the child, and response to therapy. Gentamicindoses must be adjusted for gestational and postnatal ages.1From various sources.

Viral meningitis

DIAGNOSIS AND CLINICAL FEATURESUnlike bacterial meningitis which is a life-threatening condition, viral (aseptic) meningitisis usually a benign, self-limited disorder. Theprincipal reason to identify viral meningitis is toexclude bacterial meningitis.

Many different viruses produce asepticmeningitis. Common causes include thenonpolio enteroviruses and West Nile virus. Thesigns and symptoms of viral meningitis mimicthose of bacterial disease, although they areusually less intense. Infants may have fever,vomiting, irritability, or somnolence, whereaschildren or adolescents frequently haveheadache, neck stiffness, photophobia,vomiting, and fever. Depending upon theetiology additional clinical features may includemalaise, diarrhea, rash, myalgia, cough, or chestpain. Hepatomegaly, congestive heart failure, ordisseminated intravascular coagulopathy canoccur in neonates with severe nonpolioenterovirus infections.

The diagnosis is made by examining the CSFand performing microbiologic studies. Mixed or neutrophilic pleocytosis can be commonduring the early stages of viral infections, butnormal glucose content usually distinguishesviral from bacterial meningitis. PCR can detectseveral viral pathogens, including the nonpolioenteroviruses and members of the herpesvirusfamily, and serologic studies have utility inseveral viral infections, including those due toEpstein–Barr virus and several arthropod-borneviruses.

MANAGEMENTManagement of aseptic meningitis consists ofsupportive care and anticipation of compli -cations such as liver failure, myocarditis, ordisseminated intravascular coagulation (DIC),especially in neonates. Aciclovir, using 60 mg/kg/day divided every 8 hours, shouldbe given empirically to neonates with suspectedviral meningitis, given the possibility of herpessimplex virus infection.


Encephalitis

DIAGNOSIS AND CLINICAL FEATURESVirus encephalitis occurs worldwide (textbox).

Major causes of encephalitis in thepediatric age groupViruses:• Herpes simplex viruses types 1 and 2.• Epstein–Barr virus.• West Nile virus.• Rabies virus.• Tick-borne encephalitis viruses.• LaCrosse virus.• Japanese encephalitis virus.• Nonpolio enteroviruses.Nonviral pathogens:• Mycoplasma pneumoniae.• Rickettsia.• Bartonella henselae.

In the USA the nonpolio enteroviruses,herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2), Epstein–Barr virus, West Nilevirus, and LaCrosse virus are major causes.Japanese encephalitis, the most common causeof virus encephalitis worldwide, can affectpersons in Asia and India. Rabies, although rarein the developed world, causes many deathsannually in Africa, India, Asia, and certain areasof Latin America. Several nonviral condi tions,including systemic lupus erythematosus,lymphoma, leukemia, stroke, and fungal, rick -ettsial, or parasitic infections, produce clinicalfeatures that can mimic virus encephalitis. Acutedisseminated encephalomyelitis (ADEM), apostinfectious disorder induced by manydifferent infectious agents, accounts forapproximately 15% of cases of viral encephalitis.

The clinical features of virus encephalitis ininfants are nonspecific, consisting of poorfeeding, vomiting, fever, and change inbehavior, especially somnolence or irritability.Seizures may be an early sign of neonatal HSV

encephalitis; some, but not all infants with HSVencephalitis, have skin vesicles, especially withHSV-2 (347). Children or adolescents oftenexperience headache, somno lence, seizures,vomiting, and fever. However, fever can beabsent or low-grade, especially in young infants.The examination of older children andadolescents may show hyper-reflexia, ataxia,cognitive impairment, and focal deficits (e.g.hemiparesis), especially in cases of HSV-1 orLaCrosse virus encephalitis.

Infections with Epstein–Barr virus, arelatively frequent cause of encephalitis, mayhave a lacey, erythematous rash, especially iftreated with ampicillin (348). Zoster suggestsvaricella-zoster virus infection (349). Childrenwith rabies may show agitation, irritability, ordiffuse weakness and areflexia mimickingGuillian–Barré syndrome (GBS). Subacutesclerosing panencephalitis (SSPE), a conditionthat has become uncommon in countries withcompulsory immunization against measles,produces a relatively stereotyped, progressivedisorder that begins with myoclonus andpersonality or cognitive regression and culmi -nates in debility and death.

Infants, children or adolescents withsuspected encephalitis require an expedited eval -uation that should consist of a brain imagingstudy (preferably MRI), EEG, microbiologicalstudies and examination of the CSF by lumbarpuncture. The CSF may be normal or reveal a‘viral’ pattern. EEG often shows diffuse or focalslowing or epileptiform discharges. Periodiclateralizing epileptiform discharges (PLEDs)can be seen in HSV-1 encephalitis (82),although this is not a consistent finding. MRIfindings may suggest a specific etiologic agent.Children or adolescents with HSV-1encephalitis frequently have focal areas of T2prolongation or gadolinium enhancement inthe insular cortex, mesial temporal lobe, inferiorfrontal lobe, and/or cingulate gyrus (350,351).

On the other hand, infants with neonatalHSV encephalitis usually have diffuse cerebralinfections, due to the hematogenous dissem -ination of the virus, usually HSV-2, to the brain(352). Multifocal areas of T2 prolongationsuggest ADEM (145). Children with SSPEhave leukoencephalopathy and progressivecortical atrophy (353, 354).


347

348

347 HSV skin vesicles in a neonate infectedwith HSV-2, including intact vesicles (arrow).

348 Erythematous rash affecting the legs in achild with Epstein–Barr virus infection.

349 Herpes zostervesicular rash.

350 Coronal T1-weighted MRI showinggadoliniumenhancement of theinsular corticesbilaterally in HSV-1encephalitis (arrows).

351Axial FLAIR MRIshowing signalhyperintensity in thetemporal lobe (arrow)in a child with HSV-1encephalitis.

352 Gadolinium-enhanced, axial T1-weighted MRI showingdiffuse gyriformenhancement (arrows)in an infant withneonatal HSVencephalitis.

353Axial FLAIR MRIshowing leukoencephalopathy in early SSPE (arrows).

354T2-weighted MRI showing mild, diffuse cortical atrophy and progressive leukoencephalopathy inthe later stages of SSPE.


349 350

351 352

353 354

Children with suspected viral encephalitisshould undergo a comprehensive microbio -logical evaluation that includes CSF PCRstudies and serum assays for viral pathogens(Table 44). Often, tests should be obtained forother infectious pathogens that producedisorders that may mimic viral encephalitis.These may include serologic studies forMycoplasma pneumoniae, Bartonella henselase (thecause of cat-scratch disease), Borrelia burgdorferi(the cause of Lyme disease), and variousRickettsiae, depending upon the geographicregion. Rarely, brain biopsy is needed in childrenwith progressive encephalitis of uncertain origin(355, 356). The evaluation of children withsuspected encephalitis should be tailored to theseason, geographic region, travel history, orpresence of immunocom promising disorders.

MANAGEMENTThe treatment of virus encephalitis consists ofsupportive care and provision of specific antiviralagents, when available. Infants, children, oradolescents with suspected virus encephalitisshould receive aciclovir empirically pending theidentification of the specific pathogen. If HSVtype 1 or 2 infection is confirmed or stronglysuspected, aciclovir should be continued for atotal of at least 21 days (textbox).

Aciclovir therapy for HSV types 1 and 2encephalitis• Infants and children up to 30 kg:– 60 mg/kg/d divided equally every 8 hours

for at least 21 days.• Children over 30 kg and adolescents:– 1500 mg/m2/d divided equally every

8 hours for at least 21 days.

Most authorities recommend that a CSF HSV PCR be obtained after 21 days ofaciclovir therapy. If the PCR is negative, aciclovir can be discontinued, but if the PCRremains positive for HSV DNA, at least 1additional week of aciclovir should be provided.The role of suppressive therapy in infants after completion of 21–28 days of intravenousaciclovir with HSV continues to be investigated.

Children with varicella zoster virusencephalitis should also receive aciclovir,


using 30 mg/kg/d in children <1 year of ageand 1500 mg/m2/d in older children oradolescents. Ganciclovir, using 12 mg/kg/dfor 14 or more days, should be used inimmunocompromised patients withcytomegalovirus (CMV) encephalitis.

Virus encephalitis has a variable prognosisthat depends upon the child’s age, the etiologicagent, and the presence of immunocom -promising conditions. Mortality of HSVencephalitis averages 20% or less, but as manyas 50% of survivors have sequelae despiteappropriate treatment with aciclovir (357).Survivors of many forms of virus encephalitishave permanent sequelae consisting ofcognitive or behavioral impairment, epilepsy, ormotor disability. The majority of children withLaCrosse encephalitis survive without sequelae,whereas virtually all children with rabies or SSPE die.


Table 44 Diagnostic methods for detectingviruses that cause central nervous systeminfections

Virus Microbiological testNonpolio enteroviruses CSF and serum PCRHuman herpesviruses:

Herpes simplex virus type 1 CSF PCRHerpes simplex virus type 2 CSF and serum PCRVaricella zoster virus CSF PCR; antibody

studiesCytomegalovirus Urine or CSF PCREpstein–Barr virus Serology1; CSF PCRHuman herpesvirus type 6 CSF PCRHuman herpesvirus type 7 CSF PCR

Human immunodeficiency Serology; culture; virus type 1 serum PCRWest Nile virus Serum and CSF IgMJapanese encephalitis virus SerologyLaCrosse virus CSF IgM; serologyTick-borne encephalitis viruses CSF IgM; serologyRabies virus Serology; CSF RT-PCR;

IFA2

CSF: cerebrospinal fluid; IFA: immunofluorescence assay;Ig: immunoglobulin; PCR: polymerase chain reaction; RT-PCR: reverse transcription polymerase chain reaction1Acute Epstein–Barr virus (EBV) infection is confirmed bythe presence of IgM and/or IgG antibodies to EBV viralcapsid antigen (VCA) and the absence of IgG antibodiesto Epstein–Barr nuclear antigen (EBNA).2Rabies can be diagnosed by performing immuno -fluorescence antibody staining of skin obtained by biopsyat the nape of the neck.

355

356

355 Brain biopsy in HSV encephalitis showingperivascular lymphocytic infiltration (H&E).

356 Electron microscopy showing anintranuclear cluster of herpesviruses (arrow).

357

357 Coronal T2-weighted MRI showing cysticencephalomalacia of the left temporal lobe in achild who survived HSV-1 encephalitis.

causes Horner syndrome (163), limb hypoplasia,and a cicatrix, skin scarring in a dermatomalpattern. Lympho cytic choriomeningitis virus cancause postnatal hydrocephalus via aqueductalobstruction. Syphilis produces early signs,including pseudoparalysis or osteochondritis,and late signs, consisting of dental abnor malities,saddle nose, and saber shins.

Infants with suspected congenital infectionsrequire a thorough evaluation that includesneuroimaging, ophthalmological examination,audiometry, and microbiological studies(362–364).

Congenital infection

DIAGNOSIS AND CLINICAL FEATURESCongenital (intrauterine) infection is caused bya wide variety of organisms (textbox).

Causes of congenital (intrauterine)infection• Toxoplasma gondii.• Rubella virus.• CMV.• HSV.• Varicella zoster virus (VZV).• Treponema pallidum.• Lymphocytic choriomeningitis virus.• Trypanosoma cruzi.• Venezuelan equine encephalitis virus.• HIV.

In many regions of the world CMV infectsapproximately 1% of all newborns and causescongenital disease in as many as 1 in every1000–2000 newborns. Toxoplasma gondii infects0.1–2% of the population annually and causescongenital infection in as many as 40% of thewomen who acquire the parasite during theirpregnancies. HSV-1 and HSV-2, varicella zostervirus, lymphocytic choriomeningitis virus,Trypanosma cruzi, and Treponema pallidum areinfrequent but potentially severe causes ofcongenital infection. Congenital rubellasyndrome (CRS), once the most commoncongenital infection, has disappeared in manyregions of the world because of compulsorychildhood immunization.

TORCH infection, a term introduced in the1970s to denote Toxoplasma gondii, Rubella,Cytomegalovirus, and Herpes simplex virus,remains a unifying concept that reminds cliniciansthat congenital infections can produce similarclinical manifestations independent of the specificorganism. Features common in several infections,including toxoplasmosis, CMV, HSV, VZV, andrubella, are jaundice, hepatomegaly, spleno -megaly, rash (358), cataracts (359), orchorioretinitis (360, 361), SNHL, microcephaly,or hydrocephalus. Certain congenital disordershave distinctive features. Rubella often producescardiac lesions, consisting of patent ductusarteriosus, valvular stenoses, and ventricular oratrial septal defects, whereas varicella commonly


358

358 Blueberry muffin’ rash compatible withcongenital infection with CMV or rubella.


359

359 Congenital cataract (arrow).

360

361

363 364

362

360 Chorioretinitis (arrows) in an infant withcongenital CMV infection.

361 Focal chorioretinal scar (arrow) in a childwith congenital CMV infection.

362 Uninfected human foreskin fibroblastmonolayer.

363 CMV-infected cells (arrows) stained with amonoclonal antibody specific for human CMV.

364 Human pancreatic tissue showing brownstained cells infected with CMV.


When CRS is suspected, cardiology consul -tation is required. Nonspecific laboratoryfeatures in the neonatal period can includethrombocytopenia, leukopenia, anemia, directhyperbilirubinemia, and elevations of serumtransaminases. Skeletal radiographs may showosteochondritis in infants with infections due toT. cruzi, T. pallidum, or rubella virus. Neuro -imaging studies can reveal a variety ofabnormalities including intracranial calcifi -cation(s), hydro cephalus, cortical dysplasia,lissencephaly, hydranen cephaly, or schizen -cephaly (365–371).

MANAGEMENTSpecific antimicrobial therapy is available forHSV, CMV, T. gondii, and T. pallidum. Therapywith ganciclovir, using 12 mg/kg/d, divided inequal doses every 12 hours for up to 6 weeks,may improve long-term hearing outcomes forchildren with congenital CMV disease, but thedrug’s effect on neurodevelopment has notbeen determined. Infants with asymptomaticcongenital CMV infections are at risk of late-onset or progressive SNHL, but the role ofganciclovir in such infants is unknown. Infantswith congenital HSV infections should betreated with aciclovir, using 60 mg/kg/d,divided in equal doses every 8 hours for 21 days.However, the drug has minimal effect on the

365 366

365 Noncontrast cranial CT showing multiplecerebral calcifications in a child with congenitalCMV infection.

outcome of infants with congenital HSVinfections.

Aggressive antitoxoplasma therapy cansubstantially improve the outcome of congen italinfections with T. gondii. This should consist of1 year of therapy with pyrimethamine 1mg/kg/d orally, 2–3 times per week, andsulfadiazine 100–200 mg/kg/d orally everyday. Folinic acid, 5–10 mg orally 3 times perweek should be given concurrently. Prenataldiagnosis can allow maternal antitoxoplasmatherapy, although the effect on fetal outcomes isuncertain. Infants with symptomatic congenitalsyphilis require treatment with aqueouscrystalline penicillin G 50,000 U/kg intra -venously every 12 hours during the first week oflife and every 8 hours thereafter for a total of 10days.

The prognosis of congenital infectionsdepends upon the agent and the timing of theintrauterine infection. In general, infectionsearlier in gestation are associated with fetal lossor more severe neurodevelopmental sequelae.Infants with intracranial calcifications or otherneuroimaging features, such as polymicrogyriaor lissencephaly, are likely to have permanentneurodevelopmental disabilities. PermanentSNHL is common to several congenitalinfections.

366 Coronal T2-weighted MRI showing corticaldysplasia/polymicrogyria (arrow) in a child withcongenital CMV infection.

367 Noncontrast cranial CT showing densethalamic calcifications (arrow) in an infant withcongenital HSV infection.

368 Postmortem brain specimen showingextensive gliosis, cystic change, andperiventricular calcification in congenital HSVinfection.

369 Noncontrast cranial CT in an infant withcongenital toxoplasmosis shows numerousparenchymal calcifications (1 = shunt tubing).


370 371

1

369

1

1 1

367

368

370 Coronal, T2-weighted MRI in an infant withcongenital CMV infection shows ventricular (1)enlargement, cortical dysplasia (arrow), andunilateral cerebellar hypoplasia (circle).

371 Noncontrast head CT showingperiventricular calcification and corticaldysplasia in an infant with congenitallymphocytic choriomeningitis virus infection.

Lyme disease

DIAGNOSIS AND CLINICAL FEATURESLyme disease, caused by the spirochete Borreliaburgdorferi, emerged as the cause of manydifferent neurological syndromes in the 1980s.Linked originally to an arthritis outbreak nearLyme, Connecticut and with polyradiculopathyin Scandinavia, B. burgdorferi is now recognizedas a cause of Bell’s palsy, lymphocytic meningitis,chronic encephalopathy, polyradiculopathy(known as Bannwarth’s syndrome in Europe),chronic daily headache, SNHL and a pseudo -tumor cerebri-like disorder. Ixodes scapularis(deer tick) serves as the principal vector in mostregions of the USA, but several additional ticks,including Ixodes pacificus (Western black leggedtick), Ixodes ricinus (castor bean tick), andAmblyomma americanum (lone star tick) cantransmit the spirochete to humans. I. ricinus andI. persulcatus serve as vectors for B. burgdorferiin Europe and parts of Asia.

Borrelia-induced Bell’s palsy, the mostcommon neurological condition associated withLyme disease, typically occurs from March toNovember. Approximately one-third of affectedchildren have a history of the typical Lymedisease rash, erythema migrans (372). As manyas one-third have bilateral facial nerve palsy, andmany children have mild to moderate lympho -cytic pleocytosis. Meningitis, the next mostfrequent neurological condition associated withLyme disease, causes headache, malaise, andbehavioral changes.


372

372 Erythema migrans rash in a child with Lymedisease (arrows).

Lyme-associated neurological conditions arebest diagnosed by serological studies andexamination of the CSF. The CSF typi callyshows a lymphocytic pleocytosis, elevatedprotein content, and evidence for intrathecal synthesis of Borrelia-specific IgG.Borrelia-specific DNA can be detected by PCR;rarely, the organism can be isolated from theCSF. Serodiagnosis of Lyme disease relies upona two step process to detect Borrelia-specificIgM and IgM using enzyme immunoassay andwestern immunoblot analysis (textbox).

Serological diagnosis of Lyme disease• IgM: must show reactivity against ≥2 of

the following polypeptides:– 23/24 kDa; 39 kDa; and 41 kDa.• IgG: must show reactivity against ≥5 of

the following bands:– 18 kDA; 23/24 kDa; 28 kDa; 30 kDa;

39 kDA; 41 kDa; 45 kDa, 60 kDa; 66 kDa;and 93 kDa.

MANAGEMENTTreatment of Lyme disease depends upon thestage of infection and the extent of neurologicalcondition (textbox).

Antibiotic therapy for Lyme disease• Isolated facial (Bell’s) palsy:– Doxycycline orally, 100 mg BID for

21–28 days (8 years of age or older).– Amoxicillin orally,50 mg/kg/day (max. 1.5

g) divided TID for 21–28 days OR– Cefuroxime 30 mg/kg/day IV (max. 1 g)

divided BID for 21–28 days.• Meningitis or encephalitis:– Ceftriaxone 75–100 mg/kg/day IV or IM

once daily for 14–28 days OR– Penicillin 300,000 U/kg/day IV in six

divided doses for 14–28 days.


Antibiotic therapy is recommended in casesof Bell’s palsy to eradicate the organism, buttherapy does not shorten the course of facialweakness. The vast majority of persons withLyme-associated Bell’s palsy recover completely.

Children or adolescents with Lyme-associatedmeningitis or encephalitis require extendedcourses of parenteral antibiotics. In general,treated children recover completely.

Cat-scratch disease

Cat-scratch disease, a common condition inmany regions of the USA, results from infectionwith the gram-negative bacterium, Bartonellahenselae. As many as 50% of domestic and wildcats in the USA possess antibodies to B.henselae; human infections are more likely in themore humid areas of the USA, including thecostal regions, South, and Midwest. The disease has many different clinical presentations,including fever of unknown origin, regionallymphadenopathy, disseminated infectionresembling infectious mononucleosis,Parinaud’s oculoglandular syndrome, andneurological disease. Less than 1% of childrenwith cat-scratch disease have neurologicalcomplications.

The most frequent neurological compli -cation of cat-scratch disease, an encephalitis/encephalopathy syndrome, mimics viralencephalitis and ADEM. Features includesomnolence, fever, weakness or malaise, andseizures, including status epilepticus. MRI mayshow multifocal areas of T2 prolongationwithin white matter; the CSF shows alymphocytic pleocytosis and protein elevation.In cases of suspected or proven cat-scratchdisease and neurological complications,especially encephalitis, treatment with any ofseveral effec tive antibiotics (azithromycin,erythromycin, ciprofloxacin, trimethoprim-sulfamethoxazole, or rifampin) should beconsidered. With very few exceptions patientsrecover completely.

Neurocysticercosis

Cysticercosis, infection of human tissues by thelarvae of Taenia solium, the pork tapeworm,begins when humans ingest viable eggs. Theeggs hatch in the human stomach, and thelarvae penetrate the intestinal mucosa and enterthe circulation. The larvae travel hematoge -nously to many tissues, including muscles, theeye, and brain, where they reside and formcysts. When the larvae die, inflammatoryresponses lead to clinical signs and symptoms;neuro cysticerosis reflects the death of larvaewithin the brain and spinal cord, adjacentedema, and local cerebral hypoperfusion.

In endemic regions, including Mexico,Central and South America, India, Africa, andChina, neurocysticercosis causes new-onsetseizures and obstructive hydrocephalus.Clinical manifestations of neurocysticercosis,headache, seizures, focal deficits, visual dysfunc -tion, behavioral changes, and papilledema orother signs of increased intracranial pressure,reflect, in part, the number and distribution ofdying larvae. Occasionally, larval penetration ofthe eye or spinal cord leads to blindness or corddysfunction.

The diagnosis of neurocysticercosis is usuallysuggested by the appearance of neuroimagingstudies. During the acute and subacute stages ofneurocysticercosis brain MRI and CT may showcircular or ring-enhancing lesions (373–375),typically with adjacent cerebral edema. Thelesions eventually calcify, so CT shows intracra -nial calcifications (376), often multiple, duringthe quiescent, chronic phase of the condition.During the acute stages, examination of the CSFreveals a lymphocytic or eosinophilic lympho -cytosis and protein elevation. Serologicaldiagnosis is possible; the sensitivity of detectingTaenia-specific IgG or IgM increases withincreasing numbers of active intracranial cysts.Although opinions regarding the value oftherapy vary, most authorities suggest that acourse of albendazole be considered, especiallywhen there are multiple, acute CNS lesions(textbox).

Antiparasitic therapy in suspected orproven neurocysticercosis• Albendazole:– 15 mg/kg/day PO BID with meals

(maximum of 800 mg/day) for 7 days.– For persons >60 kg, 400 mg PO BID with

meals for 7 days.– Many authorities recommend that corti -

costeroids (dexamethasome or pred -nisone) be given before or concurrentlywith albendazole to minimize symptomsassociated with parasite death.


Cerebral malaria

Malaria, the consequence of infection withPlasmodium parasites (P. falciparum, P. ovale,P. vivax, and P. malariae), remains endemicthroughout most of the southern hemisphere,especially India, Southeast Asia, and sub-Saharan Africa. As many as 500 million personsworldwide experience malaria annually, andmore than one million of these infected personsdie. Children living in the tropical regions ofAfrica are particularly vulnerable to severemalaria with P. falciparum; children in theseregions comprise approximately 75% of deathsdue to severe malaria.

Transmitted to humans by the bite ofinfected female Anopheles species mosquitoes,malaria has an incubation period of 1–4 weeks.Infected persons experience chills, fever,headache, nausea, vomiting, and malaise, oftenin cycles every 1–4 days. Fever and anemia havea high positive predictive value for malariaamong persons living in endemic regions.Persons with severe malaria have a multiorgansystem, sepsis-like disorder with renal, hepatic,and hematological disease, and cerebral signsand symptoms. The latter can include seizures,coma, focal deficits, and features of cerebraledema and increased intracranial pressure.Laboratory findings can consist of acidosis,severe hemolytic anemia, azotemia, and hypo -glycemia. Although sero logical and molecularstudies can be used to diagnose malaria,detecting parasites in a patient’s Giemsa-stainedblood smear is the gold standard for thediagnosis of malaria.

Treatment of severe, cerebral malaria remainschallenging, especially in late cases when themortality rates are as high as 75% and because ofthe emergence of drug resistance in mostendemic regions. The therapy consists ofsupportive care and administration of a rapidlyeffective, artemisinin compound (artesunate,artemether, artemotil, dihydroartemisinin) incombination with longer-acting drugs, such asdoxycycline, clindamycin, lumefantrine, sulfa -doxine–pyrimethamine, atovaquone–proguanil,or mefloquine. Quinine remains a World HealthOrganization-recommended option forchildren living in high-transmission regions.Seizures require therapy with benzodiazepines,phenobarbital, or phenytoin; fluids should beprovided to treat shock. Children who survive


374

375

373

376

373 Gadolinium-enhanced sagittal T1-weightedMRI showing solitary lesion ofneurocysticercosis (arrow).

374Axial T2-weighted MRI showing extensiveedema adjacent to a solitary neurocysticercosislesion (arrow).

375 Contrast-enhanced cranial CT showing around lesion (arrow) and adjacent cerebraledema consistent with neurocysticercosis.

376 Unenhanced CT showing a solitarycalcification (arrow) consistent withneurocysticercosis.

cerebral malaria are a risk for epilepsy and motorand cognitive deficits. Brain MRI can showhyperintensities in the white matter, thalami,and corpus callosum. Malaria can be preventedthrough the use of antimalarial medications,mosquito abatement, and the use of insecticide-treated bed nets.


HIV/AIDS

Pediatric cases of the acquired immunedeficiency syndrome (AIDS) appeared in theUSA in the early 1980s, and the causative agent,the human immunodeficiency virus type 1(HIV), a novel retrovirus, was identified byinvestigators in France in the mid-1980s. Earlycases of HIV/AIDS were attributed to bloodtransfusions or factor replacement in hemo -philia; the majority of current pediatricHIV/AIDS cases result from perinatal trans -mission from HIV-infected women. Thenumber of people living with HIV/AIDS was 33 million in 2007 (two-thirds reside in sub-Saharan Africa); 2 million of these were children(Table 45). More than 25 million infants,children, and adults have died since the firstcases of HIV/AIDS were identified in 1981.

Without antiretroviral therapies, infants andchildren with HIV/AIDS encephalopathyexhibit progressive motor dysfunction,cognitive abnormalities, developmental delay,and acquired microcephaly. Typical findingsconsist of apathy, dementia, ataxia, hyper-reflexia, weakness, seizures, or myoclonus.Infants with vertical HIV infections can becomesymptomatic after the third month of life,manifesting hepatomegaly, lymphadenopathy,failure to thrive, interstitial pneumonitis,opportunistic infections (especially withPneumocystis jiroveci or CMV), or neurologicaldisease. HIV infection can cause asepticmeningitis, meningoencephalitis, myopathy,and GBS-like conditions; HIV/AIDS has manysecondary CNS complications, including stroke(377, 378), primary CNS lymphoma, andopportunistic infections with T. gondii, CMV,VZV, Mycobacterium tuberculosis, fungi, and JC virus, the cause of progressive multifocalleukoencephalopathy (PML).

377

377Axial FLAIR MRI showing patchyhyperintensities in an HIV-infected adolescent.

378

378 MRA showing fusiform aneurysms of themiddle cerebral arteries in HIV arteriopathy.


Table 45 Revised Pediatric HIV Classification System (US Centers for Disease Control and Prevention;Updated 2008)

Category A: Mildly symptomaticChildren with 2 or more of the following conditions but none of the conditions listed in categories B and C:Lymphadenopathy (≥0.5 cm at more than two sites; bilateral = one site); hepatomegaly; splenomegaly; dermatitis;parotitis; recurrent or persistent upper respiratory infection, sinusitis, or otitis media

Category B: Moderately symptomaticChildren who have symptomatic conditions, other than those listed for category A or category C, that are attributed to HIVinfection. Examples of conditions in clinical category B include, but are not limited to, the following: Anemia (<8 g/dl),neutropenia (<1,000 cells/mm3), or thrombocytopenia (<100,000 cells/mm3) persisting ≥30 days; bacterial meningitis,pneumonia, or sepsis (single episode); candidiasis, oropharyngeal (i.e. thrush) persisting for >2 months in children aged >6 months; cardiomyopathy; cytomegalovirus infection with onset before age 1 month; diarrhea, recurrent or chronic;hepatitis; herpes simplex virus (HSV) stomatitis, recurrent (i.e. more than two episodes within 1 year); HSV bronchitis,pneumonitis, or esophagitis with onset before age 1 month; herpes zoster (i.e. shingles) involving at least two distinctepisodes or more than one dermatome; leiomyosarcoma; lymphoid interstitial pneumonia (LIP) or pulmonary lymphoidhyperplasia complex; nephropathy; nocardiosis; fever lasting >1 month; toxoplasmosis with onset before age 1 month;varicella, disseminated (i.e. complicated chickenpox)

Category C: Severely symptomatic Children who have any condition listed in the 1987 surveillance case definition for acquired immunodeficiency syndrome(below), with the exception of LIP (which is a category B condition); serious bacterial infections, multiple or recurrent (i.e. any combination of at least two culture-confirmed infections within a 2-year period), of the following types:septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitismedia, superficial skin or mucosal abscesses, and indwelling catheter-related infections); candidiasis, esophageal orpulmonary (bronchi, trachea, lungs); coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervicalor hilar lymph nodes); cryptococcosis, extrapulmonary; cryptosporidiosis or isosporiasis with diarrhea persisting >1 month;cytomegalovirus disease with onset of symptoms at age >1 month (at a site other than liver, spleen, or lymph nodes);encephalopathy (at least one of the following progressive findings present for at least 2 months in the absence of aconcurrent illness other than HIV infection that could explain the findings): a) failure to attain or loss of developmentalmilestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests; b) impairedbrain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstratedby computerized tomography or magnetic resonance imaging (serial imaging is required for children <2 years of age); c) acquired symmetric motor deficit manifested by two or more of the following: paresis, pathological reflexes, ataxia, orgait disturbance; HSV infection causing a mucocutaneous ulcer that persists for >1 month; or bronchitis, pneumonitis, oresophagitis for any duration affecting a child >1 month of age; histoplasmosis, disseminated (at a site other than or inaddition to lungs or cervical or hilar lymph nodes); Kaposi’s sarcoma; lymphoma, primary, in brain; lymphoma, small,noncleaved cell (Burkitt’s), or immunoblastic or large cell lymphoma of B-cell or unknown immunologic phenotype;Mycobacterium tuberculosis, disseminated or extrapulmonary; Mycobacterium, other species or unidentified species,disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes); Mycobacterium aviumcomplex or Mycobacterium kansasii, disseminated (at site other than or in addition to lungs, skin, or cervical or hilar lymphnodes); Pneumocystis jiroveci pneumonia; progressive multifocal leukoencephalopathy; Salmonella (nontyphoid)septicemia, recurrent; toxoplasmosis of the brain with onset at >1 month of age; wasting syndrome in the absence of aconcurrent illness other than HIV infection that could explain the following findings: a) persistent weight loss >10% ofbaseline; OR b) downward crossing of at least two of the following percentile lines on the weight-for-age chart (e.g. 95th,75th, 50th, 25th, 5th) in a child ≥1 year of age; OR c) <5th percentile on weight-for-height chart on two consecutivemeasurements, ≥30 days apart PLUS 1) chronic diarrhea (i.e. ≥ two loose stools per day for >30 days), OR 2) documented fever (for ≥30 days, intermittent or constant)

Passive transfer of maternal antibodycomplicates the diagnosis of HIV infectionduring the first 18 months of life. HIV infectionin infants can be confirmed by serial serum PCRassays with the first test in the immediatenewborn period, a second test during the first orsecond month of age, and a third test after 4months of age. If two samples are positive forHIV, the infant is considered infected; twosuccessive negative tests make infection unlikely.In children and adolescents, serological studiesusing ELISA and western blotting can identifyHIV infection. RT-PCR monitoring of virusloads guides the treatment of HIV/AIDS. TheCSF is usually normal in HIV-associatedencephalopathy, whereas the EEG maydemonstrate diffuse slowing. Neuroimagingstudies in HIV/AIDS can reveal cortical atrophy(379) and calcifications of the basal ganglia orfrontal white matter in perinatally-acquiredinfections.

Current drug antiretroviral therapy andrefined treatments for the infectious orneoplastic complications greatly improve thesurvival and the quality of life of pediatricpatients with HIV/AIDS (textbox).


379

379 Unenhanced CT showing diffuse corticalatrophy in a child with hemophilia and HIVinfection.

Current antiretroviral drugs forpediatric HIV/AIDS• Nucleoside/nucleotide analogue reverse

transcriptase inhibitors: abacavir,didanosine, emtricitabine, lamivudine,stavudine, tenofovir, and zidovudine.

• Non-nucleoside analogue reversetranscriptase inhibitors: efavirenz,etravirine, and nevirapine.

• Protease inhibitors: atazanavir, darunavir,fosamprenavir, indinavir,lopinavir/ritonavir, nelfinavir, ritonavir,saquinavir, and tipranavir.

Combined, highly-active antiretroviraltherapy (HAART) relies upon combinations ofnucleoside/nucleotide analogue reversetranscriptase inhibitors, protease inhibitors, andnon-nucleoside analogue reverse transcriptaseinhibitors. The goal of therapeutic strategies isto reduce the HIV viral load to undetectablelevels and restore immunological function. AllHIV-infected infants <12 months of age requiretreatment; decisions regarding treatment inolder infants, children, and adolescents dependupon severity of symptoms, the degree ofimmunosuppression, and the viral RNA load.Current combined drug regimens, usingantepartum and intrapartum therapy of theHIV-infected woman and postpartum therapyof exposed infants, can prevent HIVtransmission.

Given the complexities of treatment and thepotential for drug interactions or side-effects,infectious disease experts experienced in HIVtreatment of children should be consulted (for information regarding the available anti -retro viral therapies and current treatmentguidelines, see: www.aidsinfo.nih.gov). Despitethe remark able success of antiretroviraltreatment, current therapies do not eradicateHIV from infected persons. Persons who reachend-stage AIDS despite therapy frequentlyexperience AIDS-defining conditions, such asHIV dementia/encephalopathy, PML,lymphoma, or invasive CMV infections, duringthe 12 months prior to death. Vaccines toprevent HIV/AIDS are not yet available.

www.aidsinfo.nih.gov

CHAPTER 21291

Movementdisorders

Main Points• Most movement disorders, common and often benign, can usually

be managed by the generalist. Common disorders includestereotypies, tics, and tremor.

• Stereotypies can be mistaken for seizures in young children.

• Tremor is most commonly familial and benign.

• Most tics are transient and require no therapy.

• Chorea, irregular jerky movements, usually indicates rheumaticfever.

• Observation and home videos provide invaluable informationregarding movement disorders of infancy, childhood, andadolescence.

Introduction

Neurologists consider ‘movement disorders’ asa heterogeneous group of conditions in whichimpaired or excessive and involuntary move -ment occurs independent of a corticospinaltract or spinal cord disorder such as cerebralpalsy (CP) or spinal muscular atrophy (SMA).Tradi tionally, movement disorders are classifiedas hypokinetic (the prototype being Parkinsondisease) or hyperkinetic (the prototype beingHuntington disease); in the former there isa preponderance of impaired or restrictedmobility, while in the latter involuntary move -ments occur in excess.

Most hyperkinetic movement disorderssubside in sleep. Tics may persist in early stagesof sleep and sleep-onset myoclonus occurs onlywith sleep onset. A unique form of myoclonus,known as palatal myoclonus, persists in sleep.Chorea, athetosis, primary and secondarydystonias, most tremors, and all stereotypiesgenerally disappear in sleep. Movementdisorders, extremely common in children, aremostly due to relatively benign or self-limitedhyperkinetic conditions including stereotypiesand tic disorders. Movement disorders causingdisability or severe impairment are fortunatelyinfrequent.

Stereotypy

This extremely common movement disordercauses an extraordinary degree of anxiety forparents and physicians considering its benignnature. Stereotypies consist of ‘stereotyped’(meaning always the same) complex patterns ofmovement that are usually fairly symmetric andstimulus-dependent. They often take the form of‘tensing’, ‘flapping’, flipping of the fingers,dancing, or stepping up and down on toes, andso forth, sometimes associated with grimacing(380). These may begin in infancy, but peak intoddlers. The patterned movement is nearlyalways triggered when the child is anticipatingexcitement (seeing a toy or a movie) or engagingin satisfying play activities (the child colors, looksat his drawing then has his stereotypy). Stereo -typies are invariably interruptible.

A subset of stereotypies, described as‘stimming’ or ‘self-stimulatory behavior’, can beseen in normal children or in autistic spectrumdisorders (ASDs). These complex, patterned,stereotyped motor behaviors usually occur insituations when the child is over-stimulated,trying to withdraw or escape a stressful circum -stance, or tired and relaxing. A common patternis described as ‘masturbation’ when the childcrosses his or her legs and rocks the pelvisrhythmically. Children may sit or lie prone onthe floor when they engage in this behavior.

Most pediatric neurologists can make thediagnosis of stereotypies by observing thebehavior a few times or having the parents bringa short video of the movements. In rareinstances, a video-EEG may be necessary todistinguish the episodes from seizures. Themajority of stereotypies decline in frequency andeventually disappear by school age or earlier,although they can persist or be intrusive inchildren with neurodevelopmental disabili ties.Stereotypies may also persist into middlechildhood or beyond in occasional children withnormal intelligence and social skills. Gentleredirection of the child followed by engagingthe child in another activity is the most effectiveintervention. Punitive or humiliating tactics arecounterproductive.


380

380The jerky gait of Angelman syndrome andthe child’s stereotypic hand movements.

CHAPTER 21 Movement disorders 293

Tremor

DIAGNOSIS AND CLINICAL FEATURESTremor is traditionally divided into three types:postural (typical of essential tremor), resting(i.e. as in Parkinson’s disease), and intention(usually associated with cerebellar disease andataxia). Only the first is common in children.Resting tremor in children is usually limited tocases due to neuroleptic toxicity and/or to theadverse effects of these medications. Intentiontremor is discussed in Chapter 13 Disorders ofGait and Balance.

Mild to moderate postural tremor, commonin children, typically affects only the upperextremities. Rarely does one encounter truncalor head titubation, tremor of the chin, orinvolvement of the legs. A postural tremor istypically relatively fast (8–10 Hz), small ampli -tude (excursions of a few mm), and exaggeratedby sustained antigravity posture. Maneuverssuch as holding the arms outstretched withfingers splayed out or holding the arms inabduction at the shoulders, with flexion at theelbows with instruction to maintain the indexfingers ‘nearly touching’ will often enhancetremor. The intensity of a postural tremor canvary greatly; any increase in adrenergic tone canaggravate tremor. Thus, tremor increases withor after exercise and with anxiety, fear, stress,anger, strong emotion, caffeinated beverages,sympathomimetic drugs, and hypoglycemia.Finally, there is often a modest ‘intention’component to the typical postural tremor, suchthat the tremor intensifies when performingfine motor tasks such as putting a key in a lock,writing, or drinking from a cup. Unlike patho -logical cerebellar tremors, however, the intensi -fication is very modest, and the target is stillcorrectly approached.

In a healthy child with normal heart rate,blood pressure, and general examination, andwith mild to moderate tremor, laboratoryevaluation is usually unnecessary. If there isconcern, evaluation for hyperthyroidism, hypo -glycemia, abnormality of serum calcium, orWilson disease may be considered. MRI shouldbe considered in severe tremor, asymmetrictremor, when other neurological impairmentsare present, or if there is concern for acute orprogressive disease. Having the child write anddraw (spiral or ‘racetrack’ [381] )assists follow-up and monitoring of response to treatment.

MANAGEMENTTreatment of postural tremor in childhood israrely needed. The clinician should educatefamilies regarding aggravating factors (such asuse of caffeinated beverages or sympath -omimetic medications). Occupational therapyfor optimal hand and arm positioning toimprove writing may be helpful. Keyboardingshould be encouraged for completion ofwritten assignments at school. Pharmacologictreatment with propranolol or primidone maybe attempted for more disabling cases. The useother medications (levetiracetam, topiramate)is less well supported by medical evidence.

381

Patient’s copy of spiral

Patient is instructed to use to tip of pencil todraw a line inbetween existing (outer) lines.

Examiner’s example

Examiner’s example

Patient’s copyof drawing

381 Delineation of tremor.


Tic disorders andTourette syndrome

DIAGNOSIS AND CLINICAL FEATURESTics, too, are ‘stereotyped’ motor behaviors.Unlike stereotypies, however, tics are lesspredictable and often last only a few seconds orless (although they can occur repeatedly, inclusters or in longer patterns). They tend to‘wax and wane’ and change over time. Whilemore common under circumstances of stress,anger, excitement, or anxiety, they are notevoked in the same manner as stereotypies. Tics,classified as simple or complex, motor or vocal,commonly present as simple motor movementsof grimacing or sudden shaking of the head.

As many as 15% of children experience atransient tic, whereas chronic tic disorders affect1–2% of people. Tics typically begin between 5and 8 years of age, although many parentsacknowledge that previously unrecognized ticsoccurred before age 5. Tic disorders tend tospontaneously abate in late adolescence or earlyadulthood, such that many adults will perceivethat they ‘used to’ have problems with tics.

Tourette syndrome consists of at least onevocal tic and one motor tic that occur over atleast 1 year and cause subjective distress. Thelatter requirement suggests that psychologicaland cultural factors unrelated to the physicalnature of the tics themselves determine whetheror not a pattern of tics can be consideredTourette syndrome. Associations with attentiondeficit hyperactivity disorder (ADHD) (50%),obsessive compulsive disorder (OCD) (50%),anxiety, mood disorders, low frustration toler -ance, and behavioral difficulties includingimpulsive aggressiveness (‘short-fuse’ behavior)are well recognized, but very variable from childto child.

Genetic factors likely play a role in Tourettesyndrome, but single or multiple genes respon -sible for the majority of cases have yet to beidentified. Evidence supports an autosomaldominant inheritance with extremely variablepenetrance, although autosomal recessive inher -itance of a recessive trait with a very high genefrequency has also been suggested. Early studiessuggested that males tend to manifest tics whilefemales may be more prone to the OCDfeatures.

A controversial area relates to the associationof tics/OCD with prior group A beta-hemolyticstreptococcal infection, a putative immunologiccondition referred to by the acronym PANDAS(pediatric autoimmune neuropsychiatricdisorders associated with streptococcal infec -tion). At this time, this construct remainscontroversial and might best be considered as apromising hypothesis. Therapies used inchildren with rheumatic fever do not benefitchildren with presumed PANDAS.

The diagnosis of tic disorders and Tourettesyndrome remains a clinical one based on ahistory of waxing and waning stereotypicmovements and sounds. The historicalinformation provided by parents is oftensupplemented with home videos enabling theclinician to see and hear the child’s tics. Subtleobsessive–compulsive traits are common, suchas ‘making it even’ and counting (arith -momania). In the former, children must repeaton one side what was done on the other (suchas touching the arms of a chair), and in the latterthere is an urge to carry out a given behavior acertain number of times or in even or oddnumbers. Brain imaging in Tourette syndromeis normal, and thus is performed only whenevaluating children with confusing or complexcases, such as instances in which tics resembledystonia, a more serious movement disorder.EEG is occasionally needed when it is difficultto distinguish the stereotyped movement froma focal or absence seizure (such as upward eyedeviation with fluttering of the eyelids). In somecases of abrupt onset or with dystonic-like tics,Wilson disease deserves consideration. Analysisof serum copper and ceruloplasmin andophthalmologic slit lamp examination forKayser–Fleischer rings (382) may be necessary.Evaluation for prior streptococcal infection withantistreptolysin O (ASO) and antiDNAse Btiters is optional; the results are of limitedpractical value in most cases.

MANAGEMENTThe treatment of tic disorders and Tourettesyndrome must be tailored to the individualbased on the presence or absence and relativeseverity of comorbid conditions. It is oftensufficient for the clinician to reassure the familyand to provide information concerning natural

history and prognosis. Medications should bereserved for instances in which the child desiresit and not to assuage the parent’s concern aboutself-image, teasing, and so on. It can be helpfulfor the child and parent to disclose the conditionto others, even to the child’s classmates andteachers, to improve understanding and reducestigmatization. Parents must be understandingand avoid belittling or teasing the child; punitivemeasures to reduce tics are most oftencounterproductive.

Tics are the main problemIn these cases, tic suppressant medication maybe helpful. However, none is 100% effective,and all have potential adverse effects. Most childneurologists use clonidine initially; somnolencemay be a limiting side-effect, particularly inyounger children (<10 years of age). Dosage isstarted at 0.025 mg (one-quarter of a 0.1 mgtablet) TID in young children and up to 0.05mg (one-half of a 0.1 mg tablet) TID in olderchildren. An alternative is to use the transdermalclonidine patch (Catapres). Here, treatment isusually initiated with the lowest dose (the TTS-1patch, changed weekly) and titrated upwardevery 1–2 weeks as needed and tolerated. Skininflammation is the major side-effect. Whenclonidine is ineffective or not well tolerated,haloperidol and pimozide can be used. If onlyone or a few disabling tics are present, a behav -ioral therapy known as habit reversal may beeffective. This requires a skilled psychologist.

ADHD is the main problem but tics arepresentClinicians and parents may be concerned thattreatment of ADHD with stimulant medicationmay cause permanent aggravation of tics. Thisis, in fact, uncommon. Up to 50% of childrenwith tics and ADHD may experience transientworsening of tics when stimulants are admin -istered, but the change is rarely permanent.Furthermore, 40% of treated children have noworsening, and in the remainder, tics mayimprove. Thus, if ADHD is debilitating for thechild, clinicians should treat with the optimalagent for the attention difficulties while carefullymonitoring for tic worsening. If tics are signifi -cantly aggravated, then treatment with atomox -etine (Strattera), clonidine, or guanfacine may

be helpful. Behavioral manage ment of ADHDis preferable in any case.

OCD is the major problemIn this circumstance, behavioral management,psychotherapy and treatment with a selectiveserotonin-reuptake inhibitor (SSRI) areindicated. Occasionally, tics with a highlycompulsive component (usually complex motoror vocal tics, or patterned tic sequences) mayalso be ameliorated considerably by thesetherapies. Combining an SSRI with othermedications is possible, but caution is advised incircumstances where drug interactions and QTprolongation are possible (e.g. SSRI pluspimozide, for instance). Clinicians and parentsmust be alert for the emergence of suicidalideation and/or bipolar psychosis.

Behavioral problems are the major issueSeparate from ADHD, some children,particularly boys, with Tourette syndrome sufferfrom severe behavioral dyscontrol. This can bethe most disabling phenotype of this conditionand requires multimodal treatment usuallydirected by an experienced child psychiatrist. Noparticular medication is predictably helpful inthis setting, although many are used! Behavioraland cognitive therapies are the most effectivemeasures.


382

382 Kayser–Fleischer ring of Wilson disease(arrows).

Chorea

DIAGNOSIS AND CLINICAL FEATURESChorea consists of involuntary, nonsuppressible,nonstereotyped, irregular jerking or dancingmovements of the face, trunk, and limbs, distallymore than proximally. The hyperkinesis isusually symmetric, but striking asymmetryoccurs in a substantial proportion of childrenwith Sydenham chorea. Facial movements canbe tic-like, but are typically less stereotyped thantics or stereotypies. Movements can be aggra -vated by strategies used to evaluate childrenwith tremor as well as by asking the child toprotrude the tongue for as long as possible, tohold the arms and hands up toward the ceiling,to maintain a sustained, consistent handgrip onthe examiner’s fingers, to stand on one foot, andto perform a tandem walk.

The above maneuvers demonstrate aninability to maintain the sustained position (socalled motor impersistence) without extraneoustwitches, jerks, and various twisting and dartingmovements. Having the patient hold yourfingers tightly can elicit the milkmaid sign(rhythmic grasping and releasing of the patientsfingers) and having the patient keep his/hertongue protruded assesses for the chameleonsign (a darting tongue). The child with choreawill often attempt to suppress the movements bycrossing the arms or legs, holding the limbdown, or sitting on the hands. In chronicchorea, the movements will be unconsciouslymelded into a semi-purposeful action such asscratching the head or patting the thighs. Thevoice and speech may be affected, resulting indysarthria, and swallowing may be impaired.Chorea is typically accompanied by hypotoniaand pendular reflexes, and in more severe casesthe affected muscle groups may actually be weak(paralytic chorea). Spooning of an extendedhand can be an additional sign of subtle weak -ness (383). Muscle stretch reflexes, however, arepreserved but not exaggerated, and plantarresponses are flexor.

Since its resurgence in the mid 1980s,rheumatic fever again appears to be the mostcommon cause of chorea (Sydenham chorea) inchildren in the USA. The anticardiolipin anti -body syndrome with or without systemic lupuserythematosus (SLE) is probably second inimportance. Sydenham chorea is often accom -panied and sometimes preceded by subtle

personality, mood, or behavioral changes. Thechild is described as emotionally labile, inatten -tive and ‘touchy’; depression or obsessive–compulsive traits may appear.

The differential diagnosis includes, inaddition to the conditions mentioned above,focal cerebral lesions, hyperthyroidism, disor -ders of calcium regulation with calcification ofthe basal ganglia, mitochondrial diseases, otherneurodegenerative disorders, and variousobscure conditions. The clinician should care -fully inquire and examine the child for anyevidence of the major and minor criteria ofrheumatic fever (the modified Jones criteria,textbox).

The revised Jones criteria for theclinical diagnosis of rheumatic fever• Major: polyarthritis, carditis, chorea,

erythema marginatum, and subcutaneousnodules.

• Minor: fever, arthralgia, previousrheumatic fever, acute phase reactants,and prolonged PR interval.

The diagnosis requires two major criteria orone major and two minor criteria andevidence for a recent streptococcal infection.Chorea alone, however, is sufficient todiagnose rheumatic fever in children oradolescents with serologic evidence for recentstreptococcal infections.

Given the two most common diagnosticconditions (rheumatic fever and anticardiolipinantibody syndrome/SLE), initial evaluationshould begin with antistreptolysin O (ASO) andAntiDNAse B titers, anticardiolipin antibodies(IgM and IgG), antinuclear antibody (ANA),ECG, and thyroid function tests. If the choreais strikingly asymmetric, an MRI of the brainmay be appropriate. If there is any evidence ofrheumatic fever and/or if anti streptococcalantibodies are present, echocardiography isindicated to detect mitral valve regurgitation. Ifthe latter is identified, further evaluation isunnecessary, and the child is treated forrheumatic fever. If the diagnosis of rheumaticfever cannot be firmly established, imaging andadditional laboratory testing are stronglyrecommended. Clinicians should obtain MRI of


the brain with and without contrast, MRS (forlactate), serum copper and ceruloplasmin, liverenzymes, ophthalmologic consultation, serumand possible CSF lactate, blood smear foracanthocytes, careful review of the family history(for any suggestion of Huntington disease;textbox), possible genetic testing for theHuntington disease gene trinucleotide repeat,and further evaluation for autoimmune disease.Consultation with a rheumatologist may bewarranted.

Huntington chorea, an autosomal dominantdisorder, may present in childhood and exhibita hypokinetic movement disorder withParkinsonian features (the so-called Westphalvariant), rather than the slowly progressivechorea of face and limb chorea of adults.When a child has Huntington chorea, thefather is almost always the affected parent.

MANAGEMENTPenicillin prophylaxis (or alternative in case ofpenicillin allergy) is critical in patients withrheumatic chorea. When Sydenham choreainterferes with the ability to walk or eat inde -pendently, many authors suggest treatment withcorticosteroids (prednisone 1–2 mg/kg/dayorally for 1–2 weeks with subsequent taper over 1–2 weeks), although a small study suggestedthat plasmapheresis may be preferable to oralprednisone. Others favor symptomatic treat -ment. The latter is fraught with difficulty, asmany reportedly effective options are eitherineffective or result in unacceptable side-effects.Options include: benzodiazepines, valproicacid/divalproex sodium, baclofen, levetirac -etam, and typical and atypical neuroleptics.Treatment of chorea associated with SLErequires immunomodulation, and the anti -cardiolipin antibody syndrome relies onimmunomodulation plus anticoagulation, giventhe risk of stroke. Treatment of most otherforms of chorea is symptomatic with thestrategies suggested above. In severe, refractorycases, neurosurgical procedures have beenemployed.


383

383 Spooning of the left hand (arrow) as seen inchildren with chorea.

Dystonia

DIAGNOSIS AND CLINICAL FEATURESDystonia, rare in childhood, consists of variablysustained twisting deformation of a limb (384),contiguous parts of the body, or of the trunk.Dystonia may be focal (torticollis, writer’scramp, dysphonia), segmental (limb andcontiguous neck musculature), or generalized.Dystonic movements are often intermittent(spasmodic dystonia) or triggered by willfulmovement (action-induced dystonia). Given thecomplexity of evaluating children with dystonia,clinicians should initiate early referral to apediatric neurologist. Dystonias can be consid -ered primary, usually the result of a geneticdisorder, or secondary, due to medica tions or aCNS injury, often CP.

The prototype of primary dystonias isprogressive dystonia with diurnal variation, also known as dopa-responsive dystonia orSegawa disease. Recognition facilitates propertreatment and dramatic improvement in thequality of life. This autosomal dominantcondition is due to a mutation in the guanosinetriphosphate (GTP) cyclohydrolase-1 gene,resulting in impaired biosynthesis of tetrahy -drobiopterin, the essential cofactor for tyrosinehydroxylase which in turn is the rate-limitingenzyme in catecholamine biosynthesis. Thedisorder usually presents in mid-childhood(5–15 years of age) with transient andfluctuating dystonia affecting gait and posture.The condition is often mistaken for stroke,CP, localized limb trauma, malingering, orconversion disorder.

The diagnosis of Segawa disease used todepend on demonstration of a dramatic responseto low-dose L-dopa, but now analysis of CSFneurotransmitters demonstrates low concen -trations of biopterin and neopterin, whilesequencing demonstrates a pathogenic mutationof the GTP cyclohydrolase-1 gene in up to 80%of cases. The condition is exquisitely sensitive totreatment with L-dopa (and to a lesser degreewith anticholinergics such as trihexyphenidyl).Treated patients usually remain asymptomaticthroughout their life and do not generally havethe time-emergent side-effects of L-dopa seen inpatients with Parkinson disease.

A patient treated by one of the authorsprovided the following reflections several yearsafter the diagnosis of Segawa disease and theinitiation of L-dopa therapy:

“I am nearly 28 now, and not a day goes bythat I don’t think about how wonderful it isto be healthy and mobile. I am so gratefulfor your help. I was able to attend collegeand law school. I am able to live aloneand go out to explore the world withoutassistance. I am able to go work everymorning, to exercise every evening . . .Yougave me the ability to achieve my dreams.”


384

384 Dystonic posturing of the hands, especiallythe left, in a young child attempting to unwrap alollipop.

Another primary dystonia with onset inchildhood is dystonia with DYT-1 mutation.This disorder represents the prototypicautosomal dominant familial dystonia in whichvariable penetrance may lead to lack of recog -nition of subtle manifestations of dystonia inaffected relatives (e.g. writer’s cramp,torticollis, spasmodic dysphonia, and mild limbdystonia). Unlike Segawa disease wheremutations have been identified throughout theGTP cyclohydrolase-1 gene, this familialdisorder is associated with the same mutationin families from virtually all ethnic groups (a 3basepair GAG deletion in the TOR1A gene).Unfortunately, this condition is not asresponsive to pharmacotherapy. High-doseanticholinergic medication (doses oftrihexyphenidyl [Artane] of up to 60–150mg/day) may be partly effective. Botulinumtoxin injection can provide considerable relief.Neurosurgical procedures may prove necessaryin severe, refractory cases.

An unusual but unique familial formof dystonia with myoclonus, the ‘myoclonus–dystonia’ syndrome, (also known as familialdystonia, DYT) often presents in childhood withmyoclonus and spasmodic dystonia of muscles ofthe neck and shoulder girdle. Mutations in theepsilon-sarcoglycan gene (SGCE) have beenidentified in many but not all kindreds. Maternalinheritance is associated with reduced penetrance(imprinting). The move ments in this conditionrespond to ingested ethanol and treatment withbenzodiazepines, valproic acid, or topiramate.

Secondary dystonias can be drug-induced orassociated with CP. The pediatrician should beattentive to drug-induced dystonias. Commonlyused dopamine antagonists such as metoclo -pramide (Reglan), promethazine (Phenergan),and prochlorperazine (Compazine) arecommon offenders. The former can result indramatic cases of oculogyric crisis and torticollisin infants treated for gastroesophageal reflux,which will bring terrified parents to theemergency department. Such episodes are oftenmistaken for seizures. Prompt treatment withdiphenhydramine is both diagnostic andtherapeutic. Dystonia in children with CPrepresents a chronic, often disabling conditionthat may respond to medications, such asbaclofen, or botulinum toxin injections.

Myoclonus

Myoclonic movements can be difficult todistinguish from tics, but myoclonic movementsare much more rapid (‘lightening-like’),irregular, and less stereotyped. The child withmyoclonus usually lacks the subjective ‘premon -itory urge’. Massive myoclonus (whole bodyjerks) occur in certain epilepsies, in mito -chondrial disorders, and in hyperekplexia (acondition originally described in FrenchCanadian families with a specific glycinereceptor mutation, hence the term ‘jumpingFrenchmen of Maine’). Most cases result frominflammatory, toxic, or metabolic conditions. Innumerous severe cases no definitive explanationcan be discovered. Treatment depends upon theetiology.

Hypokinetic movementdisorders in childhood

Hypokinetic movement disorders are extremelyrare in children. The most common areiatrogenic, due to treatment with neurolepticmedications. The Westphal variant ofHuntington disease presents with bradykinesiaand rigidity and only minimal chorea. Familialand sporadic cases of juvenile-onset Parkinsondisease are very uncommon. Various hypoki -netic movement disorders with or withoutdystonia or choreoathetosis may follow CNSinjury from global hypoxic–ischemic injury orencephalitis. L-dopa is rarely as effective in thesedisorders as it is in typical adult-onset Parkinsondisease.


CHAPTER 22301

Seizures and otherparoxysmaldisorders

Main Points• Seizures and paroxysmal events can occur at all ages.

• The child with the first seizure, whether provoked or unprovoked,can be appropriately evaluated by the generalist.

• Benign rolandic epilepsy with centrotemporal spikes causesapproximately 10% of childhood epilepsy.

• Infants with suspected infantile spasms should be referred promptlyto a pediatric neurologist.

• Most anticonvulsants and their dose adjustments can be managedsafely by the generalist.

• Viewing videoed events is very helpful in evaluating paroxysmaldisorders.


Cardiac arrhythmia

Cardiac arrhythmias can present at any age.Often, but not always, the seizure-like event isprovoked by exercise or excitement. A screeningECG can detect features suggesting long QTsyndrome, but a normal ECG does not excludeparoxysmal cardiac arrhythmias. The correctedQT interval (QTc) can be calculated using theequation:

QTc = QT/√RR

in which √RR = the square root of the R-Rinterval.

Referral to a pediatric cardiologist shouldalways be considered when evaluating childrenwith paroxysmal events provoked by exercise orcharacterized primarily by syncope.

Introduction

The clinician’s role in the diagnosis of parox -ysmal events is to recognize the typical clinicalpresentation of epileptic seizures and to differ -entiate these from the typical presentations ofother paroxysmal disorders of infancy andchildhood. This chapter begins by discussingthe clinical features of common nonepilepticparoxysmal disorders and then focuses onthe evaluation and management of epilepticseizures.

Infants and children can experience manytypes of episodic or paroxysmal events. Todifferentiate and diagnose these events, theclinician should start with three questions:

1. What was the child doing just prior to theevent?

2. What happened during the event?3. What was the child’s condition just after

the event?

Events starting during sleep are more likelyto be seizures, whereas breathholding spells,movement disorders, self-stimulatory behav iors,migraine variants, shuddering attacks, stereo -typies, daydreaming, and conversion disordertypically occur during wakefulness. An eventduring exercise could suggest a cardiac cause,such as prolonged QT syndrome or Wolff–Parkinson–White syndrome. The descrip tion ofthe event itself can be diagnostic, such as abreathholding spell or self-stimulatory behavior.The child’s state just after the event is oftenaltered after an epileptic seizure, but not aftermovement disorders, for example. It is oftenhelpful for parents or caregivers to videotapeevents. In addition to the description of theevent, the age of the child is often an importantclue. Whereas epileptic seizures and cardiacarrhythmias can present at any age, many otherparoxysmal disorders have a typical age of onset(Table 46).

CHAPTER 22 Seizures and other paroxysmal disorders 303

Table 46 Age of onset of seizures and other paroxysmal events

AgeDisorder 0–3 mo 3–12 mo 1–4 yr 5–10 yr 11–18 yrEpileptic seizure ✓ ✓ ✓ ✓ ✓

Cardiac arrhythmia ✓ ✓ ✓ ✓ ✓

Gastroesophageal reflux ✓ ✓ +/− ✕ ✕

Breath-holding spell +/− ✓ ✓ +/− ✕

Self-stimulation ✕ ✓ +/− ✕ ✕

Migraine variant ✓ ✓ ✓ ✓ ✓

Shuddering attacks ✕ +/− ✓ +/− ✕

Stereotypies ✕ +/− ✓ ✓ ✓

Daydreaming ✕ ✕ ✓ ✓ ✓

Psychogenic nonepileptic ✕ ✕ +/− ✓ ✓

seizure

✓: can occur+/−: rare✕: usually absent

Nonepileptic events

Gastroesophageal reflux(Sandifer syndrome)Gastroesophageal reflux (GER) can produce aparoxysmal movement disorder with sustainedback arching, head turning, and fussiness thattypically occur after feeding. The neurologicalfeatures of GER are known as Sandifersyndrome, a condition that can be associatedwith a hiatal hernia. The episodes can last forseveral minutes, suggesting seizures, andafterwards the child can appear quiet, tired, orfussy. Unlike epileptic seizures, limb jerking isnot a common clinical feature. Neurologicalsymptoms associated with GER can occur frombirth onward, but usually resolve by 2–3 yearsof age.

Breath-holding spells Breath-holding spells typically occur from6 months to 4 years, but can appear as early asthe first week of life and persist into middlechildhood. They always occur in an awake childand are always provoked by minor injury,discipline, or a strong emotion such as startle,fright, anger, or frustration. There are twoclassic presentations: pallid or cyanotic. In pallidbreath-holding, the spell is provoked by frightor pain (such as bumping the head on furniture)and the child turns pale, becomes unresponsive,rigid, and apneic. In cyanotic breath-holdingspell, the child is upset or crying and thenbecomes nonresponsive, stops breathing, andturns very dusky. In either case, the child canstiffen or have transient jerking of theextremities; this can be considered severebreath-holding or convulsive syncope. Seizurescan complicate any episode of syncope,especially when the child is held upright, andstatus epilepticus in young children canoccasionally be provoked by breath-holdingspells.

Breath-holding spells are very alarming toparents and other observers, and typically last for1–2 minutes. The child may be subduedafterwards or even sleep. The child may be givenrescue breaths and brought to medicalattention. Evaluation of an initial event shouldbe comprehensive, with special attention topotential cardiac causes of syncope. Breath-

holding spells can be a manifestation of systemiciron deficiency. Thus, if breath-holding spells aresuspected, iron studies (serum iron and ironbinding capacity, serum ferritin or serumtransferrin receptor level) should be obtained,even when the hematocrit or hemoglobin isnormal. Breath-holding spells can improvedramatically with oral iron therapy.

Self-stimulatory behaviorSelf-stimulatory behavior, masturbation or‘gratification behavior’ can appear as early as thefirst month of life and can last to 5 years of ageor beyond. The event is characterized by lowerextremity posturing, rhythmic movements,quiet vocalizations or grunting, and facialflushing. The event can last for many minutesand is always interruptible. This kind of self-stimulatory behavior represents a normalelement of growth and development in infantsand children; redirection, rather than punish -ment, is the best management.

Migraine variantsMigraine variants can present from infancyonward and consist of a characteristic movement,a family history of migraine, and a strong likeli -hood for subsequent migraine headaches as thechild ages. Migraine variants, diagnoses ofexclusion, usually require neuroimaging andelectrophysiological studies. Benign paroxysmaltorticollis of infancy occurs from 1–12 monthsof age. The episodes are sometimes accompaniedby vomiting, and can last from 10 minutes to48 hours. The child is normal between theepisodes. Benign parox ysmal vertigo (BPV)typically presents in toddlers, but can also occurin younger children. The episodes are charac -terized by abrupt vertigo with nystagmus andvomiting. BPV should be differentiated frombenign paroxysmal posi tional vertigo, a disorderof adolescents and adults, characterized byvertigo and nystagmus provoked by simplemovements such as rolling over in bed.


Shuddering attacks Shuddering attacks occur from 4 months of agethrough middle childhood. They happen onlyduring wakefulness and can be provoked byexcitement. The child exhibits momentary,seconds long quivering or shivering movementsof the head, shoulders, and trunk. There is noalteration of consciousness, eye deviation, orpostictal state. As soon as the shuddering ends,the child returns to his/her normal state.Shuddering attacks are benign; propranolol canbe effective, but therapy is rarely necessary.

StereotypiesStereotypies are purposeful movements, that areoften provoked by excitement, especially inanticipation of something enjoyable. They canbegin as early as 1 year of age and last throughadolescence. The stereotypic movements have abroad range of manifestations including handflapping, vocal izations, or dystonic armextension. As the name implies, one event is likeanother. The child with stereotypies has no lossof consciousness during the event or postictalstate afterward. Stereotypies require notreatment. They can occur in children withautism or developmental delay, and in normal,healthy children.

DaydreamingDaydreaming or episodic nonresponsivenessaffects nearly all children, and can be morenoticeable in children with developmental delayor attention deficit hyperactivity disorder(ADHD). Daydreaming can be differen tiatedfrom absence seizures by an EEG thatlacks epileptiform features during a typicalevent (see discussion of absence epilepsy).Daydreaming spells are typically less frequentand longer lasting than absence seizures; theydiffer from complex partial seizures by the lackof automatisms such as eye blinking, lipsmacking or hand movements. Daydreaming istypically not provoked by hyperventilation,whereas absence seizures can be.

Psychogenic nonepilepticseizuresPsychiatric and behavioral disorders, such asconversion disorder, can manifest with a widerange of symptoms, including paroxysmal eventssuch as nonepileptic seizures. Nonepilepticseizures can start as early as 5 years of age andextend through adolescence and adulthood.Some children or adults with psychogenicnonepileptic seizures, 8–25% in some studies,also have epileptic seizures, making the diagnosisand treatment of these disorders challenging.Conversion disorder is a treatable medicalcondition. Compared with adults who havepsychogenic nonepileptic seizures, pediatricpatients have a higher likelihood (80% vs. 40%)of becoming seizure-free with early andappropriate intervention.

Other disorders Paroxysmal dyskinesias are rare, under-diagnosed movement disorders that present inchildhood. These uncontrollable movementscan be provoked by certain actions, such asplaying with toys, or becoming excited.Immediately after the provoking action, thechild experiences choreoathetoid movements ordystonic posturing of the extremities, mostcommonly the arms. There is no alteration ofconsciousness during the event or postictal state.In some cases, the seemingly bizarre posturingoccurs spontaneously and can be misdiagnosedas a psychiatric condition. The diagnosis of thesedisorders is often made by a pediatric neurol -ogist or movement disorder specialist, butgeneralists should be aware of these disorders toavoid misdiagnosis.


Seizures and epilepsy

Pediatricians and family physicians are typicallythe first providers to evaluate infants or childrenwith new-onset seizures. The generalist’s role isto use the history and physical exam to establishthe differential diagnosis, and if seizures orepilepsy remains a consideration, the generalistshould initiate the appropriate evaluation.Comprehensive practice parameters publishedby the American Academy of Neurology and theChild Neurology Society guide generalists in theinitial management of children with febrile ornonfebrile seizures. Resources can be found atwww.epilepsyfoundation.org.

Evaluation of childrenwith suspected seizuresThe acute evaluation of an infant or child with aseizure should always start with the ABCs:airway, breathing, and circulation. Once thepatient is medically stable, the clinician shoulddetermine whether the seizure was provoked orunprovoked. Examples of provoked seizuresinclude seizures in the setting of head trauma,hypernatremia, hyponatremia, hypoglycemia,hypocalcemia, meningitis, encephalitis, andfever, as well as severe breath-holding, as notedearlier in this chapter. Simple febrile seizures willbe discussed separately. For infants and childrenwith their first unprovoked seizure, currentpractice parameters in the USA recommendobtaining laboratory studies and neuroimagingon a case-by case basis, depending on the history.

EEG assists the evaluation of the child with afirst seizure, especially if an epileptic syndromecan be identified. However, a normal EEG doesnot rule out a seizure. Although an EEG within24 hours of the event is more likely to displayabnormalities, these abnormalities can be tran -siently related to the postictal state. Typically,EEG is performed on an outpatient basis in thefirst week or two after the first seizure. Anti -convulsant therapy, if necessary when the eventsare recurrent, should not be delayed whilewaiting to obtain an EEG. With the exception ofvalproic acid/divalproex sodium and the benzo -diazepines, anticon vulsants do not alter theEEG. The majority of children with unprovokedseizures should undergo neuroimaging; MRI hasthe highest diagnostic yield of neuroimagingstudies in the child with his/her first seizure.

Specific seizure typesand pediatric epilepsysyndromes

Infantile spasmsInfantile spasms typically present between 3 and6 months of age, but can begin as early as1 month of age and as late as 24 months(textbox).

Causes of symptomatic infantile spasms• Genetic: tuberous sclerosis; Down

syndrome; Miller–Dieker syndrome;Aicardi syndrome.

• Structural: schizencephaly;holoprosencephaly; cortical dysplasia(385); polymicrogyria; hydranencephaly.

• Metabolic: maple syrup urine disease;PKU; biotinidase deficiency; nonketotichyperglycinemia; pyridoxine dependency.

• Perinatal: hypoxic–ischemic (neonatal)encephalopathy.

• Infectious: congenital infections (CMV,T. gondii, rubella virus, lymphocyticchoriomeningitis virus); neonatalencephalitis (herpes simplex virus);neonatal bacterial meningitis.

The majority of infants with infantile spasmshave flexor spasms. In these, the infant abruptlyflexes the head and trunk and may extend thearms and flex at the hips (‘salaam’ or jacknifeattacks). Less commonly, infants have extensorspasms with abrupt arching of the head and backand extension of the arms similar to the Mororesponse. Each spasm lasts a few seconds, butthe spasms recur in clusters of 20 or more overa 10–30 minute interval, especially when theinfant becomes sleepy or awakens from sleep.The infant may cry, as if in discomfort, and havenystagmoid movements or upward eye devi -ation during the spasm.

Infantile spasms can be classified as symptomatic, when a cause can be identified, orcryp togenic, when no cause can be found aftera comprehensive evaluation. Approximately 20%of patients presenting with infantile spasmshave tuberous sclerosis (TS), so a thoroughskin exam can be diagnostic (268–273).West syndrome, a term sometimes used


www.epilepsyfoundation.org

synonymously with infantile spasms, describesthe triad of infantile spasms, develop -mental delay, and the EEG finding ofhypsarrhythmia.

Infants with infantile spasms require acomprehensive evaluation that includes brainMRI, EEG, ophthalmological examination,and, depending upon coexisting historical orexamination features, genetic or metabolictesting. The latter may include assays of serumamino acids and urine organic acids. The EEGoften shows hypsarrhythmia (281), a chaoticEEG pattern with poorly organized backgroundand abundant, multifocal epileptiformdischarges, but its absence does not exclude the

diagnosis of infantile spasms. Some infants havenormal EEGs at the onset of their spasms, buthypsarrhythmia or modified hypsarrhythmiaeventually appears in nearly all cases of infantilespasms. The prognosis for infants with spasmsdepends, in large part, on the etiology. Virtuallyall infants with symptomatic spasms haverecurring seizures and long-term neurode -velopmental delays. Many evolve to Lennox–Gastaut syndrome, a disorder associated withintractable epilepsy and developmentaldelay/mental retardation. By contrast, as manyas 50% of the infants with cryptogenic spasmsrespond well to treatment and have favorableneurodevelopmental outcomes.


385

385 Diffuse cortical dysplasia (circle) in a child withmacrocephaly, polymicrogyria, polydactyly, andhydrocephalus syndrome.


Febrile seizuresA simple febrile seizure consists of a generalized,tonic–clonic seizure lasting less than 15 minutesin a child between the ages of 6 months to6 years of age with fever >102°F (38.9°C). Ifthese criteria are met and the child lacks neuro -logical abnormalities or develop mental deficitsat baseline, no further evaluation is routinelyrecommended. Children with complex febrileseizures have long (>15 minutes), focal orrepetitive seizures during the acute phase.Children with complex febrile seizures or thosewith simple febrile seizures and a family historyof epilepsy may require further diagnosticevaluation with EEG and neuroimaging studies.Febrile seizures can also be features of moreserious conditions, including meningitis andencephalitis.

Benign rolandic epilepsyBenign rolandic epilepsy or centrotemporalepilepsy typically begins between 3 and 12 yearsof age and spontaneously remits by mid-adolescence in nearly all cases. Rolandicepilepsy, the most common childhood epilepsy,accounts for approximately 10% of all pediatricepilepsy. The characteristic seizure presents as apartial motor or sensory seizure of the face andarm occuring within the first hour after fallingasleep. Children often experience secondarygeneralization into brief tonic–clonic seizures.The diagnosis rests on obtaining a normaldevelopmental history and examination andfinding characteristic EEG abnormalities ofcentrotemporal spikes that are accentuated bydrowsiness and light sleep (78–80, 386). Mostchild neurologists consider treatment ofrolandic epilepsy optional; when seizures areatypical (occur during wakefulness or arerepetitive) or cause considerable parental angst,oxcarbazepine or carbamazepine can beconsidered. Rolandic seizures remit completelyby age 14 years in 95% or more of affectedchildren.

386

386 The EEG in rolandic epilepsy. Diamond box: vertex transients andsleep spindles (normal findings of stage 2 sleep); circle: centrotemporalsharp and slow wave discharges characteristic of rolandic epilepsy.


Childhood absenceepilepsyChildhood absence epilepsy presents in boysor girls between 3 and 10 years old. Absenceseizures, often called petit mal seizures, arecharacterized by brief disturbances ofconsciousness (‘spacing out’) lasting 15 secondsor so, with abrupt onset and termination andno postictal state. They can be accompanied byslow head nodding or arm elevation or byautomatic movements, such as walking. Theycan occur in clusters and are provoked byhyperventilation. Absence seizures are alwaysassociated with generalized 3 Hz spike-wavedischarges during the seizure (74). If the EEGdoes not show this abnormality during anepisode of unresponsiveness, the child does nothave absence seizures.

Juvenile myoclonicepilepsyJuvenile myoclonic epilepsy (JME) presents inboys or girls 12–18 years of age. They oftencome to medical attention because of ageneralized tonic–clonic seizure, but somepatients with JME had absence epilepsy priorto the onset of myoclonic or generalizedtonic–clonic seizures. A thorough history oftenelicits clumsiness or limb jerking (myoclonus),typically upon awakening in the morning, orprovocation of seizures by playing video gamesor watching television. Myoclonus can consistof spontaneously dropping or throwing objectsbecause of the abrupt, involuntary jerks of theupper extremities. Adolescents with JME aredevelopmentally and neurologically normal,but have abnormal EEGs with brief spike-wavebursts or photoparoxysmal discharges (76, 77).The clinical seizures in JME are oftencontrolled with a single anticonvulsant, such asdivalproex sodium, levetiracetam, orlamotrigine; however, seizures often recur ifanticonvulsants are discontinued.

Additional epilepsysyndromes of childhood• Benign familial neonatal seizures: a

dominantly inherited condition with usualonset between 2 and 5 days of age. Thedisorder, caused by mutations in voltage-gated potassium channels, remitsspontaneously in most cases within 6–12 months.

• Ohtahara syndrome: a rare, early-onsetepileptic encephalopathy syndrome withintractable seizures, including infantilespasms and later, Lennox–Gastautsyndrome. EEG shows a burst-suppressionpattern.

• Dravet syndrome: a rare, sporadic disorderwith seizure onset in the first year of life,often starting with febrile seizures. Seizuretypes include myoclonic, atypical absences,or atonic seizures. Many children with thisdisorder have mutations in SCN1A, avoltage-gated sodium channel.

• Doose syndrome (myoclonic–astaticepilepsy of childhood): an uncommondisorder associated with generalizedseizures usually beginning in the first2 years of life. All children with thisdisorder have myoclonic or myoclonic/astatic (drop) seizures. It can be refractoryto medication therapy and may improvewith the ketogenic diet. The ketogenicdiet, an additional treatment strategy forchildren with intractable epilepsy, consistsof a diet high in fat and low in protein andcarbohydrate. The ketogenic diet can causea dramatic reduction in seizure frequencyin some children.


Management of seizures

The decision to initiate an anticonvulsant for achild with seizures depends on the likelihoodof further seizures and the potential morbidityassociated with seizures in that particularpatient. Side-effects, drug interactions, and drugavailability influence the decision to start anti -convulsant therapy. Parents should be advisedthat mucocutaneous drug eruptions, includingDRESS (drug rash with eosinophilia andsystemic symptoms) syndrome are commonwith many anticon vulsants, especially pheno -barbital, phenytoin, carbamazepine, oxcar -bazepine, and lamotrigine (387, 388). Thesereactions commonly appear 1–6 weeks afterdrug initiation.

Parents should be advised that antiepilepticmedications have potential cognitive orbehavioral side-effects and may increase the riskof suicidal thoughts or behaviors.

Recurrence risk After having a single unprovoked seizure,approximately 50% of children will have anotherseizure. The risk of recurrence is increased inchildren with prior brain injury, developmentaldelay, or an abnormal EEG. Children with asingle seizure and a normal EEG have a 25% riskof seizure recurrence, whereas children with asingle seizure and an abnormal EEG withepileptiform features have a 75% recurrence risk.If the first unprovoked seizure was prolonged,the next seizure is likely to be prolonged,although the recurrence risk is the same as if thefirst seizure were brief.

In simple febrile seizures, the recurrence riskis about 30%. Children with younger age, lowertemperature at the time of the febrile seizure,and family history of febrile seizures have thehighest risk of recurrent febrile seizures. The riskof epilepsy in children with simple febrileseizures is very low. By contrast, children withcomplex febrile seizures or children with simplefebrile seizures and a family history of epilepsyhave increased rates of epilepsy duringchildhood or adolescence.

388 Characteristic rash of DRESS syndromeinvolving the legs of the same child as in 387.

387

387The face of a young child with drug rashwith eosinophilia and systemic symptoms(DRESS) syndrome secondary to phenobarbitaltherapy.

388

Choosing an anti-convulsantAge and seizure type are two important factorsto consider when choosing an anticonvulsant(Tables 47, 48). Formulation (liquid suspension,tablet, or sprinkle capsules) and time totherapeutic effect also influence medicationselection. For infants and children up to 2 or3 years of age, phenobarbital is often chosenfirst, given its ease of use and substantialclinical experience with this medication. Forinfants or children with focal onset seizures,


Table 47 Guide to anticonvulsant use

Seizure type MedicationInfantile spasms ACTH, prednisolone, vigabatrin (especially in tuberous sclerosis)Generalized tonic–clonic

<3 yr Phenobarbital, levetiracetam3 to 16 yr Divalproex sodium, levetiracetam, phenytoin>16 yr Lamotrigine, levetiracetam, divalproex sodium (avoid in girls)

Absence Ethosuximide, divalproex sodium, lamotriginePartial Carbamazepine, oxcarbazepine, levetiracetam, topiramate, lacosamide, zonisamideMyoclonic Levetiracetam, divalproex sodium (avoid divalproex sodium or valproic acid in patients with

mitochondrial disorders), lamotrigineLennox–Gastaut Divalproex sodium, benzodiazepines, zonisamide, felbamate, topiramate, lamotriginesyndrome

Table 48 Anticonvulsant dosing

Drug Loading dose Maintenance dose Tablet/capsule Suspension Serum levelCarbamazepine NA 10–30 mg/kg/day 100, 200 mg 100 mg/5 ml 4–12 μg/ml

100, 200 mg XRDivalproex sodium 10 mg/kg 15–60 mg/kg/day 125, 250, 500 mg – 50–125 μg/ml

250, 500 mg XREthosuximide NA 15–40 mg/kg/day 250 mg 250 mg/5 ml 40–100 μg/mlFelbamate* NA 15–45 mg/kg/day 400, 600 mg 600 mg/5 ml NAGabapentin NA 10–30 mg/kg/day 100, 300, 400, 250 mg/5 ml A1

600, 800 mgLacosamide NA 2–12 mg/kg/day 50, 100, 200 mg 10 mg/ml NALamotrigine** NA 2–5 mg/kg/day 2, 5, 25, 50, 100 mg – A1

(with VPA)5–15 mg/kg/day(without VPA)

Levetiracetam 10–20 mg/kg 10–60 mg/kg/day 250, 500, 750 mg 100 mg/ml A1

1000 mgOxcarbazepine NA 10–60 mg/kg/day 150, 300, 600 mg 300 mg/5 ml 15–35 μg/mlPhenobarbital 10–20 mg/kg 3–7 mg/kg/day 15, 16.2, 30, 32.4, 20 mg/5 ml 15–40 μg/ml

60, 64.8 mgPhenytoin 15–20 mg/kg 3–5 mg/kg/day 30, 50, 100 mg 125 mg/5 ml 10–20 μg/mlTopiramate NA 2–12 mg/kg/day 15, 25, 30, 50, – A1

100 mgValproic acid NA 15–60 mg/kg/day 250, 500 mg 250 mg/5 ml 50–125 μg/mlVigabatrin NA 40–100 mg/kg/day 500 mg 500 mg powder A1

Zonisamide NA 2–12 mg/kg/day 25, 50, 100 mg – A1

*Note warnings regarding aplastic anemia and hepatic failure**To avoid allergic reactions with lamotrigine, dose adjustments must be made at 2 week intervals initially, especially inchildren receiving valproic acid or divalproex sodiumA1: available, not routinely used; NA: not applicable; VPA: valproic acid or divalproex sodium; XR: extended release

oxcarbazepine or carbamazepine is often thefirst consideration. Levetiracetam, one of thenewest anticonvulsants, appears beneficial, andhas very few side-effects.

Divalproex sodium is very effective for alltypes of generalized epilepsy, including absence,generalized tonic–clonic and myoclonic, but therisk of hepatotoxicity in children under 3 yearsof age often precludes its use in this agegroup. Certain metabolic disorders, especiallymitochondrial disorders, may predispose youngchildren to divalproex sodium’s hepatic compli -cations, including fatal liver failure. Given therisk of teratogenicity (developmental delay, facialdysmorphism, and spinal bifida), divalproexsodium (or valproic acid) must be avoided inyoung women of child-bearing age. Adminis -tration of folic acid does not prevent fetalvalproate syndrome and spina bifida. Absenceseizures are treated with ethosuximide, butwhen generalized tonic–clonic seizures appear,divalproex sodium or lamotrigine is used, sinceethosuximide does not adequately protectpatients from seizure types other than absence.

Phenytoin, one of the oldest anticonvulsants,can be used for generalized tonic–clonic orpartial seizures in children, but rapidmetabolism makes its use challenging in youngpatients. Topiramate and lamotrigine are alsoused with good success in children, althoughlamotrigine carries a US Food and DrugAdministration (FDA) ‘black box’ warningregarding serious allergic reac tions, includingStevens–Johnson syndrome, in pediatricpatients <16 years of age.

Infantile spasm is the only seizure typeroutinely treated by a course of intramuscularadrenocorticotropic hormone (ACTH). Othertreatment options in infants with spasms includetopiramate, prednisolone, the ketogenic diet,and in the case of infantile spasms due to TS,vigabatrin.

Management of childrenwith epilepsy

The generalist’s role is to monitor the efficacyand side-effects of anticonvulsant therapy, toassist titration of anticonvulsants in patients(especially those receiving single anticon -vulsants) and to encourage healthy living byreviewing activity and seizure precautions atevery opportunity. In general, pediatric patientsshould be managed with the lowest therapeuticdose of a single anticonvulsant, wheneverpossible. Seizure precautions for persons withseizures include avoiding unsupervised baths orswimming and activities, such as climbing ormotor vehicle operation, in which a sudden lossof consciousness could cause severe injury to theperson or others. Participation in sports dependson the sport, the child’s seizure frequency, andthe risk of injury. ‘Above the ground’ gymnas -tics and competitive swimming should beavoided, but persons with well-controlledepilepsy can participate in virtually all othersports. Each country has specific laws regardingepilepsy and operating a motor vehicle; clini -cians should familiarize themselves with the lawsin their region. Finally, clinicians and parentsshould be aware that children and adolescentswith epilepsy have a slightly-increased risk ofsudden death, a condition known as ‘suddenunexplained death in epilepsy’ (SUDEP).


CHAPTER 23313

Pediatricneurologicalemergencies

Main Points• Seizures lasting longer than 5–10 minutes require intervention.

• Treatment of status epilepticus, seizures lasting longer than 15 minutes, requires a systematic approach beginning with theABCs and continuing with administration of rapidly acting andmaintenance anticonvulsants.

• The neurological examination is used to identify theneuroanatomical localization of unconsciousness (coma).

• Evaluation of the comatose child should include screening forsystemic causes and evaluation by CNS imaging.

• Concussion causes confusion and amnesia with or without loss ofconsciousness.

• Nonaccidental trauma should be suspected in infants with acutechanges in mental status, especially when accompanied by apnea.Funduscopic examination should be performed to detect retinalhemorrhages, a hallmark of nonaccidental trauma.

• Hypertensive encephalopathy (posterior reversible encephalopathysyndrome) should be considered in children with hypertension andseizures, headaches, and focal neurological signs, especiallyinvolving vision.

• Spinal cord injury can occur without radiographic evidence of bonyinjury.

• Respiratory function must be monitored closely in infants orchildren with neuromuscular disorders causing weakness.

• Many acute poisonings display toxidromes with specific CNSmanifestations.

Status epilepticus

DIAGNOSIS AND CLINICAL FEATURESHistorically, status epilepticus was defined ascontinuous seizure activity for 30 minutes orrepetitive seizures with incomplete recovery thatlasts for 30 minutes. This definition was based onanimal data that indicated that after this time theanimal started to experience deleterious systemiceffects from the ongoing seizure activity. Werecognize now that this definition does notadequately direct appropriate responses to theconvulsing child. Current strategies categorizestatus epilepticus according to progressive stagesof severity based on the duration and theresponse to appropriate anticonvulsant therapy(textbox).

Categories of status epilepticus• Early or impending status epilepticus:

5 minutes of continuous generalizedconvulsive seizure or 15 minutes ofnonconvulsive or focal seizure, or twoseizures without full recovery betweenthe seizures.

• Late or established status epilepticus:continuous seizure activity or repetitiveseizure activity with incomplete recoverybetween seizures that last for 30 minutesor longer.

• Refractory or persistent status epilepticus:persistent or continuous seizure activitydespite appropriate doses of two or threeanticonvulsants.

Assessment of the child with status epilep -ticus must address potential causes and mustconsider the context of the event. If the childhas had an acute febrile illness, for example, theclinician must determine if derangements ofelectrolytes, calcium, or glucose require imme -diate therapy or if an infection of the CNS mustbe treated expeditiously. In the appropriatesetting clinicians must consider whether statusepilepticus results from an acute or chronicintracranial structural process or ingestion of atoxic substance. One of the most commoncauses of status is the child with a refractoryepilepsy and the tendency for prolongedbreakthrough seizures (textbox).

Introduction

Neurological emergencies, although notcommon, require that clinicians respond rapidlyand efficiently to minimize injury to the nervoussystem. Most clinicians will encounter patientswith seizures and concussion, and many will becalled upon to manage infants or childrenaffected by ingestions, coma, or nonaccidentaltrauma. This chapter describes several pediatricneurological emergencies and managementstrategies that will enable clinicians to treat theirpatients effectively.

Seizures

Seizures represent paroxysmal, usually self-limited events that typically cease after 2 minutesor less, allowing the infant, child, or adolescentto return quickly or gradually to the baselinestate. Seizures end because of γ-aminobutyricacid-mediated recurrent CNS inhibition thatoccurs in response to the seizure. When seizuresrecur in rapid succession or become prolonged,they may not cease spontaneously, andemergency treatment becomes necessary. Thisconcept of an ‘enduring epileptic condition’ isthe basis for defining status epilepticus. Everyclinician who cares for children should be ableto provide emergency management for statusepilepticus.


Causes of status epilepticus• Metabolic: hypoglycemia, hypo- &

hypernatremia, hypocalcemia,anoxia/hypoxia.

• Infectious: meningitis, encephalitis.• Structural: congenital malformations,

trauma, tumor, vascular malformations,vascular events.

• Toxic: substance abuse, drugs, poisoning,withdrawal.

• Febrile: in the age-appropriate child.• Loss of seizure control or medication

noncompliance.

When children experience status epilepticus,the probability is at least 30% that the nextseizure event will also consist of statusepilepticus.

MANAGEMENTManaging status epilepticus begins with theABCs (airway, breathing, circulation) of patientcare. An adequate airway must be established,and the child should be given supplementaloxygen. A peripheral intravenous (IV) lineshould be started so that drugs can beadministered. As the line is being placed, bloodcan be drawn for appropriate laboratory tests todetermine if metabolic or toxic factors arecausing the seizure. Blood glucose level byDextrostix or equivalent should be obtained,and 25% glucose (2–4 ml/kg) should be givenIV if the child has hypoglycemia. After the linehas been secured, a rapidly acting anticonvulsantshould be given (textbox).

The most frequently administered initialmedication is a benzodiazepine, either diazepamor lorazepam. Both are equally effective, butlorazepam has become the drug of choicebecause of a longer duration of action and lowerrate of respiratory depression requiringintubation. Lorazepam is given in a dose of 0.1 mg/kg IV, up to 8 mg total, over 1 minute.The dose of diazepam is 0.3 mg/kg IV, up to 20 mg total, over 1 minute. If the seizure doesnot stop after one dose, a second dose should begiven. After two doses of either diazepam orlorazepam, it is unlikely that additional doses ofthese medications will be beneficial. When thesedrugs are given IV, especially in larger doses, the

CHAPTER 23 Pediatric neurological emergencies 315

clinician should be prepared to ventilate thechild, either by bag/mask or intubation.

If the child continues to have seizures, thenext drug to give is fosphenytoin. Fospheny -toin, a prodrug rapidly metabolized to pheny -toin, has several advantages over phenytoin,including neutral pH, absence of the vehiclepropyleneglycol, and ability to be mixed withdextrose-containing solutions. Thus, fospheny -toin can be given at a faster infusion rate withless tissue toxicity and fewer cardiovascular side-effects. The dosing of fosphenytoin is measuredin phenytoin equivalent (PE), with 1 PE equalto 1 mg of phenytoin. The dose of fosphenytoinis 20 PE/kg IV given at a rate not exceeding150 PE/min. This dose usually achieves a serumlevel of 20–25 μg/ml; levels of phenytoin peakin the serum 2 hours after the IV load. If theseizure persists, another 5 mg/kg of fospheny -toin can be given IV.

If seizures continue, phenobarbital is givenIV at a dose of 20 mg/kg and a rate of 100 mg/min. For every 1 mg/kg of pheno -barbital given the serum level rises by 1 μg/ml;thus, 20 mg/kg achieves a serum level of 20 μg/ml. The therapeutic range for pheno -barbital is 15–40 μg/ml. If seizures continue,additional doses of phenobarbital can be givenin increments of 5–10 mg/kg up a total of 40 mg/kg. When phenobarbital is given,especially in combination with one of thebenzodiazepines, one must be prepared tointubate and ventilate the child, given thepotential respiratory depression associated withthe medications and the continued seizures.

Drug management of status epilepticus• Lorazepam: 0.1 mg/kg IV (up to 8 mg)

over 1 minute (×2 if needed).• Diazepam: 0.3 mg/kg IV (up to 20 mg)

over 1 minute (use if lorazepam is notavailable).

• Fosphenytoin: 20 PE/kg IV at 150 PE/min(may give additional 5 PE/kg).

• Phenobarbital: 20 mg/kg IV at 100 mg/min(can give additional doses of 5–10 mg/kg).

Continued overleaf

Before concluding the discussion of statusepilepticus, it is worthwhile to mention the useof rectal diazepam (Diastat) (textbox).

Dosing for rectal diazepam• <1 yr: not used.• 1–5 yr: 0.5 mg/kg.• 6–11 yr: 0.3 mg/kg.• ≥12yr: 0.2 mg/kg (maximum dose at any

age: 20 mg).

When an IV cannot be established or whenprolonged seizures or clusters of seizures occurat home, rectal diazepam can be of value. Within5 minutes of rectal diazepam, serum levelsare equal to the levels achieved by intra -venous administration. Intranasal midazolam,0.2 mg/kg via a nasal atomizer to a maximumdose of 10 mg, is also widely used.

Drug management of status epilepticus(continued)Valproate and levetiracetam are adjuncts fortreating status epilepticus:• Levetiracetam (Keppra): 30 mg/kg IV at

5 mg/kg/min (maximum of 3 g).• Valproate (Depacon): 20–30 mg/kg IV at

5 mg/kg/min.

If seizure activity persists after the abovemedications have been given, the child isconsidered to be in refractory status epilepticus.There are several options for treating refractorystatus epilepticus, including IV propofol,midazolam (textbox), or pentobarbital. Allrequire intubation and close cardiovascularmonitoring of the patient in an intensive caresetting.

Midazolam: IV bolus 0.2 mg/kg (maximum 10 mg), may repeat ×1 then continuousinfusion starting at 0.1 mg/kg/hr and increaseas needed to a maximum of 2 mg/kg/hr.

Some clinicians prefer pentobarbital overmidazolam. The following is a protocol ofinducing pentobarbital coma as a means to stopstatus epilepticus:• Establish continuous EEG monitoring.• Pentobarbital IV 5 mg/kg boluses until

EEG is in a burst suppression pattern. (69)• Monitor for hypotension; use vasopressors

as necessary.• Once burst-suppression is obtained,

start maintenance pentobarbital at1–3 mg/kg/hr and adjust dose to main-tain burst-suppression on the EEG.

• After 24 hours slow or stop the infusionand monitor the EEG to see ifelectrographic seizures return.


Alterations ofconsciousness

DIAGNOSIS AND CLINICAL FEATURESConsciousness represents the awareness of self and the environment. Loss of or alteredconsciousness is the inability to perceive what isoccurring in the environment and to respond toenvironmental events in a manner that reflectsperception and a purposeful response. Alter -ations of consciousness can be rated rangingfrom mild to profound (textbox).

Terms that describe altered states ofconsciousness• Confusion: misperception of sensory

phenomena often associated with periodsof hyperexcitability and irritabilityalternating with drowsiness.

• Delirium: marked confusion with visualhallucinations and agitation.

• Somnolence: mild decrease in alertness,arousal to voice or light tactile stimulation.

• Lethargy: moderate decrease in alertness,decreased attention span, arousal to voicestimulation with some verbal response.

• Stupor: patient requires vigorous andrepeated stimuli to arouse then returns tounresponsiveness; there may be somepurposeful motor response to noxiousstimuli.

• Coma: unarousable, no vocalization, nopurposeful movements.

In order for a person to be aware of self andthe environment, there must be arousal and theability to process the content of the awareness.These two basic concepts have neuroanatom-ical correlates: arousal = brainstem reticularforma tion (195); content = cerebral hemi -spheres. The brain stem reticular formationextends from the midbrain to the medulla,receives rich inputs from all sensory modalities,and showers the cerebral cortex through outputvia the thalamus and direct connections. Theactivating system maintains arousal and theawake state of the cerebral hemispheres. Oncearoused, the cere bral hemispheres provide theprocessing and the content of awareness. Lossof conscious ness occurs with lesions of thebrainstem affecting the reticular formation,

thalamus bilaterally, or cerebral cortex diffusely.Lesions affecting the reticular formation

in the brainstem usually affect nearby neuro -anatomical structures that control breathing,pupillary response, eye movements, andbrainstem motor control systems. Corticaldysfunction can result from large lesions thataffect most of one cerebral hemisphere or fromdisease processes that affect neuronal functiondiffusely, such as hypoxia or hypoglycemia.Clinicians examining unconscious infants,children, or adolescents must determine if thedisease is located in the brainstem or diffusely inthe cerebral cortex or both (textbox).

Causes of loss of or alteredconsciousness• Trauma: transient brainstem and cortical

dysfunction – concussion; mass lesion –contusion, hemorrhage.

• Electrical: seizure or the postictal state.• Vascular: decreased perfusion (shock,

cardiac arrest); infarction (small brainstemor large cerebral hemisphere).

• Increased intracranial pressure: masseffect (tumor, blood, infection); edema(diffuse or focal).

• Metabolic: hypoxia; hypoglycemia;electrolyte or acid–base abnormalitiesrenal; or hepatic dysfunction.

• Toxic: ingestion, accidental or deliberate.• Infection: encephalitis, post-infectious

encephalopathy

Altered consciousness associated withconfusion and delirium is most often seen inmetabolic, toxic, or infectious etiologies. Whenaltered consciousness is from increased intracra -nial pressure, patients exhibit a constel lation offindings that can include papilledema, pupillaryabnormalities, ophthal moplegia, and flexor orextensor posturing.

The evaluation of an unconsciousness childbegins with the rapid assessment of vital signsand the ABCs of patient care. During this initialassessment, clinicians should obtain a historyfrom witnesses or knowledgeable individuals.The history should include the temporal profileof the patient’s alteration of consciousness. Thesyndromes of increased intracranial pressure and meningeal irritation are important to


recog nize as they are often associated withaltered consciousness and require urgentintervention (textbox).

• Syndrome of increased intracranialpressure: vomiting, lethargy, papilledema,dilated pupils, abducens (CN6) palsy,hypertension, bradycardia, central or uncalherniation.

• Syndrome of meningeal irritation:headache, vomiting, nuchal rigidity,alteration in consciousness.

Risk factors for alteration of consciousnessshould be sought for and pertinent past medicalhistory taken into account. After assessing vitalsigns, the Glasgow coma scale (GCS) provides aquick assessment of arousal, content, andcortical and brainstem function. Scoring enablesmonitoring of the child’s neurological statusover time.Three areas are assessed for the GCS:eye opening to assess arousal, best motorresponse to assess motor function, and bestverbal response to assess cortical content. TheGCS has been modified for children with age-appropriate expectations and norms (textbox).

Pediatric Glasgow coma scaleEye opening:Spontaneous = 4; to speech = 3; to pain = 2;none = 1.Best verbal response:Oriented = 5; words = 4; vocal sounds = 3;cries = 2; none = 1.Best motor response:Obeys commands = 5; localizes pain = 4;flexion to pain = 3; extension to pain = 2;none = 1.

Maximum aggregate scoreBirth–6 mo 96–12 mo 111–2 yr 12 2–5 yr 135 yr and older 14

After assessing the level of consciousness,clinicians should perform a physical exami-nation and attend closely to respiratory pattern,

pupil size and responsiveness, ocular movement,and motor response. When these elements ofthe neurological examination are analyzed incombination, they provide valuable insights asto the level or the anatomical localization of thebrain dysfunction that has caused the coma.Abnormal respiratory pattern can indicate levelsof abnormal brain function:• Cheynes–Stokes: breathing that crescendos

and decrescendos interspersed with briefperiods of apnea. This pattern is seen indiffuse cortical dysfunction.

• Central neurogenic hyperventilation:sustained rapid breathing, indicatesmidbrain dysfunction.

• Ataxic or gasping respirations: irregularunsustained breathing, indicates lowerbrainstem dysfunction.

Eye findings provide important informationabout the comatose patient. The pupillaryresponse indicates intact balance betweenparasympathetic and sympathetic inputs to thepupillary eye muscles. The pupillary findingshave localizing value because of this (textbox).

Pupillary findings of importance incomatose patients• Small but reactive: diffuse cortical

dysfunction, most likely metabolic or toxic.• Large fixed pupils: severe diffuse

hypoxic–ischemic injury.• Unilateral fixed, dilated pupil: uncal

herniation.• Midposition (3–4 mm) fixed: midbrain

injury.

Along with the supranuclear oculomotorpathways, the pathways that control pupillaryresponse have close anatomical proximity to thebrainstem reticular formation. Consequently,assessment of pupil size and responsivenessprovides important insights regarding brainstemfunction and herniation syndromes. After thepupillary light responses are examined, extra -ocular movements are tested. In the comatosepatient this is initially done by using the doll’seye maneuver to assess the oculocephalic reflex;if that is absent, the clinician should use icewater caloric stimulation to test the oculo -vestibular reflex (textbox).


Ocular movement reflexes ofimportance in comatose patients• Oculocephalic (Doll’s eyes reflex): turn

head one way and the eyes conjugatelyturn in the opposite direction. Reflex ispresent in comatose patient with normalbrainstem function. If there is brainstemdysfunction, such as in central herniation,this reflex is lost.

• Oculovestibular (ice water caloric): theunobstructed ear canal is irrigated with icewater. If the patient is unconscious but thebrainstem is intact, the eyes will deviate tothe side of the irrigated ear. Absence ofeye movement is seen with brainstemdysfunction. (The mnemonic COWSapplies only to the caloric responses of theconscious patient.)


389

389 Normal fundus.

390 Retinal hemorrhages (arrow) innonaccidental trauma (child abuse).

391 Papilledema.

390

391

The last key element of the eye examinationis to visualize the fundi (389). If retinalhemorrhages (390) are present in an infant ortoddler, coma may be the result of nonac -cidental trauma. If papilledema is present(391), the child likely has increased intracranialpressure (ICP). Papilledema usually requires upto 24–48 hours of increased ICP before itsappearance.

The motor examination provides additionalinsights regarding the neuroanatomical level ofneurological dysfunction. The clinician shouldassess the spontaneous motor activity, reactiveor induced purposeful movements, withdrawalto noxious stimuli, and posturing. There arebasically two types of posturing, decorticate orflexor, and decerebrate or extensor; both haveanatomical localizing value. In decorticate(flexor) posturing, the upper extremity is inflexion and the lower extremity is in extension.


This occurs with lesions that occur above thelevel of the midbrain. In decerebrate (extensor)posturing, both upper and lower extremities arein extension. This occurs with lesions that are atthe level of the midbrain or below.

The clinician must be alert for signs thatsuggest cerebral herniation. Central herniationsyndrome reflects mass effect involving bothcerebral hemispheres with herniation ofsupratentorial brain structures through thetentorial notch. Unless central herniation isrecognized early and reversed, irreversibledamage to the brainstem and cerebral cortexoccurs. Once the medullary phase is reached the process is irreversible, and the brain dies(Table 49).

MANAGEMENTAfter the airway is secure and oxygen is given,IV access should be established. A bedsideblood glucose level is obtained immediately, andan IV bolus of 25% glucose 2–4 ml/kg is givenfor hypoglycemia. Patients with suspectedmalnutrition or alcohol abuse should receivethiamine 100 mg IV before receiving glucose.At the time of establishing an IV, blood shouldbe drawn for diagnostic laboratory tests(textbox) and urine is obtained as well (usuallya Foley catheter is inserted not only to obtain aurine sample but also to monitor urine output).These tests are screening in nature; theirpurpose is not only diagnostic but to directtherapeutic intervention.

Recommended screening laboratorystudies in comatose childrenElectrolytes, glucose, calcium, liver functiontests, renal function tests, arterial blood gas,serum ammonia, serum lactate, completeblood count, toxicology screen, urinalysis.Blood and urine cultures if febrile.

If laboratory screening fails to establish a diagnosis, the patient should undergo aneuroimaging study. An unenhanced head CTscan is usually obtained first, because the studyis more readily available on an emergent basis,the scanning time is short, and CT identifiesmost conditions that require immediate inter -vention, such as space occupying lesions, cere -bral edema, and intracranial hemorrhages. Ifthe etiology of the coma is still unknown afterthe screening labs and the CT scan, an enhancedhead MRI scan should be obtained. MRIprovides more sensitive information regardingstroke and inflammation as well as superiorvisualization of the posterior fossa. If the child isfebrile, lumbar puncture should be consideredurgently. When there are signs of increased ICPand focal neurological deficits, a head CT scanshould be obtained first to identify features thatmay contraindicate an LP. If there is a high indexof suspicion for meningitis, antibiotics should begiven empirically while awaiting the head CT scan. Whenever a lumbar puncture is

Table 49 Rostral–caudal neurological deterioration of central herniation

Diencephalic Midbrain MedullaryRespiratory Cheyne–Stokes Hyperventilation Gasping,irregularPupils Small, reactive Fixed, midposition Fixed, midposition or dilatedOcular (+) Doll’s Impaired Doll’s (–) Doll’sMotor Decorticate Decerebrate Flaccid

performed, the opening pressure should berecorded. An EEG can be useful at this time inpatients with suspected seizures or encephalitisor if the child must be paralyzed and sedated forventilation.

ADDITIONAL MANAGEMENTSTRATEGIES• Focal mass and intracranial hemorrhages: if

there is a tumor, neurosurgical consultationshould be obtained. Acutely,dexamethasone 5–10 mg (approximately0.25 mg/kg) can be given to reduce theedema associated with the tumor. Surgicalintervention is needed for epiduralhematomas and subdural hematomas ofsignificant size.

• Seizures: subclinical seizures can contributeto altered consciousness. EEG monitoringhas value in this situation.

• Infection: neuroimaging, lumbar puncture,and EEG are helpful in this setting.Therapy is outlined in Chapter 20Infections of the Nervous System.

• Drug ingestion: consult a poison controlcenter for management and therapeuticintervention. Use specific antidotes, whenavailable, such as naloxone for opiateoverdose.

• Fever: hyperthermia should be treated as itwill increase cerebral blood flow and brainmetabolism. The patient should be kept atnormal body temperature. Mild systemichypothermia (33–36°C) for 24 hourspostcardiopulmonary arrest may bebeneficial.

• Increased intracranial pressure: IV fluidsshould be limited to one-half to three-quarters of maintenance to avoidover-hydration. Patients should bemonitored for signs of the syndrome ofinappropriate antidiuretic hormone(SIADH). The head should be elevated tofacilitate venous outflow. A quietenvironment is important; sedation may benecessary. Hyperventilation may have somebenefit to lower the ICP acutely byreducing cerebral blood flow, but it haslimited long term benefit; pCO2 levels lessthen 30 mmHg should be avoided.Osmotic agents, such as mannitol (0.25–1 g/kg over 10–20 minutes) orhypertonic saline, can reduce cerebral

edema. Serum osmolality should bemaintained in the 310–320 mOsm range. TheICP should be kept below 20 mmHg and thecerebral perfusion pressure above 50 mmHg.Monitoring ICP has not been shown to bebeneficial in anoxic brain injury.


Acute CNS injury

Head trauma remains a leading cause ofhospitalization, death, and disability at all ages.The type of head injury varies with age. Inflictedor nonaccidental head trauma is the major causeof craniocerebral injury in infants. Amongtoddlers and young children the leading causesare falls and motor vehicles crashes. Motorvehicle crashes, assault, and sports-relatedinjury are the major causes of head injury inadolescents.

Traumatic brain injury results from linear androtational forces. The linear forces result in siteof impact fracture, hemorrhage, and contusion,as well as countercoup brain injury. Therotational forces generate shearing injury towhite matter tracts which results in diffuseaxonal injury and microhemorrhages. Inaddition to the primary biomechanical forcesthat cause brain injury, secondary injury canresult from anoxia, ischemia, and edema.Medical intervention is directed at treating theresults of the primary brain injury andpreventing further injury from the secondarymechanisms.


Inflicted ornonaccidental traumaInflicted or nonaccidental trauma is caused byshaking, throwing, hitting, strangulation, orsmothering. The perpetrator is usually an adult.The young infant, the most vulnerable victim,has a relatively large head to body ratio, poorneck strength, and considerable skull compli -ance. The infant’s brain is not only susceptibleto the biomechanical factors that result in trau -matic injury, but is also likely to suffersecondary hypoxic–ischemic injury.

The typical clinical scenario is a previouslyhealthy infant, 2 weeks to 6 months of age, whopresents with sudden loss of consciousness,apnea, and hypotonia. The acute traumaticinjury has occurred immediately or very shortlyprior to presentation, and the perpetrator ofthe trauma is usually the caregiver at the timeof the event. Apnea results from the headtrauma; hypotension is frequently present, andseizures often occur within 24 hours of theinjury. Infants with less severe inflicted headtrauma may present with depressed level ofconsciousness, irritability, vomiting, poorfeeding, and seizures.

The clinician must examine the infantcarefully for signs of cutaneous and soft tissueinjury (textbox).

Evaluation of infants with suspectednonaccidental trauma• Noncontrast head CT scan emergently

(with bone algorithm).• Head MRI delineates ischemia/infarction

and injury to vessels and parenchyma. • Assessment for spinal cord injury.• Complete skeletal survey including skull

films (392).• Complete blood count.• Comprehensive metabolic panel to

include electrolytes, glucose, renal andliver function tests.

• Coagulation studies: prothrombin time(PT), partial thromboplastin time (PTT).

• Notification of child protective services.


393

392A plain skull radiography showing a linearskull fracture (arrow).

394 Pathological specimen of the eye showingsubretinal and optic nerve hemorrhages (arrows)consistent with nonaccidental trauma.

394

The head, neck, trunk, buttocks, andextremities should be inspected for unusualpatterns of bruises, marks, or swelling, and theskull, ribs, and long bones should be examined.Abnormal findings should be documented andphotographed. The head circumference shouldbe measured and plotted, and the suturespalpated for evidence of separation (diastasis).

Infants with suspected nonaccidental traumamust have a detailed funduscopic examinationfor retinal hemor rhages (393). Anophthalmologist should be consulted for adilated fundus examination. Retinal and opticnerve sheath hemorrhages (394), uncommonin accidental trauma or cardiopulmonaryresuscitation, usually suggest nonaccidental

392

393 Diffuse, severe retinal hemorrhages in aninfant who sustained an inflicted injury(nonaccidental trauma).

trauma. The most common intracranial injuriesare subdural hematomas, subarachnoidhemorrhages, intraparenchymal hemorrhages,infarctions, and anoxic injury (395–397).

Short falls (<4 ft [1 m] vertically), falls downstairs, walker falls, and collisions with anotherchild or adult do not generate sufficientmechanical force to cause the type of injuriesseen in nonaccidental trauma. There are rarereports that infants with glutaric aciduria type 1,Menkes disease, and type I osteogenesis imper -fecta can present with subdural hematomas, butthe clinical setting and associated findings arerarely confused with inflicted head trauma.


396Axial FLAIR MRI showing an extensivesubdural hematoma (arrows) in nonaccidentaltrauma.

395 Noncontrast cranial CT showing a subdural hematoma (arrow) in a child withnonaccidental trauma.

395 396

397An axial T2-weighted MRI showing alaceration in the right frontal lobe (arrow) in anabused child.

397

ConcussionConcussion remains the most common form ofmild traumatic brain injury in children andadolescents. Children usually recover unevent -fully unless there is recurrent head injury orassociated intracranial hemorrhage. Themanagement of children with concussiontherefore consists of an evaluation for seriousintracranial pathology and anticipatory guidanceto prevent additional head trauma (textbox).

Management of the child with a concussion• Identify impairments of neurological

status: memory, attention, cognition,coordination, headache, or nausea. Ifpresent, the child or adolescent shouldrest, be observed until the symptomsresolve, and not return to play or activityuntil he or she is totally asymptomatic. Ifsymptoms persist, then transport toemergency department for further medicalevaluation. Any loss of consciousnessrequires emergency departmentevaluation.

• Obtain neuroimaging: emergent head CTscan for persistent symptoms or loss ofconsciousness to detect intracranialhemorrhage or edema that requiresfurther intervention. Head CT scan shouldinclude bone algorithm to detect skullfractures. Not all skull fractures will bedetected by CT scan so skull X-rays may beneeded.

• If the patient’s neurological statusimproves to the point that there is noneurological impairment and if there hasbeen brief loss of consciousness andnormal CT scan, the patient can be senthome as long as there are reliablecaretakers.


Concussion represents trauma-inducedneurological dysfunction with or without lossof consciousness. The most common acutesymptoms of concussion are transient con -fusion, amnesia, headache, nausea, vomiting,and unsteadiness. Although less common,temporary cortical blindness and an immediateimpact seizure can occur. The last twosymptoms can occur without demonstrableintracranial hemorrhage, but their occu rrencemandates neuroimaging. Loss of consciousnessis considered the most severe form of concus -sion. Common postconcussive symptomsinclude persistent headache, nausea andvomiting, irritability, listlessness, poor concen -tration, and behavioral changes. Thesesymptoms are usually self-limited, althoughpostconcussion syndrome can persist for severalmonths after head injury.

The child or adolescent should not return toactivities that pose a risk of further concussionuntil totally asymptomatic. Although thepotentially lethal second impact syndromeoccurs rarely, a person who sustains a con -cussion has a high risk of recurrent concussions.Some guidelines suggest that an adolescentwho has had brief symptoms without amnesiaor loss of consciousness that resolve within 20minutes may return to sports activities that day.A more conservative approach is to preventsuch individuals from engaging in sports playuntil cleared by a medical evaluation. If theconcussion is associated with amnesia, theplayer should not return to play for a least 1week. He or she should be asymptomatic at restand upon exertion. If there has been loss ofconsciousness, the player should be out of playfor 1 month and be free of symptoms (e.g.headache, dizziness, changes in behavior) at restor exertion for at least 2 weeks prior to returnto play. The return should be gradual and lessstrenuous activities should be attempted firstbefore returning to full sports activities.

Severe intracranial injury

DIAGNOSIS AND CLINICAL FEATURESConcussion, considered at the mild end of thespectrum of traumatic brain injury, can also beassociated with more severe forms of braininjury. These include intracranial hemorrhages(398) (textbox) which can be associated withherniation syndromes, diffuse cerebral swelling,and axonal injury. Contusion indicatesdemonstrable radiographic (399, 400) injury tobrain parenchyma analogous to a bruise.

Intracranial hemorrhage• Epidural hematoma (398): can be arterial

or venous; causes acute or subacuteneurological symptoms and signs.Commonly supratentorial due to tearing ofthe middle meningeal artery; can also bein the posterior fossa. Lens-shaped on CTor MRI. Requires immediate neurosurgicalconsultation.

• Subdural hematoma (395, 396): causedby tearing of the bridging veins crossingthe subdural space; crescent-shaped onneuroimaging. Produces progressivedepression of mental status with focalneurological deficits or excessive headgrowth in infants. Requires neurosurgicalevaluation and treatment of increasedintracranial pressure.

• Subarachnoid hemorrhage (401): commonwith head trauma. Produces altered mentalstatus, meningeal irritation with headacheand nuchal rigidity, and seizures. CT or MRIshow blood in the subarachnoid spaceover the convexity of the brain or in thesulci, fissures, and cisterns.

• Intraparenchymal hemorrhage,contusions, and lacerations (397): usuallyoccur at the site of direct impact. Oftenlocated in the frontal and temporal lobesat the surface of the brain.

Infants and children with head trauma oftensustain skull fractures, most commonly linear.Fractures usually heal within 1–2 months, butfollow-up is necessary to ensure that the fractureheals and a leptomeningeal cyst does notdevelop. Leptomeningeal cysts occur most often


in the parietal area in children under 3 years ofage with initial fracture separation >3 mm.

Basilar skull fractures can be associated withperiorbital ecchymosis (raccoon eyes), retroau -ricular ecchymosis (Battle’s sign), hemo -tympanum, CSF or bloody otorrhea orrhinorrhea. Surgery may be necessary to repairCSF leaks. Evaluation of a skull fracture is bestaccomplished with a head CT scan with a bonealgorithm. Skull films can be necessary if theclinical index of suspicion for fracture remainshigh, and the CT is negative. Depressed skull fractures require CT and neurosurgicalconsultation.

MANAGEMENTThe management of the child with serve headinjury begins with the ABCs of patient care. Anintravenous line should be established andfluids given to treat shock. Stabilization of theneck is important to prevent worsening of apossible spinal cord injury until cervical spinestability can be confirmed by neurosurgicalconsultation. A GCS score should be assigned,and the neurological examination should focuson cranial nerve and motor function andsensory responses. The patient is closelyexamined to determine the extent of both CNSand systemic injuries. Imaging should includeCT of the head with bone algorithms, as well ascervical spine evaluation by CT or plainradiographs. Neurosurgery should be con -sulted. Medical management should treathypoxia, cerebral hypoperfusion, hyperthermia,and increased intracranial pressure, potentialsecondary mechanisms for worsening braininjury.

Because of the potential for early post-traumatic seizures, an anticonvulsant should beconsidered. Fosphenytoin, 20 mg/kg IV as aloading dose and 5 mg/kg/day in two divideddoses for maintenance, is often used.Levetiracetam, 30 mg/kg IV loading dose and30 mg/kg/day in two divided doses formaintenance, can be used as an alternative. Useof anticonvulsants acutely does not alter the riskof later seizures, but does decrease thecontribution of early seizures to secondarybrain injury.


399398

398A noncontrast cranial CT showing thecharacteristic appearance of an epiduralhematoma (arrows).

400 Coronal gradient recall echo MRI of thebrain in the same child as in 399 showshemosiderin staining (arrow) adjacent to thecontusion.

399Axial T2-weighted MRI showing a cerebralcontusion (arrow) secondary to a motorvehicle crash.

400 401

401A noncontrast cranial CT showing acutesubarachnoid hemorrhage (arrow).

Spinal cord injury

DIAGNOSIS AND CLINICAL FEATURESThree to five percent of spinal cord injuriesaffect persons less then 15 years of age. Motorvehicle accidents, falls, and sport-relatedaccidents cause most spinal cord injuries, mostoften involving the cervical region. Multipleanatomical and developmental factors influencethe vulnerability of infants, children, andadolescents to spinal cord injury (textbox).

Factors influencing the risk of spinalcord injuries in childhood• Relatively large head of the infant.• Underdevelopment of the neck

musculature.• Ligamentous laxity.• Wedge-shaped vertebral bodies.• Incomplete ossification and shallow

angulation of the facet joints.• Dens synchondrosis until 4 years of age.• Fulcrum of neck motion is at the C2–3

level versus C5–6 level in adults.

The mechanisms of spinal cord injury includeforward and lateral flexion, rotation, hyper -extension, and axial compression. These forcesresult in vertebral distraction, dislocation, frac -ture, and disk herniation that cause direct injuryto the cord by concussion, contusion, lacer -ation, hemorrhage, and ischemia. Because of theligamentous laxity of the pediatric spinal cord,spinal cord injury can occur without radi -ographic abnormality (SCIWORA) (textbox).

Spinal cord injury syndromes• Complete cord syndrome: complete loss of

sensory and motor below the level of thelesion; flaccid tone, autonomicdysfunction, and spinal cord shock.

• Central cord syndrome: end artery injury,upper extremities with lower motorneuron findings and dysesthesia; lowerextremities with upper motor neuronfindings.

• Anterior spinal artery syndrome: lowermotor neuron findings at level of the

lesion; upper motor neuron findings belowthe lesion and sensory level at the level ofthe spinal cord lesion; sparing of posteriorcolumn sensory modalities.

• Brown–Sequard, hemicord syndrome:ipsilateral motor and dorsal columnsensory deficit and contralateral pain andtemperature deficit below the level of thespinal cord lesion; usually incomplete;seen with penetrating spinal cord injuryand inflammatory or demyelinatinglesions.

MANAGEMENTThe acute management of childhood spinalcord injury must include immediate stabiliza -tion of the neck and the spinal column. Thisincludes placing the child on a firm backboardand preventing head movement with sandbagsor rolled towels and tape across the forehead. Inthe hospital, a hard cervical collar shouldbe used. An airway and adequate ventilationand oxygenation must be established; circula-tion should be supported with IV fluids.A nasogastric tube should be placed to emptygastric contents, and a Foley catheter should beplaced to establish and monitor urine output.The neurological examination should attend tothe cranial nerves (especially facial sensationwhich can be abnormal in high cervical cordinjury) and sensory and motor function belowthe neck. Serial exams can define the evolutionof spinal cord deficits.

Radiographic evaluation should include thecomplete pediatric spine as there can be multiplelevels of injury. If there are subtle findings orfindings that are inconclusive, CT scan of thearea in question may be needed. MRI is used toimage the injured spinal cord. Neurosurgeryshould be involved early in the management ofthe child with spinal cord injury. Controversypersists regarding the role of corticosteroids inspinal cord injury. Some evidence suggests thatIV methylprednisolone 30 mg/kg infusedwithin 8 hours after the injury followed by 5.4 mg/kg/hr for the next 23 hours mayimprove outcome of the spinal cord injury.


Acute neuromuscularweakness

DIAGNOSIS AND CLINICAL FEATURESAcute progressive bilateral weakness withoutmental status changes is usually due to disease ofthe spinal cord or one of the components of themotor unit (textbox). Spinal cord disease willusually have a combination of sensory andmotor findings, with lower motor neuronfindings at the level of the lesion and uppermotor neuron findings below the level of thelesion. Diseases acutely affecting the motor unitinclude those that affect the anterior horn cell,the nerve root and peripheral nerve, theneuromuscular junction, and the muscle.Infections or postinfectious conditions accountfor the majority of these disorders in thepediatric population.

Considerations for acute weakness inpediatric patientsSpinal cord• Transverse myelitis: weakness progressing

over hours to few days, usually thoraciclevel, sensory level, acute flaccid weaknessin the lower extremities, bladderdysfunction (188).

Anterior horn cell• Acute flaccid paralysis syndrome:

asymmetric ascending paralysis due topoliovirus, nonpolio enteroviruses, andWest Nile virus.

Nerve root and peripheral nerve• Guillain–Barré syndrome: symmetric

ascending paralysis, distal painfuldysesthesia, progression over days to 3 weeks, bladder and autonomicdysfunction. CSF albuminocytologicdissociation, lumbar–sacral nerve rootenhancement on MRI (219).

Neuromuscular junction• Infant botulism: acute descending

paralysis, pupillary dilationophthalmoplegia, constipation, respiratorydistress (325–327, 402).

• Myasthenia gravis: weakness involvingocular muscles, bulbar cranial nerves,proximal muscles; weakness is fatigue-related (338–340).

Muscle• Myositis: progressive muscle weakness,

muscle tenderness, often associated withrhabdomyolysis. When due to influenzavirus characteristically produces intensegastrocnemius muscle pain and toe-walking.

MANAGEMENTRespiratory failure must be anticipated in anyinfant, child, or adolescent with acute weakness.For the ascending paralysis syndromes, thelikelihood of respiratory failure increases consid -erably once the weakness has reached the upperextremities. Vital capacity must be assessed andmonitored serially in all cooperative patients withweakness. Tachypnea, inability to talk in fullsentences, soft muffled voice or cry, and agitationmay be signs of impending respiratory failure inyoung children. These children should beobserved in a setting where there can be a quickskilled response to possible respiratory failure.Early intubation and mechanical ventilation mustbe considered prior to overt respiratory failure.

Transverse myelitisThese patients should have a spinal cord MRI toexclude a compressive lesion, an eye exam to


402

402An infant with bilateral ptosis and dilatedpupils due to infant botulism.

exclude optic neuritis (143), monitoring forcardiovascular instability, Foley catheter forbladder autonomic dysfunction, and a bowelprogram for constipation. High dose IVmethylprednisolone 20 mg/kg/day for 5 dayshas been suggested for treatment. Physicaltherapy is started immediately. Approximately50% of children or adolescents with transversemyelitis recover completely. Unfortunately,some children have permanent paralysis.

Guillain–Barré syndrome (GBS)If the weakness progresses to the point that thepatient cannot walk, IVIG or plasma exchangecan be used. Both are equally efficacious. Werecommend that children or adolescents receiveIVIG 2 g/kg in divided doses over 2 days.Patients with GBS must be observed forrespiratory failure and cardiovascular instability.Urinary retention and dysesthetic pain must bemanaged, as well. The vast majority of childrenwith GBS recover completely.

Myasthenia gravis (MG)MG should be treated initially with an acetyl -cholinesterase inhibitor. Pyridostigmine, themost commonly used medication, is begun at 7 mg/kg/day in three or more divided doses.Muscarinic side-effects are frequent. If thepatient cannot take oral medication,pyridostigmine can be given IV at one-thirtieththe oral dose (1 mg of the IV form equals 30 mgof the oral preparation). If the patient expe -riences myasthenic crisis and cannot swallow,handle oral secretions, or breathe normally, thepatient should be intubated and supported andthe dose of acetylcholinesterase inhibitortemporarily suspended. Other therapeuticmodalities include IVIG, corticosteroids, or plasma exchange transfusion. Long-termmanagement of patients with MG usuallyincludes thymectomy and immunosuppressionwith oral prednisone.

Acute poisonings

DIAGNOSIS AND CLINICAL FEATURESPoisonings, one of the most common childhoodmedical emergencies, often present withalterations of neurological function. Mostpoisonings in childhood involve substancesfound at home. Different methods ofpoisonings should be considered for differentage groups. For the infant, poisonings resultsfrom medication errors or nonaccidental abuse,whereas poisoning in the toddler-aged child isusually an accidental ingestion. Substance abuse,recreational experimentation, and suicideattempts occur in older children or adolescents.Acute poi sonings may mimic other pathologicalprocesses such as metabolic derangements,infections, trauma, neoplasm, or psychiatricillnesses. Neurological presentations ofpoisonings include altered mental status rangingfrom coma to delirium, seizures, generalizedweakness, ataxia, extrapyramidal findings(parkinsonism or dystonia), and autonomicdysfunction. Toxidromes, defined by aconstellation of systemic and neurologicalfindings, can provide important clues to theoffending poison (Table 50). The neurologicalsymptoms and signs usually reflect the effect ofthe drug(s) on CNS neurotrans mitters and theautonomic system.

Caretakers and witnesses should bequestioned carefully about possible exposures.Drugs and substances that are found in thehouse or that the child could have been exposedto should be sought. Any medication, dose, andduration of treatment that the child may bereceiving should be noted. The child’srespiratory and cardiovascular status should beassessed immediately and adequate airway,breathing, and perfusion established. Exami -nation should focus on the toxidromes, as wellas specific organ system assessments. Laboratorystudies should be obtained, including completeblood count, electrolytes, anion gap (textbox),renal and liver function tests, arterial blood gas,and ECG. Blood alcohol or serum drug levelsare ordered when there is appropriate clinicalsuspicion. A toxicology screen of blood and/orurine is typically ordered, but screens vary acrosslaboratories.


Anion gap = [Na] − ([Cl] + [HCO3])(normal = 8 to 16 mEq/l)

Increased anion gap:• Diabetes mellitus.• Renal disease.• Nutritional deficiencies.• Dehydration.• Toxins (salicylates, ethylene glycol,

methanol, alcohol).

Decreased anion gap:• Hyponatremia.• Hyperchloremia.• Lithium intoxication.• Hypothyroidism.• Renal disease.

MANAGEMENTInducing emesis with syrup of ipecac is nolonger recommended. Orogastric lavage can beindicated for certain types of ingestions, butshould not be done in persons with alteredmental status or vulnerable airways. Otherinterventions, such as use of activated charcoal,antidotes (e.g. naloxone), acidification of theurine, or active removal with hemodialysis, arebased on the type and severity of the ingestion.A poison control center should be contacted toprovide specific diagnostic and managementrecommendations.


Table 50 Toxidromes in acute poisoning

Mechanism Signs/symptoms CausesCholinergic Depressed mental status, seizures, muscle fasciculations, and Some types of mushrooms, organophosphate

weakness (DUMBELS: diarrhea, urination, miosis, bronchospasm, pesticides and nerve agents, anticholinesterasesemesis, lacrimation, salivation)

Anticholinergic Depressed mental status, delirium, seizure, mydriasis, dry skin, Atropine, belladonna alkaloids, jimsonweed, someflushing, fever, urinary retention, hypoactive bowels mushrooms, phenothiazines, some antihistamines,

tricyclic antidepressants

Adrenergic Agitation, delirium, seizures, mydriasis, tremulous, diaphoresis, Amphetamines, cocaine, ephedrine, xanthinestachycardia, hypertension

Serotonergic Confusion, tremor, myoclonus, ataxia, fever, flushing, sweating, SSRIs (especially with MAO inhibitors), isoniazid, diarrhea tranylcypromine

Narcotic Altered mental status, seizures, ataxia, miosis, respiratory Opioids, meperidine, propoxyphenesuppression, bradycardia, hypotension, gastric hypomotility

Sedative- Mental status depression, respiratory suppression, miosis, Barbiturates, benzodiazepineshypnotic ataxia, hypotonia

Withdrawal Agitation, hallucinations, anxiety, mydriasis, lacrimation, Alcohol, narcotics, barbiturates, benzodiazepinesdiarrhea, yawning

MAO: monoamine oxidase; SSRI: selective serotonin-reuptake inhibitor

Hypertensiveencephalopathy

Hypertensive encephalopathy can occur duringthe course of any systemic condition producingabrupt elevations in blood pressure. Commoninciting conditions among children andadolescents include poststreptococcal glomeru -lonephritis and acute nephrotic syndrome.Children or adolescents with this disorder havemental status changes, headaches, seizures, andvisual dysfunction, including blurring, obscu -ration, transient blindness, or diplopia. Neuro -logical examination may show papilledema orfocal neurological deficits. Hypertension is a


403

403Axial FLAIR MRI in a child withhypertension shows increased signal intensityposteriorly (arrows) compatible with posteriorreversible encephalopathy syndrome (PRES).

major factor in the posterior reversibleencephalopathy syndrome (PRES); both PRESand hypertensive encephalopathy reflect loss ofcerebrovascular autoregulation. PRES has alsobeen observed in children with sickle cell crisisand systemic lupus erythematosus and duringtherapy with L-asparaginase, ciclosporin, ortacrolimus. Clinical features of this disorderoverlap with those of hypertensive encepha -lopathy. Imaging studies, particularly MRI,show T2 hyperin tensities, especially posteriorly(403). Manage ment consists of antihyper -tensive medication therapy, as needed, andremoval of inciting factors, when possible.

Abbreviations

333

18-FFDG fluorine-18-fluorodeoxyglucoseAABR (ABR) automated auditory brainstem

responseAASA alpha-amino adipic semialdehydeACTH adrenocorticotropic hormoneAD autosomal dominantADC apparent diffusion coefficientADEM acute disseminated encephalomyelitisADHD attention deficit hyperactivity disorderAED antiepileptic drugAIDP acute inflammatory demyelinating

polyneuropathyAIDS acquired immunodeficiency syndromeANA antinuclear antibodyAR autosomal recessiveARC arthrogryposis, renal dysfunction,

cholestasis syndromeASD autism spectrum disorderASO antistreptolysin OAT ataxia telangiectasiaAVM arteriovenous malformationBAEP brainstem auditory evoked potentialBAER brainstem auditory evoked responseBECTS benign epilepsy with centrotemporal

spikesBiPAP bilevel positive airway pressureBOLD blood oxygen level dependentBPV benign paroxysmal vertigoBS bone scanCADASIL cerebral autosomal dominant

arteriopathy with subcortical infarcts andleukoencephalopathy

CDG congenital disorders of glycosylationCGH comparative genomic hybridizationCHARGE coloboma of the eye, heart anomaly,

choanal atresia, retarded growth, genitalabnormality, and ear abnormality

CIDP chronic inflammatory demyelinatingpolyneuropathy

CK creatine kinaseCMAP compound muscle action potentialCMT Charcot–Marie–Tooth diseaseCMV cytomegalovirusCN cranial nerveCNS central nervous systemCP cerebral palsy

CPAP continuous positive airway pressureCPS complex regional pain syndromeCRP C-reactive proteinCRS congenital rubella syndromeCSF cerebrospinal fluidCSWS continuous spike-wave of slow wave

sleepCT computed tomographyCTA computed tomography angiographyDDAVP desmopressinDIC disseminated intravascular coagulationDMD Duchenne/Becker muscular dystrophyDMPK dystrophia myotonica protein kinasedMRI diffusion-weighted magnetic resonance

imagingDNA deoxyribonucleic acidDQ developmental quotientDRESS drug rash with eosinophilia and

systemic symptomsDTI diffusion tensor imagingDTR deep tendon reflexDWI diffusion-weighted imagingECG electrocardiography/electrocardiogramEEG electroencephalography/electro -

encephalogramELISA enzyme linked immunosorbent assayEMG electromyography/electromyogramERG electroretinogramESES electrical status epilepticus of sleepESR erythrocyte sedimentation rateFASD fetal alcohol spectrum disorderFGFR fibroblast growth factor receptorFIRDA frontal intermittent rhythmic delta

activityFISH fluorescent in situ hybridizationFLAIR fluid-attenuated inversion recoveryfMRI functional magnetic resonance imagingFVC forced vital capacityFXTAS fragile X-associated tremor and ataxia

syndromeGAA acid alpha-glucosidaseGAMT guanidinoacetate methyltransferaseGBS Guillain–Barré syndromeGCS Glasgow coma scaleGER gastroesophageal refluxGRE gradient recall echo

Abbreviations334

GTP guanosine triphosphateH&E hematoxylin and eosinHAART highly-active antiretroviral therapyHIE hypoxic–ischemic encephalopathyHIV human immunodeficiency virusHNPP hereditary neuropathy with liability to

pressure palsyHSV herpes simplex virusHVA homovanillic acidICP intracranial pressureIFA immunofluorescent assayIgG immunoglobulin GIIH idiopathic intracranial hypertensionIQ intelligence quotientIUGR intrauterine growth retardationIVH intraventricular hemorrhageIVIG intravenous immune globulinJME juvenile myoclonic epilepsyKF Kayser–Fleischer LCM lymphocytic choriomeningitisLD learning disabilityLGA large for gestational ageLGS Lennox–Gastaut syndromeLHON Leber’s hereditary optic neuropathyLKS Landau–Kleffner syndromeLMN lower motor neuronMAE myoclonic–astatic epilepsy of DooseMAO monoamine oxidaseMCAD medium chain acyl-coA

dehydrogenaseMeCP2 methyl CpG binding protein 2MEG magnetoencephalographyMELAS mitochondrial myopathy,

encephalopathy, lactic acidosis, and strokesyndrome

MG myasthenia gravisMIBG meta-iodobenzylguanidineMMC myelomeningoceleMPS mucopolysaccharide MRA magnetic resonance angiographyMRI magnetic resonance imagingMRS magnetic resonance spectroscopyMRV magnetic resonance venographyMS multiple sclerosisMSLT multiple sleep latency testMSR muscle stretch reflexMUP motor unit potentialNAA N-acetylaspartateNADH nicotinamide adenine dinucleotide

hydrideNARP neuropathy, ataxia, and retinitis

pigmentosaNCL neuronal ceroid lipofuscinosis

NCV nerve conduction velocityNF-1 neurofibromatosis type 1NICU newborn intensive care unitNIF negative inspiratory forceNMO neuromyelitis opticaNSAID nonsteroidal anti-inflammatory drugOAE otoacoustic emissionsOCD obsessive compulsive disorderOFC occipital-frontal circumferenceOME otitis media with effusionOMS opsoclonus–myoclonus syndromeOTC ornithine transcarbamylasePANDAS pediatric autoimmune

neuropsychiatric disorders associated withstreptococcal infection

PCA phase contrast angiographyPCR polymerase chain reactionPDD-NOS pervasive developmental disorder

not otherwise specifiedPE phenytoin equivalentPET positron emission tomographyPEX peroxisomal (gene)PF plain radiographPKU phenylketonuriaPLED periodic lateralized epileptiform

dischargePLP proteolipid proteinPML progressive multifocal

leukoencephalopathyPMP22 peripheral myelin protein 22pMRI perfusion-weighted magnetic resonance

imagingPNET primitive neuroectodermal tumorPRES posterior reversible encephalopathy

syndromePROM premature rupture of membranesPT prothrombin timePTT partial thromboplastin timePVL periventricular leukomalaciaRAS reticular activating systemREM rapid eye movementRNA ribonucleic acidRT-PCR reverse transcription polymerase

chain reactionSD standard deviationSGA small for gestational ageSIADH syndrome of inappropriate

antidiuretic hormoneSIDS sudden infant death syndromeSLE systemic lupus erythematosusSLI specific language impairmentSMA spinal muscular atrophySMN1 survival motor neuron-1

SNHL sensorineural hearing lossSPECT single photon emission computed

tomographySPGR spoiled gradient recallSSPE subacute sclerosing panencephalitisSSRI selective serotonin-reuptake inhibitorSUDEP sudden unexplained death in epilepsySWS Sturge–Weber syndromeTBI traumatic brain injuryTc-HMPAO technetium-99-m-

hexamethylpropylene amine oxime

TOF time-of-flightTS tuberous sclerosisTSC tuberous sclerosis complexTSH thyroid stimulating hormoneUMN upper motor neuronUS ultrasoundVEP visual evoked potentialVMA vanillylmandelic acidVZV varicella-zoster virusWBC white blood cellXLR X-linked recessive

Further reading and bibliography 335

Further readingand bibliographyChapter 1: THE PEDIATRICNEUROLOGICAL EXAMINATIONHaere AF (1992). DeJong’s The Neurologic

Examination, 5th edn. Lippincott Williams& Wilkins, Philadelphia.

Larsen PD, Stensas SS. NeuroLogicExamination: a neuroanatomicalapproach. (Accessed 11/10/2010.)http://library.med.utah.edu/neurologicexam/html/home_exam.html

Mayo Clinic (1997). Examinations inNeurology, 7th edn. Elsevier, Amsterdam.

Swaiman KF (2006). General aspects of thepatient’s neurologic history. In: SwaimanKF, Ashwal S, Ferriero DM (eds). PediatricNeurology. Principles and Practice, 4th edn.Mosby/Elsevier, Philadelphia, pp. 3–16.

Chapter 2: NEUROIMAGINGAtlas SW (ed) (2008). Magnetic Resonance

Imaging of the Brain and Spine, 4th edn.Lippincott-Williams & Wilkins,Philadelphia.

Barkovich AJ (ed) (2005). PediatricNeuroimaging, 4th edn. Lippincott-Williams & Wilkins, Philadelphia.

Barkovich AJ (ed) (2007). Diagnostic ImagingPediatric Neuroradiology, Amirsys Inc., SaltLake City.

Brandao LA, Domingues RC (eds) (2004).MR Spectroscopy of the Brain. Lippincott-William & Wilkins, Philadelphia.

Mukherjee P (ed) (2006). Advanced pediatricimaging. Neuroimaging Clin N Am16:1–216.

Chapter 3: ELECTROPHYSIOLOGICALEVALUATION OF INFANTS, CHILDREN,AND ADOLESCENTSBlum AS, Rutkove SB (2007). The Clinical

Neurophysiology Primer. Humana Press,Springer, New York.

Edebol Eeg-Olofson K (ed) (2006). PediatricClinical Neurophysiology. InternationalReview of Child Neurology Series,MacKeith Press, London.

http://library.med.utah.edu/neurologicexam/html/home_exam.html

http://library.med.utah.edu/neurologicexam/html/home_exam.html

Kimura J (2001). Electrodiagnosis in Diseases ofNerve and Muscle. Principles and Practice,3rd edn. Oxford University Press, NewYork.

Chapter 4: CEREBROSPINAL FLUIDFishman RA (1980). Cerebrospinal Fluid in

Diseases of the Nervous System. WB Saunders,Philadelphia.

Johansen C (2003). Choroid plexus,cerebrospinal fluid circulatory dynamics:impact on brain growth, metabolism andrepair. In: Conn PM (ed). Neuroscience inMedicine, 2nd edn. Humana Press,Totowa, pp. 173–200.

Pearl PL, Taylor JL, Trzcinski S, Skohl A(2007). The pediatric neurotransmitterdisorders. J Child Neurol 22:606–16.

Roos K (2005). Cerebrospinal fluid. In: RoosK (ed). Principles of Neurological InfectiousDisease. McGraw Hill, New York.

Wiegand C, Richards P (2007). Measurementof intracranial pressure in children: acritical review of current methods. DevMed Child Neurol 49:935–41.

Zheng W, Chodobski A (2005). TheBlood–Cerebrospinal Fluid Barrier. Chapmanand Hall/CRC, Boca Raton.

Chapter 5: GENETIC EVALUATIONGene Tests. http://www.genetests.org.

(Accessed 11/10/2010.)Jorde L, Carey JC, Bamshad M, White R

(2007). Medical Genetics. Mosby, St. Louis.OMIM. On-Line Mendelian Inheritance in

Man. (Accessed 11/10/2010.)http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim

Chapter 6: NEWBORN SCREENINGAND METABOLIC TESTINGBotkin JR, Clayton EW, Fost N, et al. (2006).

Newborn screening technology: proceedwith caution. Pediatrics 117:1793–9.

Kayser MA (2008). Inherited metabolicdiseases in neurodevelopmental andneurobehavioral disorders. Pediatr ClinNorth Am 15:27–31.

Kemper AR, Boyle CA, Aceves J, et al.(2008). Long-term follow-up afterdiagnosis resulting from newbornscreening: statement of the US Secretary ofHealth and Human Services’ AdvisoryCommittee on Heritable Disorders andGenetics Disease in Newborns andChildren. Genet Med 10:259–61.

Therrell BL, Hannon WH (2006). Nationalevaluation of US newborn screeningsystem components. Ment Retard DevDisabil Res Rev 12:236–45.

Chapter 7: DISORDERS OFDEVELOPMENTChahrour M, Zoghbi HY (2007). The story

of Rett syndrome: from clinic toneurobiology. Neuron 56:422–37.

Moeschler JB (2008). Genetic evaluation ofintellectual disabilities. Semin PediatrNeurol 21:117–22.

Shevell M (2006). Office evaluation of thechild with developmental delay. SeminPediatr Neurol 13:256–61.

Shevell M, Ashwal S, Donley D, et al. (2003).Practice parameter: evaluation of the childwith developmental delay. Report of theQuality Standards Subcommittee of theAmerican Academy of Neurology and thePractice Committee of the ChildNeurology Society. Neurology 60:367–80.

Srour M, Mazer B, Shevell M (2006). Analysisof clinical features predicting etiologic yieldin developmental delay. Pediatrics118:139–45.

Chapter 8: DISORDERS OF BEHAVIORAND COGNITIONBishop DV (2009). Genes, cognition and

communication: insights fromneurodevelopmental disorders. Ann N YAcad Sci 1156:1–18.

Calles JL Jr (2008). Use of psychotropicmedications in children withdevelopmental disabilities. Pediatr ClinNorth Am 55:1227–40.

Deokar AM, Huff MB, Omar HA (2008).Clinical management of adolescents withautism. Pediatr Clin North Am55:1147–57.

Further reading and bibliography336

http://www.genetests.org



Deutsch CK, Dube WV, McIlvane WJ (2008).Attention deficits, attention-deficithyperactivity disorder, and intellectualdisabilities. Dev Disabil Res Rev 14:285–92.

Ekinci O, Titus JB, Rodopman AA, BerkemM, Trevathan E (2009). Depression andanxiety in children with epilepsy.Prevalence, risk factors and treatment.Epilepsy Behav 14:8–18.

Kelly DP (2008). Learning disorders inadolescence: the role of the primary carephysician. Adolesc Med State Art Rev19:229–41, viii.

Myers SM, Johnson CP (2007). Managementof children with autism spectrum disorders.American Academy of Pediatrics Councilon Children with Disabilities. Pediatrics120:1162–82.

Rapin I, Tuchman RF (2008). Autism:definition neurobiology, screening,diagnosis. Pediatr Clin North Am55:1129–46.

Salpekar JA, Dunn DW (2007). Psychiatricand psychosocial consequences of pediatricepilepsy. Semin Pediatr Neurol 14:181–8.

Shipman K, Taussig H (2009). Mental healthtreatment of child abuse and neglect. Thepromise of evidence-based medicine.Pediatr Clin North Am 56:417–28.

Chapter 9: DISORDERS OF LANGUAGEAND HEARINGBertoglio K, Hendren RL (2009). New

developments in autism. Psychiatr ClinNorth Am 32:1–14.

Hone SW, Smith RJ (2002). Medicalevaluation of pediatric hearing loss:laboratory, radiographic and genetictesting. Otolaryngol Clin North Am35:751–64.

Peterson RL, McGrath LM, Smith SD,Pennington BF (2007). Neuropsychologyand genetics of speech, language andliteracy disorders. Pediatr Clin North Am54:543–61, vii.

Prasse JE, Kikano GE (2008). Stuttering: anoverview. Am Fam Phys 77:1271–6.

Shaywitz SE, Shaywitz BA (2008). Payingattention to reading: the neurobiology ofreading and dyslexia. Dev Psychopathol20:1329–49.

Smith RJ, Bale JF Jr, White KR (2005).Sensorineural hearing loss in children.Lancet 365:879–90.

Wells EM, Walsh KS, Khademian ZP, KeatingRF, Packer RJ (2008). The cerebellarmutism syndrome and its relationship tocerebellar cognitive function and cerebellaraffective disorder. Dev Disabil Res Rev14:221–8.

Chapter 10: DISORDERS OF HEAD SIZEAND SHAPECunningham ML, Heike CL (2007).

Evaluation of the infant with an abnormalskull shape. Curr Opin Pediatr 19:645–5.

Dover MS (2008). Abnormal skull shape:clinical management. Pediatr Radiol 38(Suppl 3):S484–7.

Glass RB, Fernbach SK, Norton KI, Choi PS,Naidich TP (2004). The infant skull: avault of information. Radiographics24:507–22.

Lekovic GP, Bristol RE, Rekate HL (2004).Cognitive impact of craniosynostosis.Semin Pediatr Neurol 11:305–10.

Lian G, Sheen V (2006). Cerebraldevelopment disorders. Curr Opin Pediatr18:614–20.

Losee JE, Mason AC (2005). Deformationalplagiocephaly: diagnosis, prevention andtreatment. Clin Plast Surg 32:53–64.

Vertinsky AT, Barnes PD (2007).Macrocephaly, increased intracranialpressure and hydrocephalus in the infantand young child. Top Magn Reson Imaging18:31–51.

Wilkie AO, Bochukova EG, Hansen RM, et al. (2007). Clinical dividends from themolecular genetic diagnosis ofcraniosynostosis. Am J Med Genet A143A:1941–9.

Williams CA (2005). Neurological aspects ofAngelman syndrome. Brain Dev 27:88–94.

Chapter 11: DISORDERS OF CRANIALNERVESBorchert M, Garcia-Fillon P (2008). The

syndrome of optic nerve hypoplasia. CurrNeurol Neurosci Rep 8:395–403.


Cassidy L, Taylor D (1999). Congenitalcataract and multisystem disorders. Eye13:464–73.

Hertle RW (2008). Nystagmus in infancy andchildhood. Semin Ophthalmol 23:307–17.

Lam BL, Morais CG Jr, Pasol J (2008).Drusen of the optic nerve. Curr NeurolNeurosci Rep 8:404–8.

Liam SA, Siatkowski RM (2004). Pediatricneuro-ophthalmology. Curr OpinOphthalmol 15:437–43.

McMillan HJ, Keene DL, Jacob P,Humphreys P (2007). Ophthalmoplegicmigraine: inflammatory neuropathy withsecondary migraine? Can J Neurol Sci34:349–5.

Pohl D (2008). Epidemiology,immunopathogenesis and management ofpediatric central nervous systemdemyelinating disorders. Curr Opin Neurol21:366–72.

Singhi P, Jain V (2003). Bell’s palsy inchildren. Semin Pediatr Neurol 10:289–97.

Thompson EO, Smoker WRK (1994).Hypoglossal nerve palsy: a segmentalapproach. RadioGraphics 14:939–58.

Chapter 12: DISORDERS OFPERIPHERAL NERVESConnolly AM (2001). Chronic inflammatory

demyelinating polyneuropathy inchildhood. Pediatr Neurol 24:177–82.

Hughes RA, Raphaël JC, Swan AV, vanDoorn PA (2006). Intravenousimmunoglobulin for Guillain-Barrésyndrome. Cochrane Database Syst Rev Jan25;(1):CD002063.

Malessy MJ, Pondaag W (2009). Obstetricbrachial plexus injuries. Neurosurg Clin NAm 20:1–14

McDonald CM (2001). Peripheralneuropathies of childhood. Phys MedRehabil Clin N Am 12:473–90.

Wilder RT (2006). Management of pediatricpatients with complex regional painsyndrome. Clin J Pain 22:443–8.

Williams S, Horrocks IA, Ouvier RA, Gillis J,Ryan MM (2007). Critical illnesspolyneuropathy and myopathy in pediatricintensive care: a review. Pediatr Crit CareMed 8:18–22.

Chapter 13: DISORDERS OF GAIT ANDBALANCEHaas RH, Parikh S, Falk MJ, Saneto RP, Wolf

NI, Darin N, Cohen BH (2007).Mitochondrial disease. A practicalapproach for primary care physicians.Pediatrics 120:1326–33.

Bernard G, Shevell M (2008). The wobblychild: an approach to inherited ataxias.Semin Pediatr Neurol 15:194–208.

Pandolfo M (2003). Friedreich ataxia. SeminPediatr Neurol 10:163–72.

Ryan MM, Engle CC (2003). Acute ataxia inchildhood. J Child Neurol 18:309–16.

van der Knaap MS, Pronk JC, Scheper GC(2006). Vanishing white matter disease.Lancet Neurol 5:413–23.

Waldman A, O’Connor E, Tennekoon G(2006). Childhood multiple sclerosis: areview. Ment Retard Dev Disabil Res Rev12:147–56.

Chapter 14: DISORDERS OF SLEEPKotagal S (2008). Parasomnias in childhood.

Curr Opin Pediatr 20:659–65.Peterson PC, Husain AM (2008). Pediatric

narcoplepsy. Brain Dev 30:609–23.Szuhay G, Rotenberg J (2009). Sleep apnea in

pediatric neurological conditions. CurrNeurol Neurosci Rep 9:145–52.

Trenkwalder C, Paulus W, Walters AS (2005).Restless legs syndrome. Lancet Neurol4:465–75.

Chapter 15: DISORDERS OF THENEWBORNAllen MC (2008). Neurodeveopmental

outcomes of premature infants. Curr OpinNeurol 21:123–8.

Chau V, Poskitt KJ, Miller SP (2009).Advanced neuroimaging techniques for theterm newborn with encephalopathy.Pediatr Neurol 40:181–8.

du Plessis AJ (2008). Cerebrovascular injuryin premature infants: currentunderstanding and challenges for futureprevention. Clin Perinatol 35:609–41.

Kirton A, deVeber G (2009). Advances inperinatal ischemic stroke. Pediatr Neurol40:205–14.


Laptook AR (2009). Use of therapeutichypothermia in the term infant withhypoxic-ischemic encephalopathy. PediatrClin North Am 56:601–16.

Silverstein FS, Jensen FE (2007). Neonatalseizures. Ann Neurol 62:112–20.

Chapter 16: ACUTE FOCAL DEFICITSBanwell B, Ghezzi A, Bar-Or A, Mikaeloff Y,

Tardieu M (2007). Multiple sclerosis inchildren: clinical diagnosis, therapeuticstrategies, and future directions. LancetNeurol 6:887–902.

Bernard TJ, Goldenberg NA, Armstrong-Wells J, et al. (2008). Treatment ofchildhood arterial stroke. Ann Neurol63:679–96.

Chabas D, Strober J, Waubant E (2008).Pediatric multiple sclerosis. Curr NeurolNeurosci Rep 8:434–4.

Chan AK, deVeber G, Monagle P, et al.(2003). Venous thrombosis in children. J Thromb Haemost 1:1443–55.

Kirton A, Westmacott R, deVeber G (2007).Pediatric stroke: rehabilitation of thedeveloping brain. NeuroRehabilitation22:371–82.

Menge T, Kieseier BC, Nessler S, et al.(2007). Acute disseminatedencephalomyelitis: an acute hit against thebrain. Curr Opin Neurol 20:247–54.

Pittock SJ, Lucchinetti CF (2006).Inflammatory transverse myelitis: evolvingconcepts. Curr Opin Neurol 16:362–8.

Roach ES, Golomb MR, Adams R, et al.(2008). Management of stroke in infantsand children: a scientific statement from aSpecial Writing Group of the AmericanHeart Association Stroke Council and theCouncil on Cardiovascular Disease in theYoung. American Heart Association StrokeCouncil; Council on CardiovascularDisease in the Young. Stroke 39:2644–91.

Chapter 17: THE DYSMORPHIC CHILDAu KS, Ward CH, Northrup H (2008).

Tuberous sclerosis complex: diseasemodifiers and treatment. Curr Opin Pediatr20:628–33.

Comi AM (2007). Update on Sturge–Webersyndrome: diagnosis, treatment,quantitative measures and controversies.Lymphat Res Biol 5:257–74.

Cornish K, Turk J, Hagerman R (2008). TheFragile X continuum: new advances andperspectives. J Intellect Disabil Res52:469–82.

Davidson MA (2008). Primary care forchildren and adolescents with Downsyndrome. Pediatr Clin North Am55:1099–111.

GeneTests. http://www.genetests.org.(Accessed 11/10/2010.)

Gerber PA, Antal AS, Neumann NJ, et al.(2009). Neurofibromatosis. Eur J Med Res14:102–5.

Jones K (2005). Smith’s Recognizable Patternsof Human Malformation, 6th edn. ElsevierSaunders, Philadelphia.

Lew SM, Kothbauer KF (2007). Tetheredcord syndrome: an updated review. PediatrNeurosurg 43:236–48.

Chapter 18: HEADACHESLewis DW, Ashwal S, Dahl G, et al. (2002).

Practice parameter: evaluation of childrenand adolescents with recurrent headaches:Report of the Quality StandardsSubcommittee of the American Academyof Neurology and the Practice Committeeof the Child Neurology Society. Neurology50:490–8.

Lewis DW, Ashwal SA, Hershey A, et al.(2004). Practice parameter:pharmacological treatment of migraineheadache in children and adolescents:Report of the Quality StandardsSubcommittee of the American Academyof Neurology and the Practice Committeeof the Child Neurology Society. Neurology63:2215–24.

Lewis D, Gozzo YF, Avner MT (2005). The‘other’ primary headaches in children andadolescents. Pediatr Neurol 33:303–13.

Mack KJ, Gladstein J (2008). Management ofchronic daily headaches in children andadolescents. Paediatr Drugs 10:23–9.

NINDS. Headaches: Hope through Research.http://www.ninds.nih.gov/disorders/headache/detail_headache.htm (Accessed11/10/2010.)


http://www.genetests.org

http://www.ninds.nih.gov/disorders/headache/detail_headache.htm

http://www.ninds.nih.gov/disorders/headache/detail_headache.htm

Walker DM, Teach SJ (2008). Emergencydepartment treatment of primaryheadaches in children and adolescents.Curr Opin Pediatr 20:248–54.

Winner P (2008). Pediatric headache. CurrOpin Neurol 21:316–22.

Wolf A, Hutcheson KA (2008). Advances inevaluation and management of pediatricidiopathic intracranial hypertension. CurrOpin Ophthalmol 19:391–7.

Chapter 19: HYPOTONIA ANDWEAKNESSArnon SS, Schechter R, Maslanka SE, Jewell

NP, Hatheway CL (2006). Humanbotulism immune globulin for thetreatment of infant botulism. N Engl J Med354:462–71.

Chiang LM, Darras BT, Kang PB (2009).Juvenile myasthenia gravis. Muscle Nerve39:423–43.

Hall JG (1997). Arthrogryposis multiplexcongenita: etiology, genetics, classification,diagnostic approach, and general aspects.J Pediatr Orthop B 6:159–66.

Harris SR (2008). Congenital hypotonia:clinical and developmental assessment. DevMed Child Neurol 50:889–92.

Thompson JA, Filloux FM, Van Orman CB, et al. (2005). Infant botulism in the age ofbotulism immune globulin. Neurology64:2029–32.

Tidball JG, Wehling-Henricks M (2004).Evolving therapies for Duchenne musculardystrophy: targeting downstream events.Pediatr Res 56:831–41.

Tsao CY, Mendell JR (1999). The childhoodmuscular dystrophies: making order out ofchaos. Semin Neurol 19:9–23.

Wang CH, Finkel RS, Bertini ES, et al.(2007). Consensus statement for thestandard of care in spinal muscular atrophy.J Child Neurol 22:1027–49.

Chapter 20: INFECTIONS OF THECENTRAL NERVOUS SYSTEMBale JF (2006). Viral infections of the nervous

system. In: Swaiman KF, Ashwal S,Ferriero DM (eds). Pediatric Neurology:Principles and Practice, Mosby/Elsevier,Philadelphia, pp. 1598–1629.

Cruz AT, Starke JR (2008). Treatment oftuberculosis in children. Expert Rev AntiInfect Ther 6:939–57.

Hayes EB, O’Leary DR (2004). West Nilevirus infection: a pediatric perspective.Pediatrics 113:1375–81.

Kimberlin D (2007). Herpes simplex virusinfections of the newborn. Semin Perinatol21:19–25.

Mushahwar IS (ed) (2007). Congenital andother related infectious diseases of thenewborn. Perspect Med Virol 13, Elsevier.

Peltola H, Roine I (2009). Improving theoutcomes in children with bacterialmeningitis. Curr Opin Infect Dis 22:250–5.

Riordan A, Bugembe T (2009). Update onantiretroviral therapy. Arch Dis Child94:70–4.

Whitley RJ (2008). Therapy of herpes virusinfections in children. Adv Exp Med Biol609:216–32.

Chapter 21: MOVEMENT DISORDERSDale RC (2005). Post-streptococcal

autoimmune disorders of the centralnervous system. Dev Med Child Neurol47:785–91.

Dooley JM (2006). Tic disorders in childhood.Semin Pediatr Neurol 13:231–42.

Dressler D, Benecke R (2005). Diagnosis andmanagement of acute movement disorders.J Neurol 252:1299–306.

Gilbert D (2006). Treatment of children andadolescents with tics and Tourettesyndrome. J Child Neurol 21:690–700.

Paolicchi JM (2002). The spectrum ofnonepileptic events in children. Epilepsia43 (Suppl 3):60–4.

Sanger TD (2003). Pathophysiology ofpediatric movement disorders. J ChildNeurol 18 (Suppl):S9–24.

Stern JS, Bruza S, Robertson MM (2005).Gilles de la Tourette’s syndrome and itsimpact in the UK. Postgrad Med J81:12–19.

Walker AR, Tani LY, Thompson JA, et al.(2007). Rheumatic chorea: relationship tosystemic manifestations and response tocorticosteroids. J Pediatr 151:679–83.

Wolf DS, Singer HS (2008). Pediatricmovement disorders: an update. Curr OpinNeurol 21:491–6.


Chapter 22: SEIZURES ANDPAROXYSMAL DISORDERSArzimanoglou A, Guerrine R, Aicardi J

(2004). Aicardi’s Epilepsy in Children, 3rdedn. Lippincott Williams & Wilkins,Philadelphia.

Epilepsy Foundation. http://www.epilepsyfoundation.org (Accessed 11/10/2010.)

Hirtz D, Ashwal SA, Berg A, et al. (2000).Practice parameter: evaluating a firstnonfebrile seizure in children: Report ofthe Quality Standards Subcommittee of theAmerican Academy of Neurology and thePractice Committee of the ChildNeurology Society. Neurology 55:616–23.

Hirtz D, Berg A, Bettis D, et al. (2003).Practice parameter: treatment of the childwith a first unprovoked seizure: Report ofthe Quality Standards Subcommittee of theAmerican Academy of Neurology and thePractice Committee of the ChildNeurology Society. Neurology 60:166–75.

Kossoff EH, Zupec-Kania BA, Amark PE, et al. (2009). Optimal clinical managementof children receiving the ketogenic diet:recommendations of the InternationalKetogenic Diet Study Group. Epilepsia50:304–17.

Mackay MT, Weiss SK, Adams-Webber T, et al. (2004). Practice parameter: medicaltreatment of infantile spasms: Report of theQuality Standards Subcommittee of theAmerican Academy of Neurology and thePractice Committee of the ChildNeurology Society. Neurology 62:1668–81.

Nickels K, Wirrell E (2008). Electrical statusin sleep. Semin Pediatr Neurol 15:50–60.

Panayiotopoulos CP, Michael M, Sanders S,Valeta T, Koutroumanidis M (2008).Benign childhood focal epilepsies.Assessment of established and newlyrecognized syndromes. Brain131:2264–86.

Parisi P, Bombardieri R, Curatolo P (2007).Current role of vigabatrin in infantilespasms. Eur J Paediatr Neurol 11:331.

Pellock JM, Bourgeois BFB, Dodson EW,Nordli DR, Sankar R (2008). PediatricEpilepsy and Therapy, 3rd edn. DemosMedical Publishing, New York.

Chapter 23: PEDIATRICNEUROLOGICAL EMERGENCIESChiesa A, Duhaime AC (2009). Abusive head

trauma. Pediatr Clin North Am 56:317–31.Gorelick MH, Blackwell CD (2005).

Neurologic emergencies. In: Fleisher GR,Ludwig S, Henretig FM, et al. (eds).Textbook of Pediatric Emergency Medicine,5th edn. Lippincott-Williams and Wilkins,Philadelphia, pp. 759–82.

Mami AG, Nance ML (2008). Managementof the mild head injury in the pediatricpatient. Adv Pediatr 55:385–94.

Mungan NK (2007). Update on shaken babysyndrome. Curr Opin Ophthalmol18:392–7.

Pellock JM (2007). Overview: definitions andclassifications of seizure emergencies. J Child Neurol 22:9s–13s.

Shemie SD, Pollack MM, Morioka M, BonnerS (2007). Diagnosis of brain death inchildren. Lancet Neurol 6:87–92.


http://www.epilepsyfoundation.org

http://www.epilepsyfoundation.org

Note: Page references in boldrefer to the main discussion of atopic and those in italic refer totables or boxed material.

abducens nerveassessment 19–20disorders 20, 144, 207

abscess, brain 273absence seizures 52accessory nerve 22Achilles tendon reflexes 28, 261achondroplasia 119aciclovir (acyclovir) 146, 278,

278, 282acoustic nerve disorders 147ACT algorithms 76acute disseminated

encephalomyelitis (ADEM)93, 134, 135, 168, 169, 275,276

acute inflammatorydemyelinatingpolyneuropathy (AIDP), see

Guillain–Barré syndromeacute transverse myelitis 167acylcarnitine profile 77Adie pupil 141adrenergic agents, toxicity 331adrenocorticotropic hormone

(ACTH) 232, 312adrenoleukodystrophy 77, 99,

218advanced sleep-phase syndrome

180Aicardi syndrome 19, 219Aicardi–Goutières syndrome

216ALDH7A1 gene 194alertness 13allodynia 242Alport syndrome 112, 227alternative therapies 244amblyopia 20, 142amino acids, plasma 77amitriptyline 244, 244ammonia, plasma 77amoxicillin 284ampicillin 272anal wink 26anencephaly 238–9aneurysm, middle cerebral artery

42Angelman syndrome 210, 222,

257

Angelman syndrome (continued)case scenario 90diagnosis 90gait 32, 222, 292genetics 107, 222language deficits 107, 222physical features 107, 117,

123, 124angiofibroma, facial 230angiography

catheter 42CT 40, 215MR 37–8, 191

angiomaintracranial 234, 235retinal 228

anion gap 330, 331ankle jerk 28Anopheles spp. 286anosmia 132antebrachial cutaneous nerves

156anterior fontanel 118antibiotic therapy

bacterial meningitis 272, 274congenital infections 282Lyme disease 284

anticardiolipin antibodysyndrome 93, 296

anticholinergic agents 299, 331anticonvulsant medications 306,

310–12allergic reactions 310dosing 311guide to use 311neonatal seizures 193, 193neurobehavioral effects 92, 93in traumatic brain injury 326

antidepressants, tricyclic 177antiretroviral drugs 290, 290Antley–Bixler syndrome 129Apert syndrome 129Apgar score 187, 187aphasia 12, 103, 105apraxia 103areflexia 170, 200Argyll Robertson pupil 141arm, sensory nerve anatomy 156arm weakness 200–3aromatic L-amino acid

dehydrogenase deficiency 66artemisinin compound 286arteriovenous malformations

(AVM) 37arthritis, septic 162

arthrogryposis 194, 194asphyxia, perinatal 124, 187aspirin-containing drugs 243,

244astasia/abasia 170astrocytoma, pilocytic 250asymmetric crying face

syndrome 204, 205ataxia 24, 25

acute/subacute onset 168,169

chronic/slowly progressive 170

ataxia telangiectasia 170, 171ATP7A gene 215attention deficit hyperactivity

disorder (ADHD) 48, 91, 92,294, 295

audiometry 111auditory brainstem response

(ABR) 111auditory processing disorder 113aura 242autism

definition 97‘late-onset’ 98

autism spectrum disorders(ASD) 88, 91, 97–8, 106

Babinski sign 27, 30–1, 200balance testing 58Bannayan–Riley–Ruvalcaba

syndrome 119, 236Bartonella henselae 285basilar inflammation 273Battle’s sign 326Becker muscular dystrophy 264,

264behavioral abnormalities

Angelman syndrome 222antiepileptic drugs 92, 93attention disorders 92, 93stereotypies 13, 292, 303, 305Williams syndrome 222

Bell’s palsy 21, 145–6, 204Borrelia infection 284, 285

benign paroxysmal torticollis245, 304

benign paroxysmal vertigo(BPV) 245, 304

biceps reflex 27–8bilirubin encephalopathy(kernicterus) 85, 190birth asphyxia 124, 187birth weight 96

342

Index

bladder dysfunction 166blindness, see visual lossBorrelia burgdorferi 284botulinum toxin injection 299botulism, infant 205, 260, 329,

329botulism immune globulin

(BabyBIG) 260bowel dysfunction 166brachial cutaneous nerves 156brachial plexopathy 152–4brachial plexus, anatomy 152brachycephaly 126bradykinesia 299brain death 192–3

EEG 51, 193nuclear medicine assessment

41brain growth 116brain tumors, see tumors,

intracranialbrainstem, tumor 250brainstem auditory evoked

potentials 55brainstem lesions, causing loss of

consciousness 317brainstem reticular formation

317branchio-otorenal syndrome 112breath-holding spells 303, 304Broca’s aphasia 105Broca’s area 104Brown–Sequard syndrome 328Brudzinski sign 271Brushfield spots 212, 213bruxism 178butalbital 244

CADASIL 227café au lait spots 232, 233caffeine 244calcification, intracranial 124,

216, 230, 235, 282, 283, 287calf muscle pseudohypertrophy

262, 263carbamazepine 93, 311cardiac arrhythmias 302, 303carnitine deficiency 259carnitine levels 77carpal tunnel syndrome 156–7case scenarios, developmental

delay 89–90cat-scratch disease 285cataracts 18–19, 281catheter angiography 42cavum vergae 165cefotaxime 272, 274ceftriaxone 272, 274, 284central core disease 259central herniation 320, 320cerebellar assessment 24–5cerebellar mutism syndrome 106

cerebral contusion 327cerebral edema 287, 317, 321cerebral herniation 320cerebral infarction, newborn

190, 191cerebral palsy (CP) 85–7, 148,

188, 189, 299brain injury 86, 87clinical manifestations 85, 86diagnosis 86

cerebrospinal fluid (CSF)benign extra-axial collections

120, 121infectious disease 64–5, 65,

272metabolic disorders 78multiple sclerosis 65–6neurotransmitters 66normal characteristics/values

63–4pressure 60production 60, 61sampling 60–2

contraindications 60cervical spinal cord, syrinx 202,

203chameleon sign 296Charcot–Marie–Tooth disease

(CMT) 160, 170CHARGE syndrome 132chemotherapy 106cherry red spot, macular 80Cheynes–Stokes breathing 318Chiari malformation

type I 61, 240, 247type II 119, 120, 148, 238,

239type III 120

childhood disintegrativedisorder 98

cholinergic agents, toxicity 331chorea 296–7chorioretinitis 281choroid plexus papilloma 250chromosomes 69

anomalies 70, 71, 88, 212–13, 257

normal karyogram 69studies 72–3

chronic inflammatorydemyelinatingpolyneuropathy (CIDP)

158–9Citrobacter species meningitis

272, 273clinodactyly 210clobazam 93clonidine 295Clostridium botulinum 260CMT, see Charcot–Marie–Tooth

diseaseCNTNAP2 gene 107

cochlear hypoplasia 111cochlear implants 113cognitive disorders 94–5

definitions 94learning disability 96–7management 95

coma 317comparative genomic

hybridization (CGH) 72–3complementary therapies 244complex regional pain syndrome

159compound muscle action

potential (CMAP) 56computed tomography (CT)

39–40angiography 40, 215brain malformations 124, 125craniosynostosis 130holoprosencephaly 217neonate 184nomenclature 39

concussion 251, 325confusion 317consciousness, alterations

317–21continuous spike-wave of slow

wave sleep (CSWS) 105conversion disorder 99–100,

170, 305coordination, assessment 24–5corneal reflex tests 20–1Cornelia de Lange syndrome

225corpus callosum, absent 121,

219cortical atrophy

HIV 290mucopolysaccharidosis 223

cortical thumb 85corticosteroids

acute neuromuscular weakness 330

bacterial meningitis 113chorea 297CIDP 158–9dermatomyositis 267DMD 262GBS 167optic neuritis 134‘pulse’ therapy 267spinal cord injury 328

cover test 17Cowden syndrome 236CP, see cerebral palsycranial nerves

assessment 16–23, 16CN1 (olfactory nerve) 132CN2 (optic nerve) 17–19,

133–9CN3 (oculomotor nerve) 20,

140–2, 207

Index 343

cranial nerves (continued)CN4 (trochlear nerve) 20,

143, 207CN5 (trigeminal nerve) 143CN6 (abducens nerve) 20,

144, 207, 246CN7 (facial nerve) 21, 145–6,

204–5CN8 (acoustic nerve) 147CN9 (glossopharyngeal

nerve) 22, 148CN10 (vagus nerve) 148CN11 (spinal accessory nerve)

149CN12 (hypoglossal nerve) 23,

149cranial sutures 126, 127craniosynostosis 129–30

lambdoid 128, 129metopic 126, 127, 129sagittal 129, 130

creatine kinase (CK), serum 90,262, 267

cremasteric reflex 26cri du chat syndrome 72, 73,

124, 125critical illness, polyneuro -

pathy/myopathy 160Crouzon syndrome 129cyclophosphamide 169cyproheptadine 244cysticercosis 285–7cytomegalovirus (CMV)

infectioncongenital 112, 124, 125,

227, 280–3diagnosis 65

cytotoxic edema 36, 191

Dandy–Walker malformation119, 120, 121, 254

daydreaming 303, 305deafness 227deep tendon (muscle stretch)

reflexes 12–13, 27–8, 255grading 28pathological 30–1

delayed sleep-phase syndrome180

delirium 317DeMosier syndrome (septo-

optic dysplasia) 136dermatomyositis 267desmopressin (DDAVP) 177developmental delay 84, 223–6

clinical scenarios 89–90global 88, 88, 89management 88–90motor 84–7

developmental milestoneslanguage 102, 102motor 30, 30, 84

developmental regression 88, 88Devic’s disease 134diabetes mellitus 96diadochokinesia 24diazepam 179

rectal 316diet, ketogenic 309DiGeorge/Shprinzten

(velocardiofacial/22q11deletion) syndrome 71, 96,210, 211, 220–1

diphenhydramine 243, 299diplegia 86

facial 146, 205diplopia 20, 144, 206–7, 206diskitis 162dissociated motor maturation,

syndrome 89–90divalproex sodium 244, 311, 312DNA 69

coding 69common mutations 70, 71‘junk’ 69regulatory 69

dolichocephaly (scaphocephaly)126

doll’s eye (oculocephalic) reflex16, 318, 319

Doose syndrome 309dopamine antagonists 299Doppler sonography,

transcranial 40dorsal column–medial lemniscus

system 26double vision, see diplopiaDown syndrome (trisomy 21)

70, 71, 212–13doxycycline 284Dravet syndrome 309drawing skills 16, 16DRESS syndrome 310drugs

associated with optic neuropathy 133

causing microcephaly 123mucocutaneous eruptions 310neurobehavioral effects 92, 93toxicity 321, 330–1, 331see also named drugs and drug

groupsdrusen 138, 139Duane syndrome 145Dubowitz examination 254Duchenne muscular dystrophy

(DMD) 26, 72, 90, 163,262–3case scenario 90clinical signs 85, 262–3diagnosis 262, 263management 262

dwarfism 119dysarthria 103, 296

dyslexia 96dysmorphic child

with deafness 227definition and categorization

210–11with developmental delay

223–6with encephalopathy/seizures

215–21hypotonic child 212–14with language impairment

222neural tube defects 238–40with neurological

signs/symptoms/birth marks 228–37

dystonia 298–9dystrophia myotonica protein

kinase (DMPK) gene 258dystrophin gene analysis 262

ecchymosisperiorbital (racoon eyes) 326retroauricular 326

edemacerebral 287, 317, 321cytotoxic 36, 191

edrophonium chlorideadministration 266

Ehlers–Danlos syndrome 251electrical status epilepticus of

sleep (ESES) 105electroencephalography (EEG)

amplitude/frequency 48, 49ASD 98basic principles 44–5brain death 51, 193burst-suppression pattern 50,

186epilepsy 48–9, 50–5, 306,

308frontal intermittent rhythmic

delta activity (FIRDA) 50, 51

infantile spasms 50, 51, 232, 307

LKS 104newborn 186normal patterns 45–7, 175PLEDs 55sleep 174–6video monitoring 54, 55, 308viral encephalitis 276

electromyography (EMG) 56–7,186, 260

electronystagmography 58electroretinography 58encephalitis

causing language disorders 109

CSF testing 64viral 54, 65, 109, 148, 275–9

Index344

encephalocele, occipital 120,121

encephalopathybilirubin (kernicterus) 85, 190hypertensive 251, 332hypoxic ischemic 49, 85, 88,

187neonatal 187

endocrine disorders, causingmicrocephaly 123

enteroviruses, diagnosis 65enuresis, nocturnal 177environmental factors,

microcephaly 123ependymoma 167, 250epidermal nevus syndrome 236epidural hematoma 326, 327epilepsy 96

age of onset 303benign familial neonatal

seizures 309benign rolandic 53, 54, 179,

308childhood absence (petit mal)

52, 309EEG abnormalities 48, 49,

50–5juvenile myoclonic (JME) 52,

53, 309myoclonic–astatic of

childhood (Doose syndrome) 309

seizure management 310–12, 311

seizure prevention 312status epilepticus 314–16Sturge–Weber syndrome 234tuberous sclerosis 228–32

epileptic aphasia, acquired(Landau–Kleffner syndrome)98, 98

epsilon-sarcoglycan gene(SGCE) 299

Epstein–Barr virus (EBV) 65,134, 135, 158, 276

Erb’s palsy 153ergotamine preparations 243erythema migrans 284erythrocytes, CSF 63Escherichia coli 271ESES, see electrical status

epilepticus of sleepexamination, see neurological

examinationexecutive function, disability 96eye closure, weakness 146, 261eye disorders, congenital

infections 281eye examination 18–19

acute visual loss 205, 206diplopia 20, 206headaches 242

eye movements 20abnormalities 140, 144, 206,

207assessment 19–20comatose patients 318–19,

319eye muscles 20, 20

facial appearanceAicardi syndrome 219Cornelia de Lange syndrome

225Down syndrome 212, 213fetal alcohol syndrome 226holoprosencephaly 218lissencephaly 216microcephaly 122, 123mucopolysaccharidoses 223myotonic dystrophy 258, 264,

265Noonan syndrome 225Prader–Willi syndrome 212,

257Sturge–Weber syndrome 234,

235Turner syndrome 25522q11 deletion syndrome 71,

220, 221Williams syndrome 108Zellweger syndrome 218

facial diplegia 146, 205facial hemiatrophy, progressive

(Parry–Romberg syndrome)146

facial nerve 21, 145–6, 204–5facial symmetry, testing 21facial weakness 145–6, 204–5,

261Factor V Leiden mutation 190family history 10fascioscapulohumeral dystrophy

264fatty acid oxidation, disorders

77, 80febrile seizures 308feeding, observation of newborn

17felbamate 93, 311femoral epiphysis, slipped 162fetal alcohol syndrome 88, 226fever 308, 321fibroblast growth factor

receptors (FGFRs) genes 129finger-to-nose testing 25FISH, see fluorescent in situ

hybridizationflaccid paralysis syndrome, acute

329flexor spasms 306‘floppy infant’ 254–5fluorescent in situ hybridization

(FISH) 72, 73, 124

FMR1 gene 224Foix–Chavany–Marie syndrome

148folate deficiency, cerebral 66folic acid 312fontanels 118foramen of Monro 60, 61, 230,

231, 232fortification spectrum 242fosphenytoin 315, 326FOXP2 gene 107fragile X syndrome 95, 106,

224–5genetics 72, 73, 107

fragile X-associated tremor,ataxia syndrome (FXTAS)107, 224

frataxin 170freckling, axillary 233French Canadian families 299Friedreich ataxia 157, 170frog leg posture 254, 255frontal lobe

function assessment 14–15laceration 324

funduscopy 18–19nonaccidental trauma 319normal 18, 242

gabapentin 244, 311gag reflex 22gait assessment 32, 261gait disorders

acute paraparesis with sensory level and bowel/bladder dysfunction 166–7

acute/subacute ‘ascending’ paraparesis 166, 167

acute/subacute asymmetric 168

Angelman syndrome 32, 222, 292

chronic/slowly progressive ataxias 170

evaluation 162–6localization along neuraxis

163orthopedic and rheumatologic

causes 162, 162psychogenic 170slowly progressive with lower

extremity atrophy and areflexia 170

slowly progressive with proximal muscle weakness 170

ganciclovir 278, 282gangliosidosis, GM2 99gastrocnemius muscle,

hypertrophy 262, 263gastroesophageal reflux 303, 304gaze 20, 207

Index 345

GBS, see Guillain–Barrésyndrome

gene, definition 69gene studies 73–4GeneTests 68genetic disorders

causing language disability 107–8

causing microcephaly 123causing hearing loss 112

genetic heterogeneity 71–2genetic testing

ASD 98availability 74chromosome studies 72–3future of 74gene studies 73mitochondrial studies 74resources 68value of 68

genetics, basic principles 69–71gentamicin 272, 274giant cell tumors, subependymal

230, 231, 232Glasgow coma scale 318Glasgow Coma Scale/Score

109, 318, 326glaucoma, congenital 234, 235glioblastoma multiforme 248,

249, 250glioma

brainstem 248, 250optic nerve/pathway 137,

233, 234, 250gliomatosis cerebri 93gliotic nodules, periventricular

230, 231globus pallidus, calcification 39glossopharyngeal nerve 22, 148glucose

blood 315, 320CSF 63

glutaric acidemia, type 1 78, 79,324

glycogen storage disease type II(Pompe disease) 259

glycosaminoglycans, tissueaccumulation 223

glycosylation, congenitaldisorders 163, 224

Go–No–Go test 15Gottron sign 267Gower sign 262, 263Gradenigo syndrome 144‘growing pains’ 178guanidinoacetate methyl -

transferase deficiency 79guanosine triphosphate (GTP)

cyclohydrolase deficiency 66guanosine triphosphate (GTP)

cyclohydrolase-1 gene 298,299

Guillain–Barré syndrome (GBS)146, 158–9, 163, 166–7, 200‘axonal’ variant 159clinical presentation 166diagnosis 56, 63, 66, 201, 329management 158, 167, 330Miller Fisher variant 158–9prognosis 167

HAART, see highly-activeantiretroviral therapy

Haemophilus influenzae 64, 270,271, 273, 274

hair, twisted/kinky (pili torti)215

hamartomairis (Lisch nodule) 232, 233tuber cinereum 35

handedness, early acquisition 84hands

dystonic posturing 298spooning 296, 29722q11 deletion syndrome

220, 221wringing 90

head circumference,measurement 116–18

head elevation 29head lag 260head shape, abnormalities

126–30head size charts 116, 117head trauma 322–7

anosmia 132blindness 138nonaccidental 322–4postconcussion syndrome

251, 325headaches

altitude 251brain tumors 248–50chronic daily 245–6epidemiology 241exertional 251following lumbar puncture 62ice cream 251jolts and jabs 251medication overuse 245raised intracranial pressure

246–7tension-type 246Von Hippel Lindau syndrome

234hearing

neuroanatomy 104, 110testing 22, 23, 111

hearing aids 113hearing loss 102, 147, 227

congenital bilateral permanent 110

genetic disorders 112infectious disease 112–13

hearing loss (continued)sensorineural 110

heart disease, congenital 224heavy metal toxicity 200, 201heel stick, lateral 76hemangioma, facial (port-wine

stain) 234, 235hematoma

epidural 326, 327subdural 48, 49, 324, 326

hemianopsia 242hemicord syndrome 328hemimegalencephaly 236, 237hemiparesis 10, 11, 84–6, 87,

202stroke 84, 202, 204, 204

hemiplegia 202, 203hemorrhage

intraparenchymal 324, 326intraventricular (IVH) 85, 86,

195–7retinal 19, 138, 139, 319, 323subarachnoid 326, 327

hereditary neuropathy withliability to pressure palsy(HNPP) 156–7

herpes simplex virus (HSV)CSF analysis 65encephalitis 54, 109, 148, 275type 1 146, 275, 276, 277type 2 276

herpes zoster 276, 277Heschl’s gyrus 104, 110heterochromia iridis 112heteroplasmy 74hexane inhalation 201HIE, see hypoxic-ischemic

encephalopathyhighly-active antiretroviral

therapy (HAART) 290history 10

newborn 182, 183HIV/AIDS 96, 270, 288–90

antiretroviral therapy 290, 290diagnosis 65, 290pediatric classification system

289HNPP, see hereditary

neuropathy with liability topressure palsy

holoprosencephaly 216–18Holter monitors 44Horner syndrome 20, 141human herpesviruses, diagnosis

65Hunter syndrome 223Huntington disease 72, 297

Westphal variant 299Hurler syndrome 223hydrocephalus 120–1

bacterial meningitis 272, 273brainstem glioma 248

Index346

hydrocephalus (continued)following intraventricular

hemorrhage 196head growth pattern 117, 120TSC 232

hydroxyzine 243hyperekplexia 299hypertensive encephalopathy

251, 332hypertonia 26–7hyperventilation 321hypoglossal nerve 23, 149hypoglycemia 124hypokinetic movement disorders

299hypoparathyroidism 39hypopituitarism 124hyporeflexia 200hypotension 206hypothalamic tumors 251hypothyroidism, congenital 124hypotonia 27, 212–14, 254–5

assessment of tone 26–8causes in infants 254cerebral (central) 27congenital 86diagnosis and clinical features

254–5dysmorphic child 212–14neonatal (‘floppy infant’)

254–5neuromuscular 27

hypoxic-ischemicencephalopathy, definitionand staging 187

hypoxic-ischemicencephalopathy (HIE) 49, 85,88, 187

hypoxic–ischemic injury 185,187

hysteria, see conversion disorders

ibuprofen 243, 244ice water caloric testing 22, 319idebenone 170idiopathic intracranial

hypertension (pseudotumorcerebri) 66, 246, 247

imagingbrain death 41, 193brain malformations 124, 125newborn 182, 184–6, 184nuclear medicine 41–2patient safety and preparation

34vascular 37–8, 40see also individual imaging

modalitiesimipramine 177immunoglobulin G (IgG), CSF

66incontinentia pigmenti 236, 237

infant‘floppy’ 254–5gait 32mental status examination 14muscle strength and tone

assessment 29, 29, 254–5physical examination 12–13,

16, 16sensory testing 26

infantile spasms 51, 232, 306–7causes 306EEG 50, 51, 232, 307management 311, 312

infectious diseases 270causing hearing loss 112–13causing hypotonia 254congenital 88, 124, 125, 227,

280–3triggering GBS 158

intellectual function tests 94intelligence quotient (IQ) 94–5,

96intercostobrachial nerves 156internet 74intoxication 93intracranial hypotension 60, 251intracranial pressure (ICP)

raised 60, 138, 139, 246, 247, 248, 249, 319

management 321intracranial sinovenous

thrombosis 192intravenous immunoglobulin

(IVIG) 167, 169, 330intraventricular hemorrhage

(IVH) 85, 86, 195–7iodine-131-meta-

iodobenzylguanidine (MIBG)scintiscanning 169

iris, hamartomas (Lisch nodules)232, 233

isometheptene-dichloralphenazone-acetaminophen 244

IVH, see intraventricularhemorrhage

IVIG, see intravenousimmunoglobulin

Ixodes spp. 284

Japanese encephalitis virus 65,275

jaw jerk 21Jones criteria 296juvenile myoclonic epilepsy

(JME) 52, 53, 309

Kallman syndrome 132karyogram

normal female 69trisomy 21 70

karyotype 72

Kayser–Fleischer rings 295kernicterus 85, 190Kernig sign 271Klippel–Trenaunay–Weber

syndrome 234Klumpke palsy 153knee jerk 28Krabbe disease 79Kugelberg–Welander disease 256

L-dopa therapy 298labial muscle 21laboratory studies

comatose child 320metabolic disorders 77–8, 77,

78labyrinthitis 147lacosamide 311LaCrosse virus 65, 275, 278,

279lactate, plasma 77lambdoid craniosynostosis 128,

129lamotrigine 93, 311, 312Landau–Kleffner syndrome 88,

98, 105language

assessment 15, 104neuroanatomy 104normal development 14,

102–3language disorders 102–9, 222

Angelman syndrome 107, 222ASD 106brain injury 109definitions 103epileptic causes 105genetic causes 107–8management 109meningitis and encephalitis

109neoplasia 106specific 103stroke 105Williams syndrome 108, 222see also speech disorders

lateral medullary (Wallenburg)syndrome 143

lead toxicity 200, 201learning disability (LD) 94,

96–7Leber’s hereditary optic

neuropathy (LHON) 137leg weakness

acute 200–3unilateral 202

Legg–Calve–Perthes disease 162legs, scissoring (crossing) 85Leigh disease 71Lennox–Gastaut syndrome

(LGS) 52–3, 93, 309, 311leptomeningeal cysts 326

Index 347

lethargy 317leukocytes, CSF 64leukoencephalopathy 276, 277leukomalacia, periventricular

188–9levetiracetam 312

dosing 311head injury 326neonatal seizures 193, 193neurobehavioral effects 93

LHON, see Leber’s hereditaryoptic neuropathy

limb girdle dystrophy 264lipoma, intraspinal 240LIS1 gene 216Lisch nodules 232, 233lissencephaly 216–18, 254, 264localization of neurological

disease 11–12, 163lorazepam, neonate 193, 193lower motor neuron (LMN)

lesions 163, 166, 200lumbar plexus 154, 155lumbar puncture 60–2

contraindications 60infectious diseases 64–5, 65metabolic disorders 66multiple sclerosis 65–6

lumbosacral plexopathy 154Lyme disease 146, 284–5lymphocytic choriomeningitis

(LCM) virus 124lysosomal storage disease 72,

119

macrocrania (macrocephaly)118–21causes 119evaluation 118head size chart 117hydrocephalus 120, 121subdural collection 120, 121

macular cherry red spot 80maculopathy, ‘bullseye’ 80magnetic resonance angiography

(MRA) 37–8, 191magnetic resonance imaging

(MRI) 34–9absent septum pellucidum

136advanced adjuncts 35contraindications 34conventional 34–5coronal gradient recall echo

(GRE) 189diffusion tensor (DTI) 36diffusion-weighted 35–6, 35drawbacks 35fetal 39FLAIR 49, 136, 188, 201,

277functional (fMRI) 38, 39

magnetic resonance imaging(MRI) (continued)gadolinium enhancement 142neonate 184, 185nomenclature 35perfusion-weighted (pMRI)

36vascular imaging 37–8

magnetic resonancespectroscopy (MRS) 38, 78,79, 184, 185

magnetic resonance venography(MRV) 192

magnetoencephalography(MEG) 40–1

malaria, cerebral 286–7mandible, prominent 222mannitol 64, 321maple syrup urine disease 77Marcus Gunn pupil 141Marfan syndrome 251masseter muscles 21median nerve 156medium chain acyl CoA

dehydrogenase (MCAD)deficiency 77, 80

medulloblastoma 163, 248, 250mefloquine 286mega-incisor, single central 218megalencephaly 119megavitamin therapy 246MELAS (mitochondrial

myopathy, encephalopathy,lactic acidosis, and stroke)syndrome 77

melatonin 179memory 15meningeal irritation, syndrome

318meningitis

bacterial 64, 113, 270–4causing language disorder

109viral 272, 275–9

Menkes’ disease 215, 324mental retardation 94, 94mental status examination

13–166-mercaptopurine 169metabolic disorders 76–80

causing hypotonia 254causing microcephaly 123,

124CSF testing 66divalproex sodium therapy

312imaging studies 78–9laboratory testing 77–8, 77,

78later clinical presentations 80

metachromatic leukodystrophy72, 99

methyl CpG binding protein 2(MECP2) gene 73

methylprednisolone 328, 330metoclopramide 243, 299MG, see myasthenia gravismicrobrachycephaly 210microcrania (microcephaly) 117,

122, 122–5, 218causes 122, 123head size chart 117

midazolam 316, 316middle cerebral artery

aneurysm 42thrombosis 191

migraine 202, 206, 241, 242–4acute confusional 245with aura (classic) 242, 242basilar 245hemiplegic 245management 243, 243ophthalmoplegic 142, 245prevention 244trigger factors 243variants 245, 304without aura (common) 242,

242milkmaid sign 296Miller–Dieker syndrome 124,

216miosis 141mitochondrial disorders 259mitochondrial studies 74Möbius syndrome 144, 205Mondini dysplasia 111, 147motor delay 84–7

isolated gross 86static 84, 85

motor development, milestones30, 30, 84

motor examination 26–32, 26motor unit potentials (MUPs)

56mouth, opening/closing 21movement disorders,

classification 291mucopolysaccharidoses 119,

156–7, 223multiple sclerosis (MS) 200, 201

clinical features 65lumbar puncture 65–6

multiple sleep latency test(MSLT) 176, 180

muscle atrophy 26spinal muscles 214, 255,

256–7thenar muscle 202, 203

muscle biopsydermatomyositis 267DMD 262, 263

muscle mass, assessment 26muscle strength

grading 29

Index348

muscle strength (continued)testing 28, 29

muscle stretch reflexes, see deeptendon reflexes

muscle tone 254assessment in infant 29, 29,

254–5assessment in older child 261

muscular dystrophy 264Becker 264, 264congenital 264fascioscapulohumeral 264limb girdle 264see also Duchenne muscular

dystrophymutism, cerebellar syndrome

106myasthenia gravis (MG) 142,

266, 329clinical features 266management 266, 330myasthenic crisis 330

Mycobacterium tuberculosis 270,272

mydriasis 141myelitis, transverse 202, 203myelodysplasia 85myelomeningocele 238–9myoclonic–astatic epilepsy of

Doose (MAE) 93myoclonus 169, 291, 299

nocturnal 178, 179, 291myoclonus-dystonia syndrome

299myopathy

congenital 259, 259critical illness 160

myositis 329myotonia, percussion/grip 264,

265myotonic dystrophy 85, 214,

258, 264diagnosis 264, 265

myotubular myopathy 259

nafcillin 274naproxen sodium 243, 244narcolepsy 180narcotic agents, toxicity 330,

331neck webbing 255neck–tongue syndrome 149Neisseria meningitides 270nemaline myopathy 259NEMO gene 236neonatal sleep myoclonus 179neonate

assessment 182, 183brain death 192–3hypotonia 254–5intracranial sinovenousthrombosis 192

neonate (continued)neuroimaging 184–6, 184primitive reflexes 30, 30seizures 193–4, 309

neoplasia, language disorders106

nerve conduction studies 58,186

neural tube defects 238–40neuroblastoma, occult 169neurocutaneous disorders 119,

228–37neurocysticercosis 285–7neurodevelopmental tests,

standardized 14, 14neurofibromas 232, 233neurofibromatosis 119

type 1 (NF-1) 96, 137, 232–4type 2 (NF-2) 234–5

neurological examination 9adaptation to the child 12–13contribution to evaluation and

management 12lesion identification 10lesion localization 11–12mental status 13–16

neuromuscular disorders 254newborn 194weakness/hypotonia 27,

329–30see also myasthenia gravis;

myopathy, congenital; spinal muscular atrophy, Duchenne muscular dystrophy

neuronal ceroid lipofuscinoses(NCL) 80, 99

neuropathy, ataxia and retinitispigmentosa (NARP) 58

neurotransmitter disorders 66,66

newborn screeningabnormal results 76inborn errors of metabolism

76–80, 77pitfalls 76

Niemann–Pick Type C 80night terrors 178, 179nightmares 178–9nonaccidental trauma 19, 322–4Noonan syndrome 224, 225NOTCH3 gene 227nuclear brain imaging 41–2nystagmus 22, 147

obsessive compulsive disorder(OCD) 294, 295

obstructive sleep apnea 177occipital-frontal circumference

(OFC) 90, 116–17Angelman syndrome 90measurement 116–17

occipital-frontal circumference(OFC) (continued)macrocephaly 118microcephaly 122

occupational therapy 293oculocephalic (doll’s eye) reflex

16, 318, 319oculogyric crisis 299oculomotor nerve 140–2, 207

assessment 19–20palsy 20, 20, 142

oculovestibular (ice watercaloric) response 22, 319

OFC, see occipital-frontalcircumference

Ohtahara syndrome 309olfactory nerve 17, 132, 132oligodendroglioma 250ophthalmoplegia 140, 245, 266ophthalmoplegic migraine 142ophthalmoscopy 18–19opsoclonus 169opsoclonus–myoclonus

syndrome (OMS) 93, 164,169

optic disk, appearance 18, 19optic nerve 133–9

assessment 17–19, 242atrophy 137drusen (pseudopapilledema)

138, 139glioma 137, 233, 234hemorrhages 323

optic neuritis 134–5, 206organic acids, urine 77organic brain syndromes 91, 92,

93, 98conditions causing 99

ornithine transcarbamylase(OTC) deficiency 77

orogastric lavage 331osmolality, serum 321osteogenesis imperfecta, type I

324otitis media 113otoacoustic emissions (OAE)

111oxcarbazepine 93, 311oxycephaly 126

palate, symmetry 22, 23palmar creases

Down syndrome 213fetal alcohol syndrome 226

palpebral fissure 19PANDAS 294pantothenate kinase-associated

neurodegeneration 99papilledema 19, 138–9, 246,

247, 319intracranial tumor 248, 249

papillitis, see optic neuritis

Index 349

parachute response 31paraneoplastic disorders 169parasomnias 178–9parietal lobe, assessment of

function 16paroxysmal events (nonepileptic)

99–100, 302, 303, 305age of onset 303cardiac arrhythmias 302, 303dyskinesias 305migraine variants 245, 304stereotypy 13, 292, 303, 305

paroxysmal hemicrania 251Parry–Romberg syndrome 146PCR, see polymerase chain

reactionPelizaeus–Merzbacher disease

71pelvic girdle strength 261, 262,

263Pendred syndrome 112, 227penicillins 274, 284pentobarbital 316periodic lateralizing epileptiform

discharges (PLEDs) 55, 276peripheral myelin protein 22

(PMP22) 156peripheral neuropathy 160periventricular leukomalacia

(PVL) 85, 86, 188–9peroxisomal (PEX) genes 218pes cavus 157, 160, 170Pfeiffer syndrome 129PHACES syndrome 236phasic tone 27phenobarbital

dosing 311drug eruption 310intravenous 315neonate 193, 193neurobehavioral effects 93

phenytoin 193, 193, 311, 312pheochromocytoma 234phonophobia 242, 245photophobia 242, 245pili torti 215pituitary adenoma 250plagiocephaly 126, 128plasmapheresis 167Plasmodium spp. 286PNET, see primitive

neuroectodermal tumorPneumocystis jiroveci 288, 289poisonings, acute 330–1, 331polioviruses 65polymerase chain reaction

(PCR) 73polymicrogyria 264, 282polymyositis 267polyneuropathy, critical illness

160polysomnography 57–8, 176

Pompe disease 259port-wine stain 234, 235positional plagiocephaly 128positron emission tomography

(PET) 41–2postconcussion syndrome 251,

325posterior fontanel 118posterior fossa, anomalous 236posterior reversible

encephalopathy syndrome(PRES) 93, 251, 332

postural reflexes 30–1, 31postural tone 26posturing 319–20Prader–Willi syndrome 85, 212,

254, 257prednisone 146, 262, 267prematurity 96, 182primidone 293primitive neuroectodermal

tumor (PNET) 93, 249, 250primitive reflexes 30, 30prochlorperazine 299prognathism 222promethazine 243, 299pronator drift 31propranolol 293proptosis 207protease inhibitors 290protein C deficiency 190Proteus syndrome 236, 237prothrombin G20210A

mutation 190pseudobulbar palsy 22, 148Pseudomonas aeruginosa 270pseudopapilledema (drusen)

138, 139pseudotumor cerebri 66, 246,

247psychogenic gait disorders 170psychogenic nonepileptic

paroxysmal events 99–100,100, 303, 305

PTEN gene mutations 236pterygoid muscle 21ptosis 140, 141, 205, 260,

266pupil

responses 18, 318size 141–2symmetry 18, 19

pyridostigmine 330pyridoxine (vitamin B6) 194

QT interval, calculation 302quadriparesis 79, 85, 86, 188,

189quinine 286

rabies 65, 275radial nerve 156

radiation therapy, causinglanguage disorder 106

Ramsay Hunt syndrome 146rapid eye movement (REM)

sleep 174, 174red reflex 18–19reflex hammer 12–13, 27–8reflexes

deep tendon (muscle stretch) 12–13, 27–8, 255

gag 22grading 28jaw jerk 21pathological 30–1primitive 30

Refsum disease 218respiratory muscle weakness

256, 257, 329respiratory pattern, comatose

patient 318restless leg syndrome 178reticular activating system 176,

317retinal angioma 228retinal hemorrhages 19, 138,

139, 319, 323retinopathy, lacunar 219Rett syndrome 88, 107, 117,

124, 124case scenario 90genetics 68, 71, 73

rheumatic fever 296, 296Rinne test 22, 23rituximab 169Romberg test 26, 27rubella 112, 124, 280, 282

sacral plexopathy 155Saethre–Chotzen syndrome

129St. Louis encephalitis 65Sandifer syndrome 304Sanfilippo syndrome 223Sarnat staging system 187, 187‘Saturday Night Palsy’ 157schwannoma 234, 235sciatic nerve 155screening, see newborn screeningsedation, neuroimaging 34sedatives

EEG effects 48, 49toxicity 331withdrawal 331

Segawa disease 66, 298seizures

absence 52age of onset 303evaluation 306febrile 308generalized tonic–clonic 311inborn errors of metabolism

78

Index350

seizures (continued)management 310–12, 311

emergency 314–16neonatal 193–4, 309post-traumatic 326psychogenic nonepileptic

99–100, 100, 303, 305recurrence risk 310viral encephalitis 275–6see also epilepsy; paroxysmal

events (nonepileptic)self stimulation behaviors 13,

292, 303, 304semantic knowledge 15sensory examination 26septo-optic dysplasia (DeMosier

syndrome) 136septum pallucidum, absence

136sequencing 73serotonergic agents, toxicity

331sexual maturation, incomplete

132Shprinzten–DiGeorge

syndrome, seeDiGeorge/Shprinztensyndrome

shuddering attacks 303, 305SIADH, see, syndrome of

inappropriate antidiuretichormone

Simpson–Golabi–Behmel 119single photon emission

computed tomography(SPECT) 41–2

Sjögren’s syndrome 201skin rash/lesions

‘blueberry muffin’ rash 280dermatomyositis 267DRESS syndrome 310EBV infection 276Lyme disease 284meningococcemia 271port-wine stain 234, 235TSC 228, 229viral encephalitis 276, 277

skullfractures 323, 326growth 116–18, 126sutures 126–7thickened 119, 119

sleepcommon disorders 177–80electrical status epilepticus

(ESES) 105myoclonus 178, 179, 291non-REM 174REM 174stages 174–6

‘sleep hygiene’ 180sleep patterns, adolescents 180

sleep spindles 174, 175sleep studies (polysomnograms)

57–8, 176sleep talking 178sleep walking 178, 179smell 17

loss (anosmia) 132Smith–Lemli–Opitz syndrome

124, 214‘smooth brain’ syndrome 216Snellen charts 17snoring 177somnolence 317spastic paraparesis, X-linked

71–2spastic quadriparesis 79, 85, 86,

188, 189spasticity 27, 170speech disorders 103, 109

see also language disordersspina bifida 238spinal accessory nerve 149spinal cord

tethered 240ultrasonography 40, 41

spinal cord lesions 12acute 200, 201mass 167tumors 202, 203, 240

spinal cord syndrome 166–7spinal muscular atrophy 85

congenital(Werdnig–Hoffman disease)

214, 255, 256–7spine

diskitis 162trauma 328vertebral body anomalies

219spino-thalamic system 26startle 78status epilepticus 314–16stereotypy 13, 292, 303, 305sternocleidomastoid muscle 22,

23Stevens–Johnson syndrome

312Stickler syndrome 112strabismus 20, 140Streptococcus spp., CSF 64Streptococcus pneumoniae 270,

271stroke 105, 190–1

genetic risk factors 227hemiparesis/hemiplegia 84,

202, 204, 204imaging 36language deficits 105perinatal 84, 85, 86, 87,

190–1stupor 317Sturge–Weber syndrome 234

stuttering 109subacute sclerosing

panencephalitis (SSPE) 38,99, 276, 277

subarachnoid hemorrhage 326,327

subdural fluid collection 119,120–1

subdural hematoma 48, 49, 324,326

substance abuse 330, 331succinate semialdehyde

dehydrogenase deficiency 66sudden infant death syndrome

(SIDS) 80sumatriptan 243, 243, 244survival motor neuron (SMN)

gene 256Sydenham chorea 296, 297syncope 206syndactyly 210syndrome of inappropriate

antidiuretic hormone(SIADH) 321

synophrys 223synovitis, toxic 162syphilis, congenital 280, 282syringohydromyelia (syrinx)

202, 203systemic lupus erythematosus

(SLE) 93, 201, 251, 296, 297

Taenia solium 285Tay–Sachs disease 58, 80, 88,

119teeth

anomalies 218, 236clenching 21

telangiectasias, ocular 170, 171

temporal lobe function 15temporal profile of disease 10,

11temporalis muscle 21‘tensilon test’ 142, 266teratoma 251tethered cord syndrome 240tetrahydrobiopterin 298thalamic calcifications 216thenar muscle

atrophy 202, 203percussion 264, 265

thiamine 320thrombophilic disorders 190,

192thrombosis, intracranial

sinovenous 192tiagabine 93tic douloureux 143tics 294–5tone, assessment 26–8

Index 351

tongueprotrusion 23weakness/atrophy/

fasciculations 149topiramate 93, 244, 244, 312

dosing 311TORCH infections 254, 280TORIA gene 299torticollis 128, 299

benign paroxysmal 245, 304Tourette syndrome 96, 294–5toxidromes 330, 331toxins 330–1, 331

associated with opticneuropathy 133causing microcephaly 123

Toxoplasma gondii 112, 124, 280,282

toys, use in examination 12–13,261

transverse myelitis 329–30trauma, nonaccidental 19,

322–4traumatic brain injury (TBI)

322anosmia 132causing language disorder

109see also head trauma

tremor 293Treponema pallidum 112, 280TREX1 gene 216trigeminal nerve 20–1, 143trigonocephaly 126, 127triptans 243, 243, 244trisomy 13 124, 125trisomy 18 124, 125trisomy 21 (Down syndrome)

70, 71, 212–13trochlear nerve 143, 207

assessment 19–20Trypanosoma cruzi 280, 282TS; TSC, see tuberous sclerosistuber cinereum, hamartoma 35tuberous sclerosis (TS); tuberous

sclerosis complex (TSC) 106,228–32, 306

tubers, cortical 230, 231tumors

intracranial 106, 241, 248–50, 249

spinal cord 202, 203Turner syndrome 96, 255turricephaly 12622q11 deletion syndrome 96,

210, 211, 220, 221L-tyrosine 259tyrosine hydroxylase deficiency

66

UBE3A gene 222ulnar nerve 156

ultrasonographycranial 40–1, 184, 188,

196–7spinal cord 40, 41

upper motor neuron (UMN)lesions 27, 163, 166, 200

urea cycle disorder 77Usher syndrome 112, 227uvula, position 22, 23

vagus nerve 148valaciclovir (valacyclovir) 146valproic acid 93, 244, 311

precautions 312vancomycin 272, 274vanishing white matter disease

71, 164, 165varicella zoster virus 65vascular imaging 37–8, 40vasculitis 251velocardiofacial syndrome

(22q11 deletion) 96, 210,211, 220–1genetics 71

VEPs, see visual evokedpotentials

vertebral bodies, anomalous inAicardi syndrome 219

vertigo 22, 147benign paroxysmal (BPV)

245, 304very long chain fatty acids 77vestibular aqueducts, enlarged

111vestibular system

dysfunction 22, 147, 147evaluation 58

vestibulocochlear nerve 22vigabatrin 93, 311viral infections

Bell’s palsy 146causing brachial plexitis 202CSF analysis 65, 65encephalitis 275–9meningitis 272, 275

Virchow–Robin (perivascular)spaces 223

visual acuity testing 17visual evoked potentials (VEPs)

55visual fields 17–18, 205visual loss

acute 205–6eye examination 205, 206metabolic disorders 80monocular 206post-traumatic 138–9

visual pathway 205visual spatial processing 16vitamin therapy 246vocal cord dysfunction 148vomiting, cyclic 245

Von Hippel–Lindau syndrome234

von Willebrand disease 190

Waardenburg syndrome 111,112, 112

Wada testing 39Wallenburg (lateral medullary)

syndrome 143weakness

acute neuromuscular 329–30facial 145–6, 204–5, 261gait impairment 168, 170limbs 200–3

Weaver syndrome 119Weber test 22, 23Werdnig–Hoffman disease 214,

255, 256–7Wernicke’s aphasia 105Wernicke’s area 104West Nile virus 65, 275West syndrome 306–7Williams syndrome 108, 222Wilson disease 99, 294Wolf–Hirschhorn syndrome 124,

220wormian bones 215

X-linked disorders 72Aicardi syndrome 19, 219Menkes’ disease 215spastic paraparesis 71–2

xanthochromia 63

Zellweger spectrum disorder 77,78, 218

zolmitriptan nasal spray 243, 244zonisamide 311

Index352

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