Advances in Neonatal Neurology

Contents

Foreword: Why the Human Fetus Has Such a Large Vulnerable Head AndWhy It Is Our Job to Protect It! xv

Lucky Jain

Preface: Advances in Neonatal Neurology xvii

Praveen Ballabh and Stephen A. Back

Cerebral White and Gray Matter Injury in Newborns: New Insights intoPathophysiology and Management 1

Stephen A. Back

Increasing numbers of preterm neonates survive with motor and cogni-tive disabilities related to less destructive forms of cerebral injury thatstill result in reduced cerebral growth. White matter injury results inmyelination disturbances related to aberrant responses to death ofpre-myelinating oligodendrocytes (preOLs). PreOLs are rapidly regener-ated but fail to mature to myelinating cells. Although immature projectionneurons are more resistant to hypoxia-ischemia than preOLs, they dis-play widespread disturbances in dendritic arbor maturation, which pro-vides an explanation for impaired cerebral growth. Thus, large numbersof cells fail to fully mature during a critical window in development of neu-ral circuitry. These recently recognized forms of cerebral gray and whitematter dysmaturation suggest new therapeutic directions centered onreversal of the processes that promote dysmaturation.

Brain Development in Preterm Infants Assessed Using Advanced MRI Techniques 25

Nora Tusor, Tomoki Arichi, Serena J. Counsell, and A. David Edwards

Infants who are born preterm have a high incidence of neurocognitive andneurobehavioral abnormalities, which may be associated with impairedbrain development. Advanced magnetic resonance imaging (MRI)approaches, such as diffusion MRI (d-MRI) and functional MRI (fMRI), pro-vide objective and reproducible measures of brain development. Indicesderived from d-MRI can be used to provide quantitative measures ofpreterm brain injury. Although fMRI of the neonatal brain is currentlya research tool, future studies combining d-MRI and fMRI have the poten-tial to assess the structural and functional properties of the developingbrain and its response to injury.

Pathogenesis and Prevention of Intraventricular Hemorrhage 47

Praveen Ballabh

Intraventricular hemorrhage (IVH) is a major neurologic complication of pre-maturity. Pathogenesis of IVH is attributed to intrinsic fragility of germinalmatrix vasculature and to the fluctuation in the cerebral blood flow. Germi-nal matrix exhibits rapid angiogenesis orchestrating formation of immature

Contentsviii

vessels. Prenatal glucocorticoid exposure remains the most effectivemeans of preventing IVH. Therapies targeted to enhance the stability ofthe germinal matrix vasculature and minimize fluctuation in the cerebralblood flow might lead to more effective strategies in preventing IVH.

Neuroimaging of White Matter Injury, Intraventricular and Cerebellar Hemorrhage 69

Manon J.N.L. Benders, Karina J. Kersbergen, and Linda S. de Vries

White matter injury and hemorrhage are common findings in extremelypreterm infants. Large hemorrhages and extensive cystic lesions are iden-tified with cranial ultrasound. MRI, which is more sensitive, is especiallyuseful in the identification of small intraventricular hemorrhage; cerebellarhemorrhage; punctate lesion in the white matter and cerebellum; anddiffuse, noncystic white matter injury. Imaging sequences such as diffu-sion-weighted, diffusion tensor, and susceptibility weighted imaging mayimprove recognition and prediction of outcome. These techniques improveunderstanding of the underlying pathophysiology of white matter injuryand its effects on brain development and neurodevelopmental outcome.

Chorioamnionitis in the Pathogenesis of Brain Injury in Preterm Infants 83

Vann Chau, Deborah E. McFadden, Kenneth J. Poskitt, and Steven P. Miller

Chorioamnionitis (or placental infection) is suspected to be a risk factor forbrain injury in premature infants. The suggested association between cho-rioamnionitis and cystic periventricular leukomalacia and cerebral palsy isuncertain because of the variability of study designs and definitions ofchorioamnionitis. Improvements in neonatal intensive care may haveattenuated the impact of chorioamnionitis on brain health outcomes. Largemulticenter studies using rigorous definitions of chorioamnionitis on pla-cental pathologies and quantitative magnetic resonance techniques mayoffer the optimal way to clarify the complex role of chorioamnionitis inmodifying brain health and long-term outcomes.

Fault and Blame, Insults to the Perinatal Brain may be Remote from Time of Birth 105

Sidhartha Tan

There is a certainty in malpractice cases that neurodevelopmental deficitsare caused by preventable events at birth when the onset, nature, andtiming of the insult in the antenatal and natal period are unknown. The big-gest problem is determining timing. Electronic fetal monitoring is givenexcessive importance in legal cases. Before assigning fault on events atbirth, a better understanding of developmental neurobiology and limita-tions of the present clinical biomarkers is warranted. The issues of singleversus repeated episodes, timing of antenatal insults, pros and cons oflegal arguments, interaction of various etiologic and anatomic factorsare discussed.

Pharmacologic Neuroprotective Strategies in Neonatal Brain Injury 119

Sandra E. Juul and Donna M. Ferriero

This article explains the mechanisms underlying choices of pharmacother-apy for hypoxic-ischemic insults of both preterm and term babies. Somepreclinical data are strong enough that clinical trials are now underway.

Contents ix

Challenges remain in deciding the best combination therapies for each ageand insult.

Stem Cell Therapy for Neonatal Brain Injury 133

Bobbi Fleiss, Pascale V. Guillot, Luigi Titomanlio, Olivier Baud, Henrik Hagberg,and Pierre Gressens

This article introduces the basic concepts of modeling neonatal brain injuryand provides background information regarding each of the commonlyused types of stem cells. It summarizes the findings of preclinical researchtesting the therapeutic potential of stem cells in animal models of neonatalbrain injury, reports briefly on the status of clinical trials, and discusses theimportant ongoing issues that need to be addressed before stem cell ther-apy is used to repair the injured brain.

Outcomes of Hypoxic-Ischemic Encephalopathy in Neonates Treated withHypothermia 149

Seetha Shankaran

This article examines the evidence regarding mortality and neurodevelop-mental outcomes following hypothermia for neonatal hypoxic-ischemicencephalopathy. Data from randomized controlled trials regarding neuro-developmental outcome at the end point of the major trials, and from 2 ofthe trials on childhood outcome following hypothermia for neonatal hyp-oxic-ischemic encephalopathy are presented. The predictors of outcomethat can be evaluated in the neonatal period are also reviewed, as thisinformation may assist in the counseling of families. Most trials of hypo-thermia have been performed in high-resource countries; published stud-ies from the low- and middle-income countries are also reviewed.

Mechanisms of Hypothermic Neuroprotection 161

Paul P. Drury, Eleanor R. Gunn, Laura Bennet, and Alistair J. Gunn

Prolonged, moderate cerebral hypothermia initiated within a few hoursafter severe hypoxia-ischemia and continued until resolution of the acutephase of delayed cell death can reduce acute brain injury and improvelong-term behavioral recovery in term infants and in adults after cardiacarrest. The specific mechanisms of hypothermic neuroprotection remainunclear, in part because hypothermia suppresses a broad range of poten-tial injurious factors. This article examines proposed mechanisms in rela-tion to the known window of opportunity for effective protection withhypothermia. Knowledge of the mechanisms of hypothermia will helpguide the rational development of future combination treatments to aug-ment neuroprotection with hypothermia and identify those most likely tobenefit.

Neonatal Seizures: Advances in Mechanisms and Management 177

Hannah C. Glass

Seizures occur in approximately 1 to 5 per 1000 live births and are amongthe most common neurologic conditions managed by a neonatal neuro-critical care service. There are several, age-specific factors that areparticular to the developing brain, which influence excitability and seizure

Contentsx

generation, response to medications, and impact of seizures on brainstructure and function. Neonatal seizures are often associated with seriousunderlying brain injury such as hypoxia-ischemia, stroke, or hemorrhage.Conventional, prolonged, continuous video electroencephalogram is thegold standard for detecting seizures, whereas amplitude-integrated EEGis a convenient and useful bedside tool.

Steroids and Injury to the Developing Brain: Net Harm or Net Benefit? 191

Shadi N. Malaeb and Barbara S. Stonestreet

Deleterious effects result from both glucocorticoid insufficiency and excessglucocorticoid tissue exposure in the developing brain. Accumulating evi-dence suggests a net benefit of postnatal glucocorticoid therapy whenadministered shortly after the first week of life to premature infants with earlyand persistent pulmonary dysfunction, particularly in those with evidenceof relative adrenal insufficiency. The decision to treat with steroids shouldensure maximum respiratory benefit at the lowest possible neurologicrisk, while avoiding serious systemic complications. Ongoing clinical trialsmust validate this approach.

Neonatal Pain Control and Neurologic Effects of Anesthetics and Sedatives inPreterm Infants 209

Christopher McPherson and Ruth E. Grunau

Preclinical and clinical studies have demonstrated the adverse conse-quences of untreated pain and stress on brain development in the preterminfant. Sucrose has widely been implemented as standard therapy for minorprocedural pain. Anesthetics are commonly utilized in preterm infants dur-ing major surgery. Pharmacologic agents (benzodiazepines and opioids)have been examined in clinical trials of preterm infants requiring invasivemechanical ventilation. Controversy exists regarding the safety and long-term impact of these interventions. Ongoing multidisciplinary research willhelp define the impact of these agents and identify potential alternativetherapies.

Neurogenesis and Maturation in Neonatal Brain Injury 229

Natalina Salmaso, Simone Tomasi, and Flora M. Vaccarino

The incidence of preterm birth is on the rise. The outcome of prematurebirth can vary widely, spanning completely normal development to severeneurologic deficits, with most children showing mild to moderate cognitivedelay and increased incidence of neuropsychiatric conditions such as anx-iety, attention deficit hyperactivity, and autism spectrum disorders. Sev-eral animal models have been employed to study the consequences ofprematurity, one of the most promising being chronic perinatal hypoxiain mouse, which recapitulates the cognitive impairments, partial recoveryover time and enhanced recovery with environmental enrichment.

Neurodevelopmental Outcomes of Extremely Preterm Infants 241

Betty R. Vohr

Survival of extremely preterm infants has improved since 2000. Neurode-velopmental impairment rates remain high at the limits of viability. Although

Contents xi

improved survival and neurodevelopmental impairment rates are associ-ated with higher gestational age and more recent year of birth, significantvariability in findings among geographic areas and networks is evident,and seems related to differences in population, management style, regionalprotocols, definitions, and outcome assessments. Outcome studies duringadolescence and young adult age are needed to determine the long-termimpact of extremely preterm birth.

The Role of Neuroimaging in Predicting Neurodevelopmental Outcomes of PretermNeonates 257

Soo Hyun Kwon, Lana Vasung, Laura R. Ment, and Petra S. Huppi

Magnetic resonance imaging (MRI) is a safe and high-resolution neuroi-maging modality that is increasingly used in the neonatal population toassess brain injury and its consequences on brain development. It is supe-rior to cranial ultrasound for the definition of patterns of both white andgray matter maturation and injury and therefore has the potential to pro-vide prognostic information on the neurodevelopmental outcomes of thepreterm population. Furthermore, the development of sophisticated MRIstrategies, including diffusion tensor imaging, resting state functionalconnectivity, and magnetic resonance spectroscopy, may increase theprognostic value, helping to guide parental counseling and allocate earlyintervention services.

Index 285