definition - advocate health care1 neonatal seizures ammar katerji, md hope children hospital...
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NEONATAL SEIZURES
AMMAR KATERJI, MD
HOPE CHILDREN HOSPITAL
Definition
A paroxysmal alteration in neurological
function (behavior, motor, and/or
autonomic function) results from an
excessive synchronous electrical
discharge( depolarization ) of neurons
within the CNS
Definition
Neonatal period limited to :
- first 28 days for term infants
- 44 weeks gestational age for
pre-term
Frequency
In US – incidence has not been
established clearly
Estimated frequency of 80-120 per
100,000 neonates/year
1-5:1000 live births
Frequency
0.5 % incidence -National Collaborative
Perinatal Project( population-based study on
54,000 FT and PT infants)
0.23% incidence- Scher, et al
(population of 41,000 infants)
Why do neonatal seizures have
such unusual presentations?
Immature CNS cannot sustain a
synchronized, well orchestrated
generalized seizure
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Perinatal Anatomical and Physiological
Features of Importance in Determining
Neonatal Seizure Phenomena
ANATOMICAL
Neurite outgrowth—dendritic and axonal
ramifications—in process
Synaptogenesis not complete
Deficient myelination in cortical efferent systems
Volpe JJ.Neonatal Seizures :Neurology of the Newborn.4th ed
Perinatal Anatomical and Physiological Features
of Importance in Determining Neonatal Seizure
Phenomena
PHYSIOLOGICAL
In limbic and neocortical regions—excitatory synapses
develop before inhibitory synapses NMDA receptors
and AMPA receptors overexpressed.
Deficient development of substantia nigra system for
inhibition of seizures.
Impaired propagation of electrical seizures, and
synchronous discharges.
Volpe JJ.Neonatal Seizures.In:Neurology of the Newborn.4th ed.
Probable Mechanisms of Some Neonatal Seizures
PROBABLE MECHANISM DISORDER
Failure of Na + -K + pump secondary to Hypoxemia, ischemia,
adenosine triphosphate and hypoglycemia
Excess of excitatory neurotransmitter
(eg.glutamic acid—excessive excitation) Hypoxemia, ischemia
and hypoglycemia
Deficit of inhibitory neurotransmitter Pyridoxine dependency
(i.e., relative excess of excitatory
neurotransmitter)
Membrane alteration— Na + Hypocalcemia and
Permeability hypomagnesemia
_________________________________________________________________
Volpe JJ.Neonatal Seizures:Neurology of the Newborn.4th ed.
Classification
Epileptic
Non-epileptic
Electroencephalographic seizure
I. Epileptic
Consistently associated with electro-cortical
seizure activity on the EEG
Cannot be provoked by tactile stimulation
Cannot be suppressed by restraint of
involved limb or repositioning of the infant
Related to hyper synchronous discharges of
a critical mass of neuron
Electroencephalographic
seizures
II. Non-epileptic
No electro-cortical signature
Provoked by stimulation
Suppressed by restraint or repositioning
Brainstem release phenomena (reflex)
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Jitteriness Versus Seizure
CLINICAL FEATURE JITTERINESS SEIZURE
Abnormality of gaze or eye O +
movement
Movements exquisitely stimulus + O
sensitive
Predominant movement Tremor Clonic jerking
( rhythmic, equal rate amplitude) (fast and slow)
Movements cease with passive + O
flexion
Autonomic changes O +
tachycardia, apnea, increase blood pressure
pupillary change, salivation. ------------------------------------------------------------------------------------------------------------------
Classification of Neonatal
Seizures
Clinical
Electroencephalographic
Classification
Clinical Seizure
Subtle
Tonic
Focal, Generalized
Clonic
Focal, Multifocal
Myoclonic
Focal, Multifocal, Generalized
Clinical Classification
1. Subtle More in preterm than in term
Eye deviation (term)
Blinking, fixed stare (preterm)
Repetitive mouth and tongue movements
Apnea, autonomic phenomena
Pedaling and tonic posturing of limbs
Clinical Classification
2. Tonic
Primarily in Preterm
May be focal or generalized
Sustained extension of the upper and
lower limbs (mimics decerebrate posturing)
Sustained flexion of upper with extension of
lower limbs (mimics decorticate posturing)
Signals severe ICH in preterm infants
Clinical Classification
3. Clonic
Primarily in term
Focal or multifocal
Clonic limb movements(synchronous or
asynchronous, localized or often with no anatomic
order of progression)
Consciousness may be preserved
Signals focal cerebral injury
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Clinical Classification
4. Myoclonic
Rare
Focal, multifocal or generalized
Lightning-like jerks of extremities
(upper > lower)
Classification of Neonatal Seizures
ELECTROENCEPHALOGRAPHIC SEIZURE
CLINICAL SEIZURE COMMON UNCOMMON
Subtle +*
Clonic
Focal +
Multifocal +
Tonic
Focal +
Generalized +
Myoclonic
Focal, multifocal +
Generalized +
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*Only specific varieties of subtle seizures are commonly associate with simultaneous
Electroencephalographic seizure activity.
Volpe JJ.Neonatal Seizures:Neurology of the Newborn.4th ed.
Does absence of EEG seizure
activity indicate that a clinical seizure
is non- epileptic?
Certain clinical seizures in the human
newborn originate from electrical seizures in
deep cerebral structures (limbic regions), or
in diencephalic, or brain stem structures and
thereby are either not detected by surface-
recorded EEG or inconsistently propagated to
the surface.
Most common is generalized tonic. Focal,
multifocal myoclonic, certain subtle seizures
Etiology
It is critical to recognize neonatal seizures, to
determine their etiology, and to treat them for
three major reasons:
1. Seizures are usually related to significant
illness, sometimes requiring specific therapy
Etiology
2.Neonatal seizures may interfere with
important supportive measures, such as
alimentation and assisted respirations for
associated disorders.
3.Experimental data give some reason for
concern that under certain circumstances the
seizure per se may be a cause of brain injury.
Etiology
Clinical history provides important clue
Family history may suggest genetic
syndrome
Many of these syndromes are benign
In the absence of other etiologies, family
history of seizures may suggest good
prognosis
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Etiology
Pregnancy history
Infections, fetal distress, preeclampsia
Delivery history
Type of delivery, any events during delivery
Postnatal history
Temperature, blood pressure, feeding,
Etiology
1- Hypoxic-Ischemic Encephalopathy
Single most common cause 20%
60% the onset within 12 hours
2- Intracranial hemorrhage
15% of term and 30% of preterm infant
3- Primary subarachnoid hemorrhage
Usually on the second postnatal day
Well baby with seizures
Etiology
4- Subdural Hemorrhage
5- Neonatal stroke
6- Intracranial infection
5-10%, bacterial meningitis group B, E coli
viral encephalitis TORCH
7- Developmental defects
8- Metabolic disturbances
Hypglycemia, hypocalcemia, disturbance of
AA and OA, local anesthetic intoxication
Inborn Errors of Metabolism Associated With Neonatal Seizures
Conditions That Have a Specific Treatment
Pyridoxine (B6) dependency
Folinic acid-responsive seizures
Glucose transporter defect
Creatine deficiency
Other Conditions
Nonketotic hyperglycinemia
Sulfite oxidase deficiency
Molybdenum cofactor deficiency (combined deficiency)
Carbohydrate-deficient glycoprotein disorder
Lactic acid disorders
Mitochondrial disorders
Maple syrup urine disease
Isovaleric acidemia (sweaty feet, cheesy odor)
Inborn Errors of Metabolism
Associated With Neonatal Seizures Other conditions
Isovaleric acidemia (sweaty feet, cheesy odor)
3-methylcrotonyl-CoA carbosylase deficiency
Propionic acidemia
Mevalonic aciduria
Urea cycle defects
Hyperornithemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome
Neonatal glutaric aciduria type ll
Biotin deficiencies, holocarboxylase synthetase deficiency
Fructose 1,6-diphosphatase deficiency
Hereditary Fructose intolerance
Menkes disease (trichopoliodystrophy
Peroxisomal disorders
NeoReviews vol.5 no.6 June 2004
Etiology
9- Genetics
Tuberous sclerosis
Incontinenta pigmenti
Zellweger syndrome
Smith-Lemli-Opitz syndrome
Neonatal Adrenoleukodystrophy
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Etiology
10- Epileptic Syndromes
Benign familial neonatal seizures
Benign idiopathic neonatal seizures
( Fifth-day fits )
Early myoclonic encephalopathy
Early infantile epileptic encephalopathy
( Ohtahara syndrome )
0 10 20 30 40 50
Hypoxia-ischemia
Hemorrhage
Trauma
Stroke
Meningitis
Hypocalcemia
Hypoglycemia
Malformation
Incidence (%)
1970
1987
Comparison of prominent etiologic diagnoses of
seizures in the newborn period. (Data modified
from Mizrahi and Kellaway, 1987; Rose and
Lombroso, 1970)
Fanaroff A, Martin R.Neonatal seizures. In:Neonatal and Perinatal Medicine, Diseases of the Fetus and Infant,6th ed.
Major Etiologies of Neonatal Seizures in Relation to Time of
Seizure Onset and Relative Frequency
TIME OF ONSET* RELATIVE FREQUENCY†
0-3 DAYS >3DAYS PREMATURE FULL TERM
Hypoxic-ischemic + +++ +++
encephalopathy
Intracranial + + ++ +
hemorrhage‡
Intracranial infection + + ++ ++
Developmental + + ++ ++
defects
Hypoglycemia + + +
Hypocalcaemia + + + +
Other metabolic + +
Epileptic syndromes + + +
Laboratory Studies to Evaluate
Neonatal Seizures
Indicated
Complete blood count, differential, platelet count;
urinalysis
Blood glucose (Dextrostix), BUN, Ca, P, Mg,
electrolytes
Blood oxygen and acid-base analysis
Blood, CSF and other bacterial cultures
CSF analysis
EEG
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Laboratory Studies to Evaluate
Neonatal Seizures
Clinical Suspicion of Specific Disease
Serum immunoglobulins, TORCH antibody titers, and
viral cultures
Blood and urine metabolic studies (bilirubin, ammonia
lactate, pyruvate, reducing substance.)
Blood and urine toxic screen
Blood and urine amino and organic acid screen
CT, MRI or ultrasound scan
Metabolic Evaluation for Refractory Neonatal Seizures
Consider individually by case specifics
Serum Glucose
Electrolytes (sodium, potassium, chloride, carbon dioxide), blood urea nitrogen, chromium, calcium, phosphorus, magnesium
Uric acid
Creative kinase
Serum ammonia
Lactic and pyruvic acids
Biotinidase
Amino acids
Serum carnitine, acylcarnitines
Serum transferrin
Copper and ceruloplasmin
Cholesterol
Fatty acids (short-chain, medium-chain, long-chain)
Pipecolic acid
Metabolic Evaluation for Refractory Neonatal Seizures
Urine Organic acids
Acylglycines
Uric acid
Sulfites
Xanthine, hypoxanthine
Guanidinoacetate
Pipecolic acid
Cerebrospinal Fluid Cell count, glucose,protein
Lactic and pyruvic acids
Amino acids
Organic acids
Neurotransmitters
Other Studies Skin biopsy
Muscle biopsy
Magnetic resonance imaging with magnetic resonance spectroscopy (especially for creatine)
Treatment
Identify the underlying cause:
hypoglycemia - D10 solution
hypocalcemia - Calcium gluconate
hypomagnesemia- Magnesium sulfate
pyridoxine deficiency- Pyridoxine
meningitis- initiation of antibiotics
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Treatment
To minimize brain damage
Some controversy when to start
anticonvulsants
If seizure is prolonged (longer than 3
minutes), frequent or associated
with cardiorespiratory disturbance
Acute therapy of neonatal seizures
If with hypoglycemia- Glucose 10%: 2ml/kg IV
If no hypoglycemia- Phenobarbital:20mg/kg IV
loading dose, over 10-15 minutes
If necessary : additional Phenobarbital:
5 mg/kg IV to a max of 20 mg/kg
to achieve concentration 40-50µg/ml
Fosphenytoin: 20 mg/kg, IV (1 mg/kg/min)
Lorazepam:0.05-0.10 mg/kg, IV (half life 48hrs)
or Midazolam 0.15mg/kg bolus followed by
infusion 0.4mg/kg/h, max 1.1mg/kg/h
Expected Response of Neonatal Clinical
seizures to sequence of Therapy
Anticonvulsant Drug Cessation of Seizure
Phenobarbital 20mg/kg 40%
Phenobarbital 40mg/kg 70%
Phenytoin 20mg/kg 85%
Lorazepam 0.05-0.1 mg/kg 95%
Response of Neonatal Electrographic
Seizures to Phenobarbital and Phenytoin
Extent of Control
Complete ≥80% Reduction
Phenobarbital 43%
plus phenytoin 57% 80%
Phenytoin 45%
plus phenobarbital 62% 72%
Pharmacological properties of
Phenobarbital
Enters the CSF/brain rapidly with high efficiency
The blood level is largely predictable from the dose
administered
It can be given IM or IV(more preferred)
Maintenance therapy accomplished easily with oral
therapy
Protein binding lower in newborn—free levels of drug
are higher
Entrance to the brain increased by local acidosis
associated with seizures
Drug Therapy For Neonatal Seizures Standard Therapy
AED Initial Dose Maintenance Dose Route
Phenobarbital 20mg/kg 3 to 4 mg/kg per day lV, lM, PO
Phenytoin 20 mg/kg 3 to 4 mg/kg per day lV, POª
Fosphenytoin 20 mg/kg phenytoin 3 to 4 mg/kg per day lV, lM
equivalents
Lorazepam² 0.05 to 0.1 mg/kg Every 8 to 12 hours lV
AED= andtiepileptic drug; lV= intravenous; lM= intramuscular; PO= oral
ªOral phenytoin is not well absorbed.
²Benzodiazepines typically not used for maintenance therapy.
³Lorazepam preferred over diazepam.
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Alternative Antiepileptic Drugs (AED) for Neonatal Seizures
Intravenous AEDs High-dose phenobarbital: >30 mg/kg
Pentobarbital: 10 mg/kg, then 1 mg/kg per hour
Thiopental: 10 mg/kg, then 2 to 4 mg/kg per hour
Midazolam: 0.2 mg/kg, then 0.1 to 0.4 mg/kg per hour
Levetiracetam 20-60 mg/kg/d bid or tid
Lidocaine: 2 mg/kg, up to 6 mg/kg per hour
Valproic acid: 10 to 25 mg/kg, then 20 mg/kg per day in 3 doses
Paraldehyde: 200 mg/kg, then 16 mg/kg per hour
Pyridoxine (B6): 50 to 100 mg, then 100 mg every 10 minutes (up to 500mg)
Alternative AEDs for Neonatal
Seizures
Oral AEDs
Primidone: 15 to 25 mg/kg per day in 3 doses
Clonazepam: 0.1 mg/kg in 2 to 3 doses
Carbamazepine: 10 mg/kg, then 15 to 20 mg/kg per day in 2 doses
Oxcarbamazepine: no data on neonates, young infants
Valproic acid: 10 to 25 mg/kg, then 20 mg/kg per day in 3 doses
Vigabatrin: 50 mg/kg per day in 2 doses, up to 200 mg/kg per day
Lamotrigine: 12.5 mg in 2 doses
Topiramate: 3 mg/kg per day
Zonisamide: 2.5 mg/kg per day
Levetiracetam: 10 mg/kg per day in 2 doses
Determinants of Duration of
anticonvulsant therapy for neonatal
seizures
Neonatal neurological examination
Cause of neonatal seizure
Electroencephalogram
Duration of anticonvulsant therapy-
Guidelines
Neonatal period
If neonatal neurological examination becomes normal discontinue therapy
If neonatal neurological examination is persistently abnormal, consider etiology and obtain EEG
In most such cases- Continue Phenobarbital
- Discontinue Phenytoin
- Reevaluate in 1 month
Duration of anticonvulsant therapy-
Guidelines
One month after discharge
If neurological examination has become
normal, discontinue phenobarbital
If neurological examination is persistently
abnormal,obtain EEG
If no seizure activity on EEG, discontinue
phenobarbital
Prognosis
Two most useful approaches in utilizing outcome
EEG
Recognition of the underlying neurological
disease
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Prognosis of Neonatal seizures in relation
to EEG
EEG BACKGROUND NEUROLOGICAL SEQUELAE(%)
Normal 10
Severe abnormalities† 90
Moderate abnormalities‡ ~50
Based primarily on data reported by Rowe JC, Holmes GL, Hafford J, et al:
Electroencephalogr Clin Neurophysiol 60:183-196, 1985; Lombroso CT: In
Wasterlain CG, Treeman DM, Porter R, editors: Advances in neurology, New
York, 1983, Raven Press; and includes both full-term and premature infants.
†Burst-suppression pattern, marked voltage suppression, and electrocerebral
Silence.
‡Voltage asymmetries and “immaturity.”
Prognosis of Neonatal Seizures
Relation to Maturity
Maturity Normal Dead Sequelae
Term ≥2500 g 60% 10% 30%
Pemature ≤2500 g 35% 35% 30%
Premature ≤1500 g 20% 40% 40%
Causes of Neonatal Seizures and Outcomes
Percent of
Patients Who
Have Normal
Cause Development
Hypoxic-ischemic encephalopathy 50
Intraventricular hemorrhage 10
Subarachnoid hemorrhage 90
Hypocalcemia
Early-onset 50
Later-onset 100
Hypoglycemia 50
Bacterial meningitis 50
Developmental malformations 0
Benign familial neonatal convulsions ~100
Fifth-day fits ~100
Complications
Cerebral palsy
Hydrocephalus
Epilepsy
Learning disability, mental retardation
Feeding difficulties
Further Outpatient Care
Neurology outpatient evaluation
Developmental evaluation for early identification of physical or cognitive deficits
Orthopedic evaluations if with joint deformities
Consider physical medicine/physical therapy referral if indicated
References
1.Volpe JJ.Neonatal seizures. In:Neurology of the newborn.4th
ed.Philadelphia,Pa:WB Saunders's Co;2008: 203-237
2.Hahn J,Olson D.Etiology of neonatal
seizures.NeoReviews.2004;5:327-335
3.Riviello,J.Drug therapy for neonatal seizures:Part
I.NeoReviews.2004;5:215-220
4.Riviello,J.Drug therapy for neonatal seizures:Part
II.NeoReviews.2004;5:262-268
5.Fanaroff A,Martin R,Neonatal seizures.In:Neonatal-Perinatal
Medicine-Diseases of the fetus and infant.6th
ed.St.Louis,MO:Mosby-Yearbook Inc.1997:899-911
6.Sheth R, Neonatal seizures;Emedicine.com
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