NEONATAL SEIZURES
Jamie Parrott, MD
Child Neurologist
Department of Neurology
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What We Know
Baby brains like to have seizures
Seizures are frequently the first sign of
neurologic dysfunction in the neonate
Neonatal seizures are one of the strongest
independent predictors of mortality and
morbidity
Clinical seizure expression is quite variable,
poorly organized, and often subtle
The efficacy of current therapy and the
impact of treatment on long term outcome
are not well defined
After the Smoke Clears
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The neurologist is asked to confirm the
authenticity of the seizure, classify them,
decide whether to continue, modify, or stop
treatment, and discuss prognosis with the
family
Questions
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Why are neonates at high risk for seizures?
What constitutes a neonatal seizure?
What causes neonatal seizures?
Is there a best treatment?
Do neonatal seizures cause brain injury?
Can we affect the outcome?
Epidemiology
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Incidence 1.8 to 4.4 per 1000 live births
10 fold increase incidence with gestational
age <32 weeks
Lanska et al: 57/1000 live births with
BW<1500gm (n=16,428)
Sheth et al: 8.6% of NICU admissions
The majority begin in first two days of life
The most common clinical indicator of CNS
pathology in the neonate
Pathophysiology
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Seizures represent an abnormal synchronous
discharge of a group of neurons
Excessive depolarization is the end common
pathway
Hypoxia leads to sharp decrease in energy
production, subsequent failure of Na+K+ pump, and
excessive depolarization
Hypocalcemia and/or hypomagnesemia alter
membrane potentials leading to Na+ influx and
excessive depolarization
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The developing brain appears to be highly
susceptible to seizures due to:
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An imbalance in maturation of excitatory and inhibitory
circuits
The GABA-A (Gamma-aminobutyric acid) receptor is
excitatory in the neonate hippocampus
There is a higher density of NMDA (N-methyl daspartate) receptors in hippocampus and neocortex
NMDA receptor: Greater sensitivity to glycine,
reduced ability of Mg++ to block activity, prolonged
action potential
Proconvulsant network of the substantia nigra is fully
developed, inhibitory network is immature
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There is delayed maturation of postsynaptic
inhibitory networks
A prevalence of gap junctions in the immature
brain may amplify small imbalances in neuronal
activity and aid in synchronization
Immature neural networks have a shorter
refractory or hyperpolarization periods
However, the proconvulsive state of the
neonatal brain is likely crucial to early
development of CNS
Classification
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Volpe’s classification scheme (2001) is the most
commonly cited in literature
Seizure types: Clonic, tonic, myoclonic, subtle
All seizure types may be focal, multifocal
(migratory/random), or generalized
Electrograpic seizures may have no clinical correlate
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Hellstrom-Westas: 26 neonates with electrographic
seizures, 14 with >1 hr of “silent” seizures
Scher: In 92 neonates, percent of electrographic seizures
unassociated with clinical events was 55% in preterm and
47% in term neonates
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Clonic
May affect extremities, torso, face, tongue
Rhythmic and 1 to 3 cycles per second
Multifocal are migratory/random, not a
Jacksonian march, due to immature CNS
Focal clonic often associated with focal
cortical lesion (stroke, SAH, SDH)
Increased incidence in term infants
Focal and multifocal clonic seizures have a
consistent EEG correlate
Generalized clonic seizures are not sustained
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Tonic
Focal type presents as asymmetric limb or torso
posturing, tonic eye deviation
Flexor muscles predominantly affected
Generalized type present with leg extension, arm
extension or flexion, occasional head/torso
hyperextension, and may mimic opisthoclonus
Generalized type usually associated with severe,
diffuse CNS dysfunction
Generalized with inconsistent EEG correlate
Focal with frequent EEG correlate
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Myoclonic
Rapid flexion or extention of muscle group
If repetitive, may be difficult to differentiate
from focal/multifocal clonic
Typically slower repetition rate, less rhythmic
EEG correlate will usually differentiate
repetitive myoclonic from clonic seizures
Generalized myoclonus may mimic infantile
spasms
Myoclonic seizures may have EEG correlate
Subtle
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Oral-buccal: Repetitive pucker, suck, grimace,
tongue protrusion
Ocular: Eye opening, blinking, roving movements,
nystagmus
Progression Movements: Swimming, rotary
movements of upper extremities, pedaling,
stepping
No consistent EEG correlate
Nonepileptic events
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Jitteriness/tremor/clonus (5-7 cps, alternating
movements are rhythmic bidirectionally)
Isolated apnea (pulmonary, cardiovascular,
gastrointestinal, periodic breathing)
Complex purposeless movements (thrashing,
repetitive side to side head/torso, struggling)
Benign sleep myoclonus, REM associated
sucking/stretching
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?Nonepileptic Seizures?
Adult and animal studies demonstrate clinical
seizure activity with EEG correlate detected by
depth electrode only; no surface EEG correlate
Similar studies unlikely in neonates due to ethical
concerns
Numerous studies document clinical neonatal
seizures with no EEG correlate
Electroclinical dissociation: Following
antiepileptic treatment, clinical seizure activity
may cease with persistent seizures per EEG
Scher reports incidence of 25% in one series
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Deep gray matter is prone to seizure activity in
the excitatory brain, a region undetected on
surface EEG
Mature limbic/midbrain/brainstem system may
support the entity of subcortical seizures with
subtle presentation and no EEG correlate
Stimulation may incite clinical “seizures”
Flexion of involved muscles, repositioning,
restraint, ventral suspension may halt
“seizure” activity
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Mizrahi suggests subtle, generalized tonic,
and some myoclonic seizures without EEG
correlate may represent primitive brainstem
and spinal cord motor patterns released from
tonic inhibition of forebrain structures
These seizure types are characteristically
seen in association with cortical depression
or inactivity on EEG
Etiology
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Neonatal seizures are almost always an
epiphenomena of underlying CNS
dysfunction
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Hypoxic Ischemic Encephalopathy (HIE):
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Underlying pathology in 50% or more of neonatal
seizures in the majority of studies
Morbidity/mortality exceeds 50% in most series
Diagnostic findings suggestive of HIE:
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Apgar<5 at 5 and/or 10 minutes, umbilical artery pH<7.1
or base deficit>10, multisystem failure, depressed
neurologic exam, perinatal history, placental pathology
Williams: pH<7, base deficit>16 predictive of
neonatal seizure risk associated with HIE
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Mean time to seizure onset 12 hours
Most severe in first 72 hours then subside irrespective of
treatment
Clinical: lethargy often alternating with irritability, brainstem
dysfunction, symptoms of increased ICP
Subtle, generalized tonic, myoclonic seizures most
common, often without EEG correlate
EEG typically depressed or inactive
Focal and/or multifocal clonic seizures suggest associated
stroke or hemorrhage
Often coexists with subarachnoid hemorrhage, stroke,
hypoglycemia/magnesemia/calcemia
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CNS Infection
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5 to 10% incidence
Bacterial: Group B Strep, E Coli, Listeria
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Also Serratia, Pseudomonas, Proteus,
Staphylococcus, Citrobacter, and Bacteroides
species with prolonged respiratory support or
frequent instrumentation
All seizure types may be represented
Irritability/lethargy, apnea, poor feeding, fever,
hypothermia, jaundice, abnormal tone
Morbidity and mortality approach 50%
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CMV:
 Association with IUGR, microcephaly, periventricular
calcifications, hyperbilirubinemia, thrombocytopenia,
petechiae, hepatosplenomegaly, elevated LFTs, senorineural
hearing loss, vision impairment
 Infection early in pregnancy is associated with CNS sequella
and IUGR
 Sequella are more likely with primary maternal infection
 Seizure onset DOL 1 to 3, or later in infancy
 Boppana: n=106 symptomatic infections,12% mortality
(associated with multiorgan failure), LFT/plt abnormalities
80%, microcephaly 53%, petichia/HSM/jaundice 70%
 Neurodevelopmental outcome poor in the symptomatic
neonate; 60% hearing loss, 45 % MR, 35% CP
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Toxoplasmosis:
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Association with IUGR, microcephaly,
chorioretinitis, hepatosplenomegaly,
hyperbilirubinemia, anemia, hydrocephalus,
intracranial calcifications
Transmission greatest in 3rd trimester, sequella in
neonate more common with early transmission
Seizure onset DOL1 to 3, or later in infancy
Roizen: 36 symptomatic; 6 with neonatal seizures,
2 with subsequent epilepsy at 3 to 5 year follow up.
80% with MR, CP, seizures or visual impairment
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Herpes Simplex Virus
 Irritability/coma, poor feeding, hypothermia, vesicular rash,
multifocal CNS necrosis/hemorrhage
 Onset week 2 to 3 typical
 Seizures and lethargy the most common presenting symptoms
 Sequella: microcephaly, IUGR, cataracts, CNS calcifications
 Vesicles absent in 40% with CNS (34%) or disseminated
disease (23%)
 10% with onset in first days of life, suggestive of
transplacental transmission, associated with premature birth,
IUGR, microcephaly, higher incidence of rash
 Jacobs RF: Mortality 57 % in disseminated, 15% in CNS
disease
 2000 cases per year
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Hemorrhage
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Subdural hematoma
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Subarachnoid hemorrhage
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Associated with birth trauma, contusion, cephalohematoma,
BW>4000gm, precipitous or difficult labor, primagravida
DOL 1 to 2
Focal or multifocal clonic seizures
Outcome good
“Well baby seizures”, birth history usually unremarkable
Focal clonic seizures
DOL 1 to 2 typical
Resolve quickly, outcome excellent
Intraventricular hemorrhage
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Germinal matrix hemorrhages not associated with seizures
Look for abrupt drop in hematocrit DOL 1 to 3, lethargy, symptoms of
increased intracranial pressure/hydrocephalus
Associated with subtle and generalized tonic seizures
Focal clonic seizures suggest infarction in association with IVH
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Infarction (CVA)
 Suspect in a previously normal neonate without metabolic or
infectious etiology (if primary)
 Also seen in association with SVT, IVH, SDH, HIE, infection
 Diffusion weighted MRI best test acutely
 Seen primarily in middle cerebral artery territory
 Focal, multifocal clonic seizures.
 Subtle, generalized tonic seen with large CVA with associated
increased ICP
 Risk factors: Maternal cocaine use, placental pathology,
chorioamnionitis, congenital heart disease, CNS infection, sepsis,
prothrombotic state (maternal or fetal), extracorporeal membrane
oxygenation (ECMO)
 Parish: 25 of 64 with seizures before/during ECMO, a primary risk
factor for subsequent developmental abnormalities and epilepsy
 Seizure is the most common clinical presentation with isolated
stroke, with neonate often asymptomatic otherwise
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Sinus venous thrombosis (SVT)
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Associated with pulmonary hypertension, CNS infection,
hypernatremia, thrombophylic disorders
Focal or multifocal seizures typically
Often with associated cortical infarction
Shevell: 15 of 17 SVT’s presented with seizures
Steinbok: 5 of 6 SVT’s with associated stroke
Fitzgerald: n=42, 57% presented with seizures, 60% had
stroke. Outcome 59% cognitive impairment, 67% with CP,
41% with epilepsy
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Acute Metabolic:
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Kumar: 35 neonates with seizure, 67% with
metabolic abnormalities, 16% primary cause of
seizure
Hypoglycemia:
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Primary cause in 3% of neonatal seizures
May be associated with infection, HIE, inborn errors of
metabolism, IUGR, persistent hyperinsulinemia
Infants of diabetic mothers (IDM) usually asymptomatic
Symptoms: jitteriness, apnea, stuporous, poor feeding,
hypothermia
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Hypocalcemia:
 Isolated cause of seizures in 3%
 DOL 1 to 3 typical
 Late onset unusual with advent of new formulas (phosphate)
 IUGR and IDM at risk
 Primarily seen in association with infection or HIE
 Maternal hyperparathyroidism, fetal hypoparathyroidism
 Cardiac defects common (DeGeorge syndrome)
 Lynch: 7 of 15 “primary” hypocalcemic seizures associated with
congenital heart disease
Hypomagnesemia:
 Typically associated with hypocalcemia
 Consider as the primary cause when seizures persist with
calcium normalization
Sodium abnormalities
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An uncommon cause in isolation, may be iatrogenic
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Neonatal Drug Withdrawal:
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5% present with seizure
Jitteriness, autonomic dysfunction, diarrhea common
Suspect alcohol, narcotics, hypnotics/analgesics perinatally
(propoxyphene, barbiturates)
Methadone withdrawal symptoms may present at 3 to 4
weeks postnatally (time of last dose is key)
Local anesthetic toxicity (procaine)
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Associated with saddle block, paracervical, pudendal
anesthesia
Meconium staining, flaccidity, apnea
Treatment: diuresis and urine acidification
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Cerebral Malformations
 Holoprosencephaly, hemimegalencephaly, lissencephaly, cortical
heterotopias
 Association with Nonketotic hyperglycinemia, pyruvate
dehydrogenase deficiency, peroxisomal disorders, fatty acid
oxidation disorders, neurocutaneous disorders
Pyridoxine Dependency
 Decreased GABA and increased glutamate production leads to
intractable seizures in first days of life or prenatally
 Linkage to 5q31, but appears to be heterogeneous
 Clinical outcome dependent on early treatment with pyridoxine
 Two sisters affected, one treated at age 6 with moderate MR, other
treated at birth with normal development
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Inborn Errors of Metabolism
 Rare, rule out other causes
 Amino acidopathies, organic acidopathies, urea cycle
disorders, biotinidase deficiency, mitochondrial
disorders, disorders of beta oxidation, peroxisomal
disorders, glucose transporter deficiency (treated with
ketogenic diet)
 Testing may include lactate, pyruvate, ammonia, urine
organic acids, plasma amino acids, very long chain
fatty acids, and CSF (lactate, pyruvate, amino acids,
cells, glucose)
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Benign Familial Neonatal Convulsions
 Autosomal dominant
 Onset DOL 2-3, resolve at 1 to 12 months of age
 5 to 20 seizures per day, minutes duration
 Behavioral arrest, tonic eye deviation, tonic stiffening, occasional
myoclonus
 Chromosomes 8 and 20, potassium channel
 Relatively refractory to standard antiepileptic therapies
 16% risk of developing subsequent epilepsy
 Development usually normal
Benign Idiopathic Neonatal Convulsions
 Fifth day fits. Clonic, multifocal
 Onset DOL 3-7
 5% of term neonates with convulsions
 Usually resolve in 24 hours
 Suspected CSF zinc deficiency, not familial
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Early Myoclonic Encephalopathy
 Fragmentary or violent myoclonus
 EEG with persistent burst suppression pattern
 Mapped to 11p15.5, coding a mitochondrial glutamate/H+
symporter, SLC25A22
 First direct molecular link between glutamate mitochondrial
metabolism and myoclonic epilepsy
 Associated with nonketotic hyperglycinemia, D-glyceric acidemia,
proprionic acidemia.
Early Infantile Epileptic Encephalopathy
 Otahara syndrome
 Mimic infantile spasms, and may occur in clusters
 EEG with burst suppression pattern
 Associated with cortical malformations
 33% mortality
Treatment
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Treat the underlying etiology
Debate persists regarding what constitutes
an epileptic seizure
Video EEG is useful in evaluating seizure
activity and monitoring efficacy of tx
(decoupling, nonepileptic events)
Traditional antiepileptic medications,
phenobarbitol, phenytoin, and
benzodiazepines, remain the first line
treatments
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Efficacy: Painter et al reported efficacy in 42%
treated with PB, 43% treated with PHT, and 62%
treated with both
Scher et al reports on 59 neonates with seizures; 9
electrographic only prior to treatment, 24 responded
to first choice AED, 15 of the remaining 26 had
uncoupling of electrical and clinical expression of
seizures
Gal: Symptomatic vs. prolonged (3 months)
treatment with phenobarbitol demonstrated no
difference in long term outcome
Phenobarbitol (PB)
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Associated with decrease in CNS metabolism, a
possible benefit with some seizure etiologies
A GABA agonist, possibly not the best choice
considering that the GABA-2 receptor, a
postsynaptic inhibitor, is underexpressed in the
neonate
Side effects including respiratory and cardiac
depression may exacerbate or worsen the
neonates underlying condition
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Phenytoin (PHT):
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Benzodiazepines
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Associated with purple glove syndrome due to alkalinity
Use Fosphenytoin
Highly protein bound, consider unbound level assays
Primary use as adjunctive treatment
No direct comparisons with other anticonvulsants regarding
efficacy
Lidocaine and midazolam:
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Show a trend toward efficacy as second line treatment
following initial treatment with PB or PHT
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Valproic acid
 Associated with hyperammonemia, hepatoxicity (1:500), and
platlet dysfunction
 Typically reserved for refractory seizures under age 2 years
Carbamazepine
 Per nasogastric tube was found effective and well absorbed in
one small case series
Topiramate
 Use makes empiric sense due to mechanism of NMDA block
 Two studies in rodents demonstrated antiepileptogenic properties
but limited antiepileptic ability acutely
 Deserves more study
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Zonisamide
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Lamictal:
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Slow titration is a drawback, needs study
Levetiracetam and Trileptal
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15 year history of safety and efficacy in Japan treating
neonatal seizures
Two Japanese studies showed 33 to 36% efficacy
Neuroprotective in HIE in neonatal rat studies with no effect
on seizures
Have little data supporting use in neonates, needs study
Clinical research is sorely needed!!!
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There are good theoretical reasons for suppressing
seizure activity, but little clinical evidence that
generally poor outcomes can be improved with
antiepileptic treatment
At present there is little evidence from randomized
controlled trials to support the use of therapies
Whether better control of neonatal seizures leads to
a reduction of morbidity and mortality will remain
unclear until better, more effective treatments are
found
Neonatal Seizures and Brain Injury
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Clinical and lab studies demonstrate neonatal
seizures may result in permanent
developmental abnormalities and enhanced
epileptogenicity
Neonatal seizures initiate a cascade of
diverse changes in brain development that
may become maladaptive at an older age
The mechanisms remain unclear
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A number of factors, including etiology,
seizure type and antiepileptic medications,
may influence outcome
Animal models allow for control of these
variables and provide insight into the
mechanisms of seizure induced injury
In experimental rodent models,
consequences of seizures are dependent on
age, etiology, seizure duration and frequency
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Hypoventillaton, hypoxia, and hypercapnea
lead to loss of autoregulation with the risk of
hemorrhage and increased intracranial
pressure (animal/human studies)
Recurrent seizures may result in changes in
brain connectivity, dendritic morphology,
neurogenesis, neurotransmitter receptor
subunit and ion channel populations
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Recurrent neonatal seizures
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In rodents, lead to increased susceptibility to
seizures and visuospacial learning deficits in
adolescence/adulthood
Effect alterations in dendritic spines and synaptic
reorganization in the rat hippocampus
Reduce neurogenesis of granular cells in rodents
Alter hippocampal NMDA/GABA balance resulting
in increased epileptogenicity in adult rodents
Rodents with cortical malformations are prone to
neuronal damage with recurrent seizures
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Animal studies demonstrate that the
pathophysiologic consequences of status
epilepticus in the developing brain differ from
the mature brain
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Prolonged neonatal seizures
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Developing neurons are less vulnerable to damage or death
secondary to anoxia or protracted seizures (rodent and
monkey studies)
Glutamate is less toxic to the immature brain (Reduced
density of active synapses? Immaturity of biological
cascades?)
In rats, lead to epileptogenicity and memory deficits in the
adult
Lead to permanent glutamate receptor subunit and
transporter gene expression in adult (epileptogenic)
Deplete glucose stores in thalamus and cortex of monkeys
Cell loss is greater following prolonged seizure in adult
rodents with history of neonatal seizures
Prolonged seizures worsen existing brain injury associated
with HIE
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Antiepileptic Medication Effects
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Phenobarbitol (PB) exposure in rat pups leads to
decreased CNS DNA, RNA, and protein
production, with reduced brain weight and
cholesterol content
PB and phenytoin in exposed rodents lead to
reduced protein content and neuronal cell count
Rodent spinal cord cell culture exposed to PB has
reduced neuronal cell count and acetyl
transferase, a marker of neuronal development
In rodents, abnormalities of dendritic spines seen
with 3 day exposure to phenobarbitol
Outcome
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Mortality of approximately 1/3, reflecting the
severity of underlying etiologies
Poor outcome in 25% to 35% of survivors
including cerebral palsy, mental retardation,
epilepsy, learning disabilities
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National Collaborative Perinatal Project: Multivariate
analysis predicts combined mobidity/mortality 64 to
83%
Lambroso: 46 patients. Well organized seizures have
little CNS impact. Subtle seizures associated with poor
outcome and associated with significant CNS
pathology
Mizrahi and Kelloway: 349 subjects. Clonic 71%
normal at discharge (DC), no deaths. Generalized
tonic/subtle with 50% abnormal exam at DC, 20%
mortality. Myoclonic +/_ abnormal EEG with 35%
abnormal exam at DC, 29% mortality
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Legado: 40 patients. 27 survivors. 70% poor
outcome. 56% epilepsy, 63% CP, 67% MR. 100% of
pts with HIE affected
Bergman: 131 survivors, 51 normal, 17 minor, 25
moderate, 30 severe neurologic deficits. 26 with
recurrent seizures. 41 of 77 with dx of HIE
mod/severe. 6 died. Negative predictors prolonged
resusitation effort, generalized tonic seizures and
duration of seizures
Melits: Seizures in first 24 hours or >30 minute
duration predictive of poor outcome (also AG5<5,
resuscitation>5 minutes, arterial cord blood pH<7
Watkins: <31 weeks GA, 25% with normal exam at
DC. >36 weeks GA, 60% normal.
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Garcias: n=158; recurrent seizures, 22% @ one year,
34% @ two years. Predictors abnormal EEG or
neurologic exam at DC
Doose: 42 of 72 neonates with seizures developed
epilepsy or febrile seizures by age 2 yo
Temple: “Normal” teenagers with history of neonatal
seizures found to have deficits in memory, spelling,
arithmetic
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Prognosis: Determined by etiology, seizure type
and duration
Good in SAH, benign neonatal seizures, isolated
metabolic abnormalities
Poor in HIE, CNS infection, CNS malformations
Poor with generalized tonic, subtle and myoclonic
seizure types; prolonged or persistent seizures
The relative effects of the underlying CNS pathology
coexisting with neonatal seizures may be difficult to
differentiate from the effects of the seizures and/or
their treatment
Summary
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Neonatal seizures typically signal significant underlying
neurologic disease
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Animal and human studies suggest that neonatal seizures
themselves, in addition to the etiology for the seizures, have a
significant impact on the developing brain
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Current therapies are often ineffective and possibly toxic to
the CNS
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Controversy persists regarding what constitutes seizure
activity in the neonate
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Further studies are needed regarding new and more
efficacious treatments and their impact on the outcome of
different neonatal seizure types