Neonatal Seizures

Priscilla Joe, MDChildrens Hospital & Research Center at Oakland

PathophysiologyAbnormal synchronous depolarization from large group of neurons Excessive excitatory amino acid release (glutamate)Lack of inhibitory systems (GABA)Depolarization results from Na influx into cells; repolarization from outflux of K+Disruption of Na/K ATP pump

Basic Mechanisms of SeizuresAbnormal energy production (hypoxemia, hypoglycemia)Alteration in neuronal membrane (hypocalcemia, hypomagnesemia)Relative excess of excitatory versus inhibitory neurotransmitters (GABA)

Biochemical Changes with Seizures ATP phosphocreatinePyruvate converted to lactate brain glucoseIncreased production of pyruvate from ADP

IncidenceHigher in neonates than any other age groupMost frequent in the first 10 days of life

Do Prolonged Seizures Harm the Developing Brain?Animal studies:Persistent neonatal seizures in rats induce neuronal death and changes in hippocampusChronic seizures in adults associated with memory impairment and poor psychosocial outcomePermanent reduction in seizure threshold associated with significant deficits in learning and memory

Causes of Neonatal SeizuresHIE (32%)Intracranial hemorrhage (17%)CNS infection (14%)Infarction (7%)Metabolic disorders (6%)Inborn errors (3%)Unknown (10%)Drug withdrawal (1%)

Adverse Effects of SeizuresCell division and migrationFormation and expression of receptorsSynaptogenesis and apotosisLong term effects: seizure threshold, learning, and cognition

Ferriero D. N Engl J Med 2004;351:1985-1995

Subtle SeizuresMore common in premature infantsMost frequently observed type of seizureClinical manifestations: Bicycling movements, lip smacking, apnea, and eye movements or staring, unresponsivenessTypically have no electrographic correlate, are likely primarily subcortical

Clonic Seizures

Focal or multifocal, rhythmic movements with slow return movementMay be associated with generalized or focal brain abnormalityMost commonly associated with electrographic seizures

Tonic SeizuresSustained flexion or extension of one extremity or the whole bodyExtensive neocortical damage with uninhibited subcortically generated movementsMay or may not have electrographic correlate

Myoclonic SeizuresRapid, isolated jerks which lacks the slow return phase of clonic movementsTypically not associated with electrographic correlateMyoclonic movements may be normal in preterm or term infants

Nonepileptic movementsBenign sleep myoclonusTremulousness or jitterinessStimulus evoked myoclonus from metabolic encephalopathies, CNS malformation

Benign Sleep MyoclonusOnset 1st week of lifeSynchronous jerks of upper and lower extremities during sleepNo EEG correlateProvoked by benzodiazepinesCeases upon arousalResolves by 2 monthsGood prognosis

Jitteriness vs. SeizuresNo ocular phenomenaStimulus sensitiveTremorMovements cease with passive flexion

Hypoxic Ischemic EncephalopathySeizures begin within 24-72 hours after birthAccounts for 50-60% of all neonatal seizuresMost asphyxia occurs before or during birthArterial cord pH < 7.0, base deficit < -1060% develop seizures within 1st 12 hoursRecent stress: hypotonia and unresponsivenessLonger standing dysfunction: hypertonia with cortical thumbing, joint contractures or conversely hypotonia with encephalopathy

Meningitis/ EncephalitisAccounts for 5-10% of all neonatal seizuresTORCH, enterovirus, parvovirus Usually present by day 3 of life, except for HSV which may present in 2nd week of lifeGBS, listeria, E coli, strep pneumoniae Presents at end of 1st week to 3 months of age

Intracranial HemorrhageAccounts for 10% of all seizuresGrade IV IVH/PVHSubarachnoid/subdural hemorrhageCerebral infarction (ischemia, dehydration, infection, polycythemia)

Cerebral InfarctionMost frequently involves middle cerebral arteryFocal, clonic seizures commonAt risk for spastic hemiparesisVenous sinus thrombosis may cause hemorrhage strokeECMO

Etiologies: CNS malformationsLissencephaly, pachygyria, linear sebaceous nevus syndrome, polymicrogyriaPresent with seizures at a later age

Etiologies: MetabolicHypoglycemia, hypocalcemia, hypomagnesemia, hyper/hyponatremiaInborn errors of metabolism (>72hrs of age): Aminoacidopathies, urea cycle disorders, biotinidase deficiency, mitochondrial disorders, beta oxidation disorders, glucose transporter deficiency, peroxisomal disorders

Epileptic syndromes-benignBenign familial neonatal seizuresAutosomal dominantInter-ictal exam is normalLong term outcome is goodUnusual tonic-clonic patternBenign idiopathic neonatal seizuresTerm, normal birthNormal inter-ictal state, EEGClonic, occur day 5, may be Zn deficiency

Epileptic syndromes-malignantNeonatal Myoclonic encephalopathyFragmentary partial seizures, massive myoclonusMetabolic disorders, abnormal EEGPoor prognosisOhtahara syndrome10d -3 moNumerous brief Tonic seizuresDysgenesis is cause, prognosis very poor

Metabolic EvaluationBlood: glucose, lytes, BUN, creatinine, lactate, pyruvate, ammonia, biotinidase, quantitative amino acids, very long chain fatty acidsUrine: quantitative amino acidsCSF: cell count, glucose, protein, pyruvate, lactate, quantitative amino acids, HSV PCR

EEGScalp recordings measure discharges that spread to the surfaceDischarges from frontal or temporal regions may not spread to the surfaceMore common in the newborn

Clinical Seizures Without EEG CorrelateMay represent uninhibited brainstem reflexesDischarges from deep cerebral structures and brainstem may not reach the cortical surface

TreatmentMore difficult to suppress than in older childrenTreatment is worthwhile because seizures:May cause hemodynamic or respiratory compromiseDisrupt cerebral autoregulationMay result in cerebral energy failure and further injury

TreatmentStabilize vital signs and treat underlying hypotensionCorrect transient metabolic disturbances

Phenobarbital is first line agentLorazepamPhenytoin

Prognosis based on etiologyHypoxia-ischemiaMeningitisHypoglycemiaEarly Hypocalcemia

Subarachnoid hemorrhageLate Hypocalcemia

50% normal outcomeAlmost all are normal

Prognosis based on etiologyCerebral dysgenesis has grave prognosis, almost none are normal

Prematurity and seizures associated with high risk of death or very poor outcome

Prognosis based on typeSubtle Depends on cause, other seizure types ClonicBetter prognosisGeneralized TonicPoorMyoclonicPoor

Prognosis by EEGSevere inter-ictal EEG background associated with adverse outcomeNormal EEG background at presentation associated with good outcomeIctal features less reliableBetter outcome when clinical and EEG seizures correlateIncreased number and frequency may relate to worse outcome

ConclusionsNeonatal seizures are often subtleClose examination and characterization important for prognosis and evaluationTreatment usually successful in stopping seizures, but risk of neuro-developmental abnormalities remains highPrevention of causes remains a priority

Table 2. Differential Diagnosis of Neonatal Seizures by Day of Presentation.