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.
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