NEONATAL SEIZURES

NEONATAL SEIZURES Jamie Parrott, MD Child Neurologist Department of Neurology

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 • 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 • 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 • 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 • 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

The developing brain appears to be highly susceptible to seizures due to: • 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-methyld-aspartate) 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

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 • 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 • 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

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

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

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 • 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 • 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

?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

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

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 • Neonatal seizures are almost always an epiphenomena of underlying CNS dysfunction

Hypoxic Ischemic Encephalopathy (HIE): • 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: • 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

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

CNS Infection • 5 to 10% incidence • Bacterial: Group B Strep, E Coli, Listeria • 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%

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

Toxoplasmosis: • 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

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

Hemorrhage • Subdural hematoma • Associated with birth trauma, contusion, cephalohematoma, BW>4000gm, precipitous or difficult labor, primagravida • DOL 1 to 2 • Focal or multifocal clonic seizures • Outcome good • Subarachnoid hemorrhage • “Well baby seizures”, birth history usually unremarkable • Focal clonic seizures • DOL 1 to 2 typical • Resolve quickly, outcome excellent • Intraventricular hemorrhage • 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

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

Sinus venous thrombosis (SVT) • 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

Acute Metabolic: • Kumar: 35 neonates with seizure, 67% with metabolic abnormalities, 16% primary cause of seizure • Hypoglycemia: • 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

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 An uncommon cause in isolation, may be iatrogenic

Neonatal Drug Withdrawal: • 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) • Associated with saddle block, paracervical, pudendal anesthesia • Meconium staining, flaccidity, apnea • Treatment: diuresis and urine acidification

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

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)

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

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 • 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

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) • 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

Phenytoin (PHT): • Associated with purple glove syndrome due to alkalinity • Use Fosphenytoin • Highly protein bound, consider unbound level assays • Benzodiazepines • Primary use as adjunctive treatment • No direct comparisons with other anticonvulsants regarding efficacy • Lidocaine and midazolam: • Show a trend toward efficacy as second line treatment following initial treatment with PB or PHT

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

Zonisamide • 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 • Lamictal: • Slow titration is a drawback, needs study • Levetiracetam and Trileptal • Have little data supporting use in neonates, needs study • Clinical research is sorely needed!!!

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 • 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

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

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

Recurrent neonatal seizures • 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

Animal studies demonstrate that the pathophysiologic consequences of status epilepticus in the developing brain differ from the mature brain

Prolonged neonatal seizures • 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

Antiepileptic Medication Effects • 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 • 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

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

NEONATAL SEIZURES