1. Neonatal Seizures Priscilla Joe, MD Children’s Hospital & Research Center at Oakland

2. Pathophysiology Abnormal 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

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

4. Biochemical Changes with Seizures ↓ ATP ↓ phosphocreatine Pyruvate converted to lactate ↓ brain glucose Increased production of pyruvate from ADP

5. Incidence Higher in neonates than any other age group Most frequent in the first 10 days of life

6. Do Prolonged Seizures Harm the Developing Brain? Animal studies: –Persistent neonatal seizures in rats induce neuronal death and changes in hippocampus Chronic seizures in adults associated with memory impairment and poor psychosocial outcome Permanent reduction in seizure threshold associated with significant deficits in learning and memory

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

8. Adverse Effects of Seizures Cell division and migration Formation and expression of receptors Synaptogenesis and apotosis Long term effects: seizure threshold, learning, and cognition

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

10. Subtle Seizures More common in premature infants Most frequently observed type of seizure Clinical manifestations: Bicycling movements, lip smacking, apnea, and eye movements or staring, unresponsiveness Typically have no electrographic correlate, are likely primarily subcortical

11. Clonic Seizures Focal or multifocal, rhythmic movements with slow return movement May be associated with generalized or focal brain abnormality Most commonly associated with electrographic seizures

12. Tonic Seizures Sustained flexion or extension of one extremity or the whole body Extensive neocortical damage with uninhibited subcortically generated movements May or may not have electrographic correlate

13. Myoclonic Seizures Rapid, isolated jerks which lacks the slow return phase of clonic movements Typically not associated with electrographic correlate Myoclonic movements may be normal in preterm or term infants

14. Nonepileptic movements Benign sleep myoclonus Tremulousness or jitteriness Stimulus evoked myoclonus from metabolic encephalopathies, CNS malformation

15. Benign Sleep Myoclonus Onset 1 st week of life Synchronous jerks of upper and lower extremities during sleep No EEG correlate Provoked by benzodiazepines Ceases upon arousal Resolves by 2 months Good prognosis

16. Jitteriness vs. Seizures No ocular phenomena Stimulus sensitive Tremor Movements cease with passive flexion

17. Hypoxic Ischemic Encephalopathy Seizures begin within 24-72 hours after birth Accounts for 50-60% of all neonatal seizures Most asphyxia occurs before or during birth Arterial cord pH < 7.0, base deficit < -10 60% develop seizures within 1 st 12 hours Recent stress: hypotonia and unresponsiveness Longer standing dysfunction: hypertonia with cortical thumbing, joint contractures or conversely hypotonia with encephalopathy

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

19. Intracranial Hemorrhage Accounts for 10% of all seizures Grade IV IVH/PVH Subarachnoid/subdural hemorrhage Cerebral infarction (ischemia, dehydration, infection, polycythemia)

20. Cerebral Infarction Most frequently involves middle cerebral artery Focal, clonic seizures common At risk for spastic hemiparesis Venous sinus thrombosis may cause hemorrhage stroke ECMO

21. Etiologies: CNS malformations Lissencephaly, pachygyria, linear sebaceous nevus syndrome, polymicrogyria Present with seizures at a later age

22. Etiologies: Metabolic Hypoglycemia, hypocalcemia, hypomagnesemia, hyper/hyponatremia Inborn errors of metabolism (>72hrs of age): Aminoacidopathies, urea cycle disorders, biotinidase deficiency, mitochondrial disorders, beta oxidation disorders, glucose transporter deficiency, peroxisomal disorders

23. Epileptic syndromes-benign Benign familial neonatal seizures –Autosomal dominant –Inter-ictal exam is normal –Long term outcome is good –Unusual tonic-clonic pattern Benign idiopathic neonatal seizures –Term, normal birth –Normal inter-ictal state, EEG –Clonic, occur day 5, may be Zn deficiency

24. Epileptic syndromes-malignant Neonatal Myoclonic encephalopathy –Fragmentary partial seizures, massive myoclonus –Metabolic disorders, abnormal EEG –Poor prognosis Ohtahara syndrome –10d -3 mo –Numerous brief Tonic seizures –Dysgenesis is cause, prognosis very poor

25. Metabolic Evaluation Blood: glucose, lytes, BUN, creatinine, lactate, pyruvate, ammonia, biotinidase, quantitative amino acids, very long chain fatty acids Urine: quantitative amino acids CSF: cell count, glucose, protein, pyruvate, lactate, quantitative amino acids, HSV PCR

26. EEG Scalp recordings measure discharges that spread to the surface Discharges from frontal or temporal regions may not spread to the surface More common in the newborn

27. Clinical Seizures Without EEG Correlate May represent uninhibited brainstem reflexes Discharges from deep cerebral structures and brainstem may not reach the cortical surface

28. Treatment More difficult to suppress than in older children Treatment is worthwhile because seizures: –May cause hemodynamic or respiratory compromise –Disrupt cerebral autoregulation –May result in cerebral energy failure and further injury

29. Treatment Stabilize vital signs and treat underlying hypotension Correct transient metabolic disturbances Phenobarbital is first line agent Lorazepam Phenytoin

30. Prognosis based on etiology Hypoxia-ischemia Meningitis Hypoglycemia Early Hypocalcemia Subarachnoid hemorrhage Late Hypocalcemia 50% normal outcome Almost all are normal

31. Prognosis based on etiology Cerebral dysgenesis has grave prognosis, almost none are normal Prematurity and seizures associated with high risk of death or very poor outcome

32. Prognosis based on type Subtle Depends on cause, other seizure types Clonic Better prognosis Generalized Tonic Poor Myoclonic Poor

33. Prognosis by EEG Severe inter-ictal EEG background associated with adverse outcome Normal EEG background at presentation associated with good outcome Ictal features less reliable –Better outcome when clinical and EEG seizures correlate –Increased number and frequency may relate to worse outcome

34. Conclusions Neonatal seizures are often subtle Close examination and characterization important for prognosis and evaluation Treatment usually successful in stopping seizures, but risk of neuro-developmental abnormalities remains high Prevention of causes remains a priority