Understanding Neonatal Seizures: Pathophysiology, Incidence, and Long-Term Effects

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 1st 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 1st 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 2nd week of life • GBS, listeria, E coli, strep pneumoniae Presents at end of 1st 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