Neonatal Seizures

Priscilla Joe, MDChildren’s Hospital & Research Center at Oakland

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

Basic Mechanisms of Seizures

• Abnormal energy production (hypoxemia, hypoglycemia)

• Alteration in neuronal membrane (hypocalcemia, hypomagnesemia)

• Relative excess of excitatory versus inhibitory neurotransmitters (GABA)

Biochemical Changes with Seizures

• ↓ ATP

• ↓ phosphocreatine

• Pyruvate converted to lactate

• ↓ brain glucose

• Increased production of pyruvate from ADP

Incidence

• Higher in neonates than any other age group

• Most 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 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

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%)

Adverse Effects of Seizures

• Cell division and migration

• Formation and expression of receptors

• Synaptogenesis and apotosis

• Long term effects: seizure threshold, learning, and cognition

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

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

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

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

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

Nonepileptic movements

• Benign sleep myoclonus

• Tremulousness or jitteriness

• Stimulus evoked myoclonus from metabolic encephalopathies, CNS malformation

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

Jitteriness vs. Seizures

• No ocular phenomena

• Stimulus sensitive

• Tremor

• Movements cease with passive flexion

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

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

Intracranial Hemorrhage

• Accounts for 10% of all seizures

• Grade IV IVH/PVH

• Subarachnoid/subdural hemorrhage

• Cerebral infarction (ischemia, dehydration, infection, polycythemia)

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

Etiologies: CNS malformations

• Lissencephaly, pachygyria, linear sebaceous nevus syndrome, polymicrogyria

• Present with seizures at a later age

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

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

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

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

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

Clinical Seizures Without EEG Correlate

• May represent uninhibited brainstem reflexes

• Discharges from deep cerebral structures and brainstem may not reach the cortical surface

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

Treatment

• Stabilize vital signs and treat underlying hypotension

• Correct transient metabolic disturbances

• Phenobarbital is first line agent

• Lorazepam

• Phenytoin

Prognosis based on etiology

• Hypoxia-ischemia

• Meningitis

• Hypoglycemia

• Early Hypocalcemia

• Subarachnoid hemorrhage

• Late Hypocalcemia

50% normal outcome

Almost all are normal

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

Prognosis based on type

• Subtle Depends on cause, other seizure

types

• Clonic Better prognosis

• Generalized Tonic Poor

• Myoclonic Poor

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

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