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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
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