Kejang Neonatus

01Pathophysiology

Neonatal seizures arise from excessive, synchronous neuronal depolarization in the immature brain. The neonatal brain is inherently more excitable than the mature brain due to several developmental factors.

In the immature CNS, excitatory neurotransmission predominates over inhibitory neurotransmission. GABA, which functions as an inhibitory neurotransmitter in the adult brain, paradoxically acts as an excitatory neurotransmitter in neonates. This occurs because neonatal neurons have a high intracellular chloride concentration due to robust expression of the NKCC1 chloride co-transporter (which imports chloride into the cell) and low expression of the KCC2 co-transporter (which exports chloride). When GABA opens chloride channels, chloride flows out of the neonatal neuron rather than in, causing depolarization instead of hyperpolarization. This is one reason why GABAergic drugs like phenobarbital and benzodiazepines are less effective in neonates compared to older children.

Simultaneously, glutamate receptors (particularly NMDA and AMPA receptors) are overexpressed in the developing brain, further tipping the balance toward excitation. The combination of excitatory GABA signaling and excessive glutamatergic activity creates a brain that is highly susceptible to seizure generation.

The most common trigger for neonatal seizures is hypoxic-ischemic encephalopathy (HIE). When the brain is deprived of oxygen and glucose during perinatal asphyxia, the energy-dependent $N{a}^{+}\mathrm{/}{K}^{+}Na^+/K^+$-ATPase pump fails. This leads to intracellular sodium and calcium accumulation, neuronal depolarization, and release of excitatory amino acids (primarily glutamate). The resulting excitotoxic cascade causes further calcium influx through NMDA receptors, activating proteases, lipases, and endonucleases that damage cell membranes and DNA, leading to neuronal necrosis and apoptosis. Seizures in HIE typically present within the first 12 to 24 hours of life.

Metabolic causes produce seizures through direct disruption of neuronal membrane stability. Hypoglycemia (blood glucose < 45 mg/dL in neonates) deprives neurons of their primary energy substrate, impairing the sodium-potassium pump and causing depolarization. Hypocalcemia (ionized calcium < 1.1 mmol/L) increases neuronal membrane excitability by lowering the threshold for action potential generation. This can present early (first 72 hours, associated with prematurity or maternal diabetes) or late (days 5 to 7, associated with high-phosphate formula or hypoparathyroidism).

The reason neonatal seizures often appear "subtle" rather than generalized tonic-clonic is that the neonatal brain lacks complete cortical myelination and synaptic connectivity. Without fully developed interhemispheric and corticospinal connections, electrical activity cannot propagate efficiently across the entire cortex, and the clinical manifestations remain fragmented: focal clonic movements, tonic eye deviation, or autonomic changes rather than the well-organized generalized convulsions seen in older patients.

02Classification and Clinical Manifestation

Important exam distinction: Not all paroxysmal movements in neonates are true seizures. Movements that are stimulus-provoked, suppressible by gentle restraint, and lack EEG correlates are more likely non-epileptic phenomena (e.g., jitteriness, benign neonatal sleep myoclonus). Jitteriness is the most common mimicker of neonatal seizures and can be distinguished because it is stimulus-sensitive, consists of tremor-like (equal amplitude, equal velocity) oscillatory movements, does not involve abnormal eye movements, and stops when the limb is held.

03Diagnostic Workup

The initial approach to a seizing neonate must follow two parallel tracks: stabilize and treat the seizure while simultaneously identifying and correcting the underlying cause.

The best initial test is a bedside glucose measurement, performed immediately because hypoglycemia is the most rapidly reversible cause of neonatal seizures and delay in correction causes permanent neuronal injury. If glucose is low (< 45 mg/dL), administer IV dextrose (D10W, 2 mL/kg bolus) before pursuing any further workup.

Simultaneously, obtain a basic metabolic panel including ionized calcium, magnesium, and sodium. Hypocalcemia and hypomagnesemia are common and easily correctable causes. A blood gas helps identify metabolic acidosis, which points toward HIE or an inborn error of metabolism.

The gold standard for confirming neonatal seizures is continuous video-EEG (cEEG). This is critically important because up to 50 to 80% of electrographic seizures in neonates are clinically silent (subclinical or "electrographic-only" seizures). Conversely, many clinically suspicious movements (particularly subtle and generalized tonic seizures) have no electrographic correlate and may represent brainstem release phenomena rather than true cortical seizures. cEEG is also essential for monitoring treatment response, as clinical seizures may cease with anticonvulsant therapy while electrographic seizures persist ("electroclinical uncoupling").

Cranial ultrasound is the best initial imaging modality, particularly in preterm infants, because it is portable, requires no sedation, and readily detects intraventricular hemorrhage (IVH) and major structural abnormalities. However, brain MRI is the most accurate imaging study for evaluating the etiology and extent of brain injury. In HIE, diffusion-weighted imaging (DWI) shows restricted diffusion in affected areas, which is most prominent between days 2 and 4 of life.

If the initial metabolic workup and imaging are unrevealing, pursue second-tier investigations: lumbar puncture (CSF glucose, protein, cell count, culture, HSV PCR), serum ammonia and lactate (elevated in organic acidemias and mitochondrial disease), urine organic acids and serum amino acids (to identify conditions like nonketotic hyperglycinemia, maple syrup urine disease), and TORCH serologies.

A critical test to remember is the pyridoxine (vitamin B6) trial. If seizures are refractory to phenobarbital and other standard anticonvulsants, administer IV pyridoxine 100 mg while monitoring the EEG. A dramatic cessation of seizure activity confirms pyridoxine-dependent epilepsy, a treatable autosomal recessive condition caused by ALDH7A1 mutations affecting lysine metabolism. This diagnosis requires lifelong pyridoxine supplementation.

04Management and Treatment

The first priority is to identify and correct metabolic derangements before or alongside anticonvulsant therapy. This is a frequently tested principle: the "next best step" for a seizing neonate with a glucose of 30 mg/dL is IV dextrose, not phenobarbital. Anticonvulsants will not control seizures if the underlying metabolic disturbance is uncorrected.

Once metabolic causes are addressed, phenobarbital remains the first-line anticonvulsant for neonatal seizures worldwide. It works by enhancing GABAergic inhibition (binding to the GABA-A receptor and increasing the duration of chloride channel opening). However, because GABA is paradoxically excitatory in the neonatal brain (as explained in the pathophysiology section), the efficacy of phenobarbital in neonates is limited compared to older populations, controlling seizures in only about 50% of cases as monotherapy. Despite this limitation, phenobarbital retains its first-line status based on clinical experience and guideline consensus.

If seizures persist after the initial phenobarbital loading dose, the approach is either to give additional phenobarbital boluses (5 to 10 mg/kg increments up to a maximum cumulative dose of 40 mg/kg) or to proceed directly to a second-line agent. Levetiracetam has gained favor as a second-line option. It works through a different mechanism (binding to synaptic vesicle protein SV2A, modulating neurotransmitter release) and does not rely on GABAergic pathways, which makes it theoretically more effective in the neonatal brain. It also has a more favorable side-effect profile with less respiratory depression and sedation.

Fosphenytoin (the prodrug of phenytoin) is another second-line option. Its mechanism involves blocking voltage-gated sodium channels to reduce neuronal excitability. It requires cardiac monitoring during infusion due to the risk of arrhythmias and hypotension.

For refractory neonatal seizures (persisting after adequate doses of two anticonvulsants), continuous midazolam infusion is often used, though evidence for efficacy is limited. At this point, a pyridoxine trial should be strongly considered, especially if the etiology remains unclear.

Regarding the duration of anticonvulsant therapy, the current trend favors early discontinuation. If the neonate is seizure-free for 72 hours with a normalized EEG, and the underlying etiology has been treated, phenobarbital can often be weaned before discharge. Prolonged phenobarbital exposure in the neonatal period has been associated with neuronal apoptosis in animal models and impaired neurodevelopmental outcomes.

Therapeutic hypothermia is the standard neuroprotective intervention for moderate-to-severe HIE in term or near-term infants. It involves cooling the infant to a core temperature of 33.5 degrees Celsius for 72 hours, initiated within 6 hours of birth, followed by slow rewarming over 6 to 12 hours. Hypothermia reduces cerebral metabolic rate, decreases excitotoxic neurotransmitter release, and inhibits apoptotic pathways. It has been shown to reduce mortality and long-term disability.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students get neonatal seizure questions wrong is by confusing jitteriness with seizures. A vignette describing a neonate of a diabetic mother who is tremulous, irritable, and has rhythmic limb movements might tempt you to choose "order EEG" or "give phenobarbital." But if the movements are stimulus-provoked, stop when the limb is held, and do not involve eye deviation, the correct answer is to check the blood glucose and treat hypoglycemia. The test-writer is evaluating whether you can differentiate non-epileptic from epileptic events.

A second major trap involves treatment sequencing. When a neonate is actively seizing, many students reflexively select phenobarbital as the next best step. But if the vignette includes a low glucose or low calcium value, the tested answer is to correct the metabolic abnormality first. Anticonvulsants are not first-line when a reversible metabolic cause is present.

Another frequently tested concept is the disconnect between clinical and electrographic seizures. A neonate may appear clinically seizure-free after phenobarbital, yet still have ongoing subclinical seizures on EEG. This is called electroclinical uncoupling, and it is the reason continuous EEG monitoring is essential, not just bedside clinical observation.

Remember that the timing of seizure onset provides clues to the etiology: seizures within the first 24 hours suggest HIE or hypoglycemia; day 2 to 3 suggests hypocalcemia or intracranial hemorrhage; day 3 to 7 suggests meningitis or developmental malformations; and seizures refractory to all standard therapy with no identified cause should prompt a pyridoxine trial.

Finally, do not forget therapeutic hypothermia for HIE. A common distractor will ask about the best neuroprotective strategy for a term infant with perinatal asphyxia, low Apgar scores, and cord pH < 7.0. The answer is therapeutic hypothermia initiated within 6 hours, not phenobarbital (which treats the seizures but does not protect the brain from ongoing injury).

The core competency being tested in neonatal seizure questions is the ability to integrate clinical presentation, etiology identification, appropriate diagnostic sequencing (glucose first, then EEG), and treatment prioritization (metabolic correction before anticonvulsants) in a time-sensitive clinical scenario.