Neonatal Seizures: Diagnosis, Etiologies, and Management

Julie Ziobro, MD, PhD; Renée A. Shellhaas, MD, MS


Semin Neurol. 2020;40(2):246-256. 

In This Article

Neonatal Epilepsy

Approximately 13% of neonates with seizures treated at tertiary/quaternary children's hospitals will have a diagnosis of epilepsy rather than acute symptomatic seizures.[2] Genetic testing has a very high yield in this clinical scenario, and was reported to identify a putative etiology in more than 75% of consecutive patients with neonatal epilepsy.[2] Neonatal epilepsies may be related to developmental structural brain abnormalities, genetic syndromes, or metabolic diseases (Table 2).[23]

Developmental Brain Abnormalities

Abnormal brain structure may be identified with in utero imaging or with early magnetic resonance imaging (MRI) during initial seizure workup. In utero diagnoses should be confirmed with postnatal brain MRI. Structural etiologies such as lissencephaly, hemimegalencephaly, focal cortical dysplasia, tuberous sclerosis, and polymicrogyria may present in the neonatal period with severe treatment-resistant seizures. Malformations of cortical development may be due to disorders of cell proliferation, migration, or cortical organization and are often due to pathogenic variants of specific, identifiable genes (e.g., PAFAH1B1, TSC1, and TSC2, DCX, ARX, DEPDC5). Congenital brain malformations may be associated with additional extracerebral congenital anomalies; thorough clinical evaluations and early consultation with geneticists are recommended.

Genetic Neonatal Epilepsies

Once structural and transient, reversible metabolic etiologies have been ruled out, identification of a neonatal epilepsy syndrome is a priority to establish the diagnosis and etiology, understand the pathophysiology, guide treatment, estimate prognosis, and identify expected comorbidities.[24] Neonatal epilepsies are dichotomous, with some self-limited and some very severe, even though many have common genetic loci. The neonatal epilepsy syndromes include self-limited neonatal seizures, self-limited neonatal familial epilepsy, early infantile epileptic encephalopathy (EIEE), early myoclonic encephalopathy (EME), and epilepsy of infancy with migrating focal seizures (EIMFS; Table 3).

Self-limited neonatal seizures were previously known as "fifth day fits" as they typically present between the fourth and sixth days of life in patients with an otherwise uneventful gestational and perinatal history.[24] Neonates with self-limited neonatal seizures usually present with unilateral, bilateral, or migrating clonic seizures that last minutes. Seizures often cluster and may progress to status epilepticus. Seizures occasionally result in apnea. Patients are generally asymptomatic with a normal neurologic status between seizures. The EEG background may be normal or have nonspecific features between seizures.[25,26] As this is a diagnosis of exclusion, affected neonates must be urgently evaluated for other causes of seizures, such as hypoglycemia, sepsis, or meningitis. Treatment for self-limited neonatal seizures is typically implemented immediately, as the diagnostic evaluation proceeds, but the seizures in this disorder tend to dissipate naturally within 2 days.[24,27]

Self-limited neonatal familial epilepsy often has an onset earlier than self-limited neonatal seizures.[24] Seizures in self-limited neonatal familial epilepsy usually start between days of life 2 and 3 in otherwise healthy neonates, though onset has rarely been described as late as 2 to 3 months.[28] Seizure semiology may include frequent, brief focal tonic seizures associated with apnea, vocalizations, or autonomic changes. The seizures are brief, but tend to cluster. Seizures often require treatment, though remission is expected by 6 months of age. A small study of patients with self-limited neonatal familial epilepsy showed that low-dose carbamazepine or oxcarbazepine treatment was well tolerated and rapidly effective in the setting of status epilepticus.[29] Inheritance is autosomal dominant, with most cases caused by variants in the potassium channel genes, KCNQ2 or KCNQ3, though variants in the sodium channel gene SCN2A have also been implicated.[30] A positive family history of neonatal seizures in the setting of a patient with a normal neurologic exam and a clinical course consistent with the syndrome helps establish the diagnosis of self-limited neonatal familial epilepsy.[24,27] Note that pathogenic variants in the KCNQ2 gene have also been implicated in the most common severe epileptic encephalopathies, illustrating the wide range of the phenotype–genotype correlation in genetic epilepsies.[31]

EIEE is also known as Ohtahara syndrome. It is a rare cause of neonatal epilepsy with presentation in the first 3 months of life, often within the first 2 weeks. Infants present with tonic seizures and/or epileptic spasms that can occur hundreds of times a day during both wakefulness and sleep. These frequent seizures are accompanied by an EEG pattern of burst suppression, with suppression lasting 3 to 5 seconds.[32] Patients may go on to develop other seizure types, including focal motor seizures, hemiconvulsions, or generalized tonic–clonic seizures.[32] EIEE is classically associated with structural brain malformations, though it may also be seen in association with metabolic disorders. Multiple single-gene pathogenic variants have been identified as etiologies of EIEE, including ARX, CDKL5, SLC25A22, STXBP1, KCNQ2, SPTAN1, and SCN2A.[30] Early-life mortality is high and survivors typically have severe developmental disabilities as well as medical complications. Survivors may exhibit an age-specific progression of epileptic encephalopathy from EIEE to West syndrome, and later to Lennox-Gastaut syndrome.[32]

EME is similar to EIEE, but the primary seizure type is myoclonic rather than tonic. Seizures usually begin within the first 3 months, but they may begin as early as a few hours after birth. Seizures may initially involve focal myoclonus of the face or extremities and can shift in location, appearing as erratic jerks.[32] Seizures tend to cluster but can occur continuously. Importantly, the myoclonic movements themselves are not associated with time-locked EEG changes. Like EIEE, the EEG in EME also shows a pattern of suppression burst, but the classic pattern in EME is more apparent during sleep than in wakefulness.[32] The suppression-burst pattern may evolve to an atypical pattern of hypsarrhythmia by 3 to 5 months of age in up to 50% of patients. Classically, the etiology of EME is related to metabolic disorders (glycine encephalopathy, pyridoxine/pyridoxal 5′-phosphate dependency, biotinidase deficiency, Leigh syndrome), but EME may also be associated with rare genetic variants (STXBP1, TBC1D24, GABRA1, etc.).[24,33,34] Prognosis is generally poor with mortality up to 50% by 2 years of age and severe impairment in survivors.[35]

EIMFS often presents in the neonatal period, but may not present until several months of age. Seizures evolve over time, starting as focal clonic and/or tonic semiologies, and often progress to involve more prominent autonomic features. The interictal EEG shows multifocal abnormalities affecting both hemispheres, with independent prolonged seizures that evolve simultaneously from different brain regions that migrate to contiguous or contralateral regions.[23,36] The most common identified cause of EIMFS is a de-novo gain-of-function in KCNT1, which encodes a sodium-activated potassium channel,[37] though pathogenic variants in SCN2A, SCN1A, SLC25A22, PLCB1, TBC1D24, and QARS have also been implicated as well.[30,38] Seizures are often refractory to conventional ASMs. Several case reports describe patients with KCNT1 variants who responded to a trial of quinidine, though this is likely specific to individual genotypes.[39]

Metabolic Disorders

Metabolic epileptic encephalopathies are rare but potentially treatable causes of seizures in newborns (reviewed in Pearl[33]). Recognition of inborn errors of metabolism is essential in neonatal epilepsies, as typical ASMs may be ineffective and early, appropriate treatment may prevent neurologic deterioration and long-term sequelae. An initial symptom-free period followed by feeding difficulty, lethargy and respiratory distress along with abnormal laboratory test results (e.g., elevated lactate, transaminitis), dysmorphic features, cataracts, hearing loss, or renal tubular defects may indicate an underlying inborn error of metabolism.[23,40] However, some inborn errors of metabolism present with seizures as the main symptom and lack biochemical abnormalities that would be detected through routine laboratory testing. These should be suspected in neonates with very early or antenatal seizures that are refractory to traditional ASMs and who have progressive worsening of clinical and EEG abnormalities. The interictal EEG may have a burst-suppression or hypsarrhythmia pattern. Imaging may show evidence of severe injury without any obvious hypoxic insult at birth.[40]

The metabolic encephalopathies can be divided into categories of disorders of neurotransmitter metabolism, disorders of energy metabolism, and biosynthetic defects causing brain malformations, dysfunction, or degeneration. Disorders of neurotransmitter metabolism include pyridoxine-dependent epilepsy, pyridoxal-5′-phosphate responsive encephalopathy, folinic acid–responsive seizures, mitochondrial glutamate transporter, aromatic amino acid decarboxylase deficiency, D-2-hyroxyglutaric aciduria, and GABA disorders.

Pyridoxine-dependent epilepsy is associated with pathogenic changes in the ALDH7A1 gene which encodes antiquitin, an enzyme necessary for cerebral lysine catabolism.[41] Clonic seizures usually arise in utero or during the first few days of life. These seizures are often accompanied by myoclonic jerks and tonic seizures. Seizure burden is typically high, and refractory status epilepticus is common. A trial of 100 mg of pyridoxine (given intravenously) should be given as soon as the diagnosis is suspected. Pyridoxine should be administered in a monitored setting with respiratory support available, as apnea is a possible side effect in responders, and the EEG should be performed before, during, and after administration. Response may be seen within a few minutes of pyridoxine administration, and the interictal EEG may normalize after 24 to 48 hours. However, the majority of patients will continue to have neurodevelopmental concerns even with appropriate supplementation.[33,41] Pyridoxine-5-phosphate oxidase deficiency is related to a pathogenic alteration in the PNPO gene and may have a similar presentation to pyridoxine-dependent epilepsy. Patients may be responsive to pyridoxine, but many require the active form, pyridoxal 5′-phosphate.[41]

Nonketotic hyperglycinemia (due to pathogenic variants in the AMT or GLDC genes) is a defect in the glycine cleavage system. Patients present with apnea, hypotonia, encephalopathy, and refractory neonatal seizures. Seizures are due to overactivation of NMDA excitatory amino acid receptors. The diagnosis is confirmed by documentation of elevated cerebrospinal fluid (CSF) to serum glycine ratio. Combinations of medications including sodium benzoate, dextromethorphan, or ketamine have been reported to be useful, but prognosis remains guarded.[42,43]

Disorders of energy metabolism include glucose transporter deficiency, pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, biotinidase deficiency, respiratory chain disorders, Menkes disease, fumarase deficiency, purine disorders, and creatine synthesis and transporter defects. These disorders may be remediable with specific treatments administered with guidance from by a metabolic geneticist.[33]

Other rare disorders include sulfite oxidase deficiency (due to a pathogenic variant in the SUOX gene) and molybdenum cofactor deficiency (due to variants in MOCS1). These have an autosomal recessive inheritance pattern, and affected infants frequently have poor outcomes. There is no specific treatment for sulfite oxidase deficiency.[23] Infusion of cyclic pyranopterin may be useful in molybdenum cofactor deficiency.[44]

Biosynthetic defects include peroxisomal disorders, congenital disorders of glycosylation, glycolipid synthesis, cholesterol synthesis, serine and glutamine deficiency syndromes, methylation disorders, neuronal ceroid lipofuscinosis, and lysosomal disorders. Presentations may include multiorgan involvement, severe encephalopathy, refractory seizures, and dysmorphic features.[33,45] A metabolic geneticist should be involved early in diagnosis and treatment if a neurometabolic disorder is suspected.