A Neonate with Epileptic Encephalopathy

A female neonate born by the vaginal route to a primigravida mother (nonconsanguineous couple) at 39 weeks of gestation with a birthweight of 2,400 g is admitted to the NICU for management of neonatal seizures.At 30 hours of age, she is noted to have uprolling of eyeballs with tonic posturing of all 4 limbs lasting for 30 seconds and subsiding without additional intervention. This is soon followed by multiple episodes of seizures with varying semiology, with tonic, clonic, and myoclonic spasms occurring with increasing frequency of up to 30 to 40 episodes per day. Antiepileptic agents are sequentially started as levetiracetam (60 mg/kg per day), phenytoin (8 mg/kg per day), and sodium valproate (40 mg/kg per day) without any clinical response, with new semiology of seizures occurring at variable intervals of 1 to 3 hours. These seizures were not stimulus-sensitive and did not last for more than 1 minute. Given the refractory seizures, the neonate was started on midazolam infusion on day 2 after birth, and these episodes persisted till day 5 with no significant improvement.On reevaluating the history, the mother has no significant medical or obstetric illness. Antenatal scans are suggestive of late-onset fetal growth restriction at 33 weeks of gestation with no Doppler abnormality; the cause of the same was not evaluated. She had cried immediately after birth, with a normal Apgar score, and was well in the first 30 hours of exclusive breastfeeding.Examination in the interictal phase shows normal vital parameters. Her head circumference is 13.6 in (34.5 cm) and her length is 20.7 in (52 cm) (both in the 10th–50th percentile of the modified Fenton growth chart). The remainder of the physical examination, including the head examination, findings are normal. There are no neurocutaneous markers. Neurologic examination shows moderate stupor, with a poor repertoire of spontaneous limb movements, with axial and appendicular hypotonia. The neonatal reflexes could not be elicited well considering the stuporous sensorium. The deep tendon reflexes are also just elicitable. Other systemic examination findings are within normal limits.Pyridoxine-dependent seizures.Early infantile epileptic encephalopathy (Ohtahara syndrome).Early myoclonic epilepsy syndrome.Benign familial epilepsy.Benign nonfamilial neonatal seizures.Lennox-Gastaut syndrome.Nonketotic hyperglycinemia/glycine encephalopathy.Hypoxic ischemic encephalopathy.Despite multiple antiepileptic drugs, there is no adequate seizure control. Considering a diagnosis of pyridoxine-dependent seizures, oral pyridoxine (100 mg/d) is added and the neonate is evaluated for refractory seizures, as summarized in the Table.Clinical exome sequencing revealed a heterozygous missense variant in exon 6 of the SNC2A gene (chr2:g.165309369T>C; Depth: 147x), resulting in amino acid substitution of alanine for valine at codon 208 (p.Val208Ala; ENST00000375437.7), classified as variant of uncertain significance for the disorder developmental and epileptic encephalopathy-11 (DEE-11).The term developmental and epileptic encephalopathy (DEE) is used when developmental impairment and epileptic activity have an effect on the cognitive and behavioral state of the affected person. (1) Most patients have a genetic etiology. (2) Neonatal-onset DEEs caused by mutations in SCN2A, KCNQ2, and STXBP1 may cause profound impairment in the affected individual. (3) DEE-11 occurs due to a heterozygous missense mutation in exon 6 of the SNCA 2 gene, resulting in the amino acid substitution of alanine for valine at codon 208, with the exact electrophysiologic mechanisms causing refractory seizures still unknown in these patients. DEE-11 results in the onset of refractory seizures of various types: tonic, clonic, generalized, or myoclonic. Affected individuals can have microcephaly, hypotonia, movement disorder, global developmental delay, and severe intellectual impairment, with a heightened risk of autism spectrum disorder. (4)Ohtahara syndrome is a form of developmental and epileptic encephalopathy with seizure onset occurring within the first 3 months after birth. (5) Classically, the seizures are myoclonic spasms that occur in clusters, but they can also be of varied types (partial or generalized tonic). (5) It is characterized by a burst suppression pattern on an electroencephalogram (EEG). Ohtahara syndrome is associated with SCN2A mutations in 16% of the clinical cases. (6)A study of 71 new patients and a review of 130 established patients (34 patients with neonatal onset of seizures) with SCN2A mutation showed that individuals with early onset had gain-of-function mutations responding to sodium channel blockers, including carbamazepine, whereas those with late onset may have loss-of-function mutations whose detrimental effect would be exacerbated by sodium channel blockers. (4)Early initiation of antiepileptic drugs may lead to improved cognitive outcomes. Our neonate had early-onset seizures of varied types that eventually changed to myoclonic spasms with hypotonia and responded to carbamazepine therapy. Although the genetic report of our patient showed a variant of uncertain significance, the clinical phenotype fits into the description of the disease in question. Confirmatory testing with the parent's sample could not be performed due to financial constraints. The outcome is usually not favorable, with this mutation in SCNA2 leading to global developmental delay and development of movement disorders, including dystonia and chorea. Mortality can be seen in 15% of patients by 20 years of age. (6)On diagnosis of Ohtahara syndrome and evaluation of the EEG in consultation with a pediatric neurologist, oral carbamazepine is added (400 mg/d). The frequency of seizures, which initially occur 30 to 40 times a day, reduces to 8 to 10 episodes per day during the next week and later to 2 to 3 episodes per day with the prominent semiology being tonic seizures followed by infantile spasms. The repeated EEG shows a reduction in the seizure burden with persistence of burst suppression. The neonate continues to be neurologically abnormal with exaggerated deep tendon reflexes. Oromotor incoordination is managed by a multidisciplinary team of neonatologists, occupational therapists, and lactation counselors, and she is transitioned to spoon feeds by 28 days of age. Early intervention therapy with the promotion of active movements is initiated, and she is discharged on day 40 of age after genetic counseling of the parents. The neonate is currently 4 months old and is microcephalic with a head circumference of 14.4 in (36.5 cm). The Hammersmith Infant Neurological Examination score is 44, suggestive of a 96% risk of developing cerebral palsy(7) and global developmental delay with no head control, unable to reach objects, and nonvocalizing. Brainstem auditory evoked response testing on follow-up is normal, and a visual evoked potential test is planned. Compliance with antiseizure medications is satisfactory, and regular follow-up is occurring.In neonates with refractory seizures, a genetic evaluation for neonatal epilepsy leads to better management of seizures and prediction of prognosis. SCN2A–related developmental and epileptic encephalopathy (DEE) can manifest with varied semiology of convulsions and occurs multiple times a day.Early-onset DEE due to SCN2A mutation responds to carbamazepine therapy with better seizure control.Global developmental delay in DEE requires early intervention and multidisciplinary care from the neonatal period.We thank Dr Sangeeta Ravat, dean, Seth G.S. Medical College and King Edward Memorial Hospital, Mumbai, India, for granting permission for publication and Dr S. Chandrakala, professor and head of department, Department of Hematology, Seth G.S. Medical College and King Edward Memorial Hospital, for the hematology images.