2017 January-March; 2(1): 66–73. ISSN: 2499-1783
Published online 2018 April 9. doi: 10.11138/ccre/2017.2.1.066.

A novel de novo SCN8A mutation in an Italian child treated with Levetiracetam: a case in discussion

Cecilia Galati,corresponding author Adan Rodolfo Isgrò, Elisa Lo Re, Nunzia Calabrò, Domenica Lucia Sgro, Maria Spanò, and Antonella Gagliano

Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi”, Unit of Child Neurology and Psychiatry, University of Messina, Messina, Italy

corresponding authorCorresponding author.

Corresponding author: Cecilia Galati, Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi”, Unit of Child, Neurology and Psychiatry, University of Messina, Messina, Italy, E-mail: G.cecilia86@yahoo.it


We report on a 19-months-old girl, with early onset afebrile seizures and mild developmental delay. She presented with afebrile generalized tonic-clonic seizures, after the first vaccination (Hexavalent vaccination, 5 months-old). She was referred to a child neurologist and treated with phenobarbital. The patients underwent neurological follow-up from 5 to 18 months of age. Seizures were not controlled and mild developmental delay was evident. At the age of 19 months, she presented with convulsive status epilepticus and treated with 35 mg of endorectal diazepam before admission, with subsequent cardiorespiratory failure. She was admitted to the intensive care unit of our hospital. Interictal awake electroencephalogram (EEG) showed: activity of continuous di used theta waves with sporadic Frontal focal spikes. After 13 days in intensive care unit the patient was moved to our child neurology ward, where she presented in a sleepiness state. EEG showed the presence of independent multifocal sharp waves, mostly frontal, epileptogenic abnormalities. Brain magnetic resonance imaging revealed no significant abnormalities, only mild cerebral atrophy. Due to the persistence of diffuse slowing at the EEG, an immune encephalopathy was suspected and, Dexamethasone and Immunoglobulin therapy was performed, without benefit. When the patient was seizure-free, she was discharged with Phenobarbital and Levetiracetam therapy (started in Intensive care unit). Twenty days later, at the follow-up in our Unit, the infant was significantly improved (after 3 weeks the patient was seizure-free, neurological examination showed marked improvement of gait stability and motor coordination. Next generation sequence analysis showed a heterozygous mutation (c.4423G>A (p.Gly1475 Arg) in the SCN8A gene (Chromosome 12q13). No further seizures occurred for 3 months.

This report reviewed the clinical features of a patient with a de novo SCN8A mutation. Our data suggest that therapy with Phenobarbital and Levetiracetam could be effective in treating refractory epilepsy in a case with a SCN8A (c.4423G>A (p.Gly1475Arg) mutation.

Keywords: SCN8A, epilepsy, seizures, Chromosome 12q13, EEG, Dravet-like


SCN8A is located on Chromosome 12q13 and encodes the sodium voltage-gated channel alpha subunit (Nav1.6), which functions in the rapid depolarization of sodium channels during generation of action potentials in neurons. It leads to impaired sodium channel inactivation, persistent sodium current and increased neuronal activity. A hyperpolarizing shift in voltage dependence of channel activation was observed, also leading to hyperactivity. This gain-of function mechanism is opposite to the one underlying Dravet syndrome, where loss-of-function mutations in SCN1A are most common (1) (Tab. 1).

Table 1Table 1
Differences between SCN8A-related epilepsy with encephalopathy and Dravet syndrome (10).

Rare de novo mutations of sodium channels are thought to be an important cause of sporadic epilepsy. SCN8A encephalopathy was first identified in 2012, and an understanding of the severe impact of SCN8A mutations is just beginning to emerge.

SCN8A pathogenic variants have been associated with developmental delay prior to and/or after onset of seizures, with or without cerebellar ataxia, intellectual disability without seizures and epileptic encephalopathy. Sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of published cases (2, 3).

EEG may be normal or exhibit focal or multifocal epileptiform activity at onset.

The Brain MRI is usually normal at the onset of seizures; however, abnormal findings may include cerebral atrophy and hypoplasia of the corpus callosum.

Epileptic encephalopathy is characterized by seizure activity that progresses to cerebral dysfunction leading to severe cognitive, motor and behavioral impairments (4). Approximately 1% of early infantile epileptic encephalopathies are associated with missense mutations in the SCN8A gene, and approximately 50 cases have been described in the literature (57). In a few cases, the mutation was inherited from a mosaic parent, but the majority of cases are associated to de novo missense mutations (4). Individuals present with various types of seizures, including tonic-clonic, generalized tonic, atonic, myoclonic and focal and absence seizures, whereas febrile seizures are rare (8). There is often developmental regression, and movement disorders are present with 50% of affected individuals unable to sit or walk.

In this paper we describe a case of a female patient, 19 months old, with heterozygous mutation of SCN8A gene (c.4423G>A (p.Gly1475Arg) treated with Phenobarbital and Levetiracetam, which had permitted seizure’s control for more than 3 months.

Case report

We report on 19-months-old girl, with early onset afebrile seizures. She was born at 41 weeks from uneventful pregnancy. Birth weight was 3000 gr, Apgar score 1′: 2, 3′: 6; 5′: 9, as a complication of nuchal loops around the fetal neck. At the age of 5 months, after Hexavalent vaccination (7 hours late), she had afebrile generalized tonic-clonic seizures and hospitalized. Brain magnetic resonance imaging revealed no significant abnormalities (only mild cerebral atrophy). The EEG showed diffuse slowing. She started therapy with Phenobarbital and underwent neurological follow-up up to the age of 18 months (Tab. 2).

Table 2Table 2
Therapeutic follow-up.

From the age of 5 months to 19 months, the occurrence of drug resistant seizures lead to multiple antiepileptic agents’ changes. Topiramate withdrawal was due to several adverse events (loss of appetite, weight loss, flushing, anhidrosis). She presented mild developmental delay mainly involving verbal and posturo-motor skills. After a mild seizures’ improvement and the starting of drug switching, for two consecutive days, she presented with clustering seizures, each one treated at home, with endorectal Diazepam up to a total amount of 35 mg (15 mg during the first day, 20 mg during the second day). After 24 hours from the seizures onset the patient was admitted to the hospital where she has had new seizures treated with further Diazepam (not specified the dosage). At this time, the patient presented with cardiorespiratory failure, needed activation of base life support, intubation and transfer to the Intensive care unit of our Hospital. At the admission the patient presented clonic seizures and started Levetiracetam administration.

After 13 days in Intensive Care Unit the patient was moved to our child neurology ward. At the admission, she presented in a drowsiness/sleepiness state, severe hypotonia, spontaneous motility was characterized by unvoluntary stereotyped movements, several investigations have been performed: EEG, MRI, visual evocked potentials, lumbar puncture, all unrevealing. SPETTRO-RMN (which showed delayed myelination and mild cerebral atrophy) and low-positivity of Ab anti GAD=4). Due to the above mentioned neurological status and the persistency of diffuse slowing at the eeg, an immune encephalopathy was hypothesized. Dexamethasone (2 mg four times a day) Immunoglobulin therapy (4 gr/die, for 5 days) were administered without benefits. At the hospital discharge, the patient was undertreated with Phenobarbital (started in our Unit) and Levetiracetam. At the follow-up (twenty days later) she didn’t present further seizures. However, psychomotor status was unchanged. The infant was significantly improved: she started to speak, to walk with support and a re-started good interaction with people. During the follow-up EEG showed the presence of independent multifocal sharp waves, mostly frontal, epileptogenic abnormalities. After 1 month and half the improvement described increased. The patient was admitted for a control and we received the results of NGS that showed de novo SCN8A mutation (c.4423G>A (p.Gly1475Arg). She continued treatment with Phenobarbital and Levetiracetam, which has permitted seizure’s control for more than 3 months (Tab. 3).

Table 3Table 3
SCN8A Studies in literature. References.


Here we reported on a 19-months-old girl with a de novo SCN8A mutation and suggested the initial efficacy of combination therapy of Phenobarbital and Levetiracetam for refractory epilepsy in this patient. No clear genotype-phenotype correlation emerged between SCN8A pathogenic variant and seizures’ onset, seizures’ type and neurodevelopmental impairment. Most pathogenic variants are located in the transmembrane segments of the channel. Penetrance for SCN8A-related epilepsy with encephalopathy is unknown but assumed to be complete.

To date, no clear guidelines for treatment of patients with SCN8A-related epilepsy have been provided. However, vigorous attempts to control seizures are warranted because of an increased risk for sudden unexplained death in such patients (SUDEP).

Several studies showed as patients with SCN8A-related epilepsy with encephalopathy favorably respond to the class of antiepileptic drugs (AEDs) that block sodium channels such as Phenytoin, Valproate, Carbamazepine, Lacosamide, Lamotrigine, Rufinamide and Oxcarbazepine. Treatment with Corticosteroids, Immunoglobulins, Vagus nerve stimulator, Ketogenic diet, Cannabinoids has been attempted in drug-resistant patients.

Our patient has been initially treated with valproate, but without benefits. Thereafter, only a combination of Phenobarbital and Topiramate was transiently effective, in the second time Dexamethasone and after combination of Phenobarbital and Levetiracetam (Levetiracetam is a second-generation antiepileptic drug (AED) with a unique mechanism of action that involves interactions with the synaptic vesicle protein) (9). The latter combination induced disappearance of the seizures for 3 months, while neurodevelopment of the patient improved. As opposed to our paper, other Author showed as Levetiracetam was ineffective or occasionally associated with an increase in seizure frequency in several pedigrees (10).

In conclusion, SCN8A encephalopathy is a relatively new clinical syndrome that needs to be genotypically and phenotypically defined, yet. Our case report is aimed to contribute to the development of strategies for clinical management, drug selection and individualized patient care (11).

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Figures and Tables
Figure 1Figure 1
Video-EEG monitoring of the patient during the admission in Intensive care unit where she was treated with Levetiracetam. Interictal awake electroencephalogram (EEG) showed: activity of continuous diffused theta waves with sporadic Frontal focal spikes. (more ...)
Figure 2Figure 2
SPECT-MRI: Brain magnetic resonance imaging (MRI) conducted during admission in our Unit after 20 days old Dexamethasone treatment. It showed delayed myelination and mild cerebral atrophy (may be caused by the corticosteroid therapy).