Dravet syndrome is one of the most severe epileptic encephalopathies, and one of the most studied and understood. It is caused, in 70% to 80% of cases, by mutations in the alpha 1 sodium channel subunit (SCN1A) gene. This association, however, is not straightforward. Mutations resulting in mild protein product alterations cause a clinically much more benign, very different epilepsy called ‘genetic epilepsy with febrile seizures plus’. More severe mutations in this same gene/protein are responsible for Dravet syndrome.[1, 3] In 3% of cases of Dravet syndrome, other genes, including GABRG2 and PCDH19, contain the causative mutations, and there are yet more genes to be identified – approximately 17% of patients with a clinical diagnosis of Dravet syndrome have an unspecified genetic mutation.
For years many patients with Dravet syndrome were thought to have a ‘vaccination encephalopathy,’ since many had their first seizure immediately after a vaccination. It was only when genetic analysis was possible that it became clear that most cases of so-called vaccination encephalopathy were indeed cases of Dravet syndrome with SCN1A mutations. While not all vaccination encephalopathies are cases of Dravet syndrome, Dravet syndrome should always be in the differential diagnosis. In fact, the diagnosis of Dravet syndrome on clinical grounds is not difficult. Since the original description by Charlotte Dravet the core features of the condition remain the same: onset of (often prolonged) febrile or afebrile seizures in the first year of life in a previously normal child. Seizures initially are hemiclonic or generalized tonic-clonic. Later on several other types of pharmacoresistant seizures affect the life of these children who eventually show major cognitive delay.
Kim et al. describe an atypical form of Dravet syndrome. The condition is caused by mutations in the SCN1A gene in most cases and the outcome is a severe epileptic encephalopathy. However, some of the core features of typical Dravet syndrome are different, and hence the importance of this study.
Firstly, the authors noticed that generalized spike waves (GSW), one of the most common electroencephalographic (EEG) features of Dravet syndrome, is missing in patients with the atypical form. Out of the eight patients described by Kim et al., only one showed two brief bursts of GSW discharges on the same EEG at the age of 2 years 6 months. That was the only GWS activity in 10 different EEGs for that patient over many years. All other patients had only focal or multifocal interictal epileptiform discharges. Secondly, the interictal epileptiform discharges tend to appear later on the EEG (2y 6mo-7y). Thirdly, focal tonic seizures which are rare early in the disease course, though more commonly seen in adults[8, 9] was observed in five of their eight cases. Fourthly, intellectual disability* appeared later than usual.
Why are these observations important? Because without them, the diagnosis of Dravet syndrome could be missed.
But how would missing this diagnosis harm a patient, since most epileptic encephalopathies are thought to be intractable anyway? While Dravet syndrome is not yet curable, proper management may significantly improve seizure control and perhaps the other features accompanying the syndrome. For instance, stiripentol, an orphan drug (in Canada, Europe, and Japan) has been successfully used in cases of Dravet syndrome, especially in combination with valproate and/or clobazam. Therefore, recognition of atypical forms of Dravet syndrome is invaluable for proper management.
Another important reason underscoring the recognition of atypical Dravet syndrome is the knowledge that patients with Dravet syndrome tend to have more seizures when exposed to sodium channel inhibitor antiepileptic drugs. Interestingly, sodium channel inhibitors such as carbamazepine and lamotrigine are drugs recommended for patients with partial onset or multifocal seizures. Therefore patients with atypical Dravet syndrome are the ones most at risk for misdiagnosis and mistreatment with drugs that could make their epilepsy worse.
The management of any epileptic encephalopathy is extremely challenging. Without the correct diagnosis the neurologist may further harm a child's brain by prescribing drugs that can make the seizures worse in Dravet syndrome. The atypical form of Dravet syndrome described by Kim et al. should be considered when selecting the treatment drugs in patients with focal and multifocal seizures. Further studies are needed to determine if sodium channel inhibitor drugs are also harmful in this group of patients without generalized ictal and interictal epileptic abnormalities.