Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology

Abstract

Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20–66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy.

Audit of use of stiripentol in adults with Dravet syndrome

“…More than 50% reduction in GTCs was observed in four cases (31%). It is important to note that all the reported cases had been exposed to sodium channel blockers, known to aggravate seizures and potentially precipitate status epilepticus in DS 2, 6, 9. This is likely related to the fact that ours was an adult cohort, with often late clinical (range 2–41 years) and genetic (range 12–43 years) diagnoses.…”

“…The main challenges include seizure control, prevention of status epilepticus and optimizing development of cognitive function, where possible. The adult phenotype has been described in a number of previous studies 2, 5, 6, 7, 8. Adjustment of treatment may be associated with improved seizure control, cognition and quality of life, even into later adult life 2, 6.…”

“…The adult phenotype has been described in a number of previous studies 2, 5, 6, 7, 8. Adjustment of treatment may be associated with improved seizure control, cognition and quality of life, even into later adult life 2, 6. Sodium channel blockers, for example, carbamazepine, oxcarbazepine and phenytoin, should usually be avoided as they can aggravate both seizures and interictal EEG 9.…”

“…Dravet syndrome (DS) is a severe genetic epileptic encephalopathy with onset in infancy, often associated with drug‐resistant epilepsy, developmental slowing, cognitive impairment, occurrence of status epilepticus and elevated risk of early mortality 1, 2, 3. In most cases, the cause is a mutation in the voltage‐gated sodium channel type I alpha subunit gene, SCN1A 4.…”

Association of severe myoclonic epilepsy of infancy (SMEI) with probable autoimmune lymphoproliferative syndrome-variant

“…13 Triggers for status epilepticus in SMEI are intercurrent infections and slight increases in body or ambient temperature. 13,14 In SMEI, hot bath, fever, and physical exercise may induce seizures by reducing seizure threshold temperature, as also shown by experimental data in SMEI mice with heterozygous deletion of Na v 1.1 voltage-gated sodium channel. 13 However, it was affirmed that differences in SMEI and GEFS + are not ascribable exclusively to differences in channel behavior.…”