Dravet syndrome is an important and paradigmatic epilepsy syndrome, being among the first genetic epilepsy syndromes for which the molecular basis has been unravelled, enabling functional studies and animal models to reveal fundamental insights into the underlying pathophysiology (Catterall et al., 2008
). Dravet syndrome is thought to be underestimated in prevalence and under-diagnosed in adults (Scheffer et al., 2009
). There are many gaps in the understanding of the clinical evolution of Dravet syndrome in later ages, particularly after the fourth decade of life, as for many years Dravet syndrome has been considered to be of the remit of the child neurologist. As children with Dravet syndrome were prospectively followed, it became clear that some did reach adulthood (Dravet et al., 2005
). More recently, adult patient series have been characterized (Jansen et al., 2006
; Akiyama et al., 2010
), but most adults were under 35 years of age at last follow-up. Surviving adults, over 35 years of age, with Dravet syndrome may have missed out on a diagnosis as the syndrome was only described 30 years ago (Dravet et al., 1978
) and the diagnosis is often not considered in adult clinics.
We show that diagnosis even late(r) in life, in patients previously labelled as having drug-resistant epilepsy with intellectual disability of unknown cause, can carry important implications for affected patients; rational treatment changes can be instituted, with possible benefit as we and others have shown, even after years of drug resistance. In addition, recognition of the changes in language, cognition, swallowing and gait, and determining whether specific patterns exist, may help to improve diagnostic and prognostic information and may reinforce a mandate for treatment changes.
We identified 22 adult patients with Dravet syndrome who had not been diagnosed in childhood. Two-thirds were over 39 years of age at last follow-up, a greater proportion than for other studies to date (). Two adult cases with Dravet syndrome reached their sixties; survival to the seventh decade had not been previously reported. Ours is not a systematic evaluation of the prevalence of Dravet syndrome or SCN1A mutation in adults with severe epilepsy, but an observational study of a highly selected patient group from a tertiary centre. Together with the very detailed clinical records available and the neuropathology evaluation, this provided a unique opportunity for a study on the long-term follow-up and outcome of adult patients with Dravet syndrome.
Adults with Dravet syndrome in the literature
Genotype–phenotype analyses are often complex (Kanai et al., 2009
; Scheffer, 2011
; Zuberi et al., 2011
), and more so in our selected series. Caution is required in interpretation. Considering the type of SCN1A
mutations in the two extremes of age at death, a pattern may seem to emerge: in the four children with Dravet who died early, there were no missense mutations (); of the patients who died after the age of 45 years, out of the 2 in whom genetic analysis was possible, 1 had 1 SCN1A
missense mutation, and the other was found not to have an SCN1A
mutation or deletion. No truncating mutations were found in this group. Compared with published data, there seem to be more missense than truncating SCN1A
mutations in the older Dravet group. We must emphasize limitations (ascertainment bias; selection bias; small numbers; predominance of paediatric cases in published data), but one could hypothesize that missense mutations are more frequent in patients with longer survival, testable with a prospective longitudinal study.
We acknowledge important limitations in our study. Though it includes some longitudinal data, it is a cross-sectional study. The numbers of post-mortem cases are small. We were unable to obtain DNA of sufficient quality from the two older post-mortem cases without a molecular genetic result (no frozen tissue was available). Neuropathological analyses at other levels, for example the electron microscopic, were not possible, as no appropriately fixed material was available. We cannot fully disentangle the natural history of Dravet syndrome and what may relate to other aspects, such as the chronic effects of anti-epileptic drugs. We note that for Unverricht-Lundborg disease, for example, previously reported progressive neurological deterioration was later attributed to the use of phenytoin (Eldridge et al., 1983
); and avoidance has meant life expectancy may approach normal (Kalviainen et al., 2008
). Despite these factors, the data available do generate new insights.
Features of Dravet syndrome in adults include drug-resistant seizures with a seizure repertoire that differs from that in childhood. Atypical absences and generalized interictal epileptiform discharges seen in childhood were not documented in our adult series. In many of our adult patients, the predominant seizures are nocturnal with focal semiological features and sometimes secondary generalization; focal onset was often documented on ictal EEG. This concurs with the findings of Akiyama et al. (2010)
, whose recent series of adult Dravet syndrome showed 35/40 apparently generalized seizures had frontal origin, with or without secondary generalization in the ictal EEG. No single clinical characteristic in our series allowed the distinction between SCN1A
mutation-positive and -negative adult cases, but our numbers are small for subgroup comparisons.
Although long life is possible, long-term functional, seizure-related, cognitive and social outcomes appear unfavourable, with cognitive and physical decline, gait disturbance and later dysphagia, incontinence and increasing dependence for all activities of daily life. We cannot say how earlier recognition and treatment might influence these outcomes.
Dysphagia has emerged as a shared dysfunction in older cases with Dravet syndrome. This is a novel observation in Dravet syndrome, and not a feature of other chronic epilepsies, except some of the progressive myoclonic epilepsies, epilepsies associated with cerebrovascular disease and Lennox-Gastaut ‘syndrome’ (Ogawa et al., 2001
). Dysphagia may manifest with unexplained cough, or recurrent respiratory infections, which may lead to neurological deterioration, and weight loss. Notably, for homozygous null Scn1a–/–
knock-out mice, manual feeding extends survival (Yu et al., 2006
). Awareness and early diagnosis of dysphagia may prevent complications, which include worsening of seizure control, poor nutrition and fluid intake, poor quality of life and life-threatening aspiration pneumonia. The neuropathological basis of the dysphagia is unclear, though visible changes in the brainstem were noted in two patients with Dravet syndrome and dysphagia.
The neuropathology of human Dravet syndrome has not been previously well characterized. To our knowledge, this is the first systematic neuropathological study in Dravet syndrome. We included three adult and four paediatric post-mortem cases with Dravet syndrome, and two other SCN1A mutation-carrying paediatric cases with other syndromes. Several findings are of interest.
Patients with Dravet syndrome often have autism-like behavioural features, and autism spectrum disorder has been associated with seizures in the first year of life (Saemundsen et al., 2008
). In a recent report, the neuropathological examination of one Dravet paediatric case, who died of sudden unexplained death in epilepsy, showed multifocal micronodular dysplasia of the left temporal cortex and bilateral endfolium gliosis (Le Gal et al., 2010
). We did not find other subtle malformation as reported in abstract form by Hayashi et al. (2004)
. In one of our adult cases, there was an exaggerated columnar architecture, or radial alignment of neurons involving frontal and occipital regions. This patient had a history of autistic spectrum disorder. Although studies in autism have also described abnormalities of cortical minicolumns (Casanova et al., 2010
), neuropathological data in Dravet syndrome remain very limited; we simply make this observation, but cannot draw general conclusions from our single case.
One adult case with Dravet syndrome had unilateral hippocampal sclerosis on a MRI brain scan performed in his 20's; his previous MRIs were not available for review. The SCN1A+
surgical case had unilateral hippocampal sclerosis. Previous studies have shown that in a small proportion of patients with Dravet syndrome, hippocampal sclerosis is observed (Striano et al., 2007a
), and this may not be present in the early childhood scans (Siegler et al., 2005
). Prospective MRI studies in Dravet syndrome are required. It is of note that even on quantitative analysis, there was no neuropathological evidence of neuronal loss in the post-mortem adult cases with Dravet syndrome, showing that Dravet syndrome per se
, and SCN1A
mutation (one post-mortem adult case with Dravet syndrome), are not sufficient to cause hippocampal neuronal loss despite decades of drug-resistant seizures and recurrent episodes of status epilepticus. Rarely, significant clinical and imaging changes have been reported in Dravet syndrome following status epilepticus (Sakakibara et al., 2009
; Chipaux et al., 2010
; Tang et al., 2011
). There may be age-dependent vulnerability of the brain to injury induced by seizures (Haut et al., 2004
), but it is difficult to separate out effects of seizures on the brain from the effects of the disease process per se
, and the effects of drugs and other factors. It has been suggested that SCN1A
mutation may protect hippocampal neurons (Auvin et al., 2008
), but more research is needed to determine whether (and which, if any) SCN1A
mutations (or other causes of Dravet syndrome) are actually neuroprotective, and it should be noted that Dravet syndrome is not primarily a hippocampal epilepsy.
Cerebellar atrophy was a frequent finding in cases with Dravet syndrome but did not differ, either in pattern or distribution, to that previously described in patients with chronic epilepsy without Dravet syndrome (Crooks et al., 2000
). The exact mechanism of selective Purkinje cell loss, as well as the potential relationship to observed ataxia, requires further study. In contrast to a previous post-mortem report in a paediatric Dravet syndrome case (Renier and Renkawek, 1990
), no cerebellar dysplasia was seen in any of our cases.
Vacuolar demyelinating myelopathy of the dorsal columns of the cervical cord was noted in two patients with Dravet syndrome. This is not a typical finding in patients with epilepsy, and although a toxic or metabolic cause remains possible, future studies in patients with Dravet syndrome may elucidate if this is a feature specific to Dravet syndrome. It is of interest that ataxia can be observed in Dravet syndrome. More data are required to establish whether the vacuolar myelopathy is its basis and whether such myelopathy will respond to, or be prevented by, better seizure control or modulation of Nav
1.1 function; we note in passing that Nav
1.1 channels are expressed in white matter astrocytes (Black et al., 1994
) in close relationship with oligodendrocytes (Waxman and Black, 1984
We found no significant alterations in the distribution and morphology of inhibitory interneuronal subsets in cortex, cerebellum, brainstem or hippocampus in adult Dravet syndrome, even with quantitative analysis. The prevalence of small, intensely-labelled Nav
1.1-immunopositive cells was not different in adult post-mortem cases with Dravet syndrome and post-mortem controls with no known neurological disease. This, of course, does not exclude putative functional abnormalities in any of these cell types, as reported for the mouse models (Yu et al., 2006
; Ogiwara et al., 2007
The clinical association between seizures and febrile episodes was not underpinned by any evidence of persistent excessive neuroinflammatory pathology or microglia in cases with Dravet syndrome. Cx43, GFAP and HLA-DR immunoreactivities in the frontal cortex were not different between adult post-mortem cases with Dravet syndrome and controls. In the hippocampus, higher numbers of Cx43-immunopositive cells in adult post-mortem cases with Dravet syndrome and hippocampal sclerosis post-mortem controls were observed, compared with post-mortem controls with no neurological disease, where no Cx43-immunolabelling was seen in the hippocampus. Previous studies have suggested that the upregulation of Cx43 in medial temporal lobe epilepsy with hippocampal sclerosis may facilitate seizure propagation (Fonseca et al., 2002
; Kielian, 2008
). GFAP and HLA-DR immunoreactivities were similar between adult post-mortem cases with Dravet syndrome and controls with no neurological disease, in contrast with a greater expression in hippocampal sclerosis post-mortem controls. In the cerebellum, Cx43 immunoreactivity was similar between adult post-mortem cases with Dravet syndrome and controls (low immunoreactivity). The immunoreactivity of GFAP and HLA-DR is mainly observed in the granule cell layer and white matter of adult post-mortem cases with Dravet syndrome and controls, with higher immunoreactivity in the molecular layer of cases, with loss of Purkinje cell and processes.
Overall, we have not identified any histopathological hallmark of Dravet syndrome. In fact, a striking feature was the conspicuous preservation of neurons and interneurons, including within the hippocampus, and cortex in the frontal, temporal and occipital regions, despite decades of poorly controlled seizures. Where extensive changes were seen, in the paediatric post-mortem cases, these were compatible with their agonal states; in the paediatric sudden unexplained death in epilepsy cases, there were no neuropathological abnormalities beyond changes common to chronic epilepsy. Therefore, in neither paediatric nor adult post-mortem cases, at the levels we examined the blocks available for study, were there any pathological changes to explain the observed cognitive/developmental arrest or decline.
Seizure freedom was not attained in any of our adult patients, but seizure control was significantly improved in the three cases with sufficient follow-up after specific post-diagnosis anti-epileptic drug changes, with use of appropriate drugs and withdrawal of others previously described to worsen control, such as lamotrigine, carbamazepine, vigabatrin (Guerrini et al., 1998
; Perucca et al., 1998
), phenytoin and oxcarbazepine (), which may have different effects on different seizure types in Dravet syndrome. Even if the patient had had drug-resistant seizures for many years, the suppression of at least one seizure type was possible for at least several months, as also shown in a recent report (Akiyama et al
., 2010). For our oldest living patient, at 60 years, rational drug changes proved possible once the clinical diagnosis, with confirmation from molecular genetics (which was important in this case given the lack of literature on long-term features of Dravet syndrome), gave carers confidence in such anti-epileptic drug changes. A previous anti-epileptic drug change had led to status epilepticus and strong reluctance to entertain further changes. Subsequent drug changes led to significant benefits, even after 60 years of drug-resistant seizures: convulsive seizures were controlled and the patient began speaking again for the first time for over 5 years (Video in Supplementary material
Dravet syndrome has been considered an ‘epileptic encephalopathy’ in the International League Against Epilepsy classification (Engel et al., 2001
) and a syndrome carrying higher risk of epileptic encephalopathy in the recent reorganization (Berg et al., 2010
), but controversy exists as to whether the seizures and interictal discharges themselves are responsible for the cognitive decline (Dravet et al., 2005
). Our data show Dravet syndrome is indeed at least partly an epileptic encephalopathy: extensive neuropathology has not shown any consistent cerebral structural abnormalities, cell loss or other neurodegeneration, and clinically, even after many decades of drug-resistant seizures, medication changes may improve seizure control, and be associated with cognitive improvement. Necessarily, the pathological components of our study are cross-sectional, not longitudinal. We must therefore await long-term follow-up of newly diagnosed infants and children with Dravet syndrome, who are appropriately treated, to determine formally whether effective control of seizures and interictal discharges prevents encephalopathy and other co-morbidities (Scheffer et al., 2009
)—not only cognitive decline, but also the additional features that we and others have reported. However, we have shown that the neurological substrate, at least at the levels we have examined, appears largely intact and therefore potentially capable of maintaining normal function—if seizures at least can be controlled. That unexpected longevity is possible further mandates efforts at earlier diagnosis and prompt effective treatment. We also conclude that Dravet syndrome may be found in older and younger adults and is a diagnosis that needs consideration in this group, because it has management implications. Dravet syndrome is an important example of the value of study of an apparently rare epilepsy, and the value of clinical acumen in syndrome discovery and clinical diagnosis.