A systematic literature review on the global epidemiology of Dravet syndrome and Lennox-Gastaut syndrome: Prevalence, incidence, diagnosis, and mortality.

Raising the bar: Fenfluramine sets new treatment standards for Dravet syndrome

Sudden unexpected death in epilepsy

Attitudes of Brazilian epileptologists to discussion about SUDEP with their patients: Truth may hurt, but does deceit hurt more?

Sudden unexpected death in epilepsy is the leading category of epilepsy-related death and the underlying mechanisms are incompletely understood. Risk factors can include a recent history and high frequency of generalized tonic-clonic seizures, which can depress brain activity postictally, impairing respiration, arousal and protective reflexes. Neuropathological findings in sudden unexpected death in epilepsy cases parallel those in other epilepsy patients, with no implication of novel structures or mechanisms in seizure-related deaths. Few large studies have comprehensively reviewed whole brain examination of such patients. We evaluated 92 North American Sudden unexpected death in epilepsy Registry cases with whole brain neuropathological examination by board-certified neuropathologists blinded to the adjudicated cause of death, with an average of 16 brain regions examined per case. The 92 cases included 61 sudden unexpected death in epilepsy (40 definite, 9 definite plus, 6 probable, 6 possible) and 31 people with epilepsy controls who died from other causes. The mean age at death was 34.4 years and 65.2% (60/92) were male. The average age of death was younger for sudden unexpected death in epilepsy cases than for epilepsy controls (30.0 versus 39.6 years; P = 0.006), and there was no difference in sex distribution respectively (67.3% male versus 64.5%, P = 0.8). Among sudden unexpected death in epilepsy cases, earlier age of epilepsy onset positively correlated with a younger age at death (P = 0.0005) and negatively correlated with epilepsy duration (P = 0.001). Neuropathological findings were identified in 83.7% of the cases in our cohort. The most common findings were dentate gyrus dysgenesis (sudden unexpected death in epilepsy 50.9%, epilepsy controls 54.8%) and focal cortical dysplasia (FCD) (sudden unexpected death in epilepsy 41.8%, epilepsy controls 29.0%). The neuropathological findings in sudden unexpected death in epilepsy paralleled those in epilepsy controls, including the frequency of total neuropathological findings as well as the specific findings in the dentate gyrus, findings pertaining to neurodevelopment (e.g. FCD, heterotopias) and findings in the brainstem (e.g. medullary arcuate or olivary dysgenesis). Thus, like prior studies, we found no neuropathological findings that were more common in sudden unexpected death in epilepsy cases. Future neuropathological studies evaluating larger sudden unexpected death in epilepsy and control cohorts would benefit from inclusion of different epilepsy syndromes with detailed phenotypic information, consensus among pathologists particularly for more subjective findings where observations can be inconsistent, and molecular approaches to identify markers of sudden unexpected death in epilepsy risk or pathogenesis.

Brainstem nuclei dysfunction is implicated in sudden unexpected death in epilepsy. In animal models, deficient serotonergic activity is associated with seizure-induced respiratory arrest. In humans, glia are decreased in the ventrolateral medullary pre-Botzinger complex that modulate respiratory rhythm, as well as in the medial medullary raphe that modulate respiration and arousal. Finally, sudden unexpected death in epilepsy cases have decreased midbrain volume. To understand the potential role of brainstem nuclei in sudden unexpected death in epilepsy, we evaluated molecular signalling pathways using localized proteomics in microdissected midbrain dorsal raphe and medial medullary raphe serotonergic nuclei, as well as the ventrolateral medulla in brain tissue from epilepsy patients who died of sudden unexpected death in epilepsy and other causes in diverse epilepsy syndromes and non-epilepsy control cases (n = 15–16 cases per group/region). Compared with the dorsal raphe of non-epilepsy controls, we identified 89 proteins in non-sudden unexpected death in epilepsy and 219 proteins in sudden unexpected death in epilepsy that were differentially expressed. These proteins were associated with inhibition of EIF2 signalling (P-value of overlap = 1.29 × 10−8, z = −2.00) in non-sudden unexpected death in epilepsy. In sudden unexpected death in epilepsy, there were 10 activated pathways (top pathway: gluconeogenesis I, P-value of overlap = 3.02 × 10−6, z = 2.24) and 1 inhibited pathway (fatty acid beta-oxidation, P-value of overlap = 2.69 × 10−4, z = −2.00). Comparing sudden unexpected death in epilepsy and non-sudden unexpected death in epilepsy, 10 proteins were differentially expressed, but there were no associated signalling pathways. In both medullary regions, few proteins showed significant differences in pairwise comparisons. We identified altered proteins in the raphe and ventrolateral medulla of epilepsy patients, including some differentially expressed in sudden unexpected death in epilepsy cases. Altered signalling pathways in the dorsal raphe of sudden unexpected death in epilepsy indicate a shift in cellular energy production and activation of G-protein signalling, inflammatory response, stress response and neuronal migration/outgrowth. Future studies should assess the brain proteome in relation to additional clinical variables (e.g. recent tonic–clonic seizures) and in more of the reciprocally connected cortical and subcortical regions to better understand the pathophysiology of epilepsy and sudden unexpected death in epilepsy.

Sudden Unexpected Death in Epilepsy is a leading cause of epilepsy-related mortality, and the analysis of mouse Sudden Unexpected Death in Epilepsy models is steadily revealing a spectrum of inherited risk phenotypes based on distinct genetic mechanisms. Serotonin (5-HT) signalling enhances post-ictal cardiorespiratory drive and, when elevated in the brain, reduces death following evoked audiogenic brainstem seizures in inbred mouse models. However, no gene in this pathway has yet been linked to a spontaneous epilepsy phenotype, the defining criterion of Sudden Unexpected Death in Epilepsy. Most monogenic models of Sudden Unexpected Death in Epilepsy invoke a failure of inhibitory synaptic drive as a critical pathogenic step. Accordingly, the G protein-coupled, membrane serotonin receptor 5-HT2C inhibits forebrain and brainstem networks by exciting GABAergic interneurons, and deletion of this gene lowers the threshold for lethal evoked audiogenic seizures. Here, we characterize epileptogenesis throughout the lifespan of mice lacking X-linked, 5-HT2C receptors (loxTB Htr2c). We find that loss of Htr2c generates a complex, adult-onset spontaneous epileptic phenotype with a novel progressive hyperexcitability pattern of absences, non-convulsive, and convulsive behavioural seizures culminating in late onset sudden mortality predominantly in male mice. RNAscope localized Htr2c mRNA in subsets of Gad2+ GABAergic neurons in forebrain and brainstem regions. To evaluate the contribution of 5-HT2C receptor-mediated inhibitory drive, we selectively spared their deletion in GAD2+ GABAergic neurons of pan-deleted loxTB Htr2c mice, yet unexpectedly found no amelioration of survival or epileptic phenotype, indicating that expression of 5-HT2C receptors in GAD2+ inhibitory neurons was not sufficient to prevent hyperexcitability and lethal seizures. Analysis of human Sudden Unexpected Death in Epilepsy and epilepsy genetic databases identified an enrichment of HTR2C non-synonymous variants in Sudden Unexpected Death in Epilepsy cases. Interestingly, while early lethality is not reflected in the mouse model, we also identified variants mainly among male Sudden Infant Death Syndrome patients. Our findings validate HTR2C as a novel, sex-linked candidate gene modifying Sudden Unexpected Death in Epilepsy risk, and demonstrate that the complex epilepsy phenotype does not arise solely from 5-HT2C-mediated synaptic disinhibition. These results strengthen the evidence for the serotonin hypothesis of Sudden Unexpected Death in Epilepsy risk in humans, and advance current efforts to develop gene-guided interventions to mitigate premature mortality in epilepsy.

Sudden Unexpected Death in Epilepsy (SUDEP): How Do We Prevent This Childhood Tragedy?

Sudden unexpected death in people with down syndrome and epilepsy: another piece in this complicated puzzle

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in individuals with chronic, uncontrolled epilepsy. Epidemiologists use information on death certificates to study SUDEP. Certification of seizure-related deaths varies. Multiple classification schemes have been proposed to categorize SUDEP type deaths. Nashef et al. recently proposed categorizing death into Definite SUDEP, Definite SUDEP Plus, Probable SUDEP, Possible SUDEP, Near-SUDEP, and Not SUDEP. This study analyzes certification of seizure-related deaths by our office and considers how it relates to Nashef's classifications. Investigative reports from 2011-2015 from the archives of the Jefferson County Coroner/Medical Examiner's Office were searched for the terms "seizure(s)" and "epilepsy." Cases (N=61) were categorized as Definite SUDEP (n=13), Definite SUDEP Plus (n=12), Probable SUDEP (n=1), Possible SUDEP (n=2), and Not SUDEP (n=33). The term SUDEP was only used in one case of Definite SUDEP. The other 12 cases were certified with variations of terms "seizure" and "epilepsy." Cases categorized as Definite SUDEP Plus were overwhelmingly certified as deaths due to heart disease. Categories Probable SUDEP or Possible SUDEP comprised three cases, and in one of those a seizure-related term was used on the death certificate. Thirty-three cases were classified as Not SUDEP. The finding that the majority of cases of Definite SUDEP were certified as some variation of "seizure" or "epilepsy" but not "SUDEP" has important implications for SUDEP research. Our study also suggests that cases of Definite SUDEP Plus would be difficult for epidemiologists to identify because cardiovascular diseases are more frequently implicated.

Pediatric Sudden Unexpected Death in Epilepsy

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsies, but physiological mechanisms that lead to SUDEP are unknown. Dravet syndrome (DS) is an infantile-onset intractable epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes brain type-I voltage-gated sodium channel NaV1.1. We studied the mechanism of premature death in Scn1a heterozygous KO mice and conditional brain- and cardiac-specific KOs. Video monitoring demonstrated that SUDEP occurred immediately following generalized tonic-clonic seizures. A history of multiple seizures was a strong risk factor for SUDEP. Combined video-electroencephalography-electrocardiography revealed suppressed interictal resting heart-rate variability and episodes of ictal bradycardia associated with the tonic phases of generalized tonic-clonic seizures. Prolonged atropine-sensitive ictal bradycardia preceded SUDEP. Similar studies in conditional KO mice demonstrated that brain, but not cardiac, KO of Scn1a produced cardiac and SUDEP phenotypes similar to those found in DS mice. Atropine or N-methyl scopolamine treatment reduced the incidence of ictal bradycardia and SUDEP in DS mice. These findings suggest that SUDEP is caused by apparent parasympathetic hyperactivity immediately following tonic-clonic seizures in DS mice, which leads to lethal bradycardia and electrical dysfunction of the ventricle. These results have important implications for prevention of SUDEP in DS patients.

Article Abstract†‹†‹Because this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text.To the Editor: Sudden unexpected death in epilepsy (SUDEP) occurs sometimes in people with ictal disorders. The diagnosis does not require evidence of a seizure and excludes status epilepticus as a cause of death. The postmortem examination must not reveal any toxic or anatomic pathology, and death must not be due to trauma or drowning.

Caregiver burden and therapeutic needs in Dravet syndrome - A national UK cross-sectional questionnaire study

Sudden unexpected death in epilepsy is the leading cause of epilepsy related death. Currently, there are no reliable methods for preventing sudden unexpected death in epilepsy. The precise pathophysiology of sudden unexpected death in epilepsy is unclear; however, convergent lines of evidence suggest that seizure-induced respiratory arrest plays a central role. It is generally agreed that sudden unexpected death in epilepsy could be averted if the patient could be rapidly ventilated following the seizure. The diaphragm is a muscle in the chest which contracts to draw air into the lungs. Diaphragmatic pacing is a surgical intervention which facilitates normal ventilation in situations, such as spinal cord injury and sleep apnoea, in which endogenous respiration would be inadequate or non-existent. In diaphragmatic pacing, electrodes are implanted directly onto diaphragm or adjacent to the phrenic nerves which innervate the diaphragm. These electrodes are then rhythmically stimulated, thereby eliciting contractions of the diaphragm which emulate endogenous breathing. The goal of this study was to test the hypothesis that seizure-induced respiratory arrest and death can be prevented with diaphragmatic pacing. Our approach was to induce respiratory arrest using maximal electroshock seizures in adult, male, C57BL6 mice outfitted with EEG and diaphragmatic electrodes (n = 8 mice). In the experimental group, the diaphragm was stimulated to exogenously induce breathing. In the control group, no stimulation was applied. Breathing and cortical electrographic activity were monitored using whole body plethysmography and EEG, respectively. A majority of the animals that did not receive the diaphragmatic pacing intervention died of seizure-induced respiratory arrest. Conversely, none of the animals that received the diaphragmatic pacing intervention died. Diaphragmatic pacing improved postictal respiratory outcomes (two-way ANOVA, P < 0.001) and reduced the likelyhood of seizure-induced death (Fisher’s exact test, P = 0.026). Unexpectedly, diaphragmatic pacing did not instantly restore breathing during the postictal period, potentially indicating peripheral airway occlusion by laryngospasm. All diaphragmatically paced animals breathed at some point during the pacing stimulation. Two animals took their first breath prior to the onset of pacing and some animals had significant apnoeas after the pacing stimulation. Sudden unexpected death in epilepsy results in more years of potential life lost than any other neurological condition with the exception of stroke. By demonstrating that seizure-induced respiratory arrest can be prevented by transient diaphragmatic pacing in animal models we hope to inform the development of closed-loop systems capable of detecting and preventing sudden unexpected death in epilepsy.

Epilepsy, the most prevalent serious neurological disorder, afflicts 0.5% of the general population (1). The prevalence of learning disabilities (LDs) in the general population is approximately similar (2). Both groups of conditions share a common heritage of heterogeneity, high prevalence figures, a dearth of care expertise outside major centres or institutions, and an unfortunate degree of stigmatization. Up to a fourth of patients with epilepsy are said to have LDs, and conversely, up to half of all patients with LDs are said to have seizure disorders, thus rendering this particular combination an especially common one. The paucity of authoritative studies on prognosis, mortality, and treatment of this special group belies this, however, and is all the more surprising. This encourages a substantial lacune in current knowledge of the epilepsies, and these deficiencies must be addressed appropriately. Epidemiology is the study of the dynamics of a condition in a population, and the "patient" therefore represents the community rather than an individual. A sine qua non is that data must be derived or collected from an unselected population. In this regard, there is little comprehensive information on the epidemiology of epilepsy in LDs and LDs in epilepsy. As with many epidemiologic studies in epilepsy, lack of standardization in methods used and inherent population biases have plagued estimates of prevalence of epilepsy in patients with LDs and vice versa. There are no studies of incidence, and most large-scale prevalence studies of epilepsy have seldom addressed or defined subpopulations with additional LDs. Both LDs and epilepsy have wide heterogeneity, and this should be addressed in any comprehensive study. In epidemiologic studies of LDs, true prevalence rates of epilepsy are difficult to ascertain because of the variability in screening instruments as well as the lack of standardized definitions and classifications of epilepsy. Adults are underrepresented in most such research, and the vast majority of published data pertain to children. Studies of mortality in patients with epilepsy and LDs are more readily undertaken in institutionalised patients and probably overestimate such deaths in the community. The prevalence of epilepsy varies in direct proportion to the severity of the LD. Community studies have indicated prevalence rates ranging from of 6% amongst children with mild LDs (IQ, 50–70) (3) to 24% in severe LD (IQ, <50) (4) and 50% in those with profound LDs (IQ, <20) (5). A reasonable estimate of the prevalence of epilepsy in patients with moderate to severe LDs probably ranges between 1 in 4 and 1 in 5 such patients (4–6). Some studies have addressed epidemiologic issues in individual syndromes and etiologies. In patients with cerebral palsy and LDs, the cumulative risk for developing epilepsy has been estimated at 28, 31, and 38% at ages 5, 10, and 22 years (7). Of children with Down's syndrome, 1.4% are said to have epilepsy (8), and the prevalence increases substantially in those older than 35 years (12.2%) (9). A much larger proportion of patients with fragile X syndrome have epilepsy, with prevalence rates approaching 25%(10). Both tuberous sclerosis (>60%) (11) and the Sturge–Weber syndrome (>70%) (12) have very high prevalence rates of epilepsy, although not all have LDs. Up to 90% of patients with Lennox–Gastaut syndrome or West's syndrome may have LDs (13). In several conditions, epilepsy and LDs are common associations. These range from cerebral palsy to rare conditions such as cortical dysplasias and inherited metabolic defects. Some of these associations are listed in Table 1. The prognosis for seizure control in patients with epilepsy who have LDs is probably poorer than that in those without LDs (14). No recent studies, however, specifically address the problem of seizures in populations with LDs, although observations have been made in the context of individual syndromes and etiologies. In cerebral palsy, only 13% of 531 patients with epilepsy in a large cohort achieved 2-year remission from seizures. Encouragingly, the same study found that drug discontinuation in these patients was associated with lasting remission in 60%. LDs however, did not specifically appear to influence remission (15). In Down's syndrome, prognosis for seizure control may depend on the etiology of seizures; patients with cardiovascular etiologies and idiopathic seizures generally did well, those with central nervous system (CNS) infective seizures did less well, and those with neonatal hypoxic–ischemic brain damage did least well (16). Patients with seizures in fragile X tend to have infrequent attacks and are mostly well controlled with standard therapy (10). In the neurocutaneous syndromes, seizure control can be particularly difficult. Infantile spasms occur in 40–60% of patients with tuberous sclerosis (17,18). In patients with the Sturge–Weber syndrome also, the prognosis for satisfactory seizure control is poor. In the Lennox–Gastaut syndrome, complete seizure freedom is rare. Not all patients maintain the full profile of the syndrome, but frequent disabling seizures persist in the majority. The main predictors of poor prognosis appear to be symptomatic seizures, infantile spasms, early age at onset of seizures, frequent seizures, repeated status epilepticus, long periods of worsening, and EEG abnormalities such as constant slow background activity and localized changes. Mortality in patients with epilepsy is higher than that in the general population, and subnormal mentation has traditionally been identified as a significant adverse prognostic factor (19). Again, however, few recent studies have examined this in patients with LDs. In a Swedish study, 1,478 patients with LDs, 296 of whom had epilepsy, were followed up for 7 years. Standardized mortality ratios (SMRs) in patients with LDs and epilepsy were substantially higher [SMR, 5.0 (95% CI, 3.3–7.5)] than those in patients with LDs alone [SMR, 1.6 (95% CI, 1.3–2.0)] and highest in patients who had LDs, epilepsy, and cerebral palsy [SMR, 5.8 (95% CI, 3.4–9.7)](20). Mortality was especially significant with generalised seizures and was related to seizure frequency in the year preceding death. Only 7% of deaths in patients with epilepsy and LDs appeared to be directly seizure related, and the commonest cause of death otherwise was pneumonia. In patients with LDs and very severe epilepsy, direct seizure-related deaths are much more frequent, and sudden unexpected death in epilepsy (SUDEP) is probably the commonest category. In a study of 310 patients with epilepsy and severe LDs followed up for a total of 4,135 person years, the overall SMR was 15.9 (95% CI, 10.6–23.0), and 70% of the 28 recorded deaths were seizure related (21). The incidence of SUDEP was estimated at 1:295 per year compared with 1:1,000 per year in epilepsy patients in the general population. This suggests that patients with LDs and severe epilepsy are particularly at risk of sudden death. In specific syndromes such as in the progressive myoclonic epilepsies, mortality rates can be very high, and prognosis, generally dismal. Few properly designed trials have assessed individual drugs in the treatment of epilepsy in LDs. Current treatment practice is based largely on retrospective studies, open trials, and center-based treatment policies. This approach is easily open to criticism and does not address the specific difficulties and characteristics of patients with LDs. There is some evidence, however, that, as in the general population, there is a trend toward modernizing and rationalizing therapy. The use of phenobarbitone (PB) in developed countries, for example, appears to have declined, and the majority of patients with LDs are receiving monotherapy. Lack of standardization in many studies limits the usefulness of their conclusions. No specific drugs are used in the treatment of seizure disorders in patients with LDs, and, as in the current treatment of epilepsy, choice of drug is dictated largely by seizure types. There are no randomised, controlled trials of drug treatment in large populations with LDs, although there are small open studies that have looked at newer anticonvulsant use in LD. An uncontrolled study of add-on vigabatrin (VGB) use in LD showed ≥50% seizure reduction in 42, 25, and 22% of 36 patients studied at 3 months, 2 years, and 5 years, respectively (22). In a few specific syndromes, some specific drugs are said to have moderate to high efficacy. Studies have shown that VGB, for example, significantly reduces seizures in patients with West's syndrome, both as monotherapy (23,24) and as add-on. In one study of 40 newly diagnosed children, patients were randomised to VGB monotherapy or placebo for 5 days, and then all were treated openly for 24 weeks. At the end of the study, 38% were seizure free (23). Both lamotrigine (LTG) and topiramate (TPM) are thought to be effective in Lennox–Gastaut syndrome. In a double-blind, placebo-controlled study of 169 patients with Lennox–Gastaut syndrome, 33% of patients treated with LTG had ≥50% seizure reduction compared with 16% in the placebo group (25). A trial of TPM in 98 patients showed similar results (26). Discontinuation of medication is an issue that is similarly understudied, and little information is available on the matter. In one study of 50 patients with LDs followed up for 8 years, patients in 2-year terminal seizure remission were discontinued from medication (27). In half, seizures recurred, most during the first 3 years after discontinuation. A small lifetime number of seizures, absence of gross neurologic abnormalities, low drug levels at termination of therapy, and normal EEGs before and after discontinuation of medication appeared to predict successful outcome. In summary, the association between epilepsy and LDs, both very prevalent conditions, is very common. LDs, by definition, have a childhood or adolescent onset, and a variety of seizure disorders commonly arise in these age groups. Despite high prevalence and the significant morbidity and mortality associated with these conditions, a surprising dearth of literature is focussed on prognosis, treatment, and outcomes in populations with LD. Most of the existing drug treatments for seizures in LDs, for example, are derived from studies on populations without LDs. A few studies that provide specific information on individual syndromes such as Lennox–Gastaut and infantile spasms exist, although these patients constitute but a small proportion of patients with LDs. Given the substantial implications to health professionals and health care planning, these deficiencies should be addressed. There is still a requirement for properly designed prospective incidence studies of patients with LDs developing epilepsy. In this context, it is important to emphasise that cross-sectional studies, for a range of reasons, are unsuitable and unlikely to add significantly to current knowledge. There also is a need for well-designed case–control studies analyzing etiologies and risk factors for seizures in LDs. With the advent of sophisticated neuroimaging, genetic tests, and other investigational techniques, these have become more feasible than ever. Long-term studies of prognosis using standardized epidemiologic methods are required, given the current lacunae in our understanding of seizure remission, recurrence, morbidity, and mortality in patients with epilepsy and LD. In particular, the issues surrounding SUDEP should be clarified, as patients with refractory epilepsy and LD appear to be particularly at risk of this phenomenon.