Faculty Bibliography

BACKGROUND: The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period. RESULTS: The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, -22.8 percentage points; 95% confidence interval [CI], -41.1 to -5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient's overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group. CONCLUSIONS: Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375 .).

PURPOSE: We examined the incidence of seizures following ischemic stroke in a community-based sample. METHODS: All subjects with incident ischemic strokes in the Framingham Original and Offspring cohorts between 1982 and 2003 were identified and followed for up to 20 years to determine incidence of seizures. Seizure-type was based on the 2010 International League Against Epilepsy (ILAE) classification. Disability was stratified into mild/none, moderate and severe, based on post-stroke neurological deficit documentation according to the Framingham Heart Study (FHS) protocol and functional status was determined using the Barthel Index. RESULTS: An initial ischemic stroke occurred in 469 subjects in the cohort and seizures occurred in 25 (5.3%) of these subjects. Seizure incidence was similar in both large artery atherosclerosis (LAA) (6.8%) and cardio-embolic (CE) (6.2%) strokes. No seizures occurred following lacunar strokes. The predominant seizure type was focal seizure with or without evolution to bilateral convulsive seizure. One third of participants had seizures within the first 24h from stroke onset and half of all seizures occurred within the first 30days. On multivariate analysis, moderate and severe disability following stroke was associated with increased risk of incident seizure. CONCLUSIONS: Seizures occurred in approximately 5% of subjects after an ischemic stroke. One third of these seizures occurred in the first 24h after stroke and none followed lacunar strokes. Focal seizures with or without evolution in bilateral convulsive seizures were the most common seizure type. Moderate and severe disability was predictive of incident seizures.

OBJECTIVES: Renal manifestations are the second most significant cause of morbidity and mortality in patients with tuberous sclerosis complex (TSC), and include renal cysts, angiomyolipomas, fat-poor lesions, and malignant tumors. These lesions begin in childhood and often lead to chronic kidney disease (CKD). Little is known on the incidence of early modifiable risk factors of CKD, such as proteinuria and hypertension, or subtle decreases in glomerular filtration rate that correspond to the early stages of CKD in children with TSC. The impact of genotype on these early manifestations of CKD has not been investigated. DESIGN: Retrospective chart review of 84 children and young adults with TSC. MEASUREMENTS: This study assessed the prevalence of hypertension, renal impairment, and proteinuria, as well as the genotype-phenotype correlations. RESULTS: Children and young adults with TSC2 mutations had a significantly higher rate of renal lesions, hypertension (36% vs 14%), and decreased renal function than those with TSC1 mutations. CONCLUSION: On the basis of estimated glomerular filtration rate and blood pressure, our findings are consistent with the hypothesis that TSC2 mutations are associated with more severe early renal involvement in children. There is a compelling need for close collaboration of nephrologists and neurologists to provide care to pediatric patients with TSC to improve screening and management of early manifestations of renal disease.

OBJECTIVE: Lack of standardized terminology on death certificates (DCs) of SUDEP type cases may obscure the presence of epilepsy in these deaths. Most DCs for individuals dying unexpectedly with epilepsy are certified by medical examiners (MEs). The purpose of this study was to gauge death certification practices of MEs when interpreting SUDEP cases and assess implications for valid surveillance of SUDEP. MATERIALS AND METHODS: A survey consisting of clinical vignettes describing deaths in individuals with epilepsy was sent to medical examiners. Respondents were asked to indicate how they would certify death on a DC. Similar text responses were aggregated and coded according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) coding system. RESULTS: A total of 847 responses on 11 cases were received. Depending upon the vignette, the proportion of responses within each case that did not have an ICD-10 seizure code ranged from 3% to 62%. G40.9 (Epilepsy, unspecified) resulted from 43% of responses, and R56.8 (Other and unspecified convulsion) resulted from 38% of responses. CONCLUSION: The survey indicates that a high proportion of DCs do not have a seizure code and would not be identified utilizing these ICD-10 codes. The complicated nature of deaths in SUDEP, unclear circumstances surrounding a given death, and the lack of familiarity with SUDEP by surviving relatives may all contribute to variable terminology used to certify SUDEP deaths. Our results emphasize the need for collaboration between neurologists and forensic pathologists to develop a more uniform approach to death certification in SUDEP that will facilitate SUDEP research and inform relatives of individuals who die of SUDEP.

Psychiatric and behavioral disorders are important aspects of epilepsy and have received increasing attention in the last several years. The literature upon which most of the field relies contains some biases that must be carefully examined and resolved in future studies. First, in the pediatric epilepsy literature, many reports find that children with epilepsy have high levels of behavioral and psychiatric disorders when compared to appropriate controls. Most of these studies rely on parent-proxy completed instruments to assess these behavioral endpoints. Parents' reports are not objective but reflect parents' reactions and emotions. Increasing evidence suggests inherent biases in proxy reports and highlights the need to assess children directly. Second, periictal phenomena may be mischaracterized as underlying mood disorders. Third, many studies report elevated levels of psychiatric morbidity before and after the diagnosis of epilepsy, suggesting an inherent relation between the two types of disorders. Psychogenic nonepileptic seizures, while widely recognized as posing a diagnostic dilemma in the clinic, may account for some of these research findings. Diagnostic errors between epilepsy and psychogenic nonepileptic seizures need careful consideration when evaluating studies demonstrating associations between psychiatric disorders and epilepsy or poorer seizure control in association with psychiatric disorders in people who have epilepsy. Mental health concerns are important for everyone. An accurate, undistorted understanding of the relation between mental health disorders and epilepsy is essential to ensure appropriate therapy and to avoid unnecessary and potentially harmful treatments and common misconceptions.

The North American SUDEP Registry (NASR) is a repository of clinical data and biospecimens in cases of sudden unexpected death in epilepsy (SUDEP), a leading cause of epilepsy-related deaths. We assessed whether bereaved families were aware of SUDEP before their family member's death and their preferences for SUDEP disclosure. At enrollment, next-of-kin of SUDEP cases completed an intake interview, including questions assessing premorbid SUDEP discussions. Only 18.1% of the 138 next-of-kin recalled a previous discussion of SUDEP with a healthcare provider or support resource. Of the 112 who did not recall such a discussion, 72.3% wished it was discussed, 10.7% were satisfied it was not discussed, and 17% were unsure. A history of status epilepticus predicted SUDEP discussion. Rates of SUDEP discussion were not significantly higher among SUDEPs after 2013 (the approximate study midpoint) compared with those before then. Our study suggests that SUDEP remains infrequently discussed with family members of persons with epilepsy. Nearly three-quarters of family members wished they had known of SUDEP before the death. However, some were indifferent or were satisfied that this discussion had not occurred. We must balance more systematic education of patients and families about SUDEP while respecting individual preferences about having this discussion.

Extensive pioneering studies performed in the hippocampus have greatly contributed to our knowledge of an endogenous cannabinoid system comprised of the molecular machinery necessary to process endocannabinoid lipid messengers and their associated cannabinoid receptors. Moreover, a foundation of knowledge regarding the function of hippocampal circuits, and its role in supporting synaptic plasticity has facilitated our understanding of the roles cannabinoids play in the diverse behaviors in which the hippocampus participates, in both normal and pathological states. In this review, we present an historical overview of research pertaining to the hippocampal cannabinoid system to provide context in which to understand the participation of the hippocampus in cognition, behavior, and epilepsy. We also examine potential roles for the hippocampal formation in mediating dysfunctional behavior, and assert that these phenomena reflect disordered physiological activity within the hippocampus and its interactions with other brain regions after exposure to synthetic cannabinoids, and the phytocannabinoids found in marijuana, such as Delta9-THC and cannabidiol. In this regard, we examine contemporary hypotheses concerning the hippocampal endocannabinoid system's participation in psychotic disorders, schizophrenia, and epilepsy, and examine cannabinoid-sensitive cellular mechanisms contributing to coherent network oscillations as potential contributors to these disorders.

Importance: Children with benign epilepsy with centrotemporal spikes (BECTS) have traditionally been considered to have a uniformly good prognosis. However, benign may be a misnomer because BECTS is linked to cognitive deficits, a more severe phenotype with intractable seizures, and the potential for sudden unexpected death in epilepsy (SUDEP). Objective: To determine if cases of BECTS are present in the North American SUDEP Registry (NASR). Design, Setting, and Participants: The NASR is a clinical and biospecimen repository established in 2011 to promote SUDEP research. The NASR database, which includes medical records, results of electroencephalographic tests, and interviews with family members of patients with epilepsy who died suddenly without other identifiable causes of death, was queried from June 3, 2011, to June 3, 2016, for cases of BECTS. The patients with epilepsy had died suddenly without other identifiable causes of death (eg, drowning, trauma, exposure to toxic substances, or suicide); SUDEP classification was determined by the consensus of 2 epileptologists. Main Outcomes and Measures: Cases of SUDEP among children who received a diagnosis of BECTS among patients reported in the NASR. Results: Three boys (median age at death, 12 years; range, 9-13 years) who received a diagnosis of BECTS by their pediatric epileptologist or neurologists were identified among 189 cases reported in the NASR. The median age of epilepsy onset was 5 years (range, 3-11 years), and the median duration of epilepsy was 4 years (range, 1-10 years). Two deaths were definite SUDEP, and 1 was probable SUDEP. Independent review of clinical and electroencephalographic data supported the diagnosis of BECTS in all 3 patients. None of the patients was prescribed antiseizure drugs, either owing to physician recommendation or mutual decision by the physician and parents. All 3 patients were found dead in circumstances typical of SUDEP. The 3 patients spanned the spectrum of BECTS severity: 1 had only a few seizures, 1 had more than 30 focal motor seizures, and 1 had 4 witnessed generalized tonic-clonic seizures and approximately 30 suspected generalized tonic-clonic seizures. Conclusions and Relevance: Sudden unexpected death in epilepsy is a very rare outcome in BECTS that clinicians should consider discussing in appropriate circumstances and possibly factoring into treatment decisions.

INTRODUCTION: Tuberous sclerosis is associated with three central nervous system pathologies: cortical/subcortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Tubers are associated with epilepsy, which is often medication-resistant and often leads to resective surgery. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be effective reducing seizure burden in some patients with tuberous sclerosis complex (TSC)-related refractory epilepsy. mTORi have also been shown to be an alternative for surgery treating SEGAs. We describe several cases of resected tubers that contained SEGA tissue without an intraventricular SEGA. METHODS: After institutional review board (IRB) protocol approval, we retrospectively reviewed the surgical-pathological data for all TSC patients who underwent cortical resections for treatment of refractory epilepsy at NYU Langone Medical Center and Tel Aviv Medical Center between 2003 and 2013. Data included demographics, epilepsy type, MRI characteristics, epilepsy outcome, and histopathological staining. RESULTS: We reviewed cortical resections from 75 patients with complete pathological studies. In three patients, cortical lesions demonstrated histopathological findings consistent with a SEGA within the resected tuber tissue, with no intraventricular SEGA. All lesions were cortically based and none had any intraventricular extension. No patient had been treated before surgery with an mTORi. Two of the three patients remain Engel grade I-II. All lesions stained positive for glial fibrillary acidic protein (GFAP), synaptophysin, and neuronal nuclear antigen (NeuN). CONCLUSION: This is the first description of cortical tubers harboring SEGA tissue. This observation though preliminary may suggest a subgroup of patients with intractable epilepsy in whom mTORi may be considered before surgical intervention.

OBJECTIVE: Amygdala enlargement (AE) is observed in patients with temporal lobe epilepsy (TLE), which has led to the suggestion that it represents a distinct TLE subtype; however, it is unclear whether AE is found at similar rates in other epilepsy syndromes or in healthy controls, which would limit its value as a marker for focal epileptogenicity. METHODS: We compared rates of AE, defined quantitatively from high-resolution T1-weighted MRI, in a large multi-site sample of 136 patients with nonlesional localization related epilepsy (LRE), including TLE and extratemporal (exTLE) focal epilepsy, 34 patients with idiopathic generalized epilepsy (IGE), and 233 healthy controls (HCs). RESULTS: AE was found in all groups including HCs; however, the rate of AE was higher in LRE (18.4%) than in IGE (5.9%) and HCs (6.4%). Patients with unilateral LRE were further evaluated to compare rates of concordant ipsilateral AE in TLE and exTLE, with the hypothesis that rates of ipsilateral AE would be higher in TLE. Although ipsilateral AE was higher in TLE (19.4%) than exTLE (10.5%), this difference was not significant. Furthermore, among the 25 patients with unilateral LRE and AE, 13 (52%) had either bilateral AE or AE contralateral to seizure onset. CONCLUSION: Results suggest that AE, as defined with MRI volumetry, may represent an associated feature of nonlesional localization related epilepsy with limited seizure onset localization value.