Faculty Bibliography

Objective: In this study, we tested the hypothesis that chances of subjective prediction of seizure freedom by experienced epileptologists at a Level IV epilepsy center are comparable to results actually achieved post-surgery. Background: In the era of evidence based medicine, the use of grading and scoring tools in guiding and prognosticating patient care has become a cornerstone of medical practice. However, care in the epilepsy world still remains more physician experience based, where outcome measures that predict the likelihood of post-surgical outcomes still remain underutilized. Design/Methods: We evaluated a cohort of 49 patients with treatment resistant epilepsy who were presented in multidisciplinary surgical conference (MDC) at our institution. At least two epileptologists with over 10 years of experience estimated chances of post-surgical seizure remission at the MDC. 33 of 49 patients (67%) discussed underwent intracranial EEG monitoring and resective epilepsy surgery. Seizure freedom was assessed at 1-year and 2-years post-surgery. Methods: To this end, we evaluated a cohort of 49 refractory epilepsy patients discussed at the multidisciplinary epilepsy conference (MDC) at our institution. Clinical history, imaging, EEG and neuro-psychology data was reviewed at the conference. At least two fellowship trained experts with more than 10 years of experience estimated chances of seizure remission post-surgery at the time of MDC. 33 of 49 patients (67%) discussed underwent surgery. Seizure freedom was assessed at 6-months, 1-year and 2-years post-surgery. Results: 23 of 33 patients who underwent surgery had Engel I outcomes at 2-year clinical follow-ups. Only 7 of 23 patients (30%) that achieved an Engel I outcome were estimated by expert physicians to have a 50% or more chance of seizure freedom post-surgery. Conclusions: Our results demonstrate that even experienced specialists in the field are conservative at predicting post-surgical seizure outcomes and highlight the need for development and utilization of better objective tools in the field

Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. Here, we present the genomic landscape of TSC hamartomas. We determine that TSC lesions contain a low somatic mutational burden relative to carcinomas, a subset feature large-scale chromosomal aberrations, and highly conserved molecular signatures for each type exist. Analysis of the molecular signatures coupled with computational approaches reveals unique aspects of cellular heterogeneity and cell origin. Using immune data sets, we identify significant neuroinflammation in TSC-associated brain tumours. Taken together, this molecular catalogue of TSC serves as a resource into the origin of these hamartomas and provides a framework that unifies genomic and transcriptomic dimensions for complex tumours.

OBJECTIVE: To review studies on structural pulmonary and cardiac changes in SUDEP cases as well as studies showing pulmonary or cardiac structural changes in living epilepsy patients. METHODS: We conducted electronic literature searches using the PubMed database for articles published in English, regardless of publication year, that included data on cardiac and/or pulmonary structural abnormalities in SUDEP cases or in living epilepsy patients during the postictal period. RESULTS: Fourteen postmortem studies reported pulmonary findings in SUDEP cases. Two focused mainly on assessing lung weights in SUDEP cases versus controls; no group difference were found. The other 12 reported descriptive autopsy findings. Among all SUDEP cases with available descriptive postmortem pulmonary examination, 72% had pulmonary changes, most often pulmonary edema/congestion, and, less frequently, intraalveolar hemorrhage. Eleven studies reported on cardiac pathology in SUDEP. Cardiac abnormalities were found in approximately one-fourth of cases. The most common findings were myocyte hypertrophy and myocardial fibrosis of various degrees. Among living epilepsy patients, postictal pulmonary pathology was the most commonly reported pulmonary abnormality and the most common postictal cardiac abnormality was transient left ventricular dysfunction - Takotsubo or neurogenic stunned myocardium. SIGNIFICANCE: Cardiac and pulmonary pathological abnormalities are frequent among SUDEP cases, most commonly pulmonary edema/congestion and focal interstitial myocardial fibrosis. Most findings are not quantified, with subjective elements and undefined interobserver reliability, and lack of controls such as matched epilepsy patients who died from other causes. Further, studies have not systematically evaluated potential confounding factors, including postmortem interval to autopsy, paramedic resuscitation and IV fluids administration, underlying heart/lung disease, and risk factors for cardiac or pulmonary disease. Prospective studies with controls are needed to define the heart and lung changes in SUDEP and understand their potential relationship to mechanisms of death in SUDEP.

Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 +/- 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo-controlled, double-blind trials are necessary to confirm this finding.

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.

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.

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.

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.