Faculty Bibliography

OBJECTIVE:Cannabidiol (CBD) expanded access program, initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsies (TREs) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019. METHODS:Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/ml oral solution), increasing from 2 to 10 mg/kg/day to tolerance or maximum 25-50 mg/kg/day dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit. RESULTS:Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (range = 0-74.5), and patients were taking a median of three (range = 0-10) antiseizure medications (ASMs) at baseline; the most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/day; median exposure duration was 694 days. Median percentage reduction from baseline ranged 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) ranged 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. The most common AEs (≥20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%). SIGNIFICANCE/CONCLUSIONS:Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of TREs.

BACKGROUND:The relationship between COVID-19 and epilepsy is uncertain. We studied the potential association between COVID-19 and seizures or epilepsy in the six months after infection. METHODS:We applied validated methods to an electronic health records network (TriNetX Analytics) of 81 million people. We closely matched people with COVID-19 infections to those with influenza. In each cohort, we measured the incidence and hazard ratios (HRs) of seizures and of epilepsy. We stratified data by age and by whether the person was hospitalized during the acute infection. We then explored time-varying HRs to assess temporal patterns of seizure or epilepsy diagnoses. RESULTS:We analyzed 860,934 electronic health records. After matching, this yielded two cohorts each of 152,754 patients. COVID-19 was associated with an increased risk of seizures and epilepsy compared to influenza. The incidence of seizures within 6 months of COVID-19 was 0.81% (95% CI, 0.75-0.88; HR compared to influenza 1.55 (1.39-1.74)). The incidence of epilepsy was 0.30% (0.26-0.34; HR compared to influenza 1.87 (1.54-2.28)). The HR of epilepsy after COVID-19 compared to influenza was greater in people who had not been hospitalized and in individuals aged under 16 years. The time of peak HR after infection differed by age and hospitalization status. CONCLUSIONS:The incidence of new seizures or epilepsy diagnoses in the six months following COVID-19 was low overall, but higher than in matched patients with influenza. This difference was more marked in people who were not hospitalized, highlighting the risk of epilepsy and seizures even in those with less severe infection. Children appear at particular risk of seizures and epilepsy after COVID-19 providing another motivation to prevent COVID-19 infection in pediatric populations. That the varying time of peak risk related to hospitalization and age may provide clues as to the underlying mechanisms of COVID-associated seizures and epilepsy.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

OBJECTIVE:The association between postictal electroencephalogram (EEG) suppression (PES), autonomic dysfunction, and Sudden Unexpected Death in Epilepsy (SUDEP) remains poorly understood. We compared PES on simultaneous intracranial and scalp-EEG and evaluated the association of PES with postictal heart rate variability (HRV) and SUDEP outcome. METHODS:Convulsive seizures were analyzed in patients with drug-resistant epilepsy at 5 centers. Intracranial PES was quantified using the Hilbert transform. HRV was quantified using root mean square of successive differences of interbeat intervals, low-frequency to high-frequency power ratio, and RR-intervals. RESULTS:There were 64 seizures from 63 patients without SUDEP and 11 seizures from 6 SUDEP patients. PES occurred in 99% and 87% of seizures on intracranial-EEG and scalp-EEG, respectively. Mean PES duration in intracranial and scalp-EEG was similar. Intracranial PES was regional (<90% of channels) in 46% of seizures; scalp PES was generalized in all seizures. Generalized PES showed greater decrease in postictal parasympathetic activity than regional PES. PES duration and extent were similar between patients with and without SUDEP. CONCLUSIONS:Regional intracranial PES can be present despite scalp-EEG demonstrating generalized or no PES. Postictal autonomic dysfunction correlates with the extent of PES. SIGNIFICANCE/CONCLUSIONS:Intracranial-EEG demonstrates changes in autonomic regulatory networks not seen on scalp-EEG.

Idiopathic and acquired pedophilia are two different disorders with two different etiologies. However, the differential diagnosis is still very difficult, as the behavioral indicators used to discriminate the two forms of pedophilia are underexplored, and clinicians are still devoid of clear guidelines describing the clinical and neuroscientific investigations suggested to help them with this difficult task. Furthermore, the consequences of misdiagnosis are not known, and a consensus regarding the legal consequences for the two kinds of offenders is still lacking. The present study used the Delphi method to reach a global consensus on the following six topics: behavioral indicators/red flags helpful for differential diagnosis; neurological conditions potentially leading to acquired pedophilia; neuroscientific investigations important for a correct understanding of the case; consequences of misdiagnosis; legal consequences; and issues and future perspectives. An international and multidisciplinary board of scientists and clinicians took part in the consensus statements as Delphi members. The Delphi panel comprised 52 raters with interdisciplinary competencies, including neurologists, psychiatrists, neuropsychologists, forensic psychologists, expert in ethics, etc. The final recommendations consisted of 63 statements covering the six different topics. The current study is the first expert consensus on a delicate topic such as pedophilia. Important exploitable consensual recommendations that can ultimately be of immediate use by clinicians to help with differential diagnosis and plan and guide therapeutic interventions are described, as well as future perspectives for researchers.

Epilepsy has a high prevalence and can severely impair quality of life and increase the risk of premature death. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in drug-resistant epilepsy and most often results from respiratory and cardiac impairments due to brainstem dysfunction. Epileptic activity can spread widely, influencing neuronal activity in regions outside the epileptic network. The brainstem controls cardiorespiratory activity and arousal and reciprocally connects to cortical, diencephalic, and spinal cord areas. Epileptic activity can propagate trans-synaptically or via spreading depression (SD) to alter brainstem functions and cause cardiorespiratory dysfunction. The mechanisms by which seizures propagate to or otherwise impair brainstem function and trigger the cascading effects that cause SUDEP are poorly understood. We review insights from mouse models combined with new techniques to understand the pathophysiology of epilepsy and SUDEP. These techniques include in vivo, ex vivo, invasive and non-invasive methods in anesthetized and awake mice. Optogenetics combined with electrophysiological and optical manipulation and recording methods offer unique opportunities to study neuronal mechanisms under normal conditions, during and after non-fatal seizures, and in SUDEP. These combined approaches can advance our understanding of brainstem pathophysiology associated with seizures and SUDEP and may suggest strategies to prevent SUDEP.

Introduction: Previous case-control studies of sudden unexpected death in epilepsy (SUDEP) patients failed to identify ECG features (peri-ictal heart rate, heart rate variability, corrected QT interval, postictal heart rate recovery, and cardiac rhythm) predictive of SUDEP risk. This implied a need to derive novel metrics to assess SUDEP risk from ECG. Methods: We applied Single Spectrum Analysis and Independent Component Analysis (SSA-ICA) to remove artifact from ECG recordings. Then cross-frequency phase-phase coupling (PPC) was applied to a 20-s mid-seizure window and a contour of −3 dB coupling strength was determined. The contour centroid polar coordinates, amplitude (alpha) and angle (theta), were calculated. Association of alpha and theta with SUDEP was assessed and a logistic classifier for alpha was constructed. Results: Alpha was higher in SUDEP patients, compared to non-SUDEP patients (p < 0.001). Theta showed no significant difference between patient populations. The receiver operating characteristic (ROC) of a logistic classifier for alpha resulted in an area under the ROC curve (AUC) of 94% and correctly classified two test SUDEP patients. Discussion: This study develops a novel metric alpha, which highlights non-linear interactions between two rhythms in the ECG, and is predictive of SUDEP risk.

Rationale: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is characterized by global developmental impairment and early-onset, refractory seizures. In a recent placebo-controlled study, ganaxolone reduced major motor seizure frequency (MMSF) in patients with CDD. Here we report further data at a minimum of 1-year in the open-label extension (OLE).
Method(s): Patients with CDD (aged 2-19 years) who completed the double-blind phase were eligible to receive ganaxolone in the OLE. Assessments included changes in MMSF from pre-randomization baseline to 3-month intervals in the OLE, responder rates (>=50% and >=75% MMSF reductions), Clinical Global Impression of Improvement (CGI-I), safety, and tolerability.
Result(s): Eighty-eight patients (87.1%; median age of 5; 79.5% female) continued into the OLE (101 were randomized to the double-blind study). Median baseline 28-day MMSF was 50.6. The 1-year retention rate was 70.5% with 26 discontinuations. At the time of analysis, 34 participants had discontinued due to lack of efficacy (n = 12), adverse event (n = 10), or withdrawal by caregiver (n = 10) as the most common reasons. During months 1-3, 4-6, 7-9, and 10-12, patients experienced a median reduction in MMSF of 24.7%, 32.1%, 30.0%, and 42.2%, respectively. During months 13-24, MMSF reductions ranged from 44.2% to 56.1%. At 1 year, 46.3% and 23.9% of patients experienced a >=50% and >=75% reduction in MMSF, respectively. In the OLE, clinicians and caregivers rated 60.6% and 72.5% of the patients, respectively, as improved at 1 year. The most commonly reported adverse events were seizure (22.7%), somnolence (20.5%), vomiting (18.2%), and pyrexia (17.0%). There was one death reported due to sepsis, but it was deemed unrelated to study treatment.
Conclusion(s): Reductions in MMSF at 1 year and beyond provide supportive evidence for the maintenance of effect of ganaxolone in seizures associated with CDD. Ganaxolone was generally well-tolerated in the OLE with safety findings consistent with the double-blind phase

OBJECTIVE:Identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. METHODS:Frozen brain tissue (ages 2-19 years) was obtained from control autopsy (n=14), surgical PWE (n=10), and surgical RE cases (n=27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p<0.05) and label-free quantitative mass spectrometry (false discovery rate<5%) in the three groups. RESULTS:, z=5.61). Proteomics detected fewer altered targets. SIGNIFICANCE/CONCLUSIONS:In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.

INTRODUCTION/UNASSIGNED:Alzheimer's disease (AD) and epilepsy are reciprocally related. Among sporadic AD patients, clinical seizures occur in 10-22% and subclinical epileptiform abnormalities occur in 22-54%. Cognitive deficits, especially short-term memory impairments, occur in most epilepsy patients. Common neurophysiological and molecular mechanisms occur in AD and epilepsy. The choroid plexus undergoes pathological changes in aging, AD, and epilepsy, including decreased CSF turnover, amyloid beta (Aβ), and tau accumulation due to impaired clearance and disrupted CSF amino acid homeostasis. This pathology may contribute to synaptic dysfunction in AD and epilepsy. METHODS/UNASSIGNED:= 12) using laser capture microdissection (LCM) followed by label-free quantitative mass spectrometry on the choroid plexus adjacent to the hippocampus at the lateral geniculate nucleus level. RESULTS/UNASSIGNED: DISCUSSION/UNASSIGNED:We found altered signaling pathways in the choroid plexus of severe AD cases and many correlated changes in the protein expression of cell metabolism pathways in AD and epilepsy cases. The shared molecular mechanisms should be investigated further to distinguish primary pathogenic changes from the secondary ones. These mechanisms could inform novel therapeutic strategies to prevent disease progression or restore normal function. A focus on dual-diagnosed AD/epilepsy cases, specific epilepsy syndromes, such as temporal lobe epilepsy, and changes across different severity levels in AD and epilepsy would add to our understanding.