Faculty Bibliography

Since the first antiseizure medication (ASM) was introduced in 1857, more than 30 medications have been approved by the United States Food and Drug Administration (FDA) for the treatment of epilepsy. However, limitations in efficacy and tolerability have led to one-third of patients suffering from uncontrolled seizures. Recent advances in genetics, disease modeling, high-throughput target-based and phenotype-based screening, study design, and identification of novel mechanisms of action or routes of delivery have resulted in more than 200 therapeutics currently under development in the epilepsy pipeline. This study discusses near-to-market drugs in advanced clinical development, with select drugs in earlier stages. Background regarding mechanisms, animal studies, pharmacokinetics, pharmacodynamics, efficacy, tolerability, and safety data are provided for each drug when available.

The cerebellum, a subcortical structure, is traditionally linked to sensorimotor integration and coordination, although its role in cognition and affective behavior, as well as epilepsy, is increasingly recognized. Cerebellar dysfunction in patients with epilepsy can result from genetic disorders, antiseizure medications, seizures, and seizure-related trauma. Impaired cerebellar function, regardless of cause, can cause ataxia (imbalance, impaired coordination, unsteady gait), tremor, gaze-evoked nystagmus, impaired slow gaze pursuit and saccade accuracy, as well as speech deficits (slurred, scanning, or staccato). We explore how cerebellar dysfunction can contribute to epilepsy, reviewing data on genetic, infectious, and neuroinflammatory disorders. Evidence of cerebellar dysfunction in epilepsy comes from animal studies as well as human neuropathology and structural magnetic resonance imaging (MRI), functional and diffusion tensor MRI, positron emission and single photon emission computerized tomography, and depth electrode electro-encephalography studies. Cerebellar lesions can infrequently cause epilepsy, with focal motor, autonomic, and focal to bilateral tonic-clonic seizures. Antiseizure medication-resistant epilepsy typically presents in infancy or before age 1 year with hemifacial clonic or tonic seizures ipsilateral to the cerebellar mass. Lesions are typically asymmetric benign or low-grade tumors in the floor of the fourth ventricle involving the cerebellar peduncles and extending to the cerebellar hemisphere. Electrical stimulation of the cerebellum has yielded conflicting results on efficacy, although methodological issues confound interpretation. Epilepsy-related comorbidities including cognitive and affective disorders, falls, and sudden unexpected death in epilepsy may also be impacted by cerebellar dysfunction. We discuss how cerebellar dysfunction may drive seizures and how genetic epilepsies, seizures and seizure therapies may drive cerebellar dysfunction, and how our understanding of epilepsy-related comorbidities through basic neuroscience, animals models and patient studies can advance our understanding and improve patient outcomes.

Cenobamate has demonstrated efficacy in patients with treatment-resistant epilepsy, including patients who continued to have seizures after epilepsy surgery. This article provides recommendations for cenobamate use in patients referred for epilepsy surgery evaluation. A panel of six senior epileptologists from the United States and Europe with experience in presurgical evaluation of patients with epilepsy and in the use of antiseizure medications (ASMs) was convened to provide consensus recommendations for the use of cenobamate in patients referred for epilepsy surgery evaluation. Many patients referred for surgical evaluation may benefit from ASM optimization; both ASM and surgical treatment should be individualized. Based on previous clinical studies and the authors' clinical experience with cenobamate, a substantial proportion of patients with treatment-resistant epilepsy can become seizure-free with cenobamate. We recommend a cenobamate trial and ASM optimization in parallel with presurgical evaluations. Cenobamate can be started before phase two monitoring, especially in patients who are found to be suboptimal surgery candidates. As neurostimulation therapies are generally palliative, we recommend trying cenobamate before vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (RNS). In surgically remediable cases (mesial temporal sclerosis, benign discrete lesion in non-eloquent cortex, cavernous angioma, etc.), cenobamate use should not delay imminent surgery; however, a patient may decide to defer or even cancel surgery should they achieve sustained seizure freedom with cenobamate. This decision should be made on an individual, case-by-case basis based on seizure etiology, patient preferences, potential surgical risks (mortality and morbidity), and likely surgical outcome. The addition of cenobamate after unsuccessful surgery or palliative neuromodulation may also be associated with better outcomes.

The idiopathic generalized epilepsies (IGE) make up a fifth of all epilepsies, but <1% of epilepsy research. This skew reflects misperceptions: diagnosis is straightforward, pathophysiology is understood, seizures are easily controlled, epilepsy is outgrown, morbidity and mortality are low, and surgical interventions are impossible. Emerging evidence reveals that patients with IGE may go undiagnosed or misdiagnosed with focal epilepsy if EEG or semiology have asymmetric or focal features. Genetic, electrophysiologic, and neuroimaging studies provide insights into pathophysiology, including overlaps and differences from focal epilepsies. IGE can begin in adulthood and patients have chronic and drug-resistant seizures. Neuromodulatory interventions for drug-resistant IGE are emerging. Rates of psychiatric and other comorbidities, including sudden unexpected death in epilepsy, parallel those in focal epilepsy. IGE is an understudied spectrum for which our diagnostic sensitivity and specificity, scientific understanding, and therapies remain inadequate.

OBJECTIVE:We sought to determine which combination of clinical and electroencephalography (EEG) characteristics differentiate between an antiseizure medication (ASM)-resistant vs ASM-responsive outcome for patients with idiopathic generalized epilepsy (IGE). METHODS:This was a case-control study of ASM-resistant cases and ASM-responsive controls with IGE treated at five epilepsy centers in the United States and Australia between 2002 and 2018. We recorded clinical characteristics and findings from the first available EEG study for each patient. We then compared characteristics of cases vs controls using multivariable logistic regression to develop a predictive model of ASM-resistant IGE. RESULTS:We identified 118 ASM-resistant cases and 114 ASM-responsive controls with IGE. First, we confirmed our recent finding that catamenial epilepsy is associated with ASM-resistant IGE (odds ratio [OR] 3.53, 95% confidence interval [CI] 1.32-10.41, for all study subjects) after covariate adjustment. Other independent factors seen with ASM resistance include certain seizure-type combinations (absence, myoclonic, and generalized tonic-clonic seizures [OR 7.06, 95% CI 2.55-20.96]; absence and generalized tonic-clonic seizures [OR 4.45, 95% CI 1.84-11.34]), as well as EEG markers of increased generalized spike-wave discharges (GSWs) in sleep (OR 3.43, 95% CI 1.12-11.36 for frequent and OR 7.21, 95% CI 1.50-54.07 for abundant discharges in sleep) and the presence of generalized polyspike trains (GPTs; OR 5.49, 95% CI 1.27-38.69). The discriminative ability of our final multivariable model, as measured by area under the receiver-operating characteristic curve, was 0.80. SIGNIFICANCE:Multiple clinical and EEG characteristics independently predict ASM resistance in IGE. To improve understanding of a patient's prognosis, clinicians could consider asking about specific seizure-type combinations and track whether they experience catamenial epilepsy. Obtaining prolonged EEG studies to record the burden of GSWs in sleep and assessing for the presence of GPTs may provide additional predictive value.

Objective/UNASSIGNED:Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Although lots of effort has been made in identifying clinical risk factors for SUDEP in the literature, there are few validated methods to predict individual SUDEP risk. Prolonged postictal EEG suppression (PGES) is a potential SUDEP biomarker, but its occurrence is infrequent and requires epilepsy monitoring unit admission. We use machine learning methods to examine SUDEP risk using interictal EEG and ECG recordings from SUDEP cases and matched living epilepsy controls. Methods/UNASSIGNED:This multicenter, retrospective, cohort study examined interictal EEG and ECG recordings from 30 SUDEP cases and 58 age-matched living epilepsy patient controls. We trained machine learning models with interictal EEG and ECG features to predict the retrospective SUDEP risk for each patient. We assessed cross-validated classification accuracy and the area under the receiver operating characteristic (AUC) curve. Results/UNASSIGNED:The logistic regression (LR) classifier produced the overall best performance, outperforming the support vector machine (SVM), random forest (RF), and convolutional neural network (CNN). Among the 30 patients with SUDEP [14 females; mean age (SD), 31 (8.47) years] and 58 living epilepsy controls [26 females (43%); mean age (SD) 31 (8.5) years], the LR model achieved the median AUC of 0.77 [interquartile range (IQR), 0.73-0.80] in five-fold cross-validation using interictal alpha and low gamma power ratio of the EEG and heart rate variability (HRV) features extracted from the ECG. The LR model achieved the mean AUC of 0.79 in leave-one-center-out prediction. Conclusions/UNASSIGNED:Our results support that machine learning-driven models may quantify SUDEP risk for epilepsy patients, future refinements in our model may help predict individualized SUDEP risk and help clinicians correlate predictive scores with the clinical data. Low-cost and noninvasive interictal biomarkers of SUDEP risk may help clinicians to identify high-risk patients and initiate preventive strategies.

OBJECTIVE:People with epilepsy experience increased rates of sexual dysfunction, often affecting quality of life. Sexual dysfunction may result from the underlying disorder, antiseizure or other medications, or comorbid psychosocial factors. This study evaluated the incidence and clinical associations of sexual dysfunction in adult epilepsy patients. METHODS:89 epilepsy patients 18 years and older admitted to the New York University Comprehensive Epilepsy Center epilepsy monitoring unit between 2016 and 2018 completed a survey on sexual functioning. The survey included demographic, clinical, and sexual functioning information with a validated measure of sexual function (the Arizona Sexual Experiences Scale (ASEX). RESULTS:Of 89 surveys completed, 15 (16.9 %) patients had discussed sexual functioning with a medical professional and 20 (22.5 %) reported sexual dysfunction. For the group, the mean ASEX score was 13.6 (SD 4.8). 59 (66.3 %) participants reported not being asked about sexual health by their doctor or nurse practitioner in the last year. The two independent predictors of sexual dysfunction were self-identifying as overweight/obese (OR 6.1, CI 1.4-26.5, P = 0.02) or taking strong enzyme-inducing antiseizure medications (OR 7.8, CI 1.4-44.9, P = 0.02). Other factors such as age, relationship status, duration of epilepsy, the presence of depression or anxiety, cardiovascular risk factors, and opioid/stimulant use, did not predict sexual dysfunction. SIGNIFICANCE/CONCLUSIONS:Our study showed that sexual dysfunction is common in epilepsy patients but infrequently discussed by medical professionals. Two modifiable risk factors, being overweight or taking strong enzyme-inducing antiseizure medications, were independently associated with sexual dysfunction, suggesting interventions to potentially improve sexual health.

OBJECTIVE:The aim of this study was to identify specific ictal hand postures (HPs) as localizing signs of the epileptogenic zone (EZ) in patients with frontal or temporal lobe epilepsy. METHODS:In this study, we retrospectively analyzed ictal semiology of 489 temporal lobe or frontal lobe seizures recorded over a 6-year period at the Seizure Disorder Center at University of California, Los Angeles in the USA (45 patients) or at the C. Munari Epilepsy Surgery Center at Niguarda Hospital in Milan, Italy (34 patients). Our criterion for EZ localization was at least 2 years of seizure freedom after surgery. We analyzed presence and latency of ictal HP. We then examined whether specific initial HPs are predictive for EZ localization. RESULTS:We found that ictal HPs were present in 72.5% of patients with frontal and 54.5% of patients with temporal lobe seizures. We divided HPs into 6 classes depending on the reciprocal position of the fingers ("fist," "cup," "politician's fist," "pincer," "extended hand," "pointing"). We found a striking correlation between EZ localization and ictal HP. In particular, fist and pointing HPs are strongly predictive of frontal lobe EZ; cup, politician's fist, and pincer are strongly predictive of temporal lobe EZ. INTERPRETATION:Our study offers simple ictal signs that appear to clarify differential diagnosis of temporal versus frontal lobe EZ localization. These results are meant to be used as a novel complementary tool during presurgical evaluation for epilepsy. At the same time, they give us important insight into the neurophysiology of hand movements. ANN NEUROL 2019;86:793-800.

Electrical stimulation in the anterior nucleus of the thalamus (ANT) has previously been found to be efficacious for reducing seizure frequency in patients with epilepsy. Bilateral deep brain stimulation (DBS) of the ANT is an open-loop system that can be used in the management of treatment-resistant epilepsy. In contrast, the responsive neurostimulation (RNS) system is a closed-loop device that delivers treatment in response to prespecified electrocorticographic triggers. The efficacy and safety of RNS targeting the ANT is unknown. We describe 3 patients with treatment-resistant multifocal epilepsy who were implanted with an RNS system, which included unilateral stimulation of the ANT. After >33 months of follow-up, there were no adverse effects on mood, memory or behavior. Two patients had ≥50% reduction in disabling seizures and one patient had a 50% reduction compared to pretreatment baseline. Although reduction in seizure frequency has been modest to date, these findings support responsive neurostimulation of the ANT as feasible, safe, and well-tolerated. Further studies are needed to determine optimal stimulation parameters.