Summary
Although the epilepsy and neurology communities have position papers on a number of topics pertaining to epilepsy diagnosis and management, no current paper exists for the rationale and ...appropriate indications for epilepsy monitoring unit (EMU) evaluation. General neurologists, hospital administrators, and insurers also have yet to fully understand the role this type of testing has in the diagnosis and management of individuals with paroxysmal neurologic symptoms. This review outlines the indications for long‐term video‐electroencephalography (VEEG) for typical elective admissions to a specialized inpatient setting. The common techniques used in EMUs to obtain diagnostic information are reviewed. The added benefit of safety measures and clinical testing above that available for routine or long‐term ambulatory electroencephalography is also discussed. The indications for admission to the EMU include differential diagnosis of paroxysmal spells, characterization of seizure types, presurgical epilepsy evaluations, seizure quantification, monitoring medication adjustment in a safe setting, and differentiation between seizures and side effects. We conclude that the appropriate use of this specialized testing can lead to an early and correct diagnosis in a variety of clinical circumstances. The EMU evaluation is considered the gold standard test for the definitive diagnosis of epilepsy and seizure‐like spells.
2-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of glucose-6-phosphate to ...fructose-6-phosphate, and thereby reversibly inhibits glycolysis. PET studies of regional brain glucose utilization positron-emitting 18F-2DG demonstrate that brain regions generating seizures have diminished glucose utilization during interictal conditions, but rapidly transition to markedly increased glucose delivery and utilization during seizures, particularly in status epilepticus (SE). 2-deoxy-D-glucose has acute antiseizure actions in multiple in vivo and in vitro seizure models, including models of SE induced by the chemo convulsants pilocarpine and kainic acid, suggesting that focal enhanced delivery of 2DG to ictal brain circuits is a potential novel anticonvulsant intervention for the treatment of SE.
Summary
This document was developed by the members of the Committee to Revise the Guidelines for Services, Personnel, and Facilities at Specialized Epilepsy Centers. After discussions with the ...general membership they were adopted by the Board of the National Association of Epilepsy Centers. The Guidelines will be reviewed and updated when considered necessary by the Board.
Abstract Objective The objective of this study was to describe a priori protocol-defined analyses to evaluate the safety and tolerability of adjunctive oral lacosamide (200–600 mg/day) in adults ...(ages 16–70 years) with partial-onset seizures (POS) using data pooled from three similarly designed randomized, double-blind, placebo-controlled trials (SP667, SP754 NCT00136019, SP755 NCT00220415). Methods Patients with POS (≥ 2 years' duration, ≥ 2 previous antiepileptic drugs AEDs) uncontrolled by a stable dosing regimen of 1–3 concomitant AEDs were randomized to treatment with lacosamide at doses of 200 mg/day, 400 mg/day, or 600 mg/day, or placebo. Studies comprised a 4- to 6-week titration phase to target dose followed by a 12-week maintenance phase. Safety outcomes included treatment-emergent adverse events (TEAEs) of particular relevance to patients with POS, overall TEAEs, and discontinuations due to TEAEs. Post hoc analyses included evaluation of TEAEs potentially related to cognition and TEAEs leading to discontinuation analyzed by concomitant AEDs. Results One thousand three hundred eight patients were randomized to and received treatment; 944 to lacosamide and 364 to placebo. Most patients (84.4%) were taking 2 or 3 concomitant AEDs. The most common drug-associated TEAEs (reported by ≥ 5% of patients in any lacosamide dose group and with an incidence at least twice that reported for placebo during the treatment phase) were dizziness (30.6% for lacosamide vs 8.2% for placebo), nausea (11.4% vs 4.4%), and diplopia (10.5% vs 1.9%). Common drug-associated TEAEs generally appeared to be dose-related, and the incidence of each was lower during the 12-week maintenance phase than during the titration phase. Most TEAEs were either mild or moderate in intensity; severe TEAEs were predominantly observed with lacosamide 600 mg/day. No individual serious TEAE occurred in ≥ 1% of all lacosamide-treated patients. Treatment-emergent adverse events led to discontinuation in 8.1%, 17.2%, and 28.6% of the lacosamide 200-, 400-, and 600-mg/day groups, respectively ( vs 4.9% of placebo). Few TEAEs were related to rash, weight loss/gain, changes in clinical chemistry parameters, or psychiatric disturbances, or were seizure-related. The odds of reporting any potential cognition-related TEAE vs placebo increased with dose and were similar between lacosamide doses of 200 and 400 mg/day and placebo (odds ratio 1.3, 95% confidence interval 0.7–2.4). Discontinuations due to TEAEs based on most commonly used AEDs taken in combination with lacosamide (all doses combined) were carbamazepine (15.3% 51/334 vs 3.9% 5/129 placebo), lamotrigine (19.2% 56/291 vs 4.3% 5/117), and levetiracetam (10.1% 28/278 vs 3.9% 4/103). Conclusions The safety and tolerability profile of adjunctive lacosamide in this detailed evaluation was similar to that observed in the individual double-blind trials. Adjunctive lacosamide was associated with TEAEs related to the nervous system and gastrointestinal tract, predominantly during titration.
S: The natural history of nonconvulsive status epilepticus (NCSE) is not well defined, especially mortality and morbidity. The authors hypothesized that the mortality of NCSE is higher when NCSE is ...due to acute medical causes (systemic or neurologic) or associated with severe impairment of mental status or with acute complications, and lower when associated with generalized spike-wave (SW) discharges on EEG.
The authors retrospectively identified 100 consecutive patients with NCSE from an EEG database. Data were collected from systematic review of medical records and actual EEG tracings. Specific etiologies were divided into three groups: acute medical, epilepsy, and cryptogenic.
Of the 100 patients, 18 died. Fourteen of 52 patients in the acute medical group died, 1 of 31 in the epilepsy group died, and 3 of 17 in the cryptogenic group died. Mental status impairment was severe in 33, complications occurred in 39, and generalized SW discharges occurred in 36. Mortality rates were higher in patients 1) in the acute medical group (27%) vs the epilepsy (3%) and the cryptogenic (18%) groups (p < 0.02), 2) with severe mental status impairment (39%) compared to those with mild impairment (7%, p < 0.001), and 3) with acute complications (36%) when compared with those without complications (7%, p < 0.0002). The presence of generalized SW discharges on EEG did not correlate with mortality. Mental status impairment and etiology were independently associated with mortality (p < 0.001).
NCSE is associated with substantial mortality. Mortality is associated with an acute medical cause as the underlying etiology, severe mental status impairment, and development of acute complications, but not the type of EEG discharge.
To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy.
...This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries.
The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001).
Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population.
This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.
Objective
Seizure clusters require prompt medical treatment to minimize possible progression to status epilepticus, increased health care use, and disruptions to daily life. Isolated seizures may ...exhibit cyclical patterns, including circadian and longer rhythms. However, little is known about the cyclical patterns in seizure clusters. This post hoc analysis of data from a long‐term, phase 3, open‐label, repeat‐dose safety study of diazepam nasal spray modeled the periodicity of treated seizure clusters.
Methods
Mixed‐effects cosinor analysis evaluated circadian rhythmicity, and single component cosinors using 12 and 24 h were used to calculate cosinor parameters (e.g., midline statistic of rhythm, wave ampitude, and acrophase peak). Analysis was completed for the full cohort and a consistent cohort of participants with two or more seizure clusters in each of four, 3‐month periods. The influence of epilepsy type on cosinor parameters was also analyzed.
Results
Seizure‐cluster events plotted across 24 h showed a bimodal distribution with acrophases (peaks) at ~06:30 and ~18:30. A 12‐h plot showed a single peak at ~06:30. Cosinor analyses of the full and consistent cohort aligned, with acrophases for both models predicting peak seizure activity at ~23:30 on a 24‐h scale and ~07:30 on a 12‐h scale. The consistent cohort was associated with increases in baseline and peak seizure‐cluster activity. Analysis by epilepsy type identified distinct trends. Seizure clusters in the focal epilepsy group peaked in the evening (acrophase 19:19), whereas events in the generalized epilepsy group peaked in the morning (acrophase 04:46). Together they compose the bimodal clustering observed over 24 h.
Significance
This analysis of seizure clusters treated with diazepam nasal spray demonstrated that seizure clusters occur cyclically in 12‐ and 24‐h time frames similar to that reported with isolated seizures. Further elucidation of these patterns may provide important information for patient care, ranging from improved patient‐centered outcomes to seizure‐cluster prediction.
Summary
Objective
Previous studies reporting circadian patterns of epileptiform activity and seizures are limited by (1) short‐term recording in an epilepsy monitoring unit (EMU) with altered ...antiepileptic drugs (AEDs) and sleep, or (2) subjective seizure diary reports. We studied circadian patterns using long‐term ambulatory intracranial recordings captured by the NeuroPace RNS System.
Methods
Retrospective study of RNS System trial participants with stable detection parameters over a continuous 84‐day period. We analyzed all detections and long device–detected epileptiform events (long episodes) and defined a subset of subjects in whom long episodes represented electrographic seizures (LE‐SZ). Spectrum resampling determined the dominant frequency periodicity and cosinor analysis identified significant circadian peaks in detected activity. Chi‐square analysis was used to compare subjects grouped by region of seizure onset.
Results
In the 134 subjects, detections showed a strongly circadian and uniform pattern irrespective of region of onset that peaked during normal sleep hours. In contrast, long episodes and LE‐SZ patterns varied by region. Neocortical regions had a monophasic, nocturnally dominant rhythm, whereas limbic regions showed a more complex pattern and diurnal peak. Rhythms in some individual limbic subjects were best fit by a dual oscillator (circadian + ultradian) model.
Significance
Epileptiform activity has a strong 24 h periodicity with peak nocturnal occurrence. Limbic and neocortical epilepsy show divergent circadian influences. These findings confirm that circadian patterns of epileptiform activity vary by seizure‐onset zone, with implications for treatment and safety, including SUDEP.
•Detections of long epileptiform events (LEs) were compared to diary seizures.•LEs covary with diary seizures (n = 101, mean r ± SEM = 0.26 ± 0.002, p < 10−18).•LEs were more frequent than diary ...recorded seizures (PPV: 34 %).•Diary recorded seizures were rare on days when there were no LEs (NPV: 90 %).•Chronic ambulatory electrocorticographic data could supplement seizure diaries.
To determine the feasibility of using epileptiform events detected by continuous electrocorticographic monitoring via a brain-responsive neurostimulation system to supplement patient-maintained seizure diaries.
Data were retrospectively analyzed from a randomized controlled trial of brain-responsive neurostimulation (RNS® System) for adjunctive treatment of medically intractable focal onset seizures in 191 subjects. The long-term (≥3 months) correspondence between daily counts of diary-reported seizures and device-recorded “long epileptiform events” (LEs), a proxy for electrographic seizures (ESs), was assessed using cross-correlation and logistic generalized estimating equation models.
Diary-reported seizures and LEs significantly co-varied across days in 124 patients whose detection settings were held constant, with a significantly higher correlation in 54 patients (44 %) whose LEs were usually ESs (high concordance patients). There were more days in which LEs were detected than days in which patients reported a seizure (positive predictive value (PPV): 34 %). On days when there were no LEs, there were typically no diary-reported seizures (negative predictive value (NPV): 90 %). In patients with a high concordance between LEs and ESs, the PPV and NPV were both slightly higher, 43 % (35–52 %) and 93 % (95 % CI: 86–97 %) respectively.
Although LEs can substantially outnumber diary reported seizures, the high across-day correlation and strong NPV between LEs and diary seizures suggests that LEs recorded by the RNS® System could potentially supplement seizure diaries by providing an objective biomarker for relative seizure burden.
Well‐designed placebo‐controlled clinical trials are critical to the development of novel treatments for epilepsy, but their design has not changed for decades. Patients, clinicians, regulators, and ...innovators all have concerns that recruiting for trials is challenging, in part, due to the static design of maintaining participants for long periods on add‐on placebo when there are an increasing number of options for therapy. A traditional trial maintains participants on blinded treatment for a static period (e.g., 12 weeks of maintenance), during which participants on placebo have an elevated risk of sudden unexpected death in epilepsy compared to patients on an active treatment. Time‐to‐event trials observe participants on blinded treatment until a key event occurs (e.g., post‐randomization seizure count matches pre‐randomization monthly seizure count). In this article, we review the evidence for these designs based on re‐analysis of prior trials, one published trial that used a time‐to‐second seizure design, and experience from an ongoing blinded trial. We also discuss remaining concerns regarding time‐to‐event trials. We conclude that, despite potential limitations, time‐to‐event trials are a potential promising mechanism to make trials more patient friendly and reduce placebo exposure, which are urgent needs to improve safety and increase recruitment to trials.
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