Antiseizure Medication Withdrawal in Seizure-Free Patients: Practice Advisory Update Summary: Report of the AAN Guideline Subcommittee.

OBJECTIVE: To update a 1996 American Academy of Neurology practice parameter. METHODS: The authors systematically reviewed literature published from January 1991 to March 2020. RESULTS: The long-term (24-60 months) risk of seizure recurrence is possibly higher among adults who have been seizure-free for 2 years and taper antiseizure medications (ASMs) vs those who do not taper ASMs (15% vs 7% per the 1 Class I article addressing this issue). In pediatric patients, there is probably no significant difference in seizure recurrence between those who begin tapering ASMs after 2 years vs 4 years of seizure freedom, and there is insufficient evidence of significant difference in risk of seizure recurrence between those who taper ASMs after 18 months of seizure freedom and those tapering after 24 months. There is insufficient evidence that the rate of seizure recurrence with ASM withdrawal following epilepsy surgery after 1 year of seizure freedom vs after 4 years is not significantly different than maintaining patients on ASMs. An epileptiform EEG in pediatric patients increases the risk of seizure recurrence. ASM withdrawal possibly does not increase the risk of status epilepticus in adults. In seizure-free adults, ASM weaning possibly does not change quality of life. Withdrawal of ASMs at 25% every 10 days to 2 weeks is probably not significantly different from withdrawal at 25% every 2 months in children who are seizure-free in more than 4 years of follow-up. RECOMMENDATIONS: Fourteen recommendations were developed.

Adjunctive everolimus therapy for tuberous sclerosis complex-associated refractory seizures: Results from the postextension phase of EXIST-3.

OBJECTIVE: Epilepsy is highly prevalent in patients with tuberous sclerosis complex (TSC). Everolimus showed higher efficacy than placebo for seizures in the primary analysis of the EXIST-3 study. Here, we present the long-term outcomes of everolimus at the end of the postextension phase (PEP; data cutoff date: October 25, 2017). METHODS: After completion of the extension phase, patients were invited to continue everolimus in the PEP with everolimus (targeted trough concentration = 5-15 ng/ml, investigator-judged). Efficacy assessments included changes in seizure status during the PEP collected at 12-week intervals as parent/caregiver-reported data through a structured questionnaire. RESULTS: Among 361 patients, 343 entered the extension phase and 249 entered the PEP. After 12 weeks in the PEP, 18.9% (46/244) of patients were seizure-free since the last visit of the extension phase and 64.8% (158/244) had a stable/improved seizure status. At 24 weeks, the corresponding percentages were 18.2% (42/231) and 64.5% (149/231). Among 244 patients, the response rate was 32.8% (80/244) during the 12-week maintenance period of the core phase and 63.9% (156/244) at the end of the extension phase. Of the 149 responders at the end of the extension phase, 70.5% were seizure-free or had stable/improved seizure status. Long-term efficacy data showed persistent responses were observed in 183 of 361 patients (50.7%); 63.9% of these patients had a response that lasted at least 48 weeks. The most frequent Grade 3-4 adverse events (≥2% incidence) reported throughout the study were pneumonia, status epilepticus, seizure, stomatitis, neutropenia, and gastroenteritis. Four patients died during the study. SIGNIFICANCE: The final analysis of EXIST-3 demonstrated the sustained efficacy of everolimus as adjunctive therapy in patients with TSC-associated treatment-refractory seizures, with a tolerable safety profile.

Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial.

BACKGROUND: Epilepsy occurs in 70-90% of patients with tuberous sclerosis complex. We aimed to assess the efficacy and safety of adjunctive everolimus for treatment-refractory seizures associated with tuberous sclerosis complex in paediatric patients enrolled in the EXIST-3 trial, a double-blind, placebo-controlled, randomised, phase 3 study. METHODS: This post-hoc analysis focused on paediatric patients (age <18 years) in the EXIST-3 trial, which consisted of baseline (8 weeks), core (18 weeks), and extension phases (≥48 weeks) and was done at 99 centres in 25 countries worldwide. Briefly, patients with tuberous sclerosis complex-associated treatment-refractory seizures, who were receiving a stable dose of one to three antiepileptic drugs, were randomly assigned (1:1:1) to receive placebo, low-exposure everolimus (3-7 ng/mL), or high-exposure everolimus (9-15 ng/mL). Following the core phase, patients could enter the extension phase to receive everolimus at a targeted exposure range of 3-15 ng/mL up to 48 weeks after the last patient had completed the core phase. Efficacy endpoints were response rate (≥50% of reduction from baseline in average weekly seizure frequency) and median percentage reduction in seizure frequency during the 12-week maintenance period of the core phase, and at 12-week intervals throughout the extension phase. This study is registered with ClinicalTrials.gov, number NCT01713946. FINDINGS: Between July 3, 2013, and May 29, 2015, 299 paediatric patients enrolled in the trial. In the younger subgroup (<6 years; n=104), 34 received placebo, 33 low-exposure everolimus, and 37 high-exposure everolimus; in the older subgroup (≥6 years to <18 years; n=195), 62 received placebo, 63 low-exposure everolimus, and 70 high-exposure everolimus. At the end of the core phase, response rate was higher in the treatment groups than placebo in both the younger subgroup (17·6% [6·8-34·5] for placebo vs 30·3% [95% CI 15·6-48·7; p=0·2245] for low-exposure everolimus vs 59·5% [42·1-75·2; p=0·0003] for high-exposure everolimus) and the older subgroup (12·9% [5·7-23·9] vs 27·0% [16·6-39·7; p=0·0491] vs 30·0% [19·6-42·1; p=0·0179]), as were median reduction in seizure frequency (12·3% [95% CI -10·1 to 24·8] vs 29·3% [95% CI 13·4 to 46·3; p=0·0474] vs 54·7% [43·5 to 73·1; p<0·0001] in younger patients; 13·5% [-3·0 to 26·8] vs 31·0% [16·1 to 42·9; p=0·0128] vs 34·8% [26·7 to 41·3; p=0·0006] in older patients). The efficacy persisted, with sustained seizure reduction after 1 year of treatment across both paediatric subgroups (response rate 48·9% [95% CI 38·1-59·8] for the younger subgroup vs 47·2% [39·3-55·2] for the older subgroup; median percentage reduction in seizure frequency 48·4% [95% CI 34·3-73·6] vs 48·0% [38·2-57·5]). At the cutoff date for the extension phase, grade 3 or 4 adverse events were reported in 45 (45%) younger patients (commonly pneumonia [n=16]) and 74 (38%) older patients (commonly pneumonia [n=8] and stomatitis [n=6]). Two deaths (pneumonia, which was suspected to be treatment-related, and sudden unexplained death due to epilepsy) were reported. INTERPRETATION: Adjunctive everolimus resulted in sustained reductions in seizure frequency after 1 year and was well tolerated in paediatric patients with treatment-refractory seizures associated with tuberous sclerosis complex. FUNDING: Novartis Pharmaceuticals Corporation.

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study.

BACKGROUND: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and safety of two trough exposure concentrations of everolimus, 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, eligible patients aged 2-65 years with tuberous sclerosis complex and treatment-resistant seizures (≥16 in an 8-week baseline phase) receiving one to three concomitant antiepileptic drugs were recruited from 99 centres across 25 countries. Participants were randomly assigned (1:1:1), via permuted-block randomisation (block size of six) implemented by Interactive Response Technology software, to receive placebo, low-exposure everolimus, or high-exposure everolimus. Randomisation was stratified by age subgroup (<6 years, 6 to <12 years, 12 to <18 years, and ≥18 years). Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation. The starting dose of everolimus depended on age, body-surface area, and concomitant use of cytochrome 3A4/P-glycoprotein inducers. Dose adjustments were done to attain target trough ranges during a 6-week titration period, and as needed during a 12-week maintenance period of core phase. Patients or their caregivers recorded events in a seizure diary throughout the study. The primary endpoint was change from baseline in the frequency of seizures during the maintenance period, defined as response rate (the proportion of patients achieving ≥50% reduction in seizure frequency) and median percentage reduction in seizure frequency, in all randomised patients. This study is registered with ClinicalTrials.gov, number NCT01713946. FINDINGS: Between July 3, 2013, and May 29, 2015, 366 patients were enrolled and randomly assigned to placebo (n=119), low-exposure everolimus, (n=117), or high-exposure everolimus (n=130). The response rate was 15·1% with placebo (95% CI 9·2-22·8; 18 patients) compared with 28·2% for low-exposure everolimus (95% CI 20·3-37·3; 33 patients; p=0·0077) and 40·0% for high-exposure everolimus (95% CI 31·5-49·0; 52 patients; p<0·0001). The median percentage reduction in seizure frequency was 14·9% (95% CI 0·1-21·7) with placebo versus 29·3% with low-exposure everolimus (95% CI 18·8-41·9; p=0·0028) and 39·6% with high-exposure everolimus (95% CI 35·0-48·7; p<0·0001). Grade 3 or 4 adverse events occurred in 13 (11%) patients in the placebo group, 21 (18%) in the low-exposure group, and 31 (24%) in the high-exposure group. Serious adverse events were reported in three (3%) patients who received placebo, 16 (14%) who received low-exposure everolimus, and 18 (14%) who received high-exposure everolimus. Adverse events led to treatment discontinuation in two (2%) patients in the placebo group versus six (5%) in the low-exposure group and four (3%) in the high-exposure group. INTERPRETATION: Adjunctive everolimus treatment significantly reduced seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex and treatment-resistant seizures. FUNDING: Novartis Pharmaceuticals Corporation.

Subclinical seizures identified by postoperative electroencephalographic monitoring are common after neonatal cardiac surgery.

OBJECTIVES: The American Clinical Neurophysiology Society recommends continuous electroencephalographic monitoring after neonatal cardiac surgery because seizures are common, often subclinical, and associated with worse neurocognitive outcomes. We performed a quality improvement project to monitor for postoperative seizures in neonates with congenital heart disease after surgery with cardiopulmonary bypass. METHODS: We implemented routine continuous electroencephalographic monitoring and reviewed the results for an 18-month period. Clinical data were collected by chart review, and continuous electroencephalographic tracings were interpreted using standardized American Clinical Neurophysiology Society terminology. Electrographic seizures were classified as electroencephalogram-only or electroclinical seizures. Multiple logistic regression was used to assess associations between seizures and potential clinical and electroencephalogram predictors. RESULTS: A total of 161 of 172 eligible neonates (94%) underwent continuous electroencephalographic monitoring. Electrographic seizures occurred in 13 neonates (8%) beginning at a median of 20 hours after return to the intensive care unit after surgery. Neonates with all types of congenital heart disease had seizures. Seizures were electroencephalogram only in 11 neonates (85%). Status epilepticus occurred in 8 neonates (62%). In separate multivariate models, delayed sternal closure or longer deep hypothermic circulatory arrest duration was associated with an increased risk for seizures. Mortality was higher among neonates with than without seizures (38% vs 3%, P < .001). CONCLUSIONS: Continuous electroencephalographic monitoring identified seizures in 8% of neonates after cardiac surgery with cardiopulmonary bypass. The majority of seizures had no clinical correlate and would not have been otherwise identified. Seizure occurrence is a marker of greater illness severity and increased mortality. Further study is needed to determine whether seizure identification and management lead to improved outcomes.

Brain tumor presenting as somnambulism in an adolescent.

BACKGROUND: Sleepwalking is typically a benign and self-limited non-rapid eye movement parasomnia of childhood. PATIENT: We describe an unusual 15-year-old boy referred to our sleep center for new-onset sleepwalking. RESULTS: An overnight polysomnogram was normal from a respiratory standpoint, but a concurrent extended electroencephalogram montage showed frequent epileptiform discharges from the right parietal-temporal region and two electroclinical seizures arising from the right-frontal-central-temporal region during sleep. Magnetic resonance imaging scan revealed a right parasagittal parietal region lesion consistent with a low-grade neoplasm, and surgical resection of the lesion demonstrated a right parietal dysembryoplastic neuroepithelial tumor. Complex partial seizures and sleepwalking remitted completely with anticonvulsant therapy following surgery. CONCLUSIONS: This patient highlights the differential diagnosis of nocturnal events appearing to be typical parasomnias, especially when they arise abruptly at an older age.

Common data elements in epilepsy research: development and implementation of the NINDS epilepsy CDE project.

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.

Focal seizure propagation in the intracranial EEG.

INTRODUCTION: intracranial EEG offers a unique opportunity to study epileptic seizures in humans. Seizure propagation has not been extensively studied. We aimed to compare the propagation of focal seizures with onset in different brain regions. METHODS: seven zones were defined as medial frontal (MF), dorsolateral frontal (DLF), orbitofrontal (OF), medial temporal (MF), lateral temporal (LT), parietal (P) and occipital (O). Routes and times of ipsilateral (IPT) and contralateral (CPT) propagation as well as ictal frequency in onset zone and propagation zone were compared. RESULTS: forty patients had 112 seizures. (Mean and median number of seizures per zone was 16 and 15). Preferred routes of propagation, based on ictal onset, were: MF to contralateral MF; DLF to ispilateral temporal lobe; OF to contralateral OF and ispilateral temporal lobe; MT to contralateral MT; LT to ispilateral MT and OF and contralateral LT and MT; P to ispilateral temporal lobe, DLF and O; O to ipsilateral MT. IPT and CPT varied markedly between zones. Ictal onset frequency was faster than propagated frequency. CONCLUSION: seizure propagation varies according to onset zone possibly following major pathways. This needs confirmation. The findings could aid in the interpretation of symptoms and EEG and may result useful for future treatment using brain stimulation or disconnective surgery. The limitations are clearly stated.

Intravenous levetiracetam terminates refractory focal status epilepticus.

DISCUSSION: We report a 23-year-old with complex partial status epilepticus, possibly related to underlying stroke-like migraine attacks after radiation therapy syndrome, that was refractory to benzodiazepines and phenytoin but was terminated by administration of intravenous levetiracetam.

Anticonvulsant medications in the pediatric emergency room and intensive care unit.

Seizures are common in pediatric emergency care units, either as the main medical issue or in association with an additional neurological problem. Rapid treatment prolonged and repetitive seizures or status epilepticus is important. Multiple anti-convulsant medications are useful in this setting, and each has various indications and potential adverse effects that must be considered in regard to individual patients. This review discusses new data regarding anticonvulsants that are useful in these settings, including fosphenytoin, valproic acid, levetiracetam, and topiramate. A status epilepticus treatment algorithm is suggested, incorporating changes from traditional algorithms based on these new data. Treatment issues specific to complex medical patients, including patients with brain tumors, renal dysfunction, hepatic dysfunction, transplant, congenital heart disease, and anticoagulation, are also discussed.

Novel de novo mutation of a conserved SCN1A amino-acid residue (R1596).

We report on the case of a 6-year-old boy with epilepsy involving febrile seizures and unprovoked generalized tonic clonic seizures. Genetic testing revealed a novel de novo mutation in the SCN1A gene (C>T 4786, R1596C). The epilepsy phenotype is within the spectrum of generalized epilepsy with febrile seizures plus. However, de novo mutations are more commonly reported in cases of severe myoclonic epilepsy of infancy, and are less often reported in generalized epilepsy with febrile seizures plus. The clinical utility of specific genetic testing in this case is discussed, as are criteria for determining the pathologic significance of novel DNA variants. In this case, the wild type of residue (R1596) is well-conserved across evolution from bacteria to humans, providing support for the hypothesis that this mutation causes epilepsy.