Tilman Polster

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 sponsors 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.

Transient lesion in the splenium of the corpus callosum: three further cases in epileptic patients and a pathophysiological hypothesis

OBJECTIVE Focal lesions limited to the splenium of the corpus callosum (SCC) are rare and little is known about their aetiology. Three patients were examined for presurgical evaluation in epilepsy with a transient lesion in the SCC and a pathophysiological hypothesis is presented. METHODS Three patients were identified with a circumscribed lesion in the centre of the corpus callosum. Follow up MRI was performed, the medical records examined retrospectively, and the literature reviewed. RESULTS The patients showed identical lesions in the SCC with reduced T1 and increased T2 signal intensity and an unaffected marginal hemline of a few mm. Patients were asymptomatic and control MRIs showed complete normalisation within 2 months. Patients had been treated with antiepileptic drugs (AEDs) without signs of toxicity. In all patients AEDs were rapidly reduced for diagnostic purposes, but only one had psychomotor seizures, 5 days before imaging. CONCLUSIONS A transient lesion in the SCC has so far only been described in 13 patients with epilepsy and has been interpreted either as reversible demyelination due to AED toxicity or transient oedema after secondary generalised seizures. The data confirm neither of these hypotheses. A transient lesion in the SCC seems to be a non-specific end point of different disease processes leading to a vasogenic oedema. This suggests, in these patients, a multifactorial pathology triggered by transient effects of AEDs on arginine vasopressine and its function in fluid balance systems in a condition of vitamin deficiency. The complete and rapid reversibility in all cases without specific intervention is emphasised and any invasive diagnostic or therapeutic approach is discouraged.

Detection of generalized tonic–clonic seizures by a wireless wrist accelerometer: A prospective, multicenter study

Our objective was to assess the clinical reliability of a wrist‐worn, wireless accelerometer sensor for detecting generalized tonic–clonic seizures (GTCS). Seventy‐three consecutive patients (age 6–68 years; median 37 years) at risk of having GTCS and who were admitted to the long‐term video–electroencephalography (EEG) monitoring unit (LTM) were recruited in three centers. The reference standard was considered the seizure time points identified by experienced clinical neurophysiologists, based on the video‐EEG recordings and blinded to the accelerometer sensor data. Seizure time points detected real‐time by the sensor were compared with the reference standard. Patients were monitored for 17–171 h (mean 66.8; total 4,878). Thirty‐nine GTCS were recorded in 20 patients. The device detected 35 seizures (89.7%). In 16 patients all seizures were detected. In three patients more than two thirds of the seizures were detected. The mean of the sensitivity calculated for each patient was 91%. The mean detection latency measured from the start of the focal seizure preceding the secondarily GTCS was 55 s (95% confidence interval [CI] 38–73 s). The rate of false alarms was 0.2/day. Our results suggest that the wireless wrist accelerometer sensor detects GTCS with high sensitivity and specificity. Patients with GTCS have an increased risk for injuries related to seizures and for sudden unexpected death in epilepsy (SUDEP), and many nocturnal seizures remain undetected in unattended patients. A portable automatic seizure detection device will be an important tool for helping these patients.

Diagnostic methods and treatment options for focal cortical dysplasia.

Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia (FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography (EEG)–functional magnetic resonance imaging (fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high‐frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high‐field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose–positron emission tomography (FDG‐PET) is highly sensitive for detecting FCD in MRI‐negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin (mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet (KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation (VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment‐resistant cases, initial evidence from novel approaches suggests that future success is possible.

Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study

BACKGROUND Postoperative antiepileptic drug (AED) withdrawal practices remain debatable and little is known about the optimum timing. We hypothesised that early AED withdrawal does not affect long-term seizure outcome but allows identification of incomplete surgical success earlier than late withdrawal. We aimed to assess the relation between timing of AED withdrawal and subsequent seizure recurrence and long-term seizure outcome. METHODS TimeToStop included patients aged under 18 years from 15 centres in Europe who underwent surgery between Jan 1, 2000, and Oct 1, 2008, had at least 1 year of postoperative follow-up, and who started AED reduction after having reached postoperative seizure freedom. Time intervals from surgery to start of AED reduction (TTR) and complete discontinuation (TTD) were studied in relation to seizure recurrence during or after AED withdrawal, seizure freedom for at least 1 year, and cure (defined as being seizure free and off AEDs for at least 1 year) at latest follow-up. Cox proportional hazards regression models were adjusted for identified predictors of timing intervals. FINDINGS TimeToStop included 766 children. Median TTR and TTD were 12·5 months (95% CI 11·9-13·2) and 28·8 months (27·4-30·2), respectively. 95 children had seizure recurrence during or after AED withdrawal. Shorter time intervals predicted seizure recurrence (hazard ratio [HR] 0·94, 95% CI 0·89-1·00, p=0·05 for TTR; and 0·90, 0·83-0·98, p=0·02 for TTD). After a mean postoperative follow-up of 61·6 months (SD 29·7), 728 patients were seizure free for at least 1 year. TTR and TTD were not related to regain of seizure freedom after restart of drug treatment (HR 0·98, 95% CI 0·92-1·05, p=0·62; and 0·93, 0·83-1·05, p=0·26, respectively), or to seizure freedom (0·97, 0·89-1·07, p=0·55; and 1·03, 0·93-1·14, p=0·55, respectively) or cure (0·97, 0·97-1·03, p=0·84; and 0·98, 0·94-1·02, p=0·31, respectively) at final follow-up. INTERPRETATION Early AED withdrawal does not affect long-term seizure outcome or cure. It might unmask incomplete surgical success sooner, identifying children who need continuous drug treatment and preventing unnecessary continuation of AEDs in others. A prospective randomised trial is needed to study the possible cognitive effects and confirm the safety of early AED withdrawal after epilepsy surgery in children. FUNDING Dutch National Epilepsy Fund.

Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome

Microcephaly–capillary malformation (MIC-CAP) syndrome is characterized by severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We used whole-exome sequencing of five patients with MIC-CAP syndrome and identified recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM) that has a key role in cell surface receptor–mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is notable considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP syndrome.

Vagus nerve stimulation: Outcome and predictors of seizure freedom in long-term follow-up

OBJECTIVES To present long-term outcome and to identify predictors of seizure freedom after vagus nerve stimulation (VNS). METHODS All patients who had undergone VNS implantation in the Epilepsy Centre Bethel were retrospectively reviewed. There were 144 patients who had undergone complete presurgical evaluation, including detailed clinical history, magnetic resonance imaging, and long-term video-EEG with ictal and interictal recordings. After implantation, all patients were examined at regular intervals of 4 weeks for 6-9 months. During this period the antiepileptic medication remained constant. All patients included in this study were followed up for a minimum of 2 years. RESULT Ten patients remained seizure-free for more than 1 year after VNS implantation (6.9%). Seizures improved in 89 patients (61.8%) but no changes were observed in 45 patients (31.3%). The following factors were significant in the univariate analysis: age at implantation, multifocal interictal epileptiform discharges, unilateral interictal epileptiform discharge, cortical dysgenesis, and psychomotor seizure. Stepwise multivariate analysis showed that unilateral interictal epileptiform discharges (IEDs), P=0.014, HR=0.112 (95% CIs, 0.019-0.642), cortical dysgenesis P=0.007, HR=0.065 (95% CIs, 0.009-0.481) and younger age at implantation P=0.026, HR=7.533 (95% CIs 1.28-44.50) were independent predictors of seizure freedom in the long-term follow-up. CONCLUSION VNS implantation may render patients with some forms of cortical dysgenesis (parietooccipital polymicrogyria, macrogyria) seizure-free. Patients with unilateral IEDs and earlier implantation achieved the most benefit from VNS.

Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery.

Antiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long‐term seizure outcomes. We now aimed to evaluate the effect of AED withdrawal on postoperative intelligence quotient (IQ), and change in IQ (delta IQ) following pediatric epilepsy surgery.

Trends in epilepsy surgery: stable surgical numbers despite increasing presurgical volumes

Introduction Despite the success of epilepsy surgery, recent reports suggest a decline in surgical numbers. We tested these trends in our cohort to elucidate potential reasons. Patients and methods Presurgical, surgical and postsurgical data of all patients undergoing presurgical evaluation in between 1990 and 2013 were retrospectively analysed. Patients were grouped according to the underlying pathology. Results A total of 3060 patients were presurgically studied, and resective surgery was performed in 66.8% (n=2044) of them: medial temporal sclerosis (MTS): n=675, 33.0%; benign tumour (BT): n=408, 20.0%; and focal cortical dysplasia (FCD): n=284, 13.9%. Of these, 1929 patients (94.4%) had a follow-up of 2 years, and 50.8% were completely seizure free (Engel IA). Seizure freedom rate slightly improved over time. Presurgical evaluations continuously increased, whereas surgical interventions did not. Numbers for MTS, BT and temporal lobe resections decreased since 2009. The number of non-lesional patients and the need for intracranial recordings increased. More evaluated patients did not undergo surgery (more than 50% in 2010–2013) because patients were not suitable (mainly due to missing hypothesis: 4.5% in 1990–1993 up to 21.1% in 2010–2013, total 13.4%) or declined from surgery (maximum 21.0% in 2010–2013, total 10.9%). One potential reason may be that increasingly detailed information on chances and risks were given over time. Conclusions The increasing volume of the presurgical programme largely compensates for decreasing numbers of surgically remediable syndromes and a growing rate of informed choice against epilepsy surgery. Although comprehensive diagnostic evaluation is offered to a larger group of epilepsy patients, surgical numbers remain stable.

Revised version of quality guidelines for presurgical epilepsy evaluation and surgical epilepsy therapy issued by the Austrian, German, and Swiss working group on presurgical epilepsy diagnosis and operative epilepsy treatment

The definition of minimal standards remains pivotal as a basis for a high standard of care and as a basis for staff allocation or reimbursement. Only limited publications are available regarding the required staffing or methodologic expertise in epilepsy centers. The executive board of the working group (WG) on presurgical epilepsy diagnosis and operative epilepsy treatment published the first guidelines in 2000 for Austria, Germany, and Switzerland. In 2014, revised guidelines were published and the WG decided to publish an unaltered English translation in this report. Because epilepsy surgery is an elective procedure, quality standards are particularly high. As detailed in the first edition of these guidelines, quality control relates to seven different domains: (1) establishing centers with a sufficient number of sufficiently and specifically trained personnel, (2) minimum technical standards and equipment, (3) continuous medical education of employees, (4) surveillance by trained personnel during video electroencephalography (EEG) monitoring (VEM), (5) systematic acquisition of clinical and outcome data, (6) the minimum number of preoperative evaluations and epilepsy surgery procedures, and (7) the cooperation of epilepsy centers. These standards required the certification of the different professions involved and minimum numbers of procedures. In the subsequent decade, quite a number of colleagues were certified by the trinational WG; therefore, the executive board of the WG decided in 2013 to make these standards obligatory. This revised version is particularly relevant given that the German procedure classification explicitly refers to the guidelines of the WG with regard to noninvasive/invasive preoperative video‐EEG monitoring and invasive intraoperative diagnostics in epilepsy.