Technical note: preliminary surgical experience with a new implantable epicranial stimulation device for chronic focal cortex stimulation in drug-resistant epilepsy.

PURPOSE: This study is to report some preliminary surgical considerations and outcomes after the first implantations of a new and commercially available implantable epicranial stimulation device for focal epilepsy. METHODS: We retrospectively analyzed data from clinical notes. Outcome parameters were as follows: wound healing, surgery time, and adverse events. RESULTS: Five patients were included (17-52 y/o; 3 female). Epicranial systems were uneventfully implanted under neuronavigation guidance. Some minor adverse events occurred. Wound healing in primary intention was seen in all patients. Out of these surgeries, certain concepts were developed: Skin incisions had to be significantly larger than expected. S-shaped incisions appeared to be a good choice in typical locations behind the hairline. Preoperative discussions between neurologist and neurosurgeon are mandatory in order to allow for the optimal coverage of the epileptogenic zone with the electrode geometry. CONCLUSION: In this first small series, we were able to show safe implantation of this new epicranial stimulation device. The use of neuronavigation is strongly recommended. The procedure is simple but not trivial and ideally belongs in the hands of a neurosurgeon.

Failure to use new breakthrough treatments for epilepsy.

Despite the approval of ~20 additional antiseizure medications (ASMs) since the 1980s, one-third of epilepsy patients experience seizures despite therapy. Drug-resistant epilepsy (DRE) is associated with cognitive and psychiatric comorbidities, socioeconomic impairment, injuries, and a 9.3-13.4 times higher mortality rate than in seizure-free patients. Improved seizure control can reduce morbidity and mortality. Two new ASMs were launched in the United States in 2020: cenobamate for focal epilepsy in adults and fenfluramine for Dravet syndrome (DS). They offer markedly improved efficacy. Cenobamate achieved 21% seizure freedom with the highest dose and decreased tonic-clonic seizures by 93% during maintenance treatment in a randomized clinical trial (RCT). In long-term, open-label studies, 10%-36% of patients were seizure-free for a median duration of ~30-45 months. Fenfluramine treatment in DS reduced convulsive seizure frequency by 56% over placebo at the highest dose, with 8% of patients free of convulsive seizures, and 25% with only one convulsive seizure over 14 weeks. These results were sustained for up to 3 years in open-label extension studies. Mortality was reduced 5-fold. These results are superior to all other approved ASMs, placing these two drugs among the most effective antiseizure therapies. The adverse event profiles resemble those of other ASMs. Despite greater efficacy and similar toxicity, these medications are infrequently used. Two years after US market entry, < 5% of either adults with focal DRE or patients with DS were treated with either cenobamate or fenfluramine. We believe this is a failure of our medical system, resulting from limited knowledge about these drugs stemming partly from the separation of academia from industry; restrictions to access created by health care payors, hospitals, and regulatory agencies; and insufficient post-launch information about the efficacy and safety of these ASMs.

Long-term individual retention with cenobamate in adults with focal seizures: Pooled data from the clinical development program.

OBJECTIVE: We determined retention on open-label cenobamate therapy in the clinical development program to assess the long-term efficacy and tolerability of adjunctive cenobamate in individuals with uncontrolled focal seizures. METHODS: Data from two randomized, controlled cenobamate studies and one open-label safety and pharmacokinetic study were pooled. Based on the percentage of participants remaining on treatment, retention rates were estimated using Kaplan-Meier survival analyses. We performed two additional analyses to assess factors contributing to retention, stratifying a robust data set (through 2 years) by cenobamate modal dose and frequently used concomitant anti-seizure medications. Cenobamate discontinuations and treatment-emergent adverse events were summarized. RESULTS: Data from 1844 participants were pooled: 149 from a single-dose randomized trial, 355 from a multi-dose randomized trial, and 1340 from an open-label safety and pharmacokinetic study. Most participants from randomized trials continued in open-label extensions, and pooled data represent >95% of participants exposed to cenobamate. Baseline characteristics and disease and treatment histories were similar across studies. Median duration of cenobamate exposure was 34 months, with a median modal dose of 200 mg/day. Kaplan-Meier estimates of cumulative cenobamate retention rates were 80% at 1 year and 72% at 2 years. Once participants reached the maintenance phase, retention rates were consistently high in participants receiving ≥100 mg/day cenobamate, and concomitant anti-seizure medications did not affect long-term retention. By 2 years, 535 (29%) had actually discontinued cenobamate; the most common reasons for discontinuation were adverse events (37.6%), withdrawal of consent (21.1%), and other (16.8%). SIGNIFICANCE: Treatment retention rates provide a proxy measure for long-term efficacy, safety, tolerability, and adherence. The consistently high retention rates we found suggest that cenobamate may be an effective and well-tolerated new treatment option for people with drug-resistant focal seizures.

Onset of efficacy and adverse events during Cenobamate titration period.

OBJECTIVES: Cenobamate is an antiseizure medication (ASM) approved in Europe as adjunctive therapy for adults with inadequately controlled focal seizures. This post hoc analysis reports onset of efficacy and characterizes time to onset, duration, and severity of the most common treatment-emergent adverse events (TEAEs) during cenobamate titration. MATERIALS & METHODS: Adult patients with uncontrolled focal seizures taking 1 to 3 concomitant ASMs were randomized to receive adjunctive cenobamate or placebo (double-blind studies C013 and C017) or cenobamate (open-label study C021). Outcome assessments included efficacy (median percentage change in seizure frequency and onset [studies C013 and C017]) and safety (onset, duration, and severity of TEAEs [all studies]). RESULTS: Onset of efficacy was observed by Weeks 1 to 4 of titration in studies C013 and C017 which used a faster titration schedule than study CO21. In study C013, the median percentage seizure frequency reduction was 36.7% in patients receiving cenobamate versus 16.3% in those taking placebo (p = .002); in study C017, significant differences in seizure frequency emerged in Week 1 and continued throughout titration between all cenobamate groups and placebo (p < .001). The most commonly reported TEAEs were somnolence, dizziness, fatigue, and headache, with first onset of each reported as early as Week 1; however, the majority resolved. CONCLUSIONS: Reductions in seizure frequency occurred during titration with initial efficacy observed prior to reaching the target dose. These reductions were regarded as clinically meaningful because they may indicate early efficacy at lower doses than previously expected and had a considerable impact on patient quality of life. Long-term treatment with adjunctive cenobamate was generally safe and well-tolerated.

Everolimus in adult tuberous sclerosis complex patients with epilepsy: Too late for success? A retrospective study.

OBJECTIVE: There is evidence that everolimus (EVE) significantly reduces seizure frequency in epilepsy patients with tuberous sclerosis complex (TSC). Given that TSC-related proliferative processes are more dynamic during brain development, seizure outcomes of patients treated with EVE may be age-related and may be less convincing in adult patients. The aim of this study was to assess the effectiveness and the safety profile of EVE in adults in clinical practice. METHODS: We performed a multicenter retrospective chart review of TSC subjects with active epilepsy who started EVE in adulthood (≥18 years of age) at seven German epilepsy centers. The primary endpoint was the retention rate after 6 months. RESULTS: A total of 45 subjects with a mean age of 31.6 ± 11.1 years at EVE start fulfilled the inclusion criteria. Retention rate after 6 months was 98% (43/44 evaluable subjects). Response rate (seizure reduction ≥ 50%) was 33% (14/43 evaluable subjects; four completely seizure-free). We did not find a significant relationship between epilepsy outcome parameters and patient age at EVE start. Adverse events were reported in 19 subjects and were judged to be serious in six patients. Three patients died during the observation period. SIGNIFICANCE: Evidence suggests that EVE is an effective add-on treatment for epilepsy in adult TSC patients, surprisingly without any age limit to individual benefit. A strong age-dependent effect within the period of adulthood seems unlikely. Even if there was no proof of a causal relationship between deaths and EVE intake, patients with EVE should be carefully monitored, especially for infections and stomatitis.

Epilepsy surgery: Late seizure recurrence after initial complete seizure freedom.

OBJECTIVE: This study was undertaken to improve understanding of late relapse following epilepsy surgery in pharmacoresistant epilepsy. METHODS: Retrospective comparison was made of 99 of 1278 patients undergoing surgery during 1999-2015 with seizure relapses after at least 2 years of complete seizure freedom with matched controls experiencing continued long-term seizure freedom. Univariate and multivariate analyses were performed. RESULTS: With a mean follow-up of 9.7 years, mean time to seizure relapse was 56.6 months. In multivariate analysis, incomplete resection based on magnetic resonance imaging (MRI), bilateral lesions on preoperative MRI, and epilepsy onset in the first year of life carried a significantly higher risk of late relapse. In patients with late relapse, additional functional imaging with positron emission tomography had been performed significantly more often. Although the differences were not significant in multivariate analysis, doses of antiepileptic drugs were higher in the relapse group preoperatively and in the first 24 months and complete withdrawal was more frequent in the control group (68% vs. 51%). Regarding seizure frequency, most patients had mild seizure relapse (single relapse seizure or <1/month). SIGNIFICANCE: In our predominantly lesional cohort, complete resection of the MRI lesion is the most important factor to maintain long-term seizure freedom. Two patterns of recurrence were identified: (1) incomplete resected lesions with seizure generation in proximity to the initial resection and (2) epileptogenic networks not detected preoperatively or evolving in the postoperative interval and manifesting with new clinical and diagnostic features.

Status of clinical research in neurology in Germany-A national survey.

BACKGROUND AND PURPOSE: To provide an overview on the status of clinical research in neurology in Germany. METHODS: German university hospitals, nonuniversity hospitals, and neurological medical practices were surveyed regarding their clinical research activities during the period 2013 to 2017. RESULTS: Fifty percent of university hospitals, 10.6% of nonuniversity hospitals, and 5.2% of medical practices in Germany responded to our questionnaire. More than 80% of the clinical studies conducted have been phase III/IV and noninterventional trials (NISs), whereas <1% have been phase I and 3.5% investigator-initiated trials (IITs). University hospitals have conducted most of the phase II-IV trials. NISs have been predominantly performed by medical practices. Fifty-six percent of the university hospitals and less of the nonuniversity institutions confirmed the implementation of standard operating procedures (SOPs). In university hospitals, on average, 11 physicians had acquired a good clinical practice certificate. Overall, 43% of all trials have been performed in neuroimmunology. CONCLUSIONS: The status of clinical research in neurology in Germany is predominated by NISs and late-phase trials, potentially due to a general lack of easily accessible funding, which leads to a highly competitive environment and fewer opportunities to perform early-phase clinical trials as well as IITs. Our results indicate that there is substantial need for structured support for creating and implementing SOPs to maintain quality standards and guarantee uniformity of performance. This survey assessed many aspects of clinical research and serves as guidance for providing ideas for structured improvement of clinical research in neurology in Germany.

Practical guidance for the management of adults receiving adjunctive cenobamate for the treatment of focal epilepsy-expert opinion.

Clinical trial results have demonstrated that adjunctive cenobamate (CNB) substantially decreases seizure frequency in adults with uncontrolled focal onset seizures with an acceptable and well-identified safety profile. This manuscript summarizes an expert panel's recommendations regarding optimized CNB treatment of epilepsies with focal onset seizures. Cenobamate, when slowly titrated to the target maintenance dose, represents an effective new antiseizure medication (ASM) with a comparatively high rate of seizure freedom relative to existing treatment options. This paper reviews selection of suitable CNB treatment candidates, realistic treatment expectations and goals, appropriate CNB target doses, and methods to mitigate or avoid potential adverse events. Cenobamate can be a promising therapeutic choice for adult people with epilepsy with focal onset seizures who do not reach adequate seizure control despite treatment with conventional ASMs.

Behavioral adverse events with brivaracetam, levetiracetam, perampanel, and topiramate: A systematic review.

PURPOSE: To understand the currently available post-marketing real-world evidence of the incidences of and discontinuations due to the BAEs of irritability, anger, and aggression in people with epilepsy (PWE) treated with the anti-seizure medications (ASMs) brivaracetam (BRV), levetiracetam (LEV), perampanel (PER), and topiramate (TPM), as well as behavioral adverse events (BAEs) in PWE switching from LEV to BRV. METHODS: A systematic review of published literature using the Cochrane Library, PubMed/MEDLINE, and Embase was performed to identify retrospective and prospective observational studies reporting the incidence of irritability, anger, or aggression with BRV, LEV, PER, or TPM in PWE. The incidences of these BAEs and the rates of discontinuation due to each were categorized by ASM, and where possible, weighted means were calculated but not statistically assessed. Behavioral and psychiatric adverse events in PWE switching from LEV to BRV were summarized descriptively. RESULTS: A total of 1500 records were identified in the searches. Of these, 44 published articles reporting 42 studies met the study criteria and were included in the data synthesis, 7 studies were identified in the clinical trial database, and 5 studies included PWE switching from LEV to BRV. Studies included a variety of methods, study populations, and definitions of BAEs. While a wide range of results was reported across studies, weighted mean incidences were 5.6% for BRV, 9.9% for LEV, 12.3% for PER, and 3.1% for TPM for irritability; 3.3%* for BRV, 2.5% for LEV, 2.0% for PER, and 0.2%* for TPM for anger; and 2.5% for BRV, 2.6% for LEV, 4.4% for PER, and 0.5%* for TPM for aggression. Weighted mean discontinuation rates were 0.8%* for BRV, 3.4% for LEV, 3.0% for PER, and 2.2% for TPM for irritability and 0.8%* for BRV, 2.4% for LEV, 9.2% for PER, and 1.2%* for TPM for aggression. There were no discontinuations for anger. Switching from LEV to BRV led to improvement in BAEs in 33.3% to 83.0% of patients (weighted mean, 66.6%). *Denotes only 1 study. CONCLUSIONS: This systematic review characterizes the incidences of irritability, anger, and aggression with BRV, LEV, PER, and TPM, and it provides robust real-world evidence demonstrating that switching from LEV to BRV may improve BAEs. While additional data remain valuable due to differences in methodology (which make comparisons difficult), these results improve understanding of the real-world incidences of discontinuations due to these BAEs in clinical practice and can aid in discussions and treatment decision-making with PWE.

[Cenobamate-a new perspective for epilepsy treatment]. / Cenobamat ­ eine neue Perspektive für die Epilepsietherapie.

In spite of the introduction of numerous new antiseizure drugs (ASD) over the last decades, the percentage of drug-resistant epilepsies has remained almost stable. To achieve seizure freedom in such patients with any modified ASD regimen is an exception. Cenobamate (CNB) is a new ASD that showed unusually high efficacy in the pivotal placebo controlled, randomized trials. In both studies (C013 and C017), the rate of seizure-free patients was sometimes more than 20% and thus in a range never reached over the last decades in comparable trials with other new ASDs. This suggests that CNB which is already approved in the USA might actually offer a new and encouraging perspective for epilepsy treatment concerning efficacy. In this review the pharmacological profile, the currently known mode of action, and the results of the clinical trials are summarized.

[SUDEP in brief - knowledge and practice recommendations on sudden unexpected death in epilepsy]. / SUDEP kompakt ­ praxisrelevante Erkenntnisse und Empfehlungen zum plötzlichen, unerwarteten Tod bei Epilepsie.

Sudden unexpected death in epilepsy (SUDEP) is the sudden and unexpected death of an epilepsy patient, which occurs under benign circumstances without evidence of typical causes of death. SUDEP concerns all epilepsy patients. The individual risk depends on the characteristics of the epilepsy and seizures as well as on living conditions. Focal to bilateral and generalized tonic-clonic seizures (TCS), nocturnal seizures and lack of nocturnal supervision increase the risk. Most SUDEP cases are due to a fatal cascade of apnea, hypoxemia and asystole in the aftermath of a TCS. Two thirds of SUDEP cases in unsupervised epilepsy patients with TCS could probably be prevented. Wearables can detect TCS and alert caregivers. SUDEP information is desired by most patients and relatives, has a favorable impact on treatment adherence and behavior and has no negative effects on mood and quality of life.Recommendations of the committee on patient safety of the German Society of Epileptology: the ultimate treatment goal is seizure freedom. If this cannot be achieved, control of TCS should be sought. All epilepsy patients and their relatives should be informed about SUDEP and risk factors. Patients and relatives should be informed about measures to counteract the elevated risk and imminent SUDEP. The counselling should be performed during a face-to-face discussion, at the time of first diagnosis or during follow-up visits. The counselling should be documented. Wearables for TCS detection can be recommended. If TCS persist, therapeutic efforts should be continued. The bereaved should be contacted after a SUDEP.

Desynchronization of temporal lobe theta-band activity during effective anterior thalamus deep brain stimulation in epilepsy.

BACKGROUND: Bilateral cyclic high frequency deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces the seizure count in a subset of patients with epilepsy. Detecting stimulation-induced alterations of pathological brain networks may help to unravel the underlying physiological mechanisms related to effective stimulation delivery and optimize target engagement. METHODS: We acquired 64-channel electroencephalography during ten ANT-DBS cycles (145 â€‹Hz, 90 â€‹µs, 3-5 â€‹V) of 1-min ON followed by 5-min OFF stimulation to detect changes in cortical activity related to seizure reduction. The study included 14 subjects (three responders, four non-responders, and seven healthy controls). Mixed-model ANOVA tests were used to compare differences in cortical activity between subgroups both ON and OFF stimulation, while investigating frequency-specific effects for the seizure onset zones. RESULTS: ANT-DBS had a widespread desynchronization effect on cortical theta and alpha band activity in responders, but not in non-responders. Time domain analysis showed that the stimulation induced reduction in theta-band activity was temporally linked to the stimulation period. Moreover, stimulation induced theta-band desynchronization in the temporal lobe channels correlated significantly with the therapeutic response. Responders to ANT-DBS and healthy-controls had an overall lower level of theta-band activity compared to non-responders. CONCLUSION: This study demonstrated that temporal lobe channel theta-band desynchronization may be a predictive physiological hallmark of therapeutic response to ANT-DBS and may be used to improve the functional precision of this intervention by verifying implantation sites, calibrating stimulation contacts, and possibly identifying treatment responders prior to implantation.

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

High-frequency electrical stimulation of the anterior thalamic nuclei increases vigilance in epilepsy patients during relaxed and drowsy wakefulness.

OBJECTIVE: High-frequency deep brain stimulation (DBS) of anterior thalamic nuclei (ANT) reduces the frequency and intensity of focal and focal to bilateral tonic-clonic epileptic seizures. We investigated the impact of high-frequency ANT-DBS on vigilance in epilepsy patients during relaxed and drowsy wakefulness, to better understand the effects and the mechanisms of action of this intervention in humans. METHODS: Four patients with different structural epileptic pathologies were included in this retrospective case-cohort study. Short- and long-term electroencephalography (EEG) was used to determine states of relaxed or drowsy wakefulness and the vigilance changes during stimulation-on and stimulation-off intervals. RESULTS: In relaxed, wakeful patients with eyes closed, the eyelid artifact rate increased acutely and reproducibly during stimulation-on intervals, suggesting an enhanced vigilance. This effect was accompanied by a slight acceleration of the alpha rhythm. In drowsy patients with eyes closed, stimulation generated acutely and reproducibly alpha rhythms, similar to the paradoxical alpha activation during eyes opening. The occurrence of the alpha rhythms reflected an increase in the vigilance of the drowsy subjects during ANT-DBS. SIGNIFICANCE: This is the first demonstration that ANT-DBS increases the vigilance of wakeful epilepsy patients. Our results deliver circumstantial evidence that high-frequency ANT-DBS activates thalamocortical connections that promote wakefulness.

Efficacy and safety of adjunctive perampanel 4 mg/d for the treatment of focal seizures: A pooled post hoc analysis of four randomized, double-blind, phase III studies.

OBJECTIVE: This post hoc analysis evaluated the efficacy and safety of adjunctive perampanel 4 mg/d received as modal dose, which may have differed from randomized dose, for treatment of focal seizures. METHODS: Data were pooled from four randomized, double-blind, placebo-controlled, phase III studies of adjunctive perampanel in patients (aged ≥12 years) with focal seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures: studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), and 335 (NCT01618695). Efficacy assessments included median percentage reductions in seizure frequency per 28 days and seizure-freedom rates for patients receiving placebo and perampanel 4 mg/d (modal dose). Treatment-emergent adverse events (TEAEs) were assessed in patients receiving perampanel 4 mg/d at their TEAE onset. Outcomes were also assessed with/without enzyme-inducing antiseizure medications (EIASMs). RESULTS: The full analysis set included 979 patients with focal seizures (placebo: n = 616 [235 with FBTC seizures]; perampanel 4 mg/d: n = 363 [134 with FBTC seizures]). Compared with placebo, perampanel 4 mg/d conferred significantly greater median percentage reductions in seizure frequency per 28 days for focal (12.6% vs 21.1%; P = .0004) and FBTC seizures (17.4% vs 49.8%; P < .0001), and seizure-freedom rates for focal (0.8% vs 3.6%; P = .0018) and FBTC seizures (11.1% vs 18.7%; P = .0424). Seizure improvements with perampanel 4 mg/d were greater without EIASMs than with EIASMs. For assessment of TEAEs, overall 1376 patients with focal seizures received perampanel 4 mg/d at any time (FBTC seizures, n = 499). TEAEs with perampanel 4 mg/d occurred in 419 of 1376 (30.5%) and 148 of 499 (29.7%) patients with focal and FBTC seizures, respectively; most common was dizziness. The proportion of TEAEs was similar with or without EIASMs. SIGNIFICANCE: This post hoc analysis showed adjunctive perampanel 4 mg/d was efficacious and well tolerated in patients with focal seizures, with or without FBTC seizures. This dose may be a valuable treatment option in patients unable to tolerate higher perampanel doses up to 12 mg/d.

Visual illustration supporting patient-physician communication in epilepsy: A validation and reliability study of seizure images.

Seizure manifestations may be difficult to describe in words alone. Thus, initially, 24 seizure images were developed to support communication and gain assistance during obtaining the patient's history. Before being used in clinical practice, these seizure images must be investigated for validity and reliability. We tested the images with untrained participants including patients with epilepsy, persons who had witnessed seizures, and participants who had neither had nor witnessed epileptic seizures. The participants filled in a questionnaire evaluating the images twice within 3 days. The participants were asked to choose one of the 2 written descriptions that best matched each seizure image. The validity was assessed using one-proportion z-test. The reliability was assessed by Gwet's AC1. The first analysis showed that the proportion of correctly identified seizure images was higher than 70%, except for 2 images representing dystonia and myoclonus. The dystonia image was modified, and the myoclonus image was removed. In the final evaluation, the seizure images were identified with an overall correctness ratio of 96%. The final AC1 of the seizure images was classified as very high. The final 23 seizure images are proved to be valid and have a high agreement that can be used in clinical practice.

Critique of the 2017 epileptic seizure and epilepsy classifications.

This article critiques the International League Against Epilepsy (ILAE) 2015-2017 classifications of epilepsy, epileptic seizures, and status epilepticus. It points out the following shortcomings of the ILAE classifications: (1) they mix semiological terms with epileptogenic zone terminology; (2) simple and widely accepted terminology has been replaced by complex terminology containing less information; (3) seizure evolution cannot be described in any detail; (4) in the four-level epilepsy classification, level two (epilepsy category) overlaps almost 100% with diagnostic level one (seizure type); and (5) the design of different classifications with distinct frameworks for newborns, adults, and patients in status epilepticus is confusing. The authors stress the importance of validating the new ILAE classifications and feel that the decision of Epilepsia to accept only manuscripts that use the ILAE classifications is premature and regrettable.

Is there a place for surgical treatment of nonpharmacoresistant epilepsy?

Epilepsy surgery has been shown to be the best possible treatment in well-defined and difficult-to-treat epilepsy syndromes, such as mesial temporal lobe epilepsy with unilateral hippocampal sclerosis, even early in the course of the disease if pharmacoresistance is proven. This review addresses the question if epilepsy surgery may be justified today even in nonpharmacoresistant cases. There are two possible groups of patients: first, there are epilepsy syndromes with a benign spontaneous course or with a potentially good treatment prognosis under appropriate antiepileptic drug (AED) treatment. Second, there are epilepsies with potentially worse AED treatment prognosis in which appropriate AED treatment has not yet been applied because of the short course of the disease, tolerability problems that prevented usually effective dosing, or adherence issues. In group one, the good spontaneous prognosis or the usually satisfying course under AED treatment in line with the commonly generalized underlying epileptogenesis does not suggest that epilepsy surgery is a realistic alternative, not even in cases with distinct focal clinical and/or electroencephalography (EEG) patterns like in Rolandic epilepsy with centrotemporal spikes. In the second group, the recent International League Against Epilepsy (ILAE) definition should allow assessment of individual pharmacoresistance early after the onset of the disease in order to avoid any delay. Concerns about a potential disease-specific or drug-specific cognitive decline that could be avoided in early surgery are speculative, a matter of controversial discussion, and certainly not relevant, if pharmacoresistance is consequently addressed in time according to the ILAE recommendations. One should also not forget that even in typically pharmacoresistant epilepsy syndromes that are suitable for surgical procedures, satisfying courses do exist that would not require early or any epilepsy surgery. Therefore, in almost any instance, epilepsy surgery as initial treatment or immediately after a first AED is still not recommended although, especially in cases with nonadherence to AEDs, it may be occasionally considered in order to outweigh the risks of ongoing seizures and epilepsy if surgery is not performed.

Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review.

Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases.