Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new "Integrated Epilepsy Classification"?

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".

First clinical postmarketing experiences in the treatment of epilepsies with brivaracetam: a retrospective observational multicentre study.

OBJECTIVES: Brivaracetam (BRV) is the latest approved antiepileptic drug and acts as a synaptic vesicle protein 2A ligand. The aim of the present study was to evaluate the efficacy and tolerability of BRV in the clinical setting. DESIGN: Retrospective, observational multicentre study. SETTING: We retrospectively collected clinical data of patients who received BRV in 10 epilepsy centres using a questionnaire that was answered by the reporting neurologist. PARTICIPANTS: Data of 615 epilepsy patients treated with BRV were included in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Efficacy regarding seizure frequency and tolerability of BRV were evaluated. Descriptive statistics complemented by X2 contingency tests and effect sizes were performed. RESULTS: Overall, 44% of the patients had a decreased, 38% a stable and 18% an increased seizure frequency. 17% of patients achieved seizure freedom after initiation of BRV. The seizure frequency decreased in 63% of 19 patients with BRV monotherapy. 27% reported adverse effects, but only 10% of patients with monotherapy. Brivaracetam was significantly more often associated with decreased seizure frequency in levetiracetam (LEV) naïve patients (p=0.012), but BRV also led to a decreased seizure frequency in 42% of patients who had been treated with LEV before, including 17% of patients who were completely seizure free. Adverse effects under LEV improved in 62% and deteriorated in 2% of patients after the switch to BRV. At latest follow-up (mean±SD = 26.3±6.5 months), 68% were still on BRV. CONCLUSIONS: The present study shows that results of the phase III studies on BRV match data from real life clinical settings. Brivaracetam seems to be a useful alternative in patients who have suffered adverse effects while taking LEV.

Epileptic seizures and criminal acts: Is there a relationship?

BACKGROUND: The relation between epilepsy and criminal acts has been debated for over a century. The general perception persists that epileptic seizures can be associated with violent behavior. Some studies have provided evidence for such an association; however, it remains uncertain whether it really exists. This review critically evaluates the scientific literature on the possible relation between epileptic seizures and criminal acts. METHODS: A PubMed search was undertaken using the search terms "epilepsy and crime", "epilepsy and automatism", "epilepsy and law", and "epilepsy and dyscontrol syndrome" with the aim of identifying studies examining the possible association between epileptic seizure and crime. RESULTS: The combined keywords "epilepsy and crime" yielded 495 articles, the keywords "epilepsy and automatism" 402 results, the keywords "epilepsy and law" 969 articles, and the keywords "epilepsy and dyscontrol syndrome" resulted in 22 search results. After removing publications such as reviews and opinion pieces, we identified and analyzed a total of 24 research articles with relevant original data. These included single case reports. The reviewed literature suggests that there are very rare occasions when criminal acts are committed during the ictal or postictal period, mostly by patients with focal epilepsy. CONCLUSION: The literature on the relation between epileptic seizures and criminal acts is not conclusive. Behavioral disturbances often seem more closely related to comorbidities of epilepsy than particular seizures characteristics. These comorbidities are often not well-described. There is an urgent need for more systematic and detailed data gathering and reporting, in order to allow a more detailed investigation of the relation between epileptic seizures and criminal acts.

Late heartbeat-evoked potentials are associated with survival after cardiac arrest.

RATIONALE: Cardiac arrest (CA) is a serious condition characterized by high mortality rates, even after initial successful resuscitation, mainly due to neurological damage. Whether brain-heart communication is associated with outcome after CA is unknown. Heartbeat-evoked brain potentials (HEPs) represent neurophysiological indicators of brain-heart communication. The aim of this study was to address the association between HEPs and survival after CA. METHODS: HEPs were calculated from resting EEG/ECG in 55 CA patients 24 h after resuscitation. All patients were treated with targeted temperature management and a standardized sedation protocol during assessment. We investigated the association between HEP amplitude (180-320 ms, 455-595 ms, 860-1000 ms) and 6-month survival. RESULTS: Twenty-five of 55 patients (45%) were still alive at 6-month follow-up. Survivors showed a higher HEP amplitude at frontopolar and frontal electrodes in the late HEP interval than non-survivors. This effect remained significant after controlling for between-group differences in terms of age, Fentanyl dose, and time lag between resuscitation and EEG assessment. There were no group differences in heart rate or heart rate variability. CONCLUSION: Brain-heart communication, as reflected by HEPs, is associated with survival after CA. Future studies should address the brain-heart axis in CA.

Is there an Association between Migraine and Gastrointestinal Disorders?

Migraine is a primary episodic headache disorder that represents a substantial burden and disability worldwide. Its pathogenesis is multifactorial and remains hitherto poorly elucidated. An interesting but less-well-known association is that between migraine and gastrointestinal disorders. We have reviewed the literature for relevant papers reporting on the clinical association between migraine and gastrointestinal symptoms. Several studies have shown different gastrointestinal diseases to be associated with migraine, but the underlining pathophysiology remains elusive. The data gathered and analyzed have shown great variability across studies, making it impossible to draw definitive conclusions. Further research is required to elucidate this potential relationship. An understanding of the relationship between migraine and gastrointestinal disorders is of great clinical importance for prompt diagnosis and treatment.

Hemiplegic Migraine Presenting with Prolonged Somnolence: A Case Report.

Hemiplegic migraine is a rare and complex disease, characterized by migraine with a reversible motor aura. Hemiplegic migraine can be easily misdiagnosed at its first presentation with an atypical severe form of migraine, a stroke, multiple sclerosis, metabolic disorders, conversion disorder or an epilepsy. We present the case of a young 24-year-old male patient, who since the age of 4 years had been having multiple episodes of migraine associated with hemiparesis, paraesthesia, prolonged somnolence, aphasia and confusion. We review the literature and discuss important diagnostic findings in hemiplegic migraine to help establishing a prompt diagnosis.

Peripheral (Seventh) Nerve Palsy and Multiple Sclerosis: A Diagnostic Dilemma - A Case Report.

During the last decades, only a few cases on the association between peripheral demyelinating diseases and multiple sclerosis (MS) have been reported. We describe the case of a young man who was initially diagnosed with Bell's palsy, and only after performing a brain MRI was the diagnosis of MS made. We review the literature and discuss some pitfalls which may lead to missing the diagnosis of MS.

Clinical features associated with placebo response in refractory focal epilepsy.

For clinical trial design and for clinical practice, it is of importance to assess factors associated with placebo response in patients with refractory epilepsy. We determined factors associated with placebo response in 359 adult patients with refractory focal epilepsy participating in three randomized placebo-controlled trials of the new antiepileptic drug lacosamide. At the end of the randomized 12-week maintenance period, 81 (23%) of the 359 patients randomized to placebo achieved at least a 50% seizure reduction (responders) compared to baseline. In contrast, 278 (77%) patients did not achieve a 50% seizure reduction (non-responders) compared to baseline. In multivariate analysis, five factors, which were present prior to the exposure to placebo, were found to be associated with placebo response. Higher age at study entry improved the chances of placebo response for each year [p=0.023, odds ratio (OR) 1.034 (95% confidence interval (95% CI): 1.005-1.063)]. In contrast, a lower chance of placebo response was seen with age at diagnosis of epilepsy of 6-20 years compared to ≤5 years [p=0.041, OR 0.475 (95% CI: 0.232-0.971)]. A history of 7 or more prior lifetime AEDs lowered the chance of achieving placebo response compared to 1-3 prior lifetime AEDs [p<0.001, OR 0.224 (95% CI: 0.101-0.493)] as did a baseline seizure frequency >10 seizures per 28 days compared to ≤5 seizures per 28 days [p=0.026, OR 0.431 (95% CI: 0.205-0.904)]. Prior epilepsy surgery lowered the likelihood of placebo response [p=0.02, OR 0.22 (95% CI: 0.062-0.785)]. We suggest that age at exposure to placebo, age at diagnosis of epilepsy, the number of prior lifetime AEDs, baseline seizure frequency and a history of epilepsy surgery appear to be associated with placebo response in adults with refractory focal epilepsy.

Placebo-corrected efficacy of modern nonenzyme-inducing AEDs for refractory focal epilepsy: systematic review and meta-analysis.

PURPOSE: Given serious concerns over the adverse effects of enzyme induction, modern nonenzyme-inducing antiepileptic drugs (AEDs) may be preferable, provided they have similar efficacy as enzyme-inducing AEDs. This is currently unclear. METHODS: Therefore, we performed a meta-analysis of the evidence to determine the placebo-corrected efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs versus modern enzyme-inducing AEDs that are on the market for refractory focal epilepsy. KEY FINDINGS: Of 322 potentially eligible articles reviewed in full text, 129 (40%) fulfilled eligibility criteria. After excluding 92 publications, 37 studies dealing with a total of 9,860 patients with refractory focal epilepsy form the basis for the evidence. The overall weighted pooled-risk ratio (RR) in favor of enzyme-inducing AEDs over placebo was 2.37 (95% confidence interval [CI] 1.77-3.18, p < 0.001) for at least 50% seizure reduction and 4.45 (2.26-8.76, p < 0.001) for seizure freedom. The corresponding weighted pooled RR in favor of nonenzyme-inducing AEDs over placebo was 2.28 (95% CI 2.03-2.57, p < 0.001) for at least 50% seizure reduction and 3.23 (95% CI 2.23-4.67, p < 0.001) for seizure freedom. In a meta-regression analysis in the same sample with at least 50% seizure reduction as outcome, the ratio of RRs for enzyme-inducing AEDs (eight studies) versus nonenzyme-inducing AEDs (29 studies) was 1.01 (95% CI 0.77-1.34, p = 0.92)). Similarly, the ratio of RRs for a seizure-free outcome for enzyme-inducing AEDs (six studies) versus nonenzyme-inducing AEDs (19 studies) was 1.38 (95% CI 0.60-3.16, p = 0.43). SIGNIFICANCE: Although the presence of moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings, we conclude that the efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs is similar to that of enzyme-inducing AEDs. Given the negative consequences of enzyme induction, our data suggest that nonenzyme-inducing AEDs may be useful alternatives to enzyme-inducing AEDs for treatment of refractory focal epilepsy.

Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis.

Although adjunctive treatment with modern antiepileptic drugs (AEDs) is standard care in refractory epilepsy, it is unclear how much of the effect can be attributed directly to the AEDs and how much to the beneficial changes seen with placebo. Therefore, we performed a systematic review and meta-analysis of the evidence to determine the placebo-corrected net efficacy of adjunctive treatment with modern AEDs on the market for refractory epilepsy. Of 317 potentially eligible articles reviewed in full text, 124 (39%) fulfilled eligibility criteria. After excluding 69 publications, 55 publications of 54 studies in 11,106 adults and children with refractory epilepsy form the basis of evidence. The overall weighted pooled-risk difference in favor of AEDs over placebo for seizure-freedom in the total sample of adults and children was 6% [95% confidence interval (CI) 4-8, z = 6.47, p < 0.001] and 21% (95% CI 19-24, z = 17.13, p < 0.001) for 50% seizure reduction. Although the presence of moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings, we conclude that the placebo-corrected efficacy of adjunctive treatment with modern AEDs is disappointingly small and suggest that better strategies of finding drugs are needed for refractory epilepsy, which is a major public health problem.

Presumed topiramate-induced maculopathy.

The case of a patient who developed decreased vision while taking topiramate (TPM) for symptomatic epilepsy is described. Ophthalmological examination revealed findings suggestive of maculopathy. TPM was discontinued; however, vision failed to improve significantly over 6 months of follow-up. We hypothesize that the patient's maculopathy was induced by TPM. TPM, like vigabatrin, may exert retinal toxicity causing persistent visual impairment.

Intravenous levetiracetam for epileptic seizure emergencies in older people.

PURPOSE AND BACKGROUND: Clinical experience with intravenous levetiracetam (LEV IV) is still very limited, especially in elderly subjects. The primary objective of this retrospective observational study was to describe the efficacy and tolerability of LEV IV in older patients presenting with epileptic seizure emergencies. METHODS: Medical records of 14 older people treated with LEV IV were analysed retrospectively. All patients suffered from series of complex partial seizures or convulsive or non-convulsive status epilepticus needing emergent intravenous (IV) antiepileptic drug (AED) treatment. Nine patients were taking AED therapy when LEV IV was administered. RESULTS: Mean age was 73.9 years (range 61-97). Mean dosage was 1,643 mg/day (range 500-4,000). Seizure control could be achieved in 11/14 patients (78.6%). No significant adverse events were noted besides sedation. CONCLUSION: LEV IV was effective and well tolerated in these critically ill older patients. LEV IV seems to be a reasonable practical alternative in multimorbid older patients who need IV treatment with an AED.

A prospective study of body weight and serum leptin levels in patients treated with topiramate.

OBJECTIVES: We prospectively studied 26 (10 women) patients (age, 37.4 +/- 10.3 years) with different types of refractory focal epilepsy who received topiramate as adjunctive treatment. METHODS: Body mass indices (BMI, kg/m2) and serum leptin levels (SLL) were investigated at baseline (n = 26) and 9.5 +/- 2.9 (T1; n = 21) and 25.0 +/- 3.5 (T2; n = 18) weeks after initiation of topiramate. RESULTS: We found significant reductions in BMI (T1, -0.4 +/- 0.7; T2, -1.3 +/- 2.1 kg/m2) but not in SLL, although a tendency for reduced SLL was observed for women. Serum leptin level changes were mostly within the range between fifth and 95th sex-specific BMI-adjusted reference percentiles. Significant inverse correlations were found between baseline values and changes in both BMI (T2; r = -0.76; P < 0.001) and SLL (T2; r = -0.65; P = 0.003). Patients with BMI of 30.0 kg/m2 or greater showed the highest weight loss at T2 (-4.8 +/- 3.2 kg/m2). CONCLUSIONS: Our findings do not provide evidence for a direct causal involvement of leptin in topiramate-related weight loss.

Acute confusion or altered mental state: consider nonconvulsive status epilepticus.

BACKGROUND: The diagnosis of nonconvulsive status epilepticus (NCSE) is particularly challenging in elderly patients. Confusion, personality change, dysphasia, subtle motor activity and nystagmus may be the only presenting signs. OBJECTIVE: To review current knowledge about NCSE with special focus on older people. METHODS: Systematic review of the current literature via Medline search. CONCLUSION: Although prospective studies are still lacking, NCSE may be one of the most frequently missed diagnoses in patients presenting with altered mental status. Elderly patients are at particular risk of diagnostic errors because of the broad range of presentations of NCSE, significant comorbidities (especially cerebrovascular disease), limited awareness of this particular seizure emergency or difficulties with access to electroencephalography. Although diagnostic criteria and treatment remain controversial, the diagnosis of NCSE is important because it is potentially reversible.