Standard procedures for the diagnostic pathway of sleep-related epilepsies and comorbid sleep disorders: an EAN, ESRS and ILAE-Europe consensus review.

BACKGROUND AND PURPOSE: Some epilepsy syndromes (sleep-related epilepsies, SREs) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life. Our purpose was to define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2). METHODS: The project was conducted under the auspices of the European Academy of Neurology, the European Sleep Research Society and the International League Against Epilepsy Europe. The framework entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For the literature search a stepwise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine's MEDLINE database and Cochrane Library. RESULTS: Scenario 1: Despite a low quality of evidence, recommendations on anamnestic evaluation and tools for capturing the event at home or in the laboratory are provided for specific SREs. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizure control. CONCLUSIONS: Definitive procedures for evaluating patients with SRE are lacking. Advice is provided that could be of help for standardizing and improving the diagnostic approach of specific SREs. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined.

Epidemiology and outcome of idiopathic generalized epilepsy in adults.

BACKGROUND AND PURPOSE: Drug-resistant idiopathic generalized epilepsy (IGE) remains challenging despite a favourable overall prognosis of IGE, and little is known about basic epidemiology and long-term outcome of drug-resistant IGE. The aim of the study was to describe the incidence, prevalence and outcome of IGE in an unbiased, population-based cohort. METHODS: In 2014-2018, all patients (≥17 years) with IGE inhabiting the island of Funen (496 000 inhabitants) were recruited. The socioeconomic and clinical information available for 406 individuals was assessed. Median follow-up was 15 years. RESULTS: The average IGE incidence (2008-2017) was 2.9/100 000 inhabitants/year. The point prevalence of identifiable IGE patients was 1.0/1000 adults (juvenile myoclonic epilepsy 0.4/1000; absence epilepsy 0.3/1000, epilepsy with generalized tonic-clonic seizures alone 0.3/1000); 92.1% of the patients were diagnosed before 25 years of age. When correcting for unequal age distribution in the cohort, 1102 people on the island of Funen fulfilled the diagnostic criteria for IGE at the age of 25 (estimated prevalence 2.7/1000 adults). In the year before data closure, 121 patients reported seizures. Fifty patients met the definition of drug-resistant IGE (12.1% of the cohort, 4.5% of the estimated 1102 IGE patients). The average seizure burden of all patients with drug-resistant IGE was 2.2 generalized tonic-clonic seizures per year; only 14 patients suffered more than two generalized tonic-clonic seizures per year. Drug-resistant IGE was associated with an increased risk of requiring treatment for affective disorders and a reduced probability of working full time. CONCLUSION: Idiopathic generalized epilepsy was associated with a low risk of persistent drug-resistant seizures requiring specialist medical attention. Drug resistance was associated with a negative socioeconomic outcome.

Ictal and interictal electric source imaging in pre-surgical evaluation: a prospective study.

BACKGROUND AND PURPOSE: Accurate localization of the epileptic focus is essential for surgical treatment of patients with drug-resistant epilepsy. Electric source imaging (ESI) is increasingly used in pre-surgical evaluation. However, most previous studies have analysed interictal (II) discharges. Prospective studies comparing the feasibility and accuracy of II and ictal (IC) ESI are lacking. METHODS: We prospectively analysed long-term video-electroencephalography recordings (LTM) of patients admitted for pre-surgical evaluation. We performed ESI of II and IC signals using two methods, i.e. equivalent current dipole (ECD) and a distributed source model (DSM). LTM recordings employed the standard 25-electrode array (including inferior temporal electrodes). An age-matched template head model was used for source analysis. Results were compared with intracranial recordings, conventional neuroimaging methods [magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT)] and outcome at 1 year after surgery. RESULTS: A total of 87 consecutive patients were analysed. ECD gave a significantly higher proportion of patients with localized focal abnormalities (94%) compared with MRI (70%), PET (66%) and SPECT (64%). Agreement between the ESI methods and intracranial recording was moderate to substantial (k = 0.56-0.79). A total of 54 patients were operated (47 patients more than 1 year ago) and 62% of them became seizure-free. The localization accuracy of II-ESI was 51% for DSM and 57% for ECD, and that for IC-ESI was 51% for DSM and 62% for ECD. The differences between the ESI methods were not significant. Differences in localization accuracy between ESI and MRI (55%), PET (33%) and SPECT (40%) were not significant. CONCLUSIONS: The II-ESI and IC-ESI of LTM data have high feasibility and their localization accuracy is similar to that of conventional neuroimaging methods.

Clinical utility of EEG in diagnosing and monitoring epilepsy in adults.

Electroencephalography (EEG) remains an essential diagnostic tool for people with epilepsy (PWE). The International Federation of Clinical Neurophysiology produces new guidelines as an educational service for clinicians to address gaps in knowledge in clinical neurophysiology. The current guideline was prepared in response to gaps present in epilepsy-related neurophysiological assessment and is not intended to replace sound clinical judgement in the care of PWE. Furthermore, addressing specific pathophysiological conditions of the brain that produce epilepsy is of primary importance though is beyond the scope of this guideline. Instead, our goal is to summarize the scientific evidence for the utility of EEG when diagnosing and monitoring PWE.

Add-on perampanel and aggressive behaviour in severe drug-resistant focal epilepsies.

This study aimed to investigate the incidence of aggressiveness in patients with severe drug-refractory focal epilepsy (DRE) who started perampanel (PER) as add-on treatment, and to identify possible predisposing factors. Data on 49 consecutive patients with severe DRE who initiated PER were retrospectively collected. Twelve of the 49 patients experienced aggressiveness as adverse event related to PER treatment, one third of them on low (2-4 mg/day) PER dosages. PER was discontinued in 10/12 patients because of aggressive behaviors. Aggressiveness could appear after several months or even more than one year of PER treatment. One third of patients with PER-related aggressiveness had intellectual disabilities and 5/12 patients took levetiracetam as a concomitant antiepileptic drug. Our study suggests that the occurrence of aggressive behaviors in patients with severe DRE is not uncommon during PER treatment and that it may occur after months or even years of treatment with a stable dosage, requiring PER discontinuation in the great majority of patients.

Perampanel as add-on treatment in refractory focal epilepsy. The Dianalund experience.

BACKGROUND: Perampanel (PER) is an antagonist of AMPA receptors that has been approved for adjunctive treatment of partial-onset seizures. AIMS: To evaluate effectiveness and safety of PER as add-on treatment in patients with severely refractory focal epilepsy. METHODS: PER was introduced as add-on treatment in 22 consecutive patients with drug-resistant focal epilepsy. PER was started with 2 mg/day at bedtime and was up-titrated by 2 mg/day every 2-4 weeks. RESULTS: All patients suffered from severely refractory focal epilepsy (86% took 2 or more AEDs prior PER initiation; 40% had been submitted to surgery or were surgery candidates; 7 had VNS). After 12 months since PER initiation, the retention rate was 54.5% and the responder rate was 27.2%, including 9.1% seizure-free patients. Mean PER dose in the responders was 8 mg/day (range 4-10). Most common side effects were tiredness, behavioral changes (primarily aggressivity), dizziness and were reported in 59.1% of patients, leading to PER discontinuation in 31.8% of subjects. CONCLUSIONS: PER as add-on treatment can achieve clinically meaningful improvement in patients suffering from severely refractory focal epilepses. Further studies are warranted to explore the tolerability profile, with particular focus on psychiatric adverse events.

Focal epilepsies associated with glioneuronal tumors: review article.

Glioneuronal tumors (GNTs) are an increasingly recognized cause of focal epilepsies, particularly in children and young adults. GNTs consist of a mixture of glial and neuronal elements and most commonly arise in the temporal lobe, particularly in the temporo-anterior-basal mesial site. They are often associated with cortical dysplasia or other neuronal migration abnormalities. Epilepsy associated with GNT is poorly controlled by antiepileptic drugs in many cases; but, it is extremely responsive to surgical treatment. However, the best management strategy of tumor-related focal epilepsies remains controversial and still remain one of the contemporary issues in epilepsy surgery. Temporo-mesial GNT are associated with a widespread epileptic network, defining, therefore, a distinct anatomo-clinico-pathological group with complex epileptogenic mechanisms. By using an epilepsy surgery oriented strategy GNT associated with focal epilepsies may have an excellent seizure outcome and, therefore, surgical treatment can be offered early to avoid both the consequences of uncontrolled seizures as well as the side effects of prolonged pharmacological therapy and the rare risk of tumor growth or malignant transformation.

Role of dentate gyrus alterations in mesial temporal sclerosis.

Drug-resistant chronic temporal lobe epilepsy is the most common type of epilepsy that undergoes surgical treatment. To verify if dentate gyrus alterations may play a role in patients with mesial temporal sclerosis (MTS), 14 patients, submitted to epilepsy surgery, were selected. Only cases with MTS alone were included. Granule cell dispersion (GCD) was observed in 7 cases (50%). A statistically significant correlation between GCD and the mean number of seizures/month was evidenced. The percentage of patients who did not achieve seizure relief (i.e. they were not in Engel class 1A) was 57.14% in patients without GCD, whereas that percentage dropped to 14.29% in patients with GCD. The association between a more favorable postsurgical epileptogenic outcome and granule cell pathology in patients with MTS has been observed, thus suggesting that dentate gyrus alterations may play a role in drug-resistant TLE.

SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure.

OBJECTIVE: Mutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD. METHODS: We reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1. RESULTS: Of 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found. INTERPRETATION: Mutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD.