[Progressive myoclonic epilepsy: a retrospective study of newly-diagnosed adult patients from a single center].

OBJECTIVE: To retrospectively analyze the clinical phenotype and pathogenic variants in patients with Progressive myoclonus epilepsy (PME). METHODS: Clinical data and results of genetic testing for 11 patients diagnosed with PME at the Department of Neurology, the First Affiliated Hospital of Zhejiang University School of Medicine from June 2017 to December 2022 were collected and analyzed. RESULTS: All of the patients, including 4 males and 7 females, had predominant action myoclonus. Three patients had myoclonus as the initial manifestation, whilst eight were diagnosed through genetic testing, including three cases with NEU1 gene variants, two with EPM2A gene variants (1 was novel), one with MT-TK gene variant, one with ATN1 gene variant, and one with CSTB gene variant. No pathogenic variant was identified in the remaining three cases. Among the eight patients with a genetic diagnosis, three were diagnosed with sialidosis, two with Lafora disease, one with Dentatorubral-pallidoluysian atrophy (DRPLA), one with Unverricht-Lundborg disease (ULD), and one with Myoclonic epilepsy with ragging red fibers (MERRF). CONCLUSION: Compared with pediatric patients, adult patients with PME represent a distinct subtype with slower progression and milder cognitive impairment.

The Roles of Cystatin B in the Brain and Pathophysiological Mechanisms of Progressive Myoclonic Epilepsy Type 1.

Progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disorder, also known as Unverricht-Lundborg disease (ULD). EPM1 patients suffer from photo-sensitive seizures, stimulus-sensitive myoclonus, nocturnal myoclonic seizures, ataxia and dysarthria. In addition, cerebral ataxia and impaired GABAergic inhibition are typically present. EPM1 is caused by mutations in the Cystatin B gene (CSTB). The CSTB protein functions as an intracellular thiol protease inhibitor and inhibits Cathepsin function. It also plays a crucial role in brain development and regulates various functions in neurons beyond maintaining cellular proteostasis. These include controlling cell proliferation and differentiation, synaptic functions and protection against oxidative stress, likely through regulation of mitochondrial function. Depending on the differentiation stage and status of neurons, the protein localizes either to the cytoplasm, nucleus, lysosomes or mitochondria. Further, CSTB can also be secreted to the extracellular matrix for interneuron rearrangement and migration. In this review, we will review the various functions of CSTB in the brain and discuss the putative pathophysiological mechanism underlying EPM1.

KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Detecting negative myoclonus during long-term home measurements using wearables.

OBJECTIVE: The aim of this study was to develop a feasible method for the detection of negative myoclonus (NM) through long-term home measurements in patients with progressive myoclonus epilepsy type 1. METHODS: The number and duration of silent periods (SP) associated with NM were detected during a 48 h home recording using wearable surface electromyography (EMG) sensors. RESULTS: A newly developed algorithm was able to find short (50-69 ms), intermediate (70-100 ms), and long (101- 500 ms) SPs from EMG data. Negative myoclonus assessed by the algorithm correlated significantly with the video-recorded and physician-evaluated unified myoclonus rating scale (UMRS) scores of NM and action myoclonus. Silent period duration, number, and their combination, correlated strongly and significantly also with the Singer score, which assesses functional status and ambulation. CONCLUSIONS: Negative myoclonus can be determined objectively using long-term EMG measurements in home environment. With long-term measurements, we can acquire more reliable quantified information about NM as a symptom, compared to short evaluation at the clinic. SIGNIFICANCE: As measured using SPs, NM may be a clinically useful measure for monitoring disease progression or assessing antimyoclonic drug effects objectively.

Generation of a human induced pluripotent stem cell line (UEFi004-A) from a patient with progressive myoclonic epilepsy type 1 (EPM1).

Progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disorder caused by mutations in the cystatin B gene (CSTB). Affected individual's manifest stimulus-sensitive and action myoclonus and tonic-clonic epileptic seizures. In this study, we have generated iPSCs from an EPM1 patient's skin fibroblasts with Sendai virus mediated transgene delivery. The iPSCs retained the patient specific promoter region expansion mutation, expressed pluripotency markers, differentiated into all three germ layers, and presented a normal karyotype. The line can in future be used to develop an in-vitro model for EPM1 and may help in understanding disease mechanisms at cellular and molecular level.

Progressive myoclonic epilepsy type 1 (EPM1) patients present with abnormal 1H MRS brain metabolic profiles associated with cognitive function.

PURPOSE: Progressive myoclonic epilepsy, type 1A (EPM1, Unverricht-Lundborg disease), is a rare neurodegenerative autosomal recessive disorder characterized by stimulus-sensitive and action myoclonus and tonic-clonic epileptic seizures. Patients develop neurological symptoms, including ataxia, intention tremor, and dysarthria, over time, with relatively limited and nonspecific MRI atrophy findings. The effects of the disease on brain metabolism are largely unknown. METHOD: Eighteen EPM1 patients (9 M, 9F) underwent clinical evaluation and neuropsychological testing, which included the assessment of intellectual ability, verbal memory, and psychomotor and executive functions. Magnetic resonance spectroscopy (MRS) and imaging (MRI) were performed on a 1.5 T MRI system. 2D MRS chemical shift imaging (CSI) maps (TE = 270) were obtained from the following regions of the brain: basal ganglia, thalamus, insula, splenium, and occipital white and gray matter, and N-acetyl-aspartate (NAA)-, choline (Cho)-, and lactate (Lac)-to-creatine (Cr) ratios were analyzed. Ten healthy age-and sex-matched subjects (5M, 5F) were used as controls for MRS. RESULTS: We found significant brain metabolic changes involving lactate, NAA, and choline, which are widespread in the basal ganglia, thalamic nuclei, insula, and occipital areas of EPM1 patients. Changes, especially in the right insula, basal ganglia, and thalamus, were associated with intellectual abilities and impairment of the psychomotor and executive functions of EPM1 patients. CONCLUSION: Multiple brain metabolic alterations suggest the presence of neurodegeneration associated with EPM1 progression. The changes in metabolite ratios are associated with the neurocognitive dysfunction caused by the disease. However, the role of MRS findings in understanding pathophysiology of EPM1 warrants further studies.

Negative myoclonus causes locomotory disability in progressive myoclonus epilepsy type EPM1- Unverricht-Lundborg disease.

OBJECTIVE: Patients with Unverricht-Lundborg disease/EPM1 develop increasing locomotory disability or ataxia in the course of their disease. To test our hypothesis that negative myoclonus is the reason for this increasing ataxia, we investigated a possible correlation over time. METHODS: In 15 patients with EPM1who were confirmed to have a mutation in the CSTB gene, polygraphic video-EEG-EMG recordings were performed in freely moving or standing patients. The criterion for the duration of the negative myoclonus was the measured length of the silent periods on the EMG. RESULTS: All 15 patients had documented negative myoclonus when standing and walking. The mean duration of silent periods significantly increased from 100 (SD: 19.1) ms at time point T1 to 128 (SD: 26.6) ms at T2 in seven of eight patients, based on two recordings and a mean interval of 12.8 (SD: 4.9) years. Using a cross-sectional approach, all 15 patients were classified based on whether they were ambulatory, could walk with aid, or needed a wheelchair. Ambulatory patients had a mean duration of 97.3 (SD: 16.5) ms, patients who could walk with aid had a mean duration of 106.7 (SD: 16) ms, and patients who were wheelchair-bound had a mean duration of 138 (SD: 23.6) ms. In addition to the prolongation of the silent periods, there was an observed increase in frequency of the negative myoclonus, becoming more continuous and tremulous. SIGNIFICANCE: Using simultaneous EEG/EMG recordings in freely moving or standing patients, we have shown that the locomotor disability or ataxia is due to negative myoclonus in voluntary innervated muscles. The reason for the progression is the prolongation of the silent periods as measured by the duration of the negative myoclonus and their increase in frequency.

Cortico-muscular coherence and brain networks in familial adult myoclonic epilepsy and progressive myoclonic epilepsy.

OBJECTIVE: Familial Adult Myoclonic Epilepsy (FAME) presents with action-activated myoclonus, often associated with epilepsy, sharing various features with Progressive Myoclonic Epilepsy (PMEs), but with slower course and limited motor disability. We aimed our study to identify measures suitable to explain the different severity of FAME2 compared to EPM1, the most common PME, and to detect the signature of the distinctive brain networks. METHODS: We analyzed the EEG-EMG coherence (CMC) during segmental motor activity and indexes of connectivity in the two patient groups, and in healthy subjects (HS). We also investigated the regional and global properties of the network. RESULTS: In FAME2, differently from EPM1, we found a well-localized distribution of beta-CMC and increased betweenness-centrality (BC) on the sensorimotor region contralateral to the activated hand. In both patient groups, compared to HS, there was a decline in the network connectivity indexes in the beta and gamma band, which was more obvious in FAME2. CONCLUSIONS: In FAME2, better localized CMC and increased BC in comparison with EPM1 patients could counteract the severity and the spreading of the myoclonus. Decreased indexes of cortical integration were more severe in FAME2. SIGNIFICANCE: Our measures correlated with different motor disabilities and identified distinctive brain network impairments.

Neurophysiology of Juvenile and Progressive Myoclonic Epilepsy.

SUMMARY: Myoclonus can be epileptic or nonepileptic. Epileptic myoclonus has been defined in clinical, neurophysiological, and neuroanatomical terms. Juvenile myoclonic epilepsy (JME) is typically considered to be an adolescent-onset idiopathic generalized epilepsy with a combination of myoclonic, generalized tonic-clonic, and absence seizures and normal cognitive status that responds well to anti-seizure medications but requires lifelong treatment. EEG shows generalized epileptiform discharges and photosensitivity. Recent observations indicate that the clinical picture of JME is heterogeneous and a number of neuropsychological and imaging studies have shown structural and functional abnormalities in the frontal lobes and thalamus. Advances in neurophysiology and imaging suggest that JME may not be a truly generalized epilepsy, in that restricted cortical and subcortical networks appear to be involved rather than the entire brain. Some patients with JME may be refractory to anti-seizure medications and attempts have been made to identify neurophysiological biomarkers predicting resistance. Progressive myoclonic epilepsy is a syndrome with multiple specific causes. It is distinct from JME because of the occurrence of progressive neurologic dysfunction in addition to myoclonus and generalized tonic-clonic seizures but may sometimes be difficult to distinguish from JME or misdiagnosed as drug-resistant JME. This article provides an overview of progressive myoclonic epilepsy and focuses on the clinical and neurophysiological findings in the two most commonly recognized forms of progressive myoclonic epilepsy-Unverricht-Lundborg disease (EPM1) and Lafora disease (EPM2). A variety of neurophysiological tests can be used to distinguish between JME and progressive myoclonic epilepsy and between EPM1 and EPM2.

Insights into the Genetic Profile of Two Siblings Affected by Unverricht-Lundborg Disease Using Patient-Derived hiPSCs.

Unverricht-Lundborg disease (ULD), also known as progressive myoclonic epilepsy 1 (EPM1), is a rare autosomal recessive neurodegenerative disorder characterized by a complex symptomatology that includes action- and stimulus-sensitive myoclonus and tonic-clonic seizures. The main cause of the onset and development of ULD is a repeat expansion of a dodecamer sequence localized in the promoter region of the gene encoding cystatin B (CSTB), an inhibitor of lysosomal proteases. Although this is the predominant mutation found in most patients, the physio-pathological mechanisms underlying the disease complexity remain largely unknown. In this work, we used patient-specific iPSCs and their neuronal derivatives to gain insight into the molecular and genetic machinery responsible for the disease in two Italian siblings affected by different phenotypes of ULD. Specifically, fragment length analysis on amplified CSTB promoters found homozygous status for dodecamer expansion in both patients and showed that the number of dodecamer repeats is the same in both. Furthermore, the luciferase reporter assay showed that the CSTB promoter activity was similarly reduced in both lines compared to the control. This information allowed us to draw important conclusions: (1) the phenotypic differences of the patients do not seem to be strictly dependent on the genetic mutation around the CSTB gene, and (2) that some other molecular mechanisms, not yet clearly identified, might be taken into account. In line with the inhibitory role of cystatin B on cathepsins, molecular investigations performed on iPSCs-derived neurons showed an increased expression of lysosomal cathepsins (B, D, and L) and a reduced expression of CSTB protein. Intriguingly, the increase in cathepsin expression does not appear to be correlated with the residual amount of CSTB, suggesting that other mechanisms, in addition to the regulation of cathepsins, could be involved in the pathological complexity of the disease.

Comorbidities in patients with Unverricht-Lundborg disease (EPM1).

BACKGROUND: Unverricht-Lundborg disease (EPM1) typically leads to accumulating disability. Disability may also be caused by comorbidities but there are no data available on these. AIMS OF THE STUDY: To investigate the frequency of comorbidities in EPM1. METHODS: Comorbidity data of a previously described cohort of 135 Finnish patients with EPM1 were retrieved from neurological, surgical (including subspecialities), internal medicine (including subspecialities) and intensive care patient charts of the treating hospitals. RESULTS: Mean follow-up time was 31.4 years (SD 12.4 years, range 6.8-57.8 years), during which at least one comorbidity was observed in 107 patients (79%) and three or more in 53 (39%). The most common diagnostic categories were external injuries, mental and behavioural disorders and endocrine, nutritional and metabolic diseases. The most common single comorbid diagnosis was a fracture of the ankle (in 19% of all patients). The second most common single comorbid diagnosis in the cohort was diabetes (in 13% of all patients), and the third was depression, recorded for 13% of the cohort. Malignancies and cardiovascular end-organ damage were rare, whereas phimosis/paraphimosis appeared more common than in general population. CONCLUSIONS: Patients with EPM1 often have comorbidities. Trauma and mental health risks should be especially followed and acted upon. Further studies are needed to more accurately comorbidity risks, characteristics and patient needs.

[Progressive myoclonic epilepsy in the department of neurology of the University Teaching hospital Point "G"]. / EPILEPSIES MYOCLONIQUES PROGRESSIVES AU SERVICE DE NEUROLOGIE DU CENTRE HOSPITALIER UNIVERSITAIRE DU POINT "G".

Background: Progressive Myoclonic Epilepsy (PME) is a heterogeneous group of pathologies associating epileptic seizures and other neurological and non-neurological disorders. Objectives: We aim to characterize patients with symptoms of PME and identify the underlying genetic disorder. Methods: After informed consent, the patients seen in the protocol for hereditary neurological diseases and presenting signs of epilepsy without a secondary cause were clinically evaluated over a three-year period in the Department of Neurology of the CHU Point "G". EEG, brain imaging and laboratory tests were performed to consolidate our diagnosis. DNA was extracted for genetic analysis. Results: 141 families including five families with PME totaling eight cases were enrolled. The predominant symptoms in our patients were myoclonus in 87.5% (N = 8), followed by GTCS and cognitive impairment in 50%, each. A notion of parental consanguinity was found in 60% and autosomal recessive transmission evoked in 80% (N = 5). The EEG was pathological in 62.5% and imaging showed ponto-cerebellar atrophy in 25% (N = 8). The combination of sodium valproate and clonazepam was the main treatment. One case of death was recorded. Conclusion: We report cases of PME in Mali with a possibility of discovering new genes.

Major intra-familial variability in Unverricht-Lundborg disease.

Unverricht-Lundborg disease (ULD), also called progressive myoclonic epilepsy type 1, is usually characterized by the presence of ataxia associated with myoclonus and epileptic seizures without progressive cognitive deficit, presenting during late childhood and early adolescence. Currently, there is a growing body of evidence for atypical presentations of the disease with a milder phenotype or without the full symptomatology. We describe a case report of a late-onset phenotype with progressive myoclonus-ataxia syndrome accompanied by initial recurrent falls, resulting in specific phobia and agoraphobia starting at the age of 50 years old. The examination revealed multifocal myoclonus with cerebellar ataxia and electroencephalogram showed generalized polyspikes and spike-wave discharges. Electromyogram revealed positive myoclonus of 60-ms duration in the face and the presence of C reflex. A genetic study confirmed the diagnosis of ULD in the patient and other additional family members, presenting a wide range of intra-familial variability. We discuss the challenging differential diagnosis for such a misleading presentation and its possible underlying pathophysiological mechanisms. Our case report may contribute to broadening the age and clinical boundaries for this disease and emphasizes the intra-familial age and symptom variability. Based on a suggestive family history, the diagnosis of ULD should be considered in this context, even in older patients.

Clinical and molecular characterization of Unverricht-Lundborg disease among Egyptian patients.

BACKGROUND AND PURPOSE: Unverricht-Lundborg disease (ULD) is a common type of progressive myoclonic epilepsy (PME). It is caused mostly by biallelic dodecamer repeat expansions in the promoter region of CSTB gene. Despite highly prevalent in the Mediterranean countries, no studies have been reported from Egypt. This article study the presence of CSTB gene mutations among Egyptian patients clinically suspected with ULD, and describes the clinical and genetic characteristics of those with confirmed gene mutation. METHODS: Medical records of patients following up in two specialized epilepsy clinics in Cairo, Egypt were retrospectively reviewed. Twenty patients who belonged to 13 unrelated families were provisionally diagnosed with ULD based on the clinical presentation. Genetic testing was done. Clinical characteristics, demographic data and EEG findings were documented. RESULTS: Genetic studies confirmed the presence of the CSTB dodecamer repeat expansion in 14 patients from 8 families (frequency 70 %). The mean duration of the follow-up was 5 years. Male to female distribution was 1:1 with a mean age of onset 9.7 years. Consanguinity was noted in 4 families. Eight patients had their first seizure between the age of 10 and 20 years. Myoclonic jerks ranged in severity from mild in three unrelated patients to severe in one. Only 3 had cognitive impairment. CONCLUSION: Our study confirms the presence of CSTB mutation among Egyptian patients suspected with ULD. There was no clear phenotype-genotype correlation among the studied group of patients. In addition, we noticed variable inter and intra familial severity among patients from the same family.

Wearable monitoring of positive and negative myoclonus in progressive myoclonic epilepsy type 1.

OBJECTIVE: To develop and test wearable monitoring of surface electromyography and motion for detection and quantification of positive and negative myoclonus in patients with progressive myoclonic epilepsy type 1 (EPM1). METHODS: Surface electromyography and three-dimensional acceleration were measured from 23 EPM1 patients from the biceps brachii (BB) of the dominant and the extensor digitorum communis (EDC) of the non-dominant arm for 48 hours. The patients self-reported the degree of myoclonus in a diary once an hour. Severity of myoclonus with action was evaluated by using video-recorded Unified Myoclonus Rating Scale (UMRS). Correlations of monitored parameters were quantified with the UMRS scores and the self-reported degrees of myoclonus. RESULTS: The monitoring-based myoclonus index correlated significantly (p < 0.001) with the UMRS scores (ρ = 0.883 for BB and ρ = 0.823 for EDC) and with the self-reported myoclonus degrees (ρ = 0.483 for BB and ρ = 0.443 for EDC). Ten patients were assessed as probably having negative myoclonus in UMRS, while our algorithm detected that in twelve patients. CONCLUSIONS: Wearable monitoring was able to detect both positive and negative myoclonus in EPM1 patients. SIGNIFICANCE: Our method is suitable for quantifying objective, real-life treatment effects at home and progression of myoclonus.

Cognitive functioning in progressive myoclonus epilepsy type 1 (Unverricht-Lundborg Disease, EPM1).

OBJECTIVE: The aim of this neuropsychological study of a large cohort of patients with progressive myoclonus epilepsy type 1 (Unverricht-Lundborg disease, EPM1) was to characterize the cognitive function of EPM1 patients and to explore the association between the disability caused by the disease and cognitive performance. METHOD: Sixty-eight genetically verified EPM1 patients homozygous for the expansion mutation in the CSTB gene (37 males and 31 females aged 35 ±â€¯11) participated in a neuropsychological assessment of intellectual ability, verbal memory, and executive and psychomotor function. The clinical evaluation comprised administering (and video-recording) the unified myoclonus rating scale (UMRS) to assess the severity of each patient's myoclonus. Forty-six healthy volunteers (19 males and 27 females aged 32 ±â€¯11) served as the control group for the neuropsychological tests. RESULTS: The cognitive performance of the EPM1 patient group was impaired. Verbal Intelligence Quotient (VIQ) was below the average range (VIQ < 85) in 49% of the patients; further, Performance Intelligence Quotient (PIQ) was below average in 75% of the patients. The patients performed worse than the controls in both immediate and delayed story recall (p = 0.001); however, in the word list learning task, the patients performed only slightly worse than the controls. The one-hour delayed recall of the learned words was similar in both groups, and the percentage of retained words and story contents did not differ between the patients and controls. The patients were impaired in all of the executive function tests as well as in the psychomotor speed tests (p < 0.001 for all). Also, the patients' simple psychomotor speed in the tapping task was significantly slowed in comparison to controls (p < 0.001). CONCLUSION: The patients had impaired performance in the majority of the cognitive measures; they showed the highest level of impairment in all the executive function tests and in the psychomotor speed tests. The measures of these cognitive domains are timed-therefore, it is clear that severe myoclonus limits patients' performance. In contrast, verbal memory, especially delayed recall, was the least affected cognitive domain.

Generation of human induced pluripotent stem cell lines (UNIMGi003-A and UNIMGi004-A) from two Italian siblings affected by Unverricht-Lundborg disease.

Unverricht-Lundborg disease (ULD) is an inherited form of progressive myoclonus epilepsy caused by mutations in the gene encoding Cystatin B (CSTB), an inhibitor of lysosomal proteases. The most common mutation described in ULD patients is an unstable expansion of a dodecamer sequence located in the CSTB gene promoter. This expansion is causative of the downregulation of CSTB gene expression and, consequently, of its inhibitory activity. Here we report the generation of induced pluripotent stem cell (iPSC) lines from two Italian siblings having a family history of ULD and affected by different clinical and pathological phenotypes of the disease.

Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease: An open-label, long-term follow-up trial.

This long-term open-label extension (OLE) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses in patients with epilepsy and focal (partial-onset) or generalized onset seizures, or Unverricht-Lundborg disease (ULD). A secondary objective was to evaluate efficacy of BRV in the subgroups of patients with focal or generalized onset seizures. Patients with epilepsy were eligible to enroll in this OLE (N01125; NCT00175916) and were analyzed if they had completed a previous double-blind BRV trial (N01114 [NCT00175929], N01252 [NCT00490035], N01254 [NCT00504881], N01187 [NCT00357669], and N01236 [NCT00368251]), and were expected to obtain a reasonable benefit from long-term BRV treatment. Patients entered the OLE at the BRV dose recommended at the end of the previous trial, with dose adjustments of BRV and concomitant antiseizure medications permitted. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables in patients with focal seizures were percent reduction in focal seizure frequency, 50 % responder rates, and 6- and 12-month seizure-freedom. Eight hundred and fifty-three patients (729 [85.5 %] with focal seizures, 30 [3.5 %] with generalized onset seizures, and 94 [11.0 %] with ULD) were enrolled and included in the Safety Set. Overall, 619 (72.6 %) patients discontinued the trial, mainly due to lack of efficacy (354 [41.5 %]), adverse events (100 [11.7 %]), and patient choice (98 [11.5 %]). During the OLE, 588 (68.9 %) patients received BRV for ≥12 months, 403 (47.2 %) for ≥36 months, and 223 (26.1 %) for ≥96 months. The most common modal dose of BRV was 150 mg/day (415 [48.7 %] patients). In the ULD subgroup, the most common modal BRV dose was 100 mg/day (44/94 [46.8 %] patients), and 37/94 (39.4 %) patients had ≥96 months of BRV exposure. Overall, 720/853 (84.4 %) patients reported TEAEs, 451 (52.9 %) had a drug-related TEAE, and 95 (11.1 %) discontinued BRV due to a TEAE. In the ULD subgroup, 87/94 (92.6 %) patients reported TEAEs, 60 (63.8 %) had a drug-related TEAE, and 16 (17.0 %) discontinued due to a TEAE. In patients with focal seizures, the median reduction in focal seizure frequency from Baseline was 43.1 % (n = 728), the 50 % responder rate was 43.6 % (n = 729), and 6- and 12-month seizure freedom rates were 22.2 % and 15.8 %, respectively (n = 595). Overall, BRV was well-tolerated as long-term adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease, with improvements in focal seizure frequency maintained over time.

[A case of the successful treatment of severe myoclonus with Lance-Adams syndrome by add-on perampanel showing long term effects].

Perampanel is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist that has been marked as an antiepileptic drug for partial-onset and primary generalized tonic-clonic seizures. There have been some recent reports of perampanel being effective against cortical myoclonus by Lafora disease and Unverricht-Lundborg disease. We herein report a 49-year-old man who presented with myoclonus due to Lance-Adams syndrome (LAS) after cardiopulmonary arrest caused by a severe bronchial asthma attack. Perampanel was very effective against myoclonus induced by LAS even in the chronic state, over 10 years after the remote onset. Perampanel should be considered for the treatment of extremely refractory myoclonus due to LAS.