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Background and ObjectivesTo assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.MethodsOf 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.”ResultsSixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.DiscussionThe application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

This work points out the main differences in the semantic expressions used by patients with psychogenic non-epileptic seizures (PNES) and epileptic seizures (ES). In reference to the body as a phenomenological entity, in ES the concept of the body-object prevails while in PNES the body, with all its life attributes, predominates. In description of seizures and in similitudes and metaphors used, ES patients focus on the description of the attack, trying to close the "gap" with a big effort, while patients with PNES concentrate on the context and on the presence of bystanders. Patients with PNES are unable to describe their own attack, since this it is not at the core of their distress, but rather the manifestation of something else, which is hiding the extreme anguish associated with experiences of the past that cannot be revealed (expressed). In the case of ES, instead, the ability to talk and the willingness to elaborate on the emotions become useful tools for facing the disease, an entity perhaps unsurmountable but at least manageable, to the benefit of everyone. In general, we can say that the experience of a disease (real or symbolic) deserves constant attention because it gives us the opportunity not only to probe the depth of the emotional experiences but also the psychic structure of the individual in front of us. A cure would not be a cure without considering such fundamental elements. It would become a sterile exercise of prescribing medications without paying attention to the person, which is the best way of preserving dignity in a state of illness.

Background Lafora disease (LD) is characterized by progressive myoclonus, refractory epilepsy, and cognitive deterioration. This complex neurodegenerative condition is caused by pathogenic variants in EPM2A/EPM2B genes, encoding two essential glycogen metabolism enzymes known as laforin and malin. Long-term follow-up data are lacking. We describe the clinical features and genetic findings of a cohort of 26 Italian patients with a long clinical follow-up. Methods Patients with EPM2A/EPM2B pathogenic variants were identified by direct gene sequencing or gene panels with targeted re-sequencing. Disease progression, motor functions, and mental performance were assessed by a simplified disability scale. Spontaneous/action myoclonus severity was scored by the Magaudda Scale. Results Age range was 12.2–46.2 years (mean:25.53 ± 9.14). Age at disease onset ranged from 10 to 22 years (mean:14.04 ± 2.62). The mean follow-up period was 11.48 ± 7.8 years. Twelve out of the 26 (46%) patients preserved walking ability and 13 (50%) maintained speech. A slower disease progression with preserved ambulation and speech after ≥4 years of follow-up was observed in 1 (11%) out of the 9 (35%) EPM2A patients and in 6 (35%) out of the 17 (65%) EPM2B patients. Follow-up was >10 years in 7 (41.2%) EPM2B individuals, including two harbouring the homozygous p.(D146N) pathogenic variant. Conclusions This study supports an overall worse disease outcome with severe deterioration of ambulation and speech in patients carrying EPM2A mutations. However, the delayed onset of disabling symptoms observed in the EPM2B subjects harbouring the p.(D146N) pathogenic variant suggests that the underlying causative variant may still influence LD severity.

Aims The aim of the study was to highlight the fundamental linguistic elements through a simplified scoring table to build a simplified and easier diagnostic model for linguistic evaluation by nonexperts. Methods The study was based on interviews performed in patients recruited at the University of Milano Bicocca, at the Epilepsy Center of the University of Messina, and at the Epilepsy Monitoring Unit of the University of Rochester, who experienced “seizures” and underwent video-electroencephalogram (vEEG) for differential diagnosis. All enrolled subjects underwent a video-recorded interview consisting of a fixed sequence of five questions. Subsequently, a researcher examined the video recordings, blind to the vEEG results, and filled in the simplified linguistic evaluation (SLE) scoring table. The best cutoff score for the diagnosis was determined using a ROC curve and was selected as the value leading to the maximum number of patients correctly classified. Results The study sample consisted of 35 interviews. The receiver operating characteristics (ROC) curve analysis showed that the best cutoff for the diagnosis was 12. The accuracy was 82.9% for this cutoff value. The area under the ROC curve (AUC) was 0.81 (95% confidence interval (CI): 0.66–0.97). Classifying patients using the SLE scoring table as diagnostic tool, with the selected cutoff score, 17 out of 19 patients with psychogenic nonepileptic seizures (PNES) were correctly classified (89.5% sensitivity), while 12 out of 16 patients with epileptic seizures (ES) were correctly classified (75% specificity). Positive and negative predictive values are, respectively, 81% and 85.7%. Conclusions Despite some limitations, the use of the SLE scoring table may reduce costs, and conversation analysis (CA) might help achieving a timely and reliable diagnosis of PNES.

Purpose The purpose of this study was to assess the priorities of patients with epilepsy and caring physicians and the correspondence between these priorities. Methods In this multicenter cross-sectional study, patients with epilepsy attending 21 Italian epilepsy centers and their caring physicians filled anonymously questionnaires on the needs and priorities in the management of the disease. Included were questions on patients' demographics, diagnosis, treatment, and outcome of epilepsy. The concordance between patients and their physicians was assessed on various aspects of the diagnosis and care of the disease. Patients' satisfaction with communication, services, and patient–doctor relationship was also assessed. Results Included were 432 women and 355 men aged 15 to 88 years (median: 41 years). Disease duration ranged from 6 months to 75 years. A structural/metabolic etiology predominated (52.7%), followed by a (presumed) genetic etiology (33.0%). Seizure remission was present in 56.5% of cases. Comorbidities requiring chronic treatment were present in 27.5%, and comorbidities affecting self-sufficiency in 9.5%. Psychiatric comorbidity was present in 35.0%. Patients' priorities included discovery of the cause (89.1%), use of right drug (98.7%), use of a drug without chronic side effects (94.0%), and a life without restrictions (90.4%). Physicians' priorities included choice of right drug (83.5%) and use of drugs without chronic side effects (86.8%). Priorities varied with patients' age, sex, education, and occupation. Patient–doctor relationships were at least good in most cases. The information imparted was considered unsatisfactory by 21–44% of cases on seizure circumstances and complications, side effects of drugs, limitations of daily activities, and management of physiologic or pathologic conditions. Patients declared overall satisfaction, except for appointments (21.5%) and emergencies (30.8%). Conclusion Patients and physicians' priorities in the management of epilepsy overlap only in part. Patients are satisfied with their caring physicians and less satisfied with communication and management of routine and emergency problems.

Background: Vagal nerve stimulation (VNS) is an effective palliative therapy in drug-resistant epileptic patients and is also approved as a therapy for treatment-resistant depression. Depression is a frequent comorbidity in epilepsy and it affects the quality of life of patients more than the seizure frequency itself. The aim of this systematic review is to analyze the available literature about the VNS effect on depressive symptoms in epileptic patients. Material and methods: A comprehensive search of PubMed, Medline, Scopus, and Google Scholar was performed, and results were included up to January 2020. All studies concerning depressive symptom assessment in epileptic patients treated with VNS were included. Results: Nine studies were included because they fulfilled inclusion criteria. Six out of nine papers reported a positive effect of VNS on depressive symptoms. Eight out of nine studies did not find any correlation between seizure reduction and depressive symptom amelioration, as induced by VNS. Clinical scales for depression, drug regimens, and age of patients were broadly different among the examined studies. Conclusions: Reviewed studies strongly suggest that VNS ameliorates depressive symptoms in drug-resistant epileptic patients and that the VNS effect on depression is uncorrelated to seizure response. However, more rigorous studies addressing this issue are encouraged.

Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales. Forty-nine patients aged 36.6 ± 15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2–12 mg (5.3 ± 2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4–6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy. Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the ‘Action myoclonus’ section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness. PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.

Objective The objective of this review was to examine the possible link between psychological trauma in a patient's medical history and the onset of psychogenic nonepileptic seizures (PNES). Methodology An electronic search of published reports was made using the search engines PubMed-MedLine, EBSCO, PsycINFO, SFX, and Embase and the keywords “PNES”, “psychogenic seizures”, “sexual abuse”, and “trauma”. Results A correlation emerged between history of childhood trauma and the presence of PNES. Antecedent trauma was more frequent in females than in males and in patients exhibiting psychiatric disorders but was inversely correlated with cognitive impairment. Conclusions In the presence of PNES, it is important to accurately investigate the patient's medical history in search of psychological trauma, particularly in women and in patients with psychiatric disorders.

Objective The objective of this study was to explore the short-term effects of repetitive transcranial magnetic stimulation (rTMS) on action myoclonus. Methods Nine patients with Unverricht–Lundborg (EPM1) progressive myoclonus epilepsy type underwent two series of 500 stimuli at 0.3 Hz through round coil twice a day for five consecutive days. Clinical and neurophysiological examinations were performed two hours before starting the first rTMS session and two hours after the end of the last rTMS session. Results Eight patients completed the protocol; one discontinued because of a transient increase in spontaneous jerks. The unified myoclonus rating scale indicated a 25% reduction in posttreatment myoclonus with action score associated with an increase in the cortical motor threshold and lengthening of the cortical silent period (CSP). The decrease in the myoclonus with action scores correlated with the prolongation of CSP. Conclusions Repetitive transcranial magnetic stimulation can be safely used in patients with EPM1, improves action myoclonus, and partially restores deficient cortical inhibition.

The aim of the study was to evaluate the prevalence and the etiology of sexual dysfunctions (SD) in a group of epileptic outpatients. Sixty Italian men (30 patients and 30 controls), living in Sicily, were enrolled in the study. Our diagnostic investigation included physical and neurological examination, EEG, MRI and Hamilton Depression and Anxiety Scales administration. A "semi-structured" questionnaire and the short form of the Sex relation Evaluation Schedule Assessment Monitoring were administered to the whole sample to evaluate their sexual well-being. There was no correlation between SD and type of epilepsy, EEG abnormalities and different antiepileptic drugs, while a weak correlation was observed between seizure frequency and the main SD. Forty-seven percent of the patients were affected by mild to moderate depression and 73.3% were anxious. Moreover, those patients who had uncontrolled seizures presented alteration in their social and affective area. Our findings showed a low prevalence of SD in epileptic male outpatients, especially concerning hyposexuality, and an important role of the seizure frequency in the multifactorial aetiology of sexual impairment in epilepsy. However, larger and multicenter studies are needed to better define the effects of epilepsy per se and the individual treatments on sexual function.

Objective:To explore the course of Unverricht-Lundborg disease (EPM1) and identify the risk factors for severity, we investigated the time course of symptoms and prognostic factors already detectable near to disease onset.Methods:We retrospectively evaluated the features of 59 Italian patients carrying the CSTB expansion mutation, and coded the information every 5 years after the disease onset in order to describe the cumulative time-dependent probability of reaching disabling myoclonus, relevant cognitive impairment, and inability to work, and evaluated the influence of early factors using the log-rank test. The risk factors were included in a Cox multivariate proportional hazards regression model.Results:Disabling myoclonus occurred an average of 32 years after disease onset, whereas cognitive impairment occurred a little later. An age at onset of less than 12 years, the severity of myoclonus at the time of first assessment, and seizure persistence more than 10 years after onset affected the timing of disabling myoclonus and cognitive decline. Most patients became unable to work years before the appearance of disabling myoclonus or cognitive decline.Conclusions:A younger age at onset, early severe myoclonus, and seizure persistence are predictors of a more severe outcome. All of these factors may be genetically determined, but the greater hyperexcitability underlying more severe seizures and myoclonus at onset may also play a role by increasing cell damage due to reduced cystatin B activity.

The differential diagnosis of epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) is often difficult, especially in pediatric and adolescent settings. Conversation analysis (CA) can be a worthwhile diagnostic tool in adults. The aim of this study was to assess the diagnostic value of CA in Italian children and adolescents. Ten patients (seven females and three males), diagnosed using video-EEG as having either ES or PNES, underwent a video-recorded interview by a physician from outside the center specifically trained for this purpose. An external linguistic rater then examined the video recordings and transcripts using CA. Diagnoses formulated on the basis of interactional and linguistic features of the patients' speech were compared with diagnoses made by seizure experts on the basis of all available clinical information including the video-EEG findings. Conversation analysis diagnoses corresponded to the video-EEG diagnoses in 8 out of 10 cases. In conclusion, while some conversational adaptation is necessary to enable children and adolescents to share their seizure experiences with an adult health professional, this study indicates the differential diagnostic potential of a CA approach in these young people with PNES or epilepsy. Larger samples are obviously needed to confirm these findings.

The differential diagnosis of epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES) is often difficult. The diagnostic gold standard is video-EEG, but this procedure is limited because of its high cost and is not always available. Research groups from Germany and Britain have used conversation analysis (CA) of patients' descriptions of their seizures as a means of differentiating the type of seizure. The aim of this study was to verify the value of their considerations in relation to the Italian language. Ten subjects (five with ES and five with PNES) diagnosed by means of the video-EEG recording of one seizure were studied under blind conditions by a linguist. The patients with ES described their seizures in as much detail as possible and tried to reconstruct the experience as fully as they can, making an effort to describe their subjective symptoms, quantify the duration of the phases preceding and following the seizure, and use the image of an external entity overcoming them. On the contrary, the patients with PNES repeated their extraneousness to the events that occur, refused to reply, expressed amnesia, reconstructed the happening by referring to descriptions provided by witnesses, and often describe their seizures using the image of an internal entity of which they were victims. The linguist correctly identified nine cases out of ten using CA. © 2012 Elsevier Inc.

Summary Purpose: Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment. Methods: Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk-locked back-averaging and analysis of the EEG–EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations. Key Findings: The main clinical features were adolescent–young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12–20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG–EMG signals indicating a significant EEG–EMG coupling and a direct corticospinal transfer. Significance: Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment.

Psychogenic nonepileptic seizures (PNES) can be observed in patients with or without epilepsy (mixed and pure PNES). Patients with mixed PNES are usually considered to be a homogeneous group characterized by the coexistent epilepsy. Our study found that patients with mixed PNES were not homogeneous, but could be divided into three groups based on epilepsy type, mental level, comorbid psychiatric disorders, and history of traumatic experiences. Group 1 patients have pharmacoresistant epilepsy, normal cognition, and comorbid anxiety and/or depressive disorders. Here, PNES etiology is the epilepsy-related problems. In group 2 patients, the epilepsy is associated with mental retardation and dependent personality traits. PNES etiology is represented by the reduction or cessation of seizures. The PNES allow patients to continue receiving attention from caregivers. Group 3 patients have epilepsy, normal cognition, comorbid cluster B personality disorders and anxiety disorders, and psychic trauma. Here, PNES etiology is not related to the epilepsy, but to the psychic trauma.

We conducted a search for white matter changes (WMCs) in 13 Unverricht-Lundborg disease patients and compared the prevalence of WMCs in these patients to age-matched long-term epileptics and healthy controls. ULD patients had significantly more T2-weighted high-intensity signals on MRI than control subjects, due to the increased prevalence of these signals in the basal ganglia. Interestingly, ULD patients with the basal ganglia changes were overweight. Basal ganglia T2-weighted high-intensity signals are novel findings in ULD.

Summary Objective To investigate if, when, and to what extent visual information contained in a video-recorded event allows experienced epileptologists to predict the diagnosis of psychogenic nonepileptic seizures (PNES) without the aid of electroencephalography (EEG). Methods Five neurologists actively practicing in epilepsy centers in Italy and the United States were asked to review 23 videos capturing representative events of 21 unselected consecutive patients admitted for long-term video-EEG monitoring (VEM). Four raters were blind to EEG and clinical information; one rater was not. They were requested to (1) rate the videos for quality and content; (2) choose among four diagnoses: (a) epileptic seizures (ES); (b) PNES; (c) Other nonepileptic seizures (NES; (syncope, movement disorder, migraine, etc.); (d) “Cannot Say”; and (3) explain in their own words the main reasons leading to the diagnosis of choice. Results All raters predicted the diagnosis correctly in 7 of 23 videos (all ES or PNES) (30.4%), whereas all raters failed in 5 of 23 cases (three Other NES, one PNES, one Cannot Say) (21.7%). The conditions that facilitate, and those that interfere with, a confident diagnosis were predictable. Degree of accuracy among raters was not uniform and was consistently better in three raters. Two among the four blind raters were as accurate as the rater who was not blinded. Interrater agreement was “moderate” (k = 0.52) for the overall group; “moderate” for ES (k = 0.53); “substantial” for PNES (k = 0.63); “fair” for Other NES (k = 0.21)—similar to the results obtained in a previous study evaluating the reliability of combined video-EEG. Significance In about one third of cases, a confident diagnosis of PNES/ES can be established on clinical grounds based on video data alone. Our results benefit all affected patients, particularly those with no access to video-EEG monitoring units.

Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy characterized by myoclonus, epilepsy, and ataxia, without major cognitive decline. There is no systematic study on the long-term evolution of EEG in this condition.Twenty-five patients with ULD who came to our observation before 1995 and periodically followed in our Epilepsy Centres were included. All waking EEG traces were visually reviewed for the characterization background activity, with particular regard to the frequency of the posterior dominant rhythm (PR), and for the occurrence of spontaneous generalized spike or polyspike and wave discharges (GSWD) and photoparoxysmal response (PPR). Sleep recordings were analyzed with particular regard to the preservation of the physiological sleep patterns and the occurrence of GSWD and other epileptic abnormalities.PR was normal in 68% of patients at the beginning of the disease and kept stable over the years. GSWD were present in 92% of patients at the onset of the disease and gradually disappeared during the follow-up with a significant difference (p0.001) after the 15th year of disease. PPR was present in 88% of patients at the disease onset and gradually disappeared with a significant difference (p0.001) after the 10th year of disease. A gradual reduction of GSWD and a progressive disappearance of physiological sleep patterns were observed in sleep EEGs.In patients with ULD followed for an extended period of time, EEG shows no relevant deterioration of BA while a gradual reduction of GSWD and PPR is observed over time, well correlating with the good seizure outcome in this condition.

The aim of this study was to validate a novel classification for the diagnosis of PNESs. Fifty-five PNES video-EEG recordings were retrospectively analyzed by four epileptologists and one psychiatrist in a blind manner and classified into four distinct groups: Hypermotor (H), Akinetic (A), Focal Motor (FM), and with Subjective Symptoms (SS). Eleven signs and symptoms, which are frequently found in PNESs, were chosen for statistical validation of our classification. An artificial neural network (ANN) analyzed PNES video recordings based on the signs and symptoms mentioned above. By comparing results produced by the ANN with classifications given by examiners, we were able to understand whether such classification was objective and generalizable. Through accordance metrics based on signs and symptoms (range: 0-100%), we found that most of the seizures belonging to class A showed a high degree of accordance (mean ± SD = 73% ± 5%); a similar pattern was found for class SS (80% slightly lower accordance was reported for class H (58% ± 18%)), with a minimum of 30% in some cases. Low agreement arose from the FM group. Seizures were univocally assigned to a given class in 83.6% of seizures. The ANN classified PNESs in the same way as visual examination in 86.7%. Agreement between ANN classification and visual classification reached 83.3% (SD = 17.8%) accordance for class H, 100% (SD = 22%) for class A, 83.3% (SD = 21.2%) for class SS, and 50% (SD = 19.52%) for class FM. This is the first study in which the validity of a new PNES classification was established and reached in two different ways. Video-EEG evaluation needs to be performed by an experienced clinician, but later on, it may be fed into ANN analysis, whose feedback will provide guidance for differential diagnosis. Our analysis, supported by the ML approach, showed that this model of classification could be objectively performed by video-EEG examination.

Summary Objective To evaluate efficacy, tolerability, and safety of adjunctive brivaracetam (BRV) in patients with Unverricht-Lundborg disease (EPM1). Methods Two prospective, multicenter, double-blind, phase III trials (N01187/NCT00357669; N01236/NCT00368251) in patients (≥16 years) with genetically ascertained EPM1, showing moderate–severe myoclonus (action myoclonus score ≥30/160), randomized (1:1:1) to twice-daily BRV (N01187: 50 or 150 mg/day; N01236: 5 or 150 mg/day), or placebo. Both studies comprised a baseline period (2 weeks), 2-week up-titration period, 12-week stable-dose maintenance period, and down-titration or entry into long-term follow-up study. Symptoms of myoclonus were assessed by Unified Myoclonus Rating Scale (UMRS). Primary efficacy end point was percent reduction from baseline in action myoclonus score (UMRS section 4) at last treatment visit. Safety assessments included treatment-emergent adverse events (TEAEs). Results N01187: 50 patients randomized, 47 completed; N01236: 56 patients randomized, 54 completed. Median (min–max) percent reduction from baseline in action myoclonus score is the following—N01187: placebo 5.6 (−81.3 to 53.8), pooled BRV group (primary efficacy analysis) 21.4 (−50.0 to 73.6), BRV 50 mg/day 26.3 (−35.8 to 69.2), BRV 150 mg/day 16.9 (−50.0 to 73.6); N01236: placebo 17.5 (−170 to 61.5), BRV 5 mg/day −4.6 (−430 to 81.8), BRV 150 mg/day (primary efficacy analysis) 12.3 (−58.3 to 96.9). Estimated differences versus placebo were not statistically significant. TEAEs were reported by 72–75% placebo-treated and 56–83% BRV-treated patients. Significance Effect of BRV on action myoclonus was not statistically significant. However, action myoclonus score showed wide intrapatient variability and may not have been the optimal tool to measure severity of myoclonus in EPM1. Both studies had very high completion rates (95.3% overall), and a high percentage of patients (88.7% overall) entered long-term follow-up; both likely to be influenced by good tolerability. These studies demonstrate the feasibility of rigorous trials in progressive myoclonic epilepsy.

The authors report the clinical and polygraphic features of rhythmic teeth grinding observed in a patient as the predominant symptom related to temporal lobe seizures during sleep and wakefulness. This observation demonstrates that exceptionally a teeth-grinding event can be not only a parasomnia (sleep bruxism) but also an epileptic-related motor event. Electromyographic and autonomic features of seizure-related teeth grinding support the interpretation of this motor phenomenon as a particular form of masticatory activity.

Carbamazepine-induced abnormal movements have been reported in children and adult patients, and both non-epileptic myoclonus and tic-like movements have been reported in the same patient. Although a pathogenetic mechanism underlying carbamazepine-induced epileptic negative myoclonus has been proposed, a causative role of carbamazepine for positive myoclonus has not been fully identified. Here, we describe the video-documented case of an adult patient with non-epileptic myoclonus and tic-like movements persisting for 21 years, which appeared after he started carbamazepine treatment at 10 years of age. [Published with videosequences].

Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment.Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk-locked back-averaging and analysis of the EEG-EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations.The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12-20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG-EMG signals indicating a significant EEG-EMG coupling and a direct corticospinal transfer.Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment.

The aims of this study were to clarify if patients with Unverricht–Lundborg disease (ULD) have adequate cognitive functioning and to delineate their neuropsychological profile. We evaluated 20 patients with ULD and 20 healthy, matched controls. Mean age of the patients was 35 years, and mean duration of disease, 22 years. Patients underwent a neuropsychological battery exploring intelligence, executive functions, visuospatial and verbal memory, depression, and anxiety. Eleven of 20 subjects with ULD had mild to moderate cognitive impairment. Compared with controls, patients with ULD had lower scores on all short-term memory and executive function tasks. Linear regression analysis disclosed significant associations between impaired performance on some memory tests and duration of disease and between severity of myoclonus and performance on most executive function tests. In conclusion, most patients with ULD seem to be impaired with respect to cognitive abilities. Longitudinal prospective studies are needed to confirm and further expand our findings.

A 76-year-old patient, since the age of 45, presented with frequent attacks often triggered by emotional stimuli and characterised by forward head drop and a fall to the ground without loss of consciousness. Clinically these episodes were misinterpreted as pseudoseizures and treated with clomipramine for more than 20 years. In spite of this chronic therapy, during the last year, the attacks presented with a daily recurrence and, moreover, after arbitrary clomipramine withdrawal, they increased in frequency until they became subcontinuous. Videopolygraphic analysis, multiple sleep latency test (MSLT) and human leukocyte antigen (HLA) association studies were suggestive of narcolepsy and the recurrent episodes, diagnosed as status cataplecticus, recovered after citalopram administration.

In Diagnostic and Statistical Manual of Mental Disorders, fifth edition, psychogenic non-epileptic seizures (PNES) do not have a unique classification as they can be found within different categories: conversion, dissociative, and somatization disorders. The ICD-10, instead, considers PNES within dissociative disorders, merging the dissociative disorders and conversion disorders, although the underlying defense mechanisms are different. The literature data show that PNES are associated with cluster B (mainly borderline) personality disorders and/or to people with depressive or anxiety disorders. Defense mechanisms in patients with PNES with a prevalence of anxious/depressive symptoms are of "neurotic" type; their goal is to lead to a "split", either vertical (dissociation) or horizontal (repression). The majority of patients with this type of PNES have alexithymia traits, meaning that they had difficulties in feeling or perceiving emotions. In subjects where PNES are associated with a borderline personality, in which the symbolic function is lost, the defense mechanisms are of a more archaic nature (denial). PNES with different underlying defense mechanisms have different prognoses (despite similar severity of PNES) and need usually a different treatment (pharmacological or psychological). Thus, it appears superfluous to talk about psychiatric comorbidity, since PNES are a different symptomatic expression of specific psychiatric disorders.

Summary: Purpose: To assess the long-term evolution of Unverricht–Lundborg disease (ULD), especially concerning myoclonus, seizures, and EEG characteristics. Methods: We retrospectively evaluated 20 patients (six women, 14 men; mean age, 37.9 years; range, 26–53 years) with ULD who had been closely followed up since the onset of the disease (mean age, 12.3 years; range, 6–17 years) for an average of 25.6 years (range, 13–41 years). ULD was confirmed by genetic tests in all. We used simplified myoclonus and seizure rating scales. Results: The geographic origin of the patients was Northern Africa in nine, France in two, Italy in six, and mixed European in three. Three patients were severely handicapped, six led fully autonomous lives, and 11 required various degrees of social support. Myoclonus progressed only during the first 5 years of disease. Major seizures occurred in 19. Three patients had a single seizure, and eight became seizure free, whereas six had rare seizures, and two had frequent attacks. Overall, seizures became much less frequent after 10 years of evolution. EEG changes abated during follow-up: background activity remained stable or improved, spontaneous discharges disappeared, and photoparoxysmal responses were abolished in all patients but two. Conclusions: This study shows that ULD progresses only over a limited period and stabilizes thereafter. This self-limited progression may be the consequence of age-related apoptosis of selected neuronal populations.

Summary: Purpose: Disabling myoclonus is the main symptom in long-standing Unverricht–Lundborg disease (ULD), and levetiracetam (LEV) appears to be an effective anticonvulsant with promising short-term antimyoclonic properties. Methods: LEV was prescribed to 13 patients with ULD. We retrospectively analyzed the efficacy of LEV on seizure frequency and on myoclonus, by using a simplified myoclonus rating score, and compared the patients' status before LEV and at the last follow-up. They were two women and 11 men, aged 14 to 52 years (mean, 36.5 years), with a disease duration of 4 to 40 years (mean, 24.3 years). LEV was given at 2,000 to 4,000 mg/d for 0.5 to 26 months (mean, 13.8 months). Results: One patient stopped LEV within 2 weeks because of side effects and lack of efficacy. None of the other 12 patients reported side effects. The average myoclonus score significantly changed from 3.1 to 2.4 (p = 0.01), but only eight had a measurable improvement. Conclusions: The best effects were noted in the younger patients. In patients previously treated with high-dose piracetam (PIR), discontinuation of PIR was not always well tolerated, and a combination of PIR at lower doses and LEV appeared to be a practical solution. LEV should probably be considered as a major treatment option early in the course of ULD.

We report the case of a patient who, following a right thalamic haemorrhage, developed thalamic syndrome characterised by burning pain and hyperalgesia in the left side of the body. Three years later, following a further (contralateral ischaemic) stroke, she reported the complete disappearance of the pain and hyperalgesia. To our knowledge, this is the first described case of disappearance of thalamic syndrome following a second stroke, different in nature from and contralateral to the first. Various hypotheses, based on the nervous tracts and nuclei involved in pain processing, may be advanced to explain this occurrence.

We evaluated the use of felbamate in 379 adults and children with refractory epilepsies in an open-label, compassionate clinical use setting. Prior to the termination of the program, because of reports of aplastic anemia, 351 patients had completed 2 months of treatment with felbamate at a dose of 2400–3600 mg/day for adults or 30–45 mg/kg/day for children. Of the 246 patients who had a diagnosis of therapy-refractory localization-related ipelepsy with or without secondary generalization, 52% ( 126 246 ) achieved a seizure reduction of 50% or more, including 10% ( 25 246 ) who became seizure free. There was no difference in response rate between adults and children. Of the 80 patients who had a diagnosis of Lennox-Gastaut syndrome (LGS), 60% ( 48 80 ) achieved a seizure reduction of 50% or more, including 6% ( 5 80 ) who became seizure free. Of the 25 patients with a diagnosis of generalized epilepsy (other than LGS) or undetermined epilepsy whether focal or generalized, 60% ( 15 25 ) achieved a seizure reduction of 50% or more, including 12% ( 3 24 ) who became seizure free. The results of this uncontrolled study suggest that felbamate could be useful in patients with epilepsies which are refractory to other antiepileptic drugs after careful risk-benefit assessment and consideration of all circumstances involved.

In each of 2 unrelated Algerian families, we observed 2 sisters with a severe static encephalopathy which was detected in the first weeks of life. Anoxia at birth occurred in only one case. This previously unreported familial encephalopathy is characterized by severe mental retardation, hypotrophy, abnormal movements with unprovoked startles, major EEG abnormalities with undifferentiated sleep stages and a very particular periodic breathing pattern that persists during waking and sleep. EEG, polygraphic and video recordings were obtained for all patients. The evolution is chronic and stable. There are no major dysmorphic features. No metabolic or anatomic abnormality was found. Gynecotropy is uncertain and the transmission is likely to be recessive.

No familial cases of epilepsy associated with bilateral occipital calcifications (EBOC) have been reported so far. This paper describes the clinical, electrophysiological and radiological study of two sisters affected by partial epilepsy, one with unilateral and the other with bilateral occipital calcifications. Celiac disease was excluded in both patients, even though they presented the same HLA pattern usually found in coeliac subjects.