Spanish consensus on the management of concomitant antiseizure medications when using cenobamate in adults with drug-resistant focal seizures.

OBJECTIVE: Cenobamate is an antiseizure medication (ASM) associated with high rates of seizure freedom and acceptable tolerability in patients with focal seizures. To achieve the optimal cenobamate dose for maximal potential effectiveness while avoiding or minimizing drug-related adverse events (AEs), the administration of cenobamate with other ASMs must be managed through concomitant ASM load reduction. A panel of Spanish epilepsy experts aimed to provide a Spanish consensus on how to adjust the dose of concomitant ASMs in patients with drug-resistant epilepsy (DRE) in order to improve the effectiveness and tolerability of adjunctive cenobamate. METHODS: A three-stage modified Delphi consensus process was undertaken, including six Spanish epileptologists with extensive experience using cenobamate. Based on current literature and their own expert opinion, the expert panel reached a consensus on when and how to adjust the dosage of concomitant ASMs during cenobamate titration. RESULTS: The expert panel agreed that tailored titration and close follow-up are required to achieve the best efficacy and tolerability when initiating cenobamate in patients receiving concomitant ASMs. When concomitant clobazam, phenytoin, phenobarbital, and sodium channel blockers are taken at high dosages, or when the patient is receiving two or more sodium channel blockers, dosages should be proactively lowered during the cenobamate titration period. Other concomitant ASMs should be reduced only if the patient reports a moderate/severe AE at any stage of the titration period. SIGNIFICANCE: Cenobamate is an effective ASM with a dose-dependent effect. To maximize effectiveness while maintaining the best tolerability profile, co-medication management is needed. The recommendations included herein provide practical guidance for proactive and reactive management of co-medication in cenobamate-treated patients with DRE and a high drug load. PLAIN LANGUAGE SUMMARY: Patients with epilepsy may continue to have seizures even after treatment with several different antiseizure medications (ASMs). Cenobamate is an ASM that can reduce seizures in these patients. In this study, six Spanish experts in epilepsy discussed the best way to use cenobamate in drug-resistant epilepsy. They provide practical guidance on when and how the dose of other ASMs might be adjusted to reduce side effects and optimize the use of cenobamate.

Effect of intracerebroventricular administration of alglucosidase alfa in two mouse models of Lafora disease: Relevance for clinical practice.

Lafora disease is a rare and fatal form of progressive myoclonic epilepsy with onset during early adolescence. The disease is caused by mutations in EPM2A, encoding laforin, or EPM2B, encoding malin. Both proteins have functions that affect glycogen metabolism, including glycogen dephosphorylation by laforin and ubiquitination of enzymes involved in glycogen metabolism by malin. Lack of function of laforin or malin results in the accumulation of polyglucosan that forms Lafora bodies in the central nervous system and other tissues. Enzyme replacement therapy through intravenous administration of alglucosidase alfa (Myozyme®) has shown beneficial effects removing polyglucosan aggregates in Pompe disease. We evaluated the effectiveness of intracerebroventricular administration of alglucosidase alfa in the Epm2a-/- knock-out and Epm2aR240X knock-in mouse models of Lafora disease. Seven days after a single intracerebroventricular injection of alglucosidase alfa in 12-month-old Epm2a-/- and Epm2aR240X mice, the number of Lafora bodies was not reduced. Additionally, a prolonged infusion of alglucosidase alfa for 2 or 4 weeks in 6- and 9-month-old Epm2a-/- mice did not result in a reduction in the number of LBs or the amount of glycogen in the brain. These findings hold particular significance in guiding a rational approach to the utilization of novel therapies in Lafora disease.

Epm2aR240X knock-in mice present earlier cognitive decline and more epileptic activity than Epm2a-/- mice.

Lafora disease is a rare recessive form of progressive myoclonic epilepsy, usually diagnosed during adolescence. Patients present with myoclonus, neurological deterioration, and generalized tonic-clonic, myoclonic, or absence seizures. Symptoms worsen until death, usually within the first ten years of clinical onset. The primary histopathological hallmark is the formation of aberrant polyglucosan aggregates called Lafora bodies in the brain and other tissues. Lafora disease is caused by mutations in either the EPM2A gene, encoding laforin, or the EPM2B gene, coding for malin. The most frequent EPM2A mutation is R241X, which is also the most prevalent in Spain. The Epm2a-/- and Epm2b-/- mouse models of Lafora disease show neuropathological and behavioral abnormalities similar to those seen in patients, although with a milder phenotype. To obtain a more accurate animal model, we generated the Epm2aR240X knock-in mouse line with the R240X mutation in the Epm2a gene, using genetic engineering based on CRISPR-Cas9 technology. Epm2aR240X mice exhibit most of the alterations reported in patients, including the presence of LBs, neurodegeneration, neuroinflammation, interictal spikes, neuronal hyperexcitability, and cognitive decline, despite the absence of motor impairments. The Epm2aR240X knock-in mouse displays some symptoms that are more severe that those observed in the Epm2a-/- knock-out, including earlier and more pronounced memory loss, increased levels of neuroinflammation, more interictal spikes and increased neuronal hyperexcitability, symptoms that more precisely resemble those observed in patients. This new mouse model can therefore be specifically used to evaluate how new therapies affects these features with greater precision.

Familial adult myoclonus epilepsy: Clinical findings, disease course, and comorbidities.

Familial adult myoclonus epilepsy (FAME) is an autosomal dominant condition characterized by the association of myoclonic tremor and epilepsy mainly with onset in adulthood. The clinical course is non-progressive or slowly progressive, as epilepsy is commonly controlled with appropriate antiseizure medication and individuals have a normal life expectancy. However, the myoclonus severity increases with age and leads to some degree of disability in the elderly. Because the non-coding repeat expansions responsible for FAME are not detected by routine genetic tests being used at this time, a clinical diagnosis accompanied by neurophysiological testing remains essential to guide the geneticist on the selection of the specific genetic technique.

Antiepileptogenesis after stroke-trials and tribulations: Methodological challenges and recruitment results of a Phase II study with eslicarbazepine acetate.

There is currently no evidence to support the use of antiseizure medications to prevent unprovoked seizures following stroke. Experimental animal models suggested a potential antiepileptogenic effect for eslicarbazepine acetate (ESL), and a Phase II, multicenter, randomized, double-blind, placebo-controlled study was designed to test this hypothesis and assess whether ESL treatment for 1 month can prevent unprovoked seizures following stroke. We outline the design and status of this antiepileptogenesis study, and discuss the challenges encountered in its execution to date. Patients at high risk of developing unprovoked seizures after acute intracerebral hemorrhage or acute ischemic stroke were randomized to receive ESL 800 mg/d or placebo, initiated within 120 hours after primary stroke occurrence. Treatment continued until Day 30, then tapered off. Patients could receive all necessary therapies for stroke treatment according to clinical practice guidelines and standard of care, and are being followed up for 18 months. The primary efficacy endpoint is the occurrence of a first unprovoked seizure within 6 months after randomization ("failure rate"). Secondary efficacy assessments include the occurrence of a first unprovoked seizure during 12 months after randomization and during the entire study; functional outcomes (Barthel Index original 10-item version; National Institutes of Health Stroke Scale); post-stroke depression (Patient Health Questionnaire-9; PHQ-9); and overall survival. Safety assessments include the evaluation of treatment-emergent adverse events; laboratory parameters; vital signs; electrocardiogram; suicidal ideation and behavior (PHQ-9 question 9). The protocol aimed to randomize approximately 200 patients (1:1), recruited from 21 sites in seven European countries and Israel. Despite the challenges encountered, particularly during the COVID-19 pandemic, the study progressed and included a remarkable number of patients, with 129 screened and 125 randomized. Recruitment was stopped after 30 months, the first patient entered in May 2019, and the study is ongoing and following up on patients according to the Clinical Trial Protocol.

Number needed to treat and associated cost analysis of cenobamate versus third-generation anti-seizure medications for the treatment of focal-onset seizures in patients with drug-resistant epilepsy in Spain.

INTRODUCTION: Epilepsy is a serious neurological disease, ranking high in the top causes of disability. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, approximately 40% of patients suffer from Drug-Resistant Epilepsy (DRE) despite the availability of the latest options called third-generation Anti-Seizure Medications(ASMs). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. The introduction of a new drug increases the number of therapeutic options available, making it important to compare it with existing alternatives in terms of clinical benefit and efficiency. PURPOSE: This study aimed to compare the clinical benefit, in terms of the Number Needed to Treat (NNT), and the efficiency, in terms of Cost per NNT (CNT), associated with cenobamate versus third-generation ASMs used in Spain for the adjunctive treatment of FOS in patients with DRE. METHODS: The Number Needed to Treat data was calculated based on the ≥50% responder rate and seizure freedom endpoints (defined as the percentage of patients achieving 50% and 100% reduction in seizure frequency, respectively), obtained from pivotal clinical trials performed with cenobamate, brivaracetam, perampanel, lacosamide, and eslicarbazepine acetate. The NNT was established as the inverse of the treatment responder rate minus the placebo responder rate and was calculated based on the minimum, mid-range Daily Defined Dose (DDD), and maximum doses studied in the pivotal clinical trials of each ASM. CNT was calculated by multiplying the annual treatment cost by NNT values for each treatment option. RESULTS: In terms of NNT, cenobamate was the ASM associated with the lowest values at all doses for both ≥50% responder rate and seizure freedom compared with the alternatives. In terms of CNT, for ≥50% responder rate, cenobamate was the ASM associated with the lowest CNT values at DDD and lacosamide and eslicarbazepine acetate at the minimum and maximum dose, respectively. For seizure freedom, cenobamate was associated with the lowest CNT value at DDD and the maximum dose and lacosamide at the minimum dose. CONCLUSIONS: Cenobamate could represent the most effective ASM in all doses studied compared to the third-generation ASMs and the most efficient option at DDD for both ≥50% responder rate and seizure freedom. This study could represent an important contribution towards informed decision-making regarding the selection of the most appropriate therapy for FOS in adult patients with DRE from a clinical and economical perspective in Spain.

Early Treatment with Metformin Improves Neurological Outcomes in Lafora Disease.

Lafora disease is a fatal form of progressive myoclonic epilepsy caused by mutations in the EPM2A or NHLRC1/EPM2B genes that usually appears during adolescence. The Epm2a-/- and Epm2b-/- knock-out mouse models of the disease develop behavioral and neurological alterations similar to those observed in patients. The aim of this work is to analyze whether early treatment with metformin (from conception to adulthood) ameliorates the formation of Lafora bodies and improves the behavioral and neurological outcomes observed with late treatment (during 2 months at 10 months of age). We also evaluated the benefits of metformin in patients with Lafora disease. To assess neurological improvements due to metformin administration in the two mouse models, we evaluated the effects on pentylenetetrazol sensitivity, posturing, motor coordination and activity, and memory. We also analyzed the effects on Lafora bodies, neurodegeneration, and astrogliosis. Furthermore, we conducted a follow-up study of an initial cohort of 18 patients with Lafora disease, 8 treated with metformin and 10 untreated. Our results indicate that early metformin was more effective than late metformin in Lafora disease mouse models improving neurological alterations of both models such as neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreasing the formation of Lafora bodies. Moreover, patients receiving metformin had a slower progression of the disease. Overall, early treatment improves the outcome seen with late metformin treatment in the two knock-out mouse models of Lafora disease. Metformin-treated patients exhibited an ameliorated course of the disease with slower deterioration of their daily living activities.

Initial monotherapy with eslicarbazepine acetate for the management of adult patients with focal epilepsy in clinical practice: a meta-analysis of observational studies.

AIM OF THE STUDY: To assess the effectiveness, overall tolerability of eslicarbazepine acetate (ESL) as an initial or early monotherapy treatment of adult patients with focal epilepsy under real-world practice conditions. MATERIALS AND METHODS: We focused on real-world longitudinal studies that included or separately reported the results of at least one of the efficacy outcomes of interest. A DerSimonian-Laird random effects model was used with the presentation of the 95% confidence intervals of the estimate. RESULTS: 5 studies met our selection criteria and were included in the quantitative synthesis. All studies were observational and uncontrolled studies, and all but one were retrospective studies. The pooled proportion of patients who were seizure-free for the entire study period was 64.6% (95% CI, 45.7 to 79.8) at month 6 and 56.6% (95% CI, 50.2 to 62.8) at month 12. Pooled retention rates were 95.0% (95% CI, 90.3 to 97.5) at 6 months and 83.6% (95% CI, 73.9 to 90.1) at 12 months. The pooled proportion of patients who reported at least one adverse event was 27.2% (95% CI, 21.7 to 33.6), and the pooled proportion of patients who discontinued ESL due to adverse events was 8.9% (95% CI 6.2 to 12.6). CONCLUSIONS: Our results suggest that initial or early monotherapy with ESL is effective and well-tolerated for the management of adult patients with focal epilepsy in clinical practice, with results that are at least similar to those reported in the pivotal randomized clinical trial of ESL monotherapy. No new safety signals with ESL have been identified in this systematic review.

Gene replacement therapy for Lafora disease in the Epm2a -/- mouse model.

Lafora disease is a rare and fatal form of progressive myoclonic epilepsy typically occurring early in adolescence. Common symptoms include seizures, dementia, and a progressive neurological decline leading to death within 5-15 years from onset. The disease results from mutations transmitted with autosomal recessive inheritance in the EPM2A gene, encoding laforin, a dual-specificity phosphatase, or the EPM2B gene, encoding malin, an E3-ubiquitin ligase. Laforin has glucan phosphatase activity, is an adapter of enzymes involved in glycogen metabolism, is involved in endoplasmic reticulum-stress and protein clearance, and acts as a tumor suppressor protein. Laforin and malin work together in a complex to control glycogen synthesis and prevent the toxicity produced by misfolded proteins via the ubiquitin-proteasome system. Disruptions in either protein can lead to alterations in this complex, leading to the formation of Lafora bodies that contain abnormal, insoluble, and hyperphosphorylated forms of glycogen called polyglucosans. We used the Epm2a -/- knock-out mouse model of Lafora disease to apply a gene replacement therapy by administering intracerebroventricular injections of a recombinant adeno-associated virus carrying the human EPM2A gene. We evaluated the effects of this treatment by means of neuropathological studies, behavioral tests, video-electroencephalography recording, and proteomic/phosphoproteomic analysis. Gene therapy with recombinant adeno-associated virus containing the EPM2A gene ameliorated neurological and histopathological alterations, reduced epileptic activity and neuronal hyperexcitability, and decreased the formation of Lafora bodies. Differential quantitative proteomics and phosphoproteomics revealed beneficial changes in various molecular pathways altered in Lafora disease. Improvements were observed for up to nine months following a single intracerebroventricular injection. In conclusion, gene replacement therapy with human EPM2A gene in the Epm2a -/- knock-out mice shows promise as a potential treatment for Lafora disease.

Onset of efficacy and adverse events during Cenobamate titration period.

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

Efficacy and safety of adjunctive cenobamate: Post-hoc analysis of study C017 in patients grouped by mechanism of action of concomitant antiseizure medications.

PURPOSE: To assess how efficacy and safety outcomes were affected when cenobamate was co-administered with antiseizure medications (ASMs) that use either sodium channel blocker (SCB) or non-sodium channel blocker (non-SCB) mechanisms of action (MoAs) in patients with uncontrolled focal seizures. METHODS: An exploratory post-hoc analysis of a randomized, double-blind, placebo-controlled clinical study (YKP3089C017) was conducted. Baseline concomitant ASMs were grouped as either those that employed an SCB or non-SCB MoA. Efficacy was examined by cenobamate dose (100 mg, 200 mg, and 400 mg/day) and concomitant ASM group using responder rates (≥50%, ≥75%, ≥90% seizure reduction; 100% seizure reduction/seizure freedom) during the maintenance phase and median percentage seizure reduction during the double-blind period. Treatment-emergent adverse events (TEAEs) were examined in the double-blind period. RESULTS: When co-administered with SCBs or non-SCBs, significantly higher percentages of patients achieved ≥50%, ≥75%, and ≥90% responder rates with cenobamate 200 mg/day and/or 400 mg/day versus placebo. Additionally, significantly higher percentages of patients achieved seizure freedom with cenobamate 400 mg/day versus placebo (SCB group, 17.5% versus 1.2%; non-SCB group, 40.0% versus 0.0%). Patients receiving 200 mg/day and 400 mg/day and concomitant SCBs and all patients taking cenobamate combined with non-SCB concomitant ASMs had significantly greater median percentage reductions in focal seizure frequency versus placebo. TEAEs were similar across groups; however, dizziness was more frequently reported in the SCB group. CONCLUSION: Cenobamate is a highly effective new treatment option for patients with uncontrolled focal seizures when co-administered with SCB or non-SCB ASMs.

An empirical pipeline for personalized diagnosis of Lafora disease mutations.

Lafora disease (LD) is a fatal childhood dementia characterized by progressive myoclonic epilepsy manifesting in the teenage years, rapid neurological decline, and death typically within ten years of onset. Mutations in either EPM2A, encoding the glycogen phosphatase laforin, or EPM2B, encoding the E3 ligase malin, cause LD. Whole exome sequencing has revealed many EPM2A variants associated with late-onset or slower disease progression. We established an empirical pipeline for characterizing the functional consequences of laforin missense mutations in vitro using complementary biochemical approaches. Analysis of 26 mutations revealed distinct functional classes associated with different outcomes that were supported by clinical cases. For example, F321C and G279C mutations have attenuated functional defects and are associated with slow progression. This pipeline enabled rapid characterization and classification of newly identified EPM2A mutations, providing clinicians and researchers genetic information to guide treatment of LD patients.

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

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

4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy.

Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)­encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment.

Structural and Functional Brain Abnormalities in Mouse Models of Lafora Disease.

Mutations in the EPM2A and EPM2B genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, decreased glucose brain uptake and alterations on different brain metabolites mainly in the frontal cortex, basal ganglia and cerebellum. Mice deficient for laforin and malin present many features similar to those observed in patients, including cognitive, motor, histological and epileptic hallmarks. We describe the neuroimaging features found in two mouse models of Lafora disease. We found altered volumetric values in the cerebral cortex, hippocampus, basal ganglia and cerebellum using magnetic resonance imaging (MRI). Positron emission tomography (PET) of the cerebral cortex, hippocampus and cerebellum of Epm2a-/- mice revealed abnormal glucose uptake, although no alterations in Epm2b-/- mice were observed. Magnetic resonance spectroscopy (MRS) revealed significant changes in the concentration of several brain metabolites, including N-acetylaspartate (NAA), in agreement with previously described findings in patients. These data may provide new insights into disease mechanisms that may be of value for developing new biomarkers for diagnosis, prevention and treatment of Lafora disease using animal models.

¿Espasmo del sollozo prolongado o crisis epiléptica?: descripción de tres niñas con crisis epilépticas desencadenadas por anoxia / Breath-holding spell or epileptic seizure? A description of three girls with epileptic seizures triggered by anoxia

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Neuroinflammation and progressive myoclonus epilepsies: from basic science to therapeutic opportunities.

Progressive myoclonus epilepsies (PMEs) are a group of genetic neurological disorders characterised by the occurrence of epileptic seizures, myoclonus and progressive neurological deterioration including cerebellar involvement and dementia. The primary cause of PMEs is variable and alterations in the corresponding mutated genes determine the progression and severity of the disease. In most cases, they lead to the death of the patient after a period of prolonged disability. PMEs also share poor information on the pathophysiological bases and the lack of a specific treatment. Recent reports suggest that neuroinflammation is a common trait under all these conditions. Here, we review similarities and differences in neuroinflammatory response in several PMEs and discuss the window of opportunity of using anti-inflammatory drugs in the treatment of several of these conditions.

De novo truncating mutation in SCN1A as a cause of febrile seizures plus (FS+).

SCN1A is one of the most relevant epilepsy genes. In general, de novo severe mutations, such as truncating mutations, lead to a classic form of Dravet syndrome (DS), while missense mutations are associated with both DS and milder phenotypes within the GEFS+ spectrum, however, these phenotype-genotype correlations are not entirely consistent. Case report. We report an 18-year-old woman with a history of recurrent febrile generalized tonic-clonic seizures (GTCS) starting at age four months and afebrile asymmetric GTCS and episodes of arrest, suggestive of focal impaired awareness seizures, starting at nine months. Her psychomotor development was normal. Sequencing of SCN1A revealed a heterozygous de novo truncating mutation (c.5734C>T, p.Arg1912X) in exon 26. Conclusion. Truncating mutations in SCN1A may be associated with milder phenotypes within the GEFS+ spectrum. Accordingly, SCN1A gene testing should be performed as part of the assessment for sporadic patients with mild phenotypes that fit within the GEFS+ spectrum, since the finding of a mutation has diagnostic, therapeutic and genetic counselling implications.

Expanding the clinical and EEG spectrum of CNKSR2-related encephalopathy with status epilepticus during slow sleep (ESES).

OBJECTIVE: To investigate the clinical and EEG features of Encephalopathy with Status Epilepticus during slow Sleep (ESES) related to CNKSR2 pathogenic variants. METHODS: Detailed clinical history, repeated wakefulness/overnight sleep EEGs, brain MRI were collected in five patients, including one female, with CNKSR2-related ESES. RESULTS: Neurodevelopment in infancy was normal in two patients, delayed in three. Epilepsy onset (age range: 2-6 years) was associated with appearance or aggravation of cognitive impairment, language regression and/or behavioral disorders. Worsening of epilepsy and of cognitive/behavioral disturbances paralleled by enhancement of non-rapid eye movement (NREM) sleep-related, frontally predominant, EEG epileptic discharges [spike-wave-index (SWI): range 60-96%] was consistent with ESES. In three patients, episodes of absence status epilepticus or aggravation of atypical absences occurred, in this latter case associated with striking increment of awake SWI. Speech/oro-motor dyspraxia was diagnosed in four patients. In two patients, long-term follow-up showed epilepsy remission and persistence of mild/moderate cognitive disorders and behavioral disturbances into adulthood. CONCLUSIONS: Novel findings of our study are occurrence also in females, normal neurodevelopment before epilepsy onset, epilepsy aggravation associated with enhanced awake SWI, mild/moderate evolution in adulthood and language disorder due to speech/oro-motor dyspraxia. SIGNIFICANCE: Our findings expand the phenotypic spectrum of CNKSR2-related ESES.

The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic.

Lafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain. The workshop brought together nearly 100 clinicians, academic and industry scientists, trainees, National Institutes of Health (NIH) representation, and friends and family members of patients with LD. The workshop covered aspects of LD ranging from defining basic scientific mechanisms to elucidating a LD therapy or cure and a recently launched LD natural history study.