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OBJECTIVE: Posttraumatic epilepsy (PTE) significantly impacts morbidity and mortality, yet local PTE data remain scarce. In addition, there is a lack of evidence on cognitive comorbidity in individuals with PTE in the literature. We sought to identify potential PTE predictors and evaluate cognitive comorbidity in patients with PTE. METHODS: A 2-year retrospective cohort study was employed, in which adults with a history of admission for traumatic brain injury (TBI) in 2019 and 2020 were contacted. Three hundred one individuals agreed to participate, with a median follow-up time of 30.75 months. The development of epilepsy was ascertained using a validated tool and confirmed by our neurologists during visits. Clinical psychologists assessed the patients' cognitive performance. RESULTS: The 2-year cumulative incidence of PTE was 9.3% (95% confidence interval [CI] 5.9-12.7). The significant predictors of PTE were identified as a previous history of brain injury [hazard ratio [HR] 4.025, p = .021], and intraparenchymal hemorrhage (HR: 2.291, p = .036), after adjusting for other confounders. TBI patients with PTE performed significantly worse on the total ACE-III cognitive test (73.5 vs 87.0, p = .018), CTMT (27.5 vs 33.0, p = .044), and PSI (74.0 vs 86.0, p = .006) than TBI patients without PTE. A significantly higher percentage of individuals in the PTE group had cognitive impairment, compared to the non-PTE group based on ACE-III (53.6% vs 46.4%, p = .001) and PSI (70% vs 31.7%, p = .005) scores at 2 years post-TBI follow-up. SIGNIFICANCE: This study emphasizes the link between TBI and PTE and the chance of developing cognitive impairment in the future. Clinicians can target interventions to prevent PTE by identifying specific predictors, which helps them make care decisions and develop therapies to improve patients' quality of life.
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Lesiones Traumáticas del Encéfalo , Disfunción Cognitiva , Epilepsia Postraumática , Humanos , Lesiones Traumáticas del Encéfalo/epidemiología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/psicología , Femenino , Masculino , Estudios Retrospectivos , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Malasia/epidemiología , Adulto , Incidencia , Epilepsia Postraumática/epidemiología , Epilepsia Postraumática/etiología , Persona de Mediana Edad , Estudios de Cohortes , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. METHODS: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. RESULTS: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants. SIGNIFICANCE: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.
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Encefalopatías , Epilepsia Generalizada , Epilepsia , Discapacidad Intelectual , Humanos , Estudios Retrospectivos , Hipotonía Muscular , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Epilepsia/complicaciones , Encefalopatías/genética , Convulsiones/complicaciones , Epilepsia Generalizada/complicaciones , Electroencefalografía/métodos , Discapacidad Intelectual/genética , Discapacidad Intelectual/complicaciones , Homólogo 4 de la Proteína Discs Large/genéticaRESUMEN
The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.
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Epilepsia , ATPasas de Translocación de Protón Vacuolares , Humanos , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Epilepsia/genética , Adenosina TrifosfatoRESUMEN
Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).
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Proteínas Transportadoras de GABA en la Membrana Plasmática , Estudios de Asociación Genética , Mutación Missense , Humanos , Proteínas Transportadoras de GABA en la Membrana Plasmática/genética , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , FenotipoRESUMEN
OBJECTIVE: To evaluate the effectiveness and tolerability of fenfluramine (FFA) in routine clinical practice treating real-world populations with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). METHODS: This was a retrospective analysis of patients with DS or LGS who initiated FFA treatment from 2018 to 2022 at a single center. Patient demographics, medical history, seizure characteristics, and treatment outcomes were collected from electronic medical records. Duration of FFA treatment, dosage regimens, seizure frequency, seizure severity, improvements in cognitive, social, and motor outcomes, and adverse events were extracted and analyzed. Effectiveness was assessed using ≥50 % sustained reduction in monthly seizure frequency vs baseline for ≥2 consecutive months at 12 months; seizure freedom was a secondary measure. RESULTS: Seizure frequency data was available for 56 of 68 patients included in the study. At 12 months, 50 patients (89.3 %) remained on FFA treatment; 58 % of these patients achieved a ≥50 % sustained response and 10 % experienced seizure freedom. Cognitive, motor, and social improvement were noted in 70.7 %, 36.2 %, and 27.6 % of patients, respectively. The total number of concomitant antiseizure medications was reduced by ≥1 in 29.4 % of patients. No differences were found between DS and LGS patients in these outcomes; age at start of FFA and age at the 12-month timepoint did not have an effect. At least one AE was experienced by 59.7% of patients; in 86.5% of the cases, AEs were plausibly related to treatment. While 70.3% of AEs were self-resolving and 81.8% of the remaining patients experienced mild AEs, 1 patient experienced a serious AE unrelated to FFA which resulted in the patient's death. There were no cases of pulmonary arterial hypertension or ventricular heart disease. SIGNIFICANCE: The effectiveness and tolerability of FFA treatment in patients with DS or LGS in this retrospective analysis of real-world data were consistent with those seen in randomized clinical trials.
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Epilepsias Mioclónicas , Síndrome de Lennox-Gastaut , Humanos , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Estudios Retrospectivos , Fenfluramina/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , ConvulsionesRESUMEN
AIM: To describe the experiences and unmet medical care needs of a group of parents of children with developmental and epileptic encephalopathies (DEEs) caused by the SCN1A, KCNQ2, CDKL5, PCDH19, and GNAO1 variants. METHOD: A qualitative descriptive study was conducted. Participants were recruited using purposeful sampling. The inclusion criteria consisted of parents of children with DEEs caused by the SCN1A, KCNQ2, CDKL5, PCDH19, or GNAO1 variants, aged between 4 and 10 years old. In total, 21 parents were included. Data were acquired via researcher field notes and in-depth interviews. A thematic analysis was performed. RESULTS: Three main themes were identified: (1) managing symptoms: epileptic seizures are experienced with great uncertainty and are accompanied by cognitive, behavioural, and motor symptoms; (2) accepting treatment: the ideal medication regimen is a challenge and the decision to withdraw or start a new therapy falls on the parents; and (3) therapeutic relationship and medical care: behaviours related to the health professional can hinder the therapeutic relationship with the parents. Parents are apprehensive about going to the emergency department. INTERPRETATION: Professionals in emergency departments should acquire better knowledge of DEEs, welcome parents, and improve treatment for the children. The results of this study can serve as a starting point for a roadmap of relevant caregiver-reported outcomes in DEEs, to be implemented with new clinical trials and aetiology-targeted therapies. WHAT THIS PAPER ADDS: Epileptic seizures are the symptom that is most experienced and feared by parents. The medication regime has no defined protocol and the decision to withdraw a medication is frequently left to parents.
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Epilepsia , Niño , Humanos , Preescolar , Epilepsia/genética , Epilepsia/terapia , Convulsiones/genética , Atención a la Salud , Padres/psicología , Protocadherinas , Subunidades alfa de la Proteína de Unión al GTP Gi-GoRESUMEN
Developmental and epileptic encephalopathies (DEEs) cause disability and dependence affecting both children and the family. The aim of the study was to describe the perspective of parents of children with DEEs regarding the impact of the disease on the family. We carried out a qualitative study based on the interpretivist paradigm. Twenty-one participants were selected using purposive sampling. Parents of children with DEEs of SCN1A, KCNQ2, CDKL5, PCDH19, and GNAO1 variants were included. In-depth interviews and researcher notes were used for data collection. A thematic analysis was performed on the data. Three themes were identified in the results: (a) Assuming conflicts and changes within the couple, causing them to distance themselves, reducing their time and intimacy and leading them to reconsider having more children; (b) impact of the disorder on siblings and grandparents, where siblings perceived DEE as a burden in their lives, felt neglected, and needed to grow and mature alone; conversely, the grandparents suffered for their grandchildren and the parents, in addition to perceiving that their health worsened, and (c) reconciling the care of the child with family life and work; this led the parents to share tasks, abandon or reduce working hours and ask for help.Conclusions: Caring for a child with DEE can result in neglect of social, psychological, emotional, recreational, educational, or occupational needs and obligations that ultimately impact all family members. What is Known: ⢠Children with DEE may develop seizures and experience developmental and cognitive problems. ⢠Caring for a child with DEE has a social and psychological impact on the entire family.
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Padres , Investigación Cualitativa , Humanos , Masculino , Femenino , Niño , Preescolar , Adulto , Padres/psicología , Adolescente , Persona de Mediana Edad , Lactante , Costo de Enfermedad , Síndromes Epilépticos/psicología , Síndromes Epilépticos/genética , Espasmos Infantiles/psicologíaRESUMEN
Glycosylphosphatidylinositol anchoring disorders (GPI-ADs) are a subgroup of congenital disorders of glycosylation. GPI biosynthesis requires proteins encoded by over 30 genes of which 24 genes are linked to neurodevelopmental disorders. Patients, especially those with PIGA-encephalopathy, have a high risk of premature mortality which sometimes is attributed to cardiomyopathy. We aimed to explore the occurrence of cardiomyopathy among patients with GPI-ADs and to raise awareness about this potentially lethal feature. Unpublished patients with genetically proven GPI-ADs and cardiomyopathy were identified through an international collaboration and recruited through the respective clinicians. We also reviewed the literature for published patients with cardiomyopathy and GPI-AD and contacted the corresponding authors for additional information. We identified four novel and unrelated patients with GPI-AD and cardiomyopathy. Cardiomyopathy was diagnosed before adulthood and was the cause of early demise in two patients. Only one patients underwent cardiac workup after being diagnosed with a GPI-AD. All were diagnosed with PIGA-encephalopathy and three had a disease-causing variant at the same residue. The literature reports five additional children with GPI-AD related cardiomyopathy, three of which died before adulthood. We have shown that patients with GPI-ADs are at risk of developing cardiomyopathy and that regular cardiac workup with echocardiography is necessary.
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Encefalopatías , Cardiomiopatías , Niño , Humanos , Adulto , Glicosilfosfatidilinositoles/genética , Cardiomiopatías/diagnóstico , Cardiomiopatías/genéticaRESUMEN
INTRODUCTION: Epilepsy is a serious neurological disorder affecting the quality of life (QoL) of people with this condition. A survey was conducted in five European countries (France, Germany, Italy, Spain, and the UK) to understand the impact and burden of epilepsy and its treatment on the lives of people with epilepsy (PWE). METHODS: Five hundred PWE (taking >1 antiseizure medication [ASM]) and 500 matched controls completed a 30-minute online questionnaire. The 12-Item Short Form Survey (SF-12) was used to measure QoL and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was used to screen for major depressive disorder (MDD) symptoms. RESULTS: Comorbidities such as migraine, high cholesterol, osteoporosis, and Type 1 diabetes were reported more commonly in PWE, while anxiety disorders, high blood pressure, skin disorders, and mood disorders were more common in controls. However, compared to controls, a significantly higher percentage of PWE had an NDDI-E score of 15-24 (54% vs 35%; p < 0.0001), indicative of MDD symptoms. Significantly more PWE than controls were part-time employed (15% vs 11%; p = 0.03). People with epilepsy had a significantly lower total SF-12 score than controls across the physical and the mental components; compared to controls, a significantly higher proportion of PWE defined their general health as 'poor' or 'fair' and felt limited in carrying out daily and work activities. Among PWE, those taking ≥3 ASMs were more likely to experience difficulties in carrying out these activities than those on two ASMs. Ability to drive, mood, and level of self-esteem were reported as concerns for PWE. CONCLUSION: Epilepsy has a major impact on the physical and mental health of PWE, interfering with their daily and work activities and overall QoL, and its treatment might also contribute to a lower QoL. The impact of epilepsy on mood and mental health might be under-recognized.
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Trastorno Depresivo Mayor , Epilepsia , Humanos , Calidad de Vida/psicología , Trastorno Depresivo Mayor/diagnóstico , Epilepsia/complicaciones , Epilepsia/epidemiología , Epilepsia/tratamiento farmacológico , Depresión/psicología , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To assess the impact of epilepsy and antiseizure medications (ASMs) on sleep quality in people with epilepsy (PWE). METHODS: An online survey was conducted in France, Germany, Italy, Spain and the UK among PWE taking >1 ASM and matched controls. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Associations between sleep quality (global PSQI) and overall quality of life (QoL; assessed using the 12-Item Short Form Survey [SF-12]) and sleep quality and depressive symptoms (assessed using the Neurological Disorders Depression Inventory for Epilepsy [NDDI-E]) were also evaluated. RESULTS: Overall, 500 PWE and 500 matched controls were included. PWE had significantly greater mean global PSQI scores than controls (9.32 vs 7.56; p < 0.0001), with 80% reporting a score >5 versus 66% of controls (p < 0.001). PWE experienced significantly more problems with most PSQI components than controls. Mean global PSQI scores in PWE receiving 2 versus ≥3 ASMs were 9.03 and 10.18, respectively (p < 0.004); global PSQI scores >5 were reported in 76% versus 90%, respectively (p = 0.001). Regimens containing lamotrigine or phenobarbital were associated with poorer sleep quality than those without these ASMs. In PWE, negative correlations were identified between global PSQI scores and both the SF-12 physical and mental components (Pearson's correlation coefficient [PCC], -0.61 and -0.40, respectively); NDDI-E and global PSQI scores were positively correlated (PCC, 0.6). CONCLUSIONS: PWE experience significantly worse sleep quality than people without epilepsy, with some ASMs contributing to poorer sleep. QoL and physical and mental health were all affected by sleep quality in PWE.
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Epilepsia , Calidad de Vida , Adulto , Humanos , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Anticonvulsivantes/uso terapéutico , Sueño , Encuestas y CuestionariosRESUMEN
Malformations of cortical development (MCD) comprise a broad spectrum of structural brain lesions frequently associated with epilepsy. Disease definition and diagnosis remain challenging and are often prone to arbitrary judgment. Molecular classification of histopathological entities may help rationalize the diagnostic process. We present a retrospective, multi-center analysis of genome-wide DNA methylation from human brain specimens obtained from epilepsy surgery using EPIC 850 K BeadChip arrays. A total of 308 samples were included in the study. In the reference cohort, 239 formalin-fixed and paraffin-embedded (FFPE) tissue samples were histopathologically classified as MCD, including 12 major subtype pathologies. They were compared to 15 FFPE samples from surgical non-MCD cortices and 11 FFPE samples from post-mortem non-epilepsy controls. We applied three different statistical approaches to decipher the DNA methylation pattern of histopathological MCD entities, i.e., pairwise comparison, machine learning, and deep learning algorithms. Our deep learning model, which represented a shallow neuronal network, achieved the highest level of accuracy. A test cohort of 43 independent surgical samples from different epilepsy centers was used to test the precision of our DNA methylation-based MCD classifier. All samples from the test cohort were accurately assigned to their disease classes by the algorithm. These data demonstrate DNA methylation-based MCD classification suitability across major histopathological entities amenable to epilepsy surgery and age groups and will help establish an integrated diagnostic classification scheme for epilepsy-associated MCD.
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Metilación de ADN , Aprendizaje Profundo , Malformaciones del Desarrollo Cortical/clasificación , Malformaciones del Desarrollo Cortical/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Epilepsia/etiología , Femenino , Humanos , Lactante , Masculino , Malformaciones del Desarrollo Cortical/genética , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of syndromes, including Lennox-Gastaut syndrome (LGS), which are refractory to multiple therapies. Perampanel efficacy has been reported in LGS but further real-world evidence is needed in DEEs. METHODS: A multicenter, retrospective, 1-year observational study in patients with DEEs on adjuvant perampanel treatment was conducted to assess perampanel safety and effectiveness in this type of patients in a real-world setting. Seizure types [focal onset seizures (FOS), generalized tonic-clonic seizures (GTCS), tonic seizures (TS), atonic seizures (AtS), atypical absences (AA), and myoclonic seizures (MS)] and seizure clusters were divided in different frequency groups: daily, weekly, and monthly seizures, and absent or seizure freedom. Patients could have more than one seizure type. For each frequency group, group change and seizure freedom were analyzed. RESULTS: Eighty-seven patients diagnosed with DEEs (45 males) of median age 22 [1-70] years were included. The most frequent DEEs were LGS (35.6%) and Lennox-like syndrome (37.9%). At baseline 20 patients had three to five types of seizures, 36 patients had two types of seizures and 31 patients had one predominant type of seizure. The mean number of seizure types per patient at baseline was 2.12 ± 0.97 which was reduced to 1.62 ± 0.91 at 12 months (p < 0.001). Overall, 51.7% of patients had a significant improvement in at least one seizure type. At baseline, 45 patients had GTCS, 42 FOS, 41 TS, 18 AA, 16 AtS, 11 MS, and 30 seizures clusters. Seizure freedom for each specific type at 12 months was significantly achieved by 35% of patients with GTCS (p < 0.001), 17% (p = 0.016) with TS and 37% with seizure clusters (p < 0.001). Patients achieved seizure freedom from other seizure types but with no statistical significance: 7% FOS-free, 28% AA-free, 6% Ats-free, and 18% MS-free. Regarding changes of group at 12 months, 22% of TS and 19% of FOS improved significantly to a group with lower seizure frequency (p = 0.004 and p = 0.02, respectively). In remaining groups (4% of GTCS, 11% of AA, 18% of Ats, 18% of MS, and 13% of seizure clusters), the improvement was not statistically significant. Twenty-nine patients discontinued perampanel: 18 (21%) due to AEs, 8 (9%) due to lack of efficacy, and 3 (3%) due to seizure worsening. Adverse events, mostly mild or moderate, were reported in 53% of patients, and irritability/mood changes (22%) and somnolence (17%) were the most frequent. CONCLUSION: This is the first large-scale real-world study with perampanel across different seizure types in patients with DEEs. Perampanel was effective, especially in GTCS, TS, and FOS, as well as in seizure clusters. Perampanel was generally well-tolerated without unexpected AEs.
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Epilepsias Mioclónicas , Epilepsia Generalizada , Síndrome de Lennox-Gastaut , Adulto , Anticonvulsivantes , Humanos , Masculino , Nitrilos , Piridonas , Estudios Retrospectivos , Convulsiones , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: To evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP). METHODS: This was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. RESULTS: One hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together. CONCLUSIONS: Cannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.
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Cannabidiol , Epilepsias Mioclónicas , Epilepsia , Síndrome de Lennox-Gastaut , Estado Epiléptico , Adulto , Niño , Humanos , Adolescente , Cannabidiol/uso terapéutico , Anticonvulsivantes/uso terapéutico , Estudios Retrospectivos , Calidad de Vida , Epilepsia/tratamiento farmacológico , Epilepsia/inducido químicamente , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Epilepsias Mioclónicas/tratamiento farmacológico , Estado Epiléptico/tratamiento farmacológico , Resultado del TratamientoRESUMEN
AIM: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy. METHOD: Participants with genetically confirmed GPI deficiency were treated with oral pyridoxine or P5P as compassionate use in an agreed-upon clinical regimen. Pyridoxine (20-30 mg/kg/day) was used for 3 months. Baseline evaluation included 4 weeks of prospective seizure data and one video electroencephalogram (EEG). Seizure frequency was captured daily. The EEG was repeated after reaching maximum dosage of pyridoxine. Pyridoxine was switched to P5P (20-30 mg/kg/day) if seizure burden was unchanged after 3 months' treatment. Another EEG was done after 3 months of P5P treatment. Primary outcome measures were reduction of seizure frequency and EEG improvements. RESULTS: Seven participants (one female, six males; age range 5-23 year; mean age 11 years 10 months, SD 5 year 2 months) were included. The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency. All had drug-resistant epilepsy and neurodevelopmental impairment. We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom. No remarkable changes in electrophysiological findings were observed in 6 out of 7 participants treated with pyridoxine or P5P when comparing the baseline and follow-up EEGs. INTERPRETATION: We observed no long-lasting electrophysiological improvements during treatment but pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. WHAT THIS PAPER ADDS: Inherited glycosylphosphatidylinositol (GPI) deficiency often causes early-onset and drug-resistant epilepsy. Vitamin B6 is a potential disease-specific treatment; however, efficacy and safety are ill-defined. Pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. Pyridoxine and P5P could prove to be a useful treatment in some individuals with inherited GPI deficiency and epilepsy.
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Epilepsia Refractaria , Epilepsia , Estudios de Cohortes , Epilepsia Refractaria/tratamiento farmacológico , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Femenino , Glicosilfosfatidilinositoles/deficiencia , Glicosilfosfatidilinositoles/uso terapéutico , Humanos , Lactante , Masculino , Fosfatos/uso terapéutico , Estudios Prospectivos , Fosfato de Piridoxal/uso terapéutico , Piridoxina/uso terapéutico , Convulsiones/tratamiento farmacológico , Convulsiones/etiologíaRESUMEN
OBJECTIVE: This study was aimed to analyze the effectiveness of sodium channel blockers (SCBs) in CDKL5 deficiency disorder (CDD)-related epilepsy. METHODS: A retrospective, observational study was performed, including patients with CDD diagnosis evaluated between 2016 and 2019 at three tertiary Epilepsy Centers. Demographic, electroclinical and genetic features, as well as ASM treatments and their outcomes were analyzed, with special focus on SCBs. RESULTS: Twenty-one patients evaluated at three tertiary Epilepsy Centers were included, of which 19 presented with epilepsy (90.5%); all had pathogenic mutations of CDKL5. Six patients (31.6%) were classified as SCB responders (more than 50% reduction), four being currently seizure free (mean seizure-free period of 8â¯years). Most frequent SCB drugs were oxcarbazepine (OXC), carbamazepine (CBZ), and lacosamide (LCM). None of them presented relevant adverse events. In contrast, three patients showed seizure aggravation in the non-responder group. When comparing both groups, responders had statistically significant younger age at SCB treatment and epilepsy onset, higher proportion of focal epileptiform activity and less frequent history of West syndrome. CONCLUSIONS: The results of this study indicate that treatment with SCBs might be effective and safe in a subset of patients with CDD-related epilepsy.
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Epilepsia , Bloqueadores de los Canales de Sodio/uso terapéutico , Espasmos Infantiles , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Síndromes Epilépticos , Humanos , Lactante , Proteínas Serina-Treonina Quinasas/genética , Estudios Retrospectivos , Espasmos Infantiles/complicaciones , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/genéticaRESUMEN
OBJECTIVE: To develop and validate an epilepsy-specific scale for comprehensive functional assessment of patients with epilepsy, named Epidaily. METHODS: The multidisciplinary research group created through brainstorming a list of 47 items to explore the cognitive, social, basic and instrumental functionality of the patient. A group of epilepsy experts independent of the research group evaluated the suitability of all the items, which then were selected and reviewed by the research group to conform the Epidaily scale. On a sample of 102 patients, a reliability analysis was performed, as well as a validation one using as reference scale the score on the Activities of Daily Living Questionnaire (ADLQ), which evaluates basic and instrumental functionality. RESULTS: Epidaily consisted of 10 items distributed in four dimensions, with a possible score from 0 to 100 (perfect functionality). Inter-observer reliability was excellent, with an intraclass correlation coefficient of 0.98 (95% confidence interval 0.97-0.99). Criterion validity was demonstrated by the high positive correlation of the Epidaily score with the ADLQ score (Spearman's rho coefficient 0.85, pâ¯<â¯0.001). Significant relation was found between ADLQ and Epidaily in the linear regression analysis (pâ¯<â¯001), which reported that Epidaily explains 85.5% of the variability of ADLQ (R-squared 0.85). Discriminant validity was also proved, as Epidaily allowed to classify epilepsy severity based on Cramer et al epilepsy severity classification. The median time to obtain the Epidaily score was 5â¯min (interquartile range 4-6). SIGNIFICANCE: Epidaily is a brief and versatile scale, with excellent inter-observer reliability, which has been validated for comprehensive functional assessment of patients with epilepsy.
Asunto(s)
Actividades Cotidianas , Epilepsia , Epilepsia/diagnóstico , Humanos , Psicometría , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
BACKGROUND: To assess the prevalence, severity, and mortality of COVID-19 in people with epilepsy (PWE) and evaluate seizure control in PWE during and after COVID-19. METHODS: Retrospective, observational, multicenter study conducted in 14 hospitals. Medical records of randomly selected PWE followed at neurology outpatient clinics were reviewed. Proportion of PWE with a positive test for SARS-CoV-2 during 2020 was calculated. Risk factors associated with COVID-19 and its morbimortality were evaluated. RESULTS: 2751 PWE were included, mean age 48.8â¯years (18-99), 72.4% had focal epilepsy, and 35% were drug-refractory. COVID-19 prevalence in PWE was 5.53%, while in the Spanish population was 4.26%. Proportion of admissions to hospital, ICU, and deaths in PWE were 17.1%, 2%, and 4.61% of COVID-19 cases, while in Spanish population were 10.81%, 0.95%, and 2.57%, respectively. A severe form of COVID-19 occurred in 11.8%; dyslipidemia, institutionalization at long-term care facilities, intellectual disability, and older age were associated risk factors. Older age, hypertension, dyslipidemia, cardiac disease, and institutionalization were associated with mortality from COVID-19. Seizure control was stable in 90.1% of PWE during acute COVID-19, while 8.6% reported an increase in seizure frequency. During post-COVID-19 follow-up, 4.6% reported seizure control worsening. CONCLUSIONS: COVID-19 was moderately prevalent in PWE. One out of 5 patients required medical attention and 4.6% died due to COVID-19. Older age, dyslipidemia, institutionalization, and intellectual disability were significant risk factors associated with severe COVID-19. Seizure control remained stable during COVID-19 and throughout long-term follow-up in most PWE who contracted the infection.
Asunto(s)
COVID-19 , Epilepsia , Anciano , Epilepsia/epidemiología , Humanos , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Mesial temporal lobe epilepsy (mTLE) is a neurological disorder associated with histopathological changes in different subfields of the hippocampus. These alterations have been associated with memory difficulties. In this study, we tested the hypothesis that these difficulties stem on mnemonic discrimination impairment due to a reduced ability to make similar representations more distinct, leading to an increased susceptibility to interference. With this aim, we used a visual mnemonic discrimination task and evaluated the ability of a group of patients with unilateral mTLE, relative to controls, to discriminate between a studied item and a new foil item, as a function of the similarity between them, and of the number of exemplars from a category stored in memory. We found that patients performed worse than controls when the studied item had to be discriminated from a physically similar new object from the same basic-level category. Crucially, reliable differences between groups were observable in the conditions in which more exemplars from a category were held in memory. In the conditions in which the studied item had to be discriminated from a foil from a different basic-level category, there were no differences between groups, with one exception. Neither a general cognitive impairment nor a general memory impairment could account for this pattern of results. Current findings indicate that patients found more difficulties in conditions with higher interference, which poses greater demands for pattern separation. A disruption of pattern separation processes resulting from hippocampal damage provides a reasonable interpretation for these results. Future studies should explore the causal relationship between hippocampal subfields integrity and mnemonic discrimination capacity in mTLE patients.
Asunto(s)
Discriminación en Psicología , Epilepsia del Lóbulo Temporal/psicología , Memoria , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Reconocimiento en Psicología , Adulto JovenRESUMEN
OBJECTIVE: This study aimed to evaluate the access to advanced diagnostic tests in patients with epilepsy and intellectual disability, with special focus on genetics. METHODS: Patients with epilepsy and intellectual disability evaluated between 2016 and 2018 at the Epilepsy Unit of two hospitals in Madrid, Spain were included. The main inclusion criterion was an undetermined etiological diagnosis after clinical assessment, neuroimaging, and electroencephalogram (EEG). RESULTS: Two hundred and five patients with epilepsy and intellectual disability were evaluated, with 124 fulfilling the inclusion criteria (mean age: 33.9â¯years). Regarding the etiological workup, advanced neuroimaging, prolonged video-EEG, and any type of genetic test had been performed in 58%, 41%, and 40%, respectively. An etiological diagnosis was reached in 18.5%. The workup was considered incomplete in 67%. Variables that showed the strongest association with an incomplete diagnostic workup in the multivariate analysis were current age and seizure freedom. CONCLUSIONS: Despite the multiple implications of modern diagnostic techniques, especially genetic testing, there is a large proportion of patients with epilepsy and intellectual disability who do not have access to them. Older age and seizure freedom seem to be associated with the highest diagnostic gap.
Asunto(s)
Epilepsia/diagnóstico , Epilepsia/genética , Pruebas Genéticas/tendencias , Accesibilidad a los Servicios de Salud/tendencias , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Preescolar , Electroencefalografía/métodos , Electroencefalografía/tendencias , Epilepsia/epidemiología , Femenino , Pruebas Genéticas/métodos , Humanos , Discapacidad Intelectual/epidemiología , Masculino , Persona de Mediana Edad , España/epidemiología , Adulto JovenRESUMEN
BACKGROUND: In cases undergoing epilepsy surgery, postoperative psychogenic nonepileptic seizures (PNES) may be underdiagnosed complicating the assessment of postsurgical seizures' outcome and the clinical management. We conducted a survey to investigate the current practices in the European epilepsy monitoring units (EMUs) and the data that EMUs could provide to retrospectively detect cases with postoperative PNES and to assess the feasibility of a subsequent postoperative PNES research project for cases with postoperative PNES. METHODS: We developed and distributed a questionnaire survey to 57 EMUs. Questions addressed the number of patients undergoing epilepsy surgery, the performance of systematic preoperative and postoperative psychiatric evaluation, the recording of sexual or other abuse, the follow-up period of patients undergoing epilepsy surgery, the performance of video-electroencephalogram (EEG) and postoperative psychiatric assessment in suspected postoperative cases with PNES, the existence of electronic databases to allow extraction of cases with postoperative PNES, the data that these bases could provide, and EMUs' interest to participate in a retrospective postoperative PNES project. RESULTS: Twenty EMUs completed the questionnaire sheet. The number of patients operated every year/per center is 26.7 (⯱â¯19.1), and systematic preoperative and postoperative psychiatric evaluation is performed in 75% and 50% of the EMUs accordingly. Sexual or other abuse is systematically recorded in one-third of the centers, and the mean follow-up period after epilepsy surgery is 10.5⯱â¯7.5â¯years. In suspected postoperative PNES, video-EEG is performed in 85% and psychiatric assessment in 95% of the centers. An electronic database to allow extraction of patients with PNES after epilepsy surgery is used in 75% of the EMUs, and all EMUs that sent the sheet completed expressed their interest to participate in a retrospective postoperative PNES project. CONCLUSION: Postoperative PNES is an underestimated and not well-studied entity. This is a European survey to assess the type of data that the EMUs surgical cohorts could provide to retrospectively detect postoperative PNES. In cases with suspected PNES, most EMUs perform video-EEG and psychiatric assessment, and most EMUs use an electronic database to allow extraction of patients developing PNES.