RESUMEN
PURPOSE: Recent research in epilepsy patients confirms our understanding of epilepsy as a network disorder with widespread cortical compromise. Here, we aimed to investigate the neocortical laminar architecture in patients with focal cortical dysplasia (FCD) and periventricular nodular heterotopia (PNH) using clinically feasible 3 T MRI. METHODS: Eighteen epilepsy patients (FCD and PNH groups; n = 9 each) and age-matched healthy controls (n = 9) underwent T1 relaxation 3 T MRI, from which component probability T1 maps were utilized to extract sub-voxel composition of 6 T1 cortical layers. Seventy-eight cortical areas of the automated anatomical labeling atlas were divided into 1000 equal-volume sub-areas for better detection of cortical abnormalities, and logistic regressions were performed to compare FCD/PNH patients with healthy controls with the T1 layers composing each sub-area as regressors. Statistical significance (p < 0.05) was determined by a likelihood-ratio test with correction for false discovery rate using Benjamini-Hochberg method. RESULTS: Widespread cortical abnormalities were observed in the patient groups. Out of 1000 sub-areas, 291 and 256 bilateral hemispheric cortical sub-areas were found to predict FCD and PNH, respectively. For each of these sub-areas, we were able to identify the T1 layer, which contributed the most to the prediction. CONCLUSION: Our results reveal widespread cortical abnormalities in epilepsy patients with FCD and PNH, which may have a role in epileptogenesis, and likely related to recent studies showing widespread structural (e.g., cortical thinning) and diffusion abnormalities in various human epilepsy populations. Our study provides quantitative information of cortical laminar architecture in epilepsy patients that can be further targeted for study in functional and neuropathological studies.
Asunto(s)
Epilepsia , Malformaciones del Desarrollo Cortical , Epilepsia/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical/complicaciones , Malformaciones del Desarrollo Cortical/diagnóstico por imagenRESUMEN
INTRODUCTION: Previous studies showed concordance between the typical Periodic Sharp Wave Complex (PSWC) activity in EEG of Creutzfeldt-Jakob Disease (CJD) patients and the MRI findings, while the concordance with slow activity in EEG is less established. The aim of this study was to better characterize the association between MRI findings and EEG changes using quantitative EEG (qEEG) analysis. METHODS: The demographics, clinical features, and the MRI findings of 12 familial E200K patients with CJD were gathered. EEG test was done and reviewed for the typical PSWC and for the non-specific slow activity. A possible association between the MRI findings and the EEG activity was examined. Then, EEG was analyzed using qEEG tool, and the association between the qEEG finding and the MRI was examined. RESULTS: Twelve patients were included in the study (67% women). Cortical MRI lesions finding were seen in 6/12 (50%) of the patients, and deep gray mater lesions were seen in 8/12 patients (67%). EEG showed the classic PSWC in 6/12 (50%) of the patients where slow activity was seen in 10/12 (83%). Slow activity and cortical MRI findings were associated in only 2/6 (33%) where deep gray matter findings and the slow activity had concordance of 4/8 (50%). qEEG analysis improved this concordance between slow activity and cortical findings to 3/6 (50%) and with the deep gray matter findings to 5/8 (63%). CONCLUSIONS: Quantitative EEG analysis modesty but not significantly, improves the association of EEG slow activity in familial E200K CJD patients with MRI findings.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/fisiopatología , Electroencefalografía/métodos , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Síndrome de Creutzfeldt-Jakob/patología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Primary coenzyme Q10 (CoQ10 ; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10 , and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. Whole-exome and subsequent whole-genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement and increased the concentrations of CoQ10 in blood. This is the first report of primary CoQ10 deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological, and molecular features, and insights regarding targeted treatment with CoQ10 supplementation.
Asunto(s)
Vías Biosintéticas/genética , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Metiltransferasas/deficiencia , Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/deficiencia , Ubiquinona/análogos & derivados , Biopsia , Ataxia Cerebelosa/dietoterapia , Ataxia Cerebelosa/metabolismo , Variaciones en el Número de Copia de ADN , Suplementos Dietéticos , Transporte de Electrón , Femenino , Fibroblastos/metabolismo , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucocitos/metabolismo , Metiltransferasas/genética , Encefalomiopatías Mitocondriales/dietoterapia , Encefalomiopatías Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Músculos/patología , Consumo de Oxígeno , Linaje , Polimorfismo de Nucleótido Simple , Hermanos , Ubiquinona/biosíntesisRESUMEN
BACKGROUND: Computed tomography (CT) brain perfusion is a relatively new imaging method that can be used to differentiate patients following epileptic seizures in the setting of acute neurological deficits (e.g., hemiparesis, hemiplegia, hemianopsia, aphasia) who arrive at the emergency room with a suspected stroke. OBJECTIVES: To evaluate brain perfusion changes in patients who had an epileptic seizure. METHODS: We retrospectively identified 721 patients who presented at our stroke center between 2012 and 2015 with a suspected acute stroke and underwent examination thorough a stroke protocol, including cerebral CT perfusion (CTP) and CT angiography (CTA) within 8 hours from the onset of symptoms. RESULTS: Out of 721 patients, 25 presented with ictal electroencephalography (EEG) findings within 24-72 hours from symptom onset without evidence of vascular occlusion on CTA. While 15 patients had to be excluded from the study due to concomitant brain pathology, we found a specific reduction in cerebral blood volume and cerebral blood flow occurring at the ictal zone, which was identified by a post hoc EEG investigation. CONCLUSIONS: Our study shows that CTP is an easily accessible tool in emergency department setting for the detection of changes in blood flow dynamics among postictal patients. Thus, we propose the use of CTP in emergency settings to discriminate between postictal changes and acute vascular events.
Asunto(s)
Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Angiografía Cerebral/métodos , Circulación Cerebrovascular , Angiografía por Tomografía Computarizada/métodos , Epilepsia/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagen , Diagnóstico Diferencial , Electroencefalografía , Humanos , Estudios Retrospectivos , Factores de TiempoRESUMEN
OBJECTIVE: The aim of the study was to characterize the clinical features of nine patients in three families with chorea-acanthocytosis (ChAc) sharing the same rare c.2343del mutation in the VPS13A gene. METHODS: Genetic test results, clinical description, magnetic resonance imaging (MRI), and electroencephalography (EEG), as well as laboratory results are summarized. RESULTS: ChAc is a rare genetic disorder characterized by hyperkinetic movements, seizures, cognitive decline, neuropsychiatric symptoms, and acanthocytes on peripheral blood smear. This unique cohort of nine patients is characterized by seizures as a first and prominent symptom. In our patients, other features of ChAc appeared later, including tics, other movement disorders, dysarthria, and mild to moderate cognitive decline. SIGNIFICANCE: Patients with chorea-acanthocytosis carrying the described rare mutation can present with focal, treatment-resistant seizures.
Asunto(s)
Mutación/genética , Neuroacantocitosis/diagnóstico , Neuroacantocitosis/genética , Convulsiones/diagnóstico , Convulsiones/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Diagnóstico Diferencial , Electroencefalografía/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Neuroacantocitosis/complicaciones , Linaje , Convulsiones/etiología , Adulto JovenRESUMEN
The human leukocyte antigen (HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-related hospitalizations were obtained from the Israeli Ministry of Health (MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin.
Asunto(s)
Anticonvulsivantes/efectos adversos , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Árabes , Hipersensibilidad a las Drogas/epidemiología , Hipersensibilidad a las Drogas/etnología , Epilepsia/tratamiento farmacológico , Epilepsia/etnología , Femenino , Humanos , Incidencia , Israel/epidemiología , Israel/etnología , Judíos , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
In this study, we aimed to assess sleep function in patients with recent-onset familial Creutzfeldt-Jakob disease (fCJD). The largest cluster of fCJD patients is found in Jews of Libyan origin, linked to the prion protein gene (PRNP) E200K mutation. The high index of suspicion in these patients often leads to early diagnosis, with complaints of insomnia being a very common presenting symptom of the disease. The study included 10 fCJD patients diagnosed by clinical manifestations, magnetic resonance imaging (MRI) scan of the brain, elevated tau protein in the cerebrospinal fluid (CSF) and positive PRNP E200K mutation. Standard polysomnography was performed after a brief interview confirming the presence of sleep disturbances. All patients showed a pathological sleep pattern according to all scoring evaluation settings. The sleep stages were characterized by (i) disappearance of sleep spindles; (ii) outbursts of periodic sharp waves and shallowing of sleep consisting in increased Stage 2 and wake periods during the night, as well as decrease of slow-wave sleep and rapid eye movement (REM) sleep. Recordings of respiratory functions reported irregular breathing with central and obstructive apnea and hypopnea. The typical hypotonia occurring during the night and atonia during REM sleep were replaced by hyperactive sleep consisting of multiple jerks, movements and parasomnia (mainly talking) throughout the night. In conclusion, we report unique pathological sleep patterns in early fCJD associated with the E200K mutation. Specific respiratory disturbances and lack of atonia could possibly serve as new, early diagnostic tools in the disease.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/complicaciones , Síndrome de Creutzfeldt-Jakob/fisiopatología , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Trastornos del Inicio y del Mantenimiento del Sueño/fisiopatología , Anciano , Encéfalo/fisiopatología , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Parasomnias/complicaciones , Parasomnias/genética , Parasomnias/fisiopatología , Polisomnografía , Proteínas Priónicas/genética , Respiración , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/genética , Apnea Obstructiva del Sueño/fisiopatología , Trastornos del Inicio y del Mantenimiento del Sueño/genética , Fases del Sueño , Proteínas tau/líquido cefalorraquídeoRESUMEN
PURPOSE: The aim of the study was to identify trends in utilization of antiepileptic drugs (AEDs) over time in a nation-wide population in Israel. METHODS: Data on AED utilization (for all indications) for the period 2010-2014 were obtained from pharmaceutical companies that distribute AEDs in Israel. Prevalence of AED utilization was reported as defined daily doses (DDD)/1000 inhabitants/day. RESULTS: The utilization of most AEDs included in our analysis remained stable over the study period. The greatest increases in utilization of drugs established in Israel were observed for lamotrigine (33%), oxcarbazepine (31%), and primidone (18%). Decreases in use were recorded for carbamazepine (18%) and phenobarbital (15%). Use of older AEDs appeared to be relatively high, compared with the use of newer AEDs. CONCLUSIONS: During the study period of 2010-2014, conventional AEDs remained a main treatment choice in Israel, in certain cases in contrast to current recommendations and guidelines, for reasons yet to be revealed in further research.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Utilización de Medicamentos/estadística & datos numéricos , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Humanos , Israel/epidemiologíaRESUMEN
OBJECTIVE: The aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults. METHODS: Patients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy-Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55weeks of treatment and efficacy by patient age and drug-resistant status. RESULTS: Of the 217 patients who completed PREVAIL (USL255, n=103; placebo, n=114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥50years of age. Improvements in CGI-C and QOLIE-31-P were also observed. SIGNIFICANCE: The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS.
Asunto(s)
Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Epilepsia Refractaria/tratamiento farmacológico , Epilepsias Parciales/tratamiento farmacológico , Fructosa/análogos & derivados , Convulsiones/tratamiento farmacológico , Adulto , Envejecimiento , Anticonvulsivantes/administración & dosificación , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/psicología , Preparaciones de Acción Retardada , Método Doble Ciego , Epilepsia Refractaria/psicología , Femenino , Fructosa/administración & dosificación , Fructosa/efectos adversos , Fructosa/uso terapéutico , Humanos , Masculino , Calidad de Vida , Convulsiones/psicología , Encuestas y Cuestionarios , Topiramato , Resultado del TratamientoRESUMEN
BACKGROUND: Early identification of cardiac asystole as a reason for syncope is of uttermost significance, as insertion of a cardiac pacemaker can save the patient's life and prevent severe injury. The aim of this work was to emphasize the subtle and unusual presentations of asystole in patients evaluated in epilepsy units. METHODS: We reviewed the clinical presentation, ECG and EEG data of a series of seven patients who were evaluated in four epilepsy units and were diagnosed with asystole. RESULTS: Three patients had unusual clinical manifestations of cardiac asystole, resembling epileptic seizures. Three patients had asystole induced by epileptic seizures and in one patient the diagnosis was not clear. All patients except one were implanted with a pacemaker and improved clinically. CONCLUSIONS: Seizure-induced asystole is a rare complication of epilepsy and asystole may clinically mimic epileptic seizures. A high level of suspicion and thorough prolonged cardiac and EEG monitoring are mandatory for reaching the right diagnosis. As the diagnosis is rare and difficult to reach, a flow chart to assist diagnosis is suggested.
Asunto(s)
Paro Cardíaco/diagnóstico , Convulsiones/diagnóstico , Inconsciencia/diagnóstico , Adulto , Electrocardiografía , Electroencefalografía , Paro Cardíaco/etiología , Paro Cardíaco/fisiopatología , Humanos , Persona de Mediana Edad , Convulsiones/complicaciones , Convulsiones/fisiopatología , Inconsciencia/fisiopatología , Adulto JovenRESUMEN
Thrombin and other clotting factors regulate long-term potentiation (LTP) in the hippocampus through the activation of the protease activated receptor 1 (PAR1) and consequent potentiation of N-methyl-d-aspartate receptor (NMDAR) functions. We have recently shown that the activation of PAR1 either by thrombin or the anticoagulant factor activated protein C (aPC) has differential effects on LTP. While thrombin activation of PAR1 induces an NMDAR-mediated slow onset LTP, which saturates the ability to induce further LTP in the exposed network, aPC stimulation of PAR1 enhances tetanus induced LTP through a voltage-gated calcium channels mediated mechanism. In this study, we addressed the mechanisms by which aPC enhances LTP in hippocampal slices. Using extracellular recordings, we show that a short tetanic stimulation, which does not induce LTP, is able to enhance plasticity in the presence of aPC through a mechanism that requires the activation of sphingosine-1 phosphate receptor 1 and intracellular Ca(2+) stores. These data identify aPC as a "metaplastic molecule", capable of shifting the threshold of LTP towards further potentiation. Our findings propose novel strategies to enhance plasticity in neurological diseases associated with the breakdown of the blood brain barrier and alterations in synaptic plasticity.
Asunto(s)
Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Neuronas/fisiología , Proteína C/metabolismo , Receptor PAR-1/metabolismo , Receptores de Lisoesfingolípidos/metabolismo , Animales , Factores de Coagulación Sanguínea/metabolismo , Calcio/metabolismo , Estimulación Eléctrica , Hipocampo/efectos de los fármacos , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Receptores de Superficie Celular/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Esfingosina-1-Fosfato , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene have been identified in patients with benign (familial) infantile convulsions (B(F)IC), infantile convulsions with choreoathetosis (ICCA) and paroxysmal dyskinesias (PDs). However it remains unknown whether PRRT2 mutations are causal in other epilepsy syndromes. After we discovered a PRRT2 mutation in a large family with ICCA containing one individual with febrile seizures (FS) and one individual with West syndrome, we analysed PRRT2 in a heterogeneous cohort of patients with different types of infantile epilepsy. METHODS: We screened a cohort of 460 patients with B(F)IC or ICCA, fever related seizures or infantile epileptic encephalopathies. All patients were tested for point mutations using direct sequencing. RESULTS: We identified heterozygous mutations in 16 individuals: 10 familial and 6 sporadic cases. All patients were diagnosed with B(F)IC, ICCA or PD. We were not able to detect mutations in any of the other epilepsy syndromes. Several mutation carriers had learning disabilities and/or impaired fine motor skills later in life. CONCLUSIONS: PRRT2 mutations do not seem to be involved in the aetiology of FS or infantile epileptic encephalopathies. Therefore B(F)IC, ICCA and PD remain the core phenotypes associated with PRRT2 mutations. The presence of learning disabilities or neuropsychiatric problems in several mutation carriers calls for additional clinical studies addressing this developmental aspect in more detail.
Asunto(s)
Epilepsia/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Mutación Puntual/genética , Epilepsia/complicaciones , Epilepsia/diagnóstico , Femenino , Humanos , Discapacidades para el Aprendizaje/complicaciones , Discapacidades para el Aprendizaje/genética , Masculino , Trastornos de la Destreza Motora/complicaciones , Trastornos de la Destreza Motora/genética , Linaje , FenotipoRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of USL255, Qudexy(™) XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs. METHODS: In this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥ 50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated. RESULTS: Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life. SIGNIFICANCE: The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Epilepsias Parciales/diagnóstico , Epilepsias Parciales/tratamiento farmacológico , Fructosa/análogos & derivados , Adolescente , Adulto , Anciano , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Epilepsias Parciales/fisiopatología , Femenino , Fructosa/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Topiramato , Resultado del Tratamiento , Adulto JovenRESUMEN
Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, Qudexy™ XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having "highly" drug-resistant seizures (≥ 2 concurrent AEDs and ≥ 4 lifetime AEDs) or having "less" drug-resistant seizures (1 concurrent AED or <4 lifetime AEDs) at baseline. For each subgroup, median percent reduction in POS frequency (primary endpoint), responder rate, Clinical Global Impression of Change (CGI-C), and Quality of Life in Epilepsy--Problems (QOLIE-31-P) survey were assessed. Of 249 PREVAIL patients, 115 were classified as having highly drug-resistant seizures (USL255: n = 52, placebo: n = 63), and 134 were classified as having less drug-resistant seizures (USL255: n = 72, placebo: n = 62) at baseline. For the primary endpoint, USL255 resulted in significantly better seizure outcomes compared with placebo regardless of drug-resistant status (P = .004 and P = .040 for "highly" and "less", respectively). Responder rate was also significantly improved in patients with highly drug-resistant group (P = .023). The CGI-C scores indicated significant improvement in both subgroups (P = .003 and P = .013 for "highly" and "less", respectively). On the QOLIE-31-P, a significant improvement on the seizure worry subscale for the group with less drug-resistant seizures was noted in USL255-treated patients compared with placebo-treated patients (P = .003); the overall score and all other subscales were not significantly different for both subgroups. We conclude that USL255 led to significant improvements across multiple outcomes compared with placebo, including in those classified as having highly drug-resistant seizures to prior treatment, making it a valuable treatment option for patients with epilepsy.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Fructosa/análogos & derivados , Adolescente , Adulto , Anciano , Anticonvulsivantes/administración & dosificación , Preparaciones de Acción Retardada , Método Doble Ciego , Resistencia a Medicamentos , Femenino , Fructosa/administración & dosificación , Fructosa/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Convulsiones/tratamiento farmacológico , Topiramato , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Familial hyperkalemic hypertension (FHHt) is an inherited disease characterized by hyperkalemia, hypertension, and hyperchloremic acidosis (HCA). The primary defect is a hyperactive sodium chloride co-transporter, expressed in the renal distal tubule. FHHt is caused by mutation in either WNK1, WNK4, KLHL3, or Cul3. The mechanism of HCA is not completely understood. METHODS: Clinical and genetic data were collected from the largest family with FHHt described in the literature. Urine ammonia was measured in 26 family members. Epilepsy was diagnosed clinically. RESULTS: Of the 85 family members, 44 are affected by the Q565E WNK4 mutation, and 28 are newly described. In genetically engineered mice, urinary ammonium was decreased. In our study, urine ammonium did not change. In 11 unaffected subjects, urine ammonia per creatinine was 8.013 ± 3.620 m
Asunto(s)
Acidosis Tubular Renal , Compuestos de Amonio , Epilepsia , Hiperpotasemia , Hipertensión , Seudohipoaldosteronismo , Niño , Ratones , Animales , Humanos , Hiperpotasemia/complicaciones , Hiperpotasemia/genética , Acidosis Tubular Renal/complicaciones , Acidosis Tubular Renal/genética , Amoníaco , Proteínas Serina-Treonina Quinasas/genética , Hipertensión/complicaciones , Hipertensión/genética , Seudohipoaldosteronismo/genética , Epilepsia/complicaciones , Epilepsia/genética , ConvulsionesRESUMEN
Genetic workup is becoming increasingly common in the clinical assessment of neurological disorders. We evaluated its yield among middle-aged and elderly neurological patients, in a real-world context. This retrospective study included 368 consecutive Israeli patients aged 50 years and older (202 [54.9%] males), who were referred to a single neurogenetics clinic between 2017 and mid-2023. All had neurological disorders, without a previous molecular diagnosis. Demographic, clinical and genetic data were collected from medical records. The mean age at first genetic counseling at the clinic was 62.3 ± 7.8 years (range 50-85 years), and the main indications for referral were neuromuscular, movement and cerebrovascular disorders, as well as cognitive impairment and dementia. Out of the 368 patients, 245 (66.6%) underwent genetic testing that included exome sequencing (ES), analysis of nucleotide repeat expansions, detection of specific mutations, targeted gene panel sequencing or chromosomal microarray analysis. Overall, 80 patients (21.7%) received a molecular diagnosis due to 36 conditions, accounting for 32.7% of the patients who performed genetic testing. The diagnostic rates were highest for neuromuscular (58/186 patients [31.2%] in this group, 39.2% of 148 tested individuals) and movement disorders (14/79 [17.7%] patients, 29.2% of 48 tested), but lower for other disorders. Testing of nucleotide repeat expansions and ES provided a diagnosis to 28/73 (38.4%) and 19/132 (14.4%) individuals, respectively. Based on our findings, genetic workup and testing are useful in the diagnostic process of neurological patients aged ≥50 years, in particular for those with neuromuscular and movement disorders.
Asunto(s)
Pruebas Genéticas , Enfermedades del Sistema Nervioso , Humanos , Anciano , Masculino , Femenino , Persona de Mediana Edad , Anciano de 80 o más Años , Estudios Retrospectivos , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/epidemiología , Pruebas Genéticas/métodos , Israel/epidemiologíaRESUMEN
Seizures are a common outcome of cerebrovascular events as well as of traumatic brain injuries. Thrombin, a protease-activated receptor (PAR) agonist, has been implicated in the onset of seizures in these settings, yet its mode of action is not entirely clear. In this study, the effect of thrombin and a PAR-1 agonist on neuronal excitability and synaptic currents was assessed by whole cell-patch recordings of pyramidal neurons in rat hippocampal slices. In addition, PAR-1 distribution in different hippocampal regions was assessed using immunohistochemistry. We found that thrombin caused an increase in spontaneous action potential discharges of CA3 but not of CA1 pyramidal neurons. When excitatory synaptic activity was blocked, thrombin caused a marked reduction in spontaneous IPSCs in CA3 neurons and a marked increase in the frequency of IPSCs in CA1 neurons. These effects are likely to be local, as they were reproduced in TTX-treated slices. In parallel, thrombin increased both the frequency and the amplitude of mEPSCs only in CA3 neurons. These effects were blocked by a selective PAR-1 antagonist. The higher expression of PAR-1 in stratum lucidum of CA3 is correlated with the effects of thrombin in this region. These results suggest that thrombin triggers the generation of epileptic seizures by reducing the inhibitory and increasing the excitatory tone in CA3 neurons, providing a novel insight to the pathophysiology of seizures following cerebrovascular events and present new avenues for therapeutic intervention.
Asunto(s)
Células Piramidales/metabolismo , Convulsiones/metabolismo , Transmisión Sináptica/fisiología , Trombina/metabolismo , Animales , Hipocampo/metabolismo , Hipocampo/fisiopatología , Inmunohistoquímica , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Células Piramidales/fisiopatología , Ratas , Ratas Wistar , Receptor PAR-1/metabolismo , Convulsiones/fisiopatologíaRESUMEN
BACKGROUND: The management of intractable epilepsy in children and adults is challenging. For patients who do not respond to anti-epileptic drugs and are not suitable candidates for epilepsy surgery, vagal nerve stimulation (VNS) is a viable alternative for reducing seizure frequency. METHODS: In this retrospective multicenter open-label study we examined the efficacy and tolerability of VNS in patients in five adult and pediatric epilepsy centers in Israel. All patients had drug-resistant epilepsy and after VNS implantation in 2006-2007 were followed for a minimum of 18 months. Patients were divided into two age groups: < 21 and > 21 years old. RESULTS: Fifty-six adults and children had a stimulator implanted in 2006-2007. At 18 months post-VNS implantation, none of the patients was seizure-free, 24.3% reported a reduction in seizures of > or = 75%, 19% reported a 50-75% reduction, and 10.8% a 25-50% reduction. The best response rate occurred in patients with complex partial seizures. Among these patients, 7 reported a > or = 75% reduction, 5 patients a 50-75% reduction, 3 patients a 25-50% reduction, and 8 patients a < 25% reduction. A comparison of the two age groups showed that the older group (< 21 years old) had fewer seizures than the younger group. CONCLUSIONS: VNS is a relatively effective and safe palliative method for treating refractory epilepsy in both adults and children. It is an alternative treatment for patients with drug-resistant epilepsy, even after a relatively long disease duration, who are not candidates for localized epilepsy surgery.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/terapia , Estimulación del Nervio Vago/métodos , Adolescente , Adulto , Factores de Edad , Niño , Resistencia a Medicamentos , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Israel , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Estimulación del Nervio Vago/efectos adversos , Adulto JovenRESUMEN
Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Mutación , Neuroacantocitosis/genética , Proteínas de Transporte Vesicular/genética , Secuencia de Bases , Western Blotting , Membrana Eritrocítica/metabolismo , Humanos , Immunoblotting , Neuroacantocitosis/etiología , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Proteínas de Transporte Vesicular/deficienciaRESUMEN
OBJECTIVES: Electroencephalogram (EEG) pattern in Creutzfeldt-Jakob disease (CJD) is characterized by diffuse abnormal activity, although lateralization to one hemisphere has been described in the first stages of the disease. This study aimed to determine whether abnormal EEG activity predominantly occurs in anterior versus posterior brain regions. METHODS: As part of a prospective study, the demographics, clinical features and MRI findings of genetic E200K CJD patients were collected. EEG was performed and the recordings reviewed for the typical periodic sharp wave complex (PSWC) and non-specific slow activity. Data were analyzed using the qEEG tool, and the activity in anterior and posterior regions of the brain compared. RESULTS: Eleven genetic E200K CJD patients were included in the study (67% women). The average age was 59.1⯱â¯8.4 SD years and the average disease duration was 2.4⯱â¯2.1 months. EEG showed the classic PSWC pattern in 5/11 (45%) of the patients, and slow activity was seen in 9/11 (82%). EEG was normal in 2 patients. PSWC activity was diffuse in 2/5 patients and unilateral in 3/5 patients; slow activity was diffuse in 9 patients. Quantitative analysis of PSWC and slow activity showed no significant difference between anterior and posterior distribution. CONCLUSION: The abnormal EEG activity in CJD is diffuse with no clear spatial predominance in anterior or posterior brain regions.