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Objective: A Phase 3 open‐label safety study (NCT02721069) evaluated long‐term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters. Methods: Patients were 6–65 years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12 months, with study visits at Day 30 and every 60 days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment‐emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded. Results: Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was ≥12 months for 81.6% of patients. There was one death (sudden unexpected death in epilepsy) and one withdrawal owing to a TEAE (major depression), both considered unlikely to be related to treatment. Diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with 485 clusters treated with a second dose within 24 h; 53.4% of patients had monthly average usage of one to two doses, 41.7% two to five doses, and 4.9% more than five doses. No serious TEAEs were considered to be treatment related. TEAEs possibly or probably related to treatment (n = 30) were most commonly nasal discomfort (6.1%); headache (2.5%); and dysgeusia, epistaxis, and somnolence (1.8% each). Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis. Significance: In this large open‐label safety study, the safety profile of diazepam nasal spray was consistent with the established profile of rectal diazepam, and the high retention rate supports effectiveness in this population. A second dose was used in only 12.6% of seizure clusters. [ABSTRACT FROM AUTHOR]

Objective: Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness. Methods: A long‐term, phase 3, open‐label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen. Results: Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6–65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no‐benzodiazepine group. Findings were similar in a sub‐analysis of patients who were (n = 44) or were not (n = 75) taking clobazam. Significance: This analysis of patients from a long‐term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub‐analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use. [ABSTRACT FROM AUTHOR]

White Matter Abnormalities Across Different Epilepsy Syndromes in Adults: An ENIGMA-Epilepsy Study Hatton SN, Huynh KH, Bonilha L, et al. Brain. 2020;143(8):2454-2473. doi:10.1093/brain/awaa200. PMID: 32814957 The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicenter sample of adult epilepsy patients. Diffusion-weighted magnetic resonance imaging (MRI) data were analyzed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182), and nonlesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P <.001). Across "all epilepsies" lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum, and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiate, and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicenter study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum, and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric comorbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research. [ABSTRACT FROM AUTHOR]

Association of Levels of Specialized Care With Risk of Premature Mortality in Patients With Epilepsy Lowerison MW, Josephson CB, Jetté N, et al. JAMA Neurol. 2019;76:1352-1358. Importance: Patients with epilepsy are at an elevated risk of premature mortality. Interventions to reduce this risk are crucial. Objective: To determine if the level of care (non-neurologist, neurologist, or comprehensive epilepsy program) is negatively associated with the risk of premature mortality. Design, Setting, and Participants: In this retrospective open cohort study, all adult patients 18 years or older who met the administrative case definition for incident epilepsy in linked databases (Alberta Health Services administrative health data and the Comprehensive Calgary Epilepsy Programme Registry [CEP]) inclusive of the years 2002 to 2016 were followed up until death or loss to follow-up. The final analyses were performed on May 1, 2019. Exposures: Evaluation by a non-neurologist, neurologist, or epileptologist. Main Outcomes and Measures: The outcome was all-cause mortality. We used extended Cox models treating exposure to a neurologist or the CEP as time-varying covariates. Age, sex, socioeconomic deprivation, disease severity, and comorbid burden at index date were modeled as fixed-time coefficients. Results: A total 23 653 incident cases were identified (annual incidence of 89 per 100 000); the mean age (SD) at index date was 50.8 (19.1) years and 12 158 (50.3%) were women. A total of 14 099 (60%) were not exposed to specialist neurological care, 9554 (40%) received care by a neurologist, and 2054 (9%) received care in the CEP. In total, 4098 deaths (71%) occurred in the nonspecialist setting, 1481 (26%) for those seen by a neurologist, and 176 (3%) for those receiving CEP care. The standardized mortality rate was 7.2% for the entire cohort, 9.4% for those receiving nonspecialist care, 5.6% for those seen by a neurologist, and 2.8% for those seen in the CEP. The hazard ratio (HR) of mortality was lower in those receiving neurologist (HR, 0.85; 95% CI, 0.77-0.93) and CEP (HR, 0.49; 95% CI, 0.38-0.62) care. In multivariable modeling, specialist care, the age at index, and disease severity were retained in the final model of the association between specialist care and mortality. Conclusions and Relevance: Exposure to specialist care is associated with incremental reductions in the hazard of premature mortality. Those referred to a comprehensive epilepsy program received the greatest benefit. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND AND PURPOSE To demonstrate the accuracy across different acquisition and analysis methods, we evaluated the variability in hippocampal volumetric and surface displacement measurements resulting from two different MRI (magnetic resonance imaging) acquisition protocols. METHODS Nine epilepsy patients underwent two independent T1-weighted magnetization prepared spoiled gradient sequences during a single 3T MRI session. Using high-dimension mapping-large deformation (HDM-LD) segmentation, we calculated volumetric estimates and generated a vector-based 3-dimensional surface model of each subject's hippocampi, and evaluated volume and surface changes, the latter using a cluster-based noise estimation model. RESULTS Mean hippocampal volumes and standard deviations for the left hippocampi were 2,750 (826) mm3 and 2,782 (859) mm3 ( P = .13), and for the right hippocampi were 2,558 (750) mm3 and 2,547 (692) mm3 ( P = .76), respectively for the MPR1 and MPR2 sequences. Average Dice coefficient comparing overlap for segmentations was 86%. There was no significant effect of MRI sequence on volume estimates and no significant hippocampal surface change between sequences. CONCLUSION Statistical comparison of hippocampal volumes and statistically thresholded HDM-LD surfaces in TLE patients showed no differences between the segmentations obtained in the two MRI acquisition sequences. This validates the robustness across MRI sequences of the HDM-LD technique for estimating volume and surface changes in subjects with epilepsy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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Los autores revisan los escritos de John Hughlings-Jackson sobre el "estado onírico" y sus conclusiones sobre los diferentes niveles de conciencia. Método: Revisaron las publicaciones de Hughlings-Jackson desde la descripción inicial del testado onírico de 1876 hasta su trabajo sobre el "grupo de crisis uncinadas" de 1899. A continuación examinaron de que forma Hughlings-Jackson utilizó los signos y síntomas que acompañaban al "estado onírico" en la formulación de sus ideas sobre la conciencia humana. Resultados: HughIings-Jackson definió eI "estado onírico" como un estado de "hiperconciencia" o de agudización máxima del estado intelectual. Como síntomas acompañantes describió sensaciones olfativas y gustativas "rudimentarias" y sensaciones epigástricas atípicas, movimiento de mascar y de relamerse, automatismos, síntomas postictales y, al menos, cierto grado de alteración de la conciencia. Utilizando su observación del "estado onírico" como modelo, Hughlings-Jackson propuso tres niveles de conciencia, cada uno con un componente objetivo y subjetivo. Conclusiones: A través de su descripción del "estado oníricos" Hughlings-Jackson definió y localizó de forma precisa la epilepsia temporal medial. Relacionando la semiología ictal del "estado onírico" con el estado de conciencia, desarrollo una teoría de la conciencia que sigue siendo vigente todavía para la comprensión actual de la relación entre la mente y el cerebro. [ABSTRACT FROM PUBLISHER]

Objectives: To assess patterns of postictal cerebral blood flow in the mesial temporal lobe by coregistration of postictal 99mTc-HMPAO SPECT with MRI in patients with confirmed mesial temporal lobe epilepsy.Methods: Ten postictal and interictal 99mTc-HMPAO SPECT scans were coregistered with MRI in 10 patients with confirmed mesial temporal lobe epilepsy. Volumetric tracings of the hippocampus and amygdala from the MRI were superimposed on the postictal and interictal SPECT. Asymmetries in hippocampal and amygdala SPECT signal were then calculated using the equation: % Asymmetry =100 x (right - left) / (right + left)/2.Results: In the postictal studies, quantitative measurements of amygdala SPECT intensities were greatest on the side of seizure onset in all cases, with an average % asymmetry of 11.1, range 5.2-21.9. Hippocampal intensities were greatest on the side of seizure onset in six studies, with an average % asymmetry of 9.6, range 4.7-12.0. In four scans the hippocampal intensities were less on the side of seizure onset, with an average % asymmetry of 10.2, range 5.7-15.5. There was no localising quantitative pattern in interictal studies.Conclusions: Postictal SPECT shows distinctive perfusion patterns when coregistered with MRI, which assist in lateralisation of temporal lobe seizures. Hyperperfusion in the region of the amygdala is more consistently lateralising than hyperperfusion in the region of the hippocampus in postictal studies. [ABSTRACT FROM AUTHOR]