Defining benchmark outcomes for mesial temporal lobe epilepsy surgery: A global multicenter analysis of 1119 cases.

OBJECTIVE: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff. RESULTS: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months). SIGNIFICANCE: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques.

Adjunctive brivaracetam and sustained seizure frequency reduction in very active focal epilepsy.

OBJECTIVE: This study aimed to explore the effectiveness of brivaracetam (BRV) according to baseline seizure frequency and past treatment history in subjects with focal epilepsy who were included in the Brivaracetam Add-On First Italian Network Study (BRIVAFIRST). METHODS: BRIVAFIRST was a 12-month retrospective, multicenter study including adults prescribed adjunctive BRV. Study outcomes included sustained seizure response (SSR), sustained seizure freedom (SSF), and the rates of treatment discontinuation and adverse events (AEs). Baseline seizure frequency was stratified as <5, 5-20, and >20 seizures per month, and the number of prior antiseizure medications (ASMs) as <5 and ≥6. RESULTS: A total of 994 participants were included. During the 1-year study period, SSR was reached by 45.8%, 39.3%, and 22.6% of subjects with a baseline frequency of <5, 5-20, and >20 seizures per month (p < .001); the corresponding figures for the SSF were 23.4%, 9.8%, and 2.8% (p < .001). SSR was reached by 51.2% and 26.5% participants with a history of 1-5 and ≥6 ASMs (p < .001); the corresponding rates of SSF were 24.7% and 4.5% (p < .001). Treatment discontinuation due to lack of efficacy was more common in participants with >20 seizures compared to those with <5 seizures per month (25.8% vs. 9.3%, p < .001), and in participants with history of ≥6 prior ASMs compared to those with history of 1-5 ASMs (19.6% vs. 12.2%, p = .002). There were no differences in the rates of BRV withdrawal due to AEs and the rates of AEs across the groups of participants defined according to the number of seizures at baseline and the number of prior ASMs. SIGNIFICANCE: The baseline seizure frequency and the number of previous ASMs were predictors of sustained seizure frequency reduction with adjunctive BRV in subjects with focal epilepsy.

3D4K exoscope in epilepsy surgery: a seminal experience.

BACKGROUND AND OBJECTIVES: To report the progressive introduction of the exoscope (EX) from surface lesionectomy to antero-mesial temporal lobectomy (AMTL) in an epilepsy surgery practice. METHODS: We describe a population of ten consecutive patients undergoing EX surgery, with a minimum follow-up of 6 months, that was compared to a similar population of patients referred to operative microscopic surgery (OM). RESULTS: All surgeries were performed with the use of EX or OM alone. Transient neurological complications for surgery in eloquent regions were recorded in one patient for each population. Nine and seven patients undergoing, respectively, EX and OM surgery resulted in Engel class Ia (90% vs. 70%). The mean duration of EX and OM surgery resulted in 265.5 and 237.9 min, respectively, with a mean of 308.3 and 253.3 min for AMTL cases, respectively. CONCLUSIONS: This preliminary study revealed that ORBEYE EX can be safe and effective in different types of epilepsy surgeries. The transition from OM to EX is fast, even though it is slower for the more challenging mesial temporal structure removal. Ergonomic and operative team interaction is improved by the use of EX. Our data need to be confirmed by larger studies.

Daytime sleepiness and sleep quality in Charcot-Marie-Tooth disease.

BACKGROUND: Sleep abnormalities have been reported in Charcot-Marie-Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients' series. METHODS: Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use. RESULTS: ESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23% and 56% of patients; such patients had more frequently anxiety/depression, abnormal fatigue, and positive sensory symptoms than those with normal ESS/PSQI. Moreover, patients with PSQI score > 5 had more severe disease (median CMT Examination Score, CMTES, 8 vs 6, p = 0.006) and more frequent use of anxiolytic/antidepressant drugs (29% vs 7%, p < 0.001). CONCLUSIONS: Bad sleep quality and daytime sleepiness are frequent in CMT and correlated with anxiety, depression and fatigue, confirming that different components affect sleep. Sleep disorders, such as sleep apnea and restless leg syndrome, not specifically investigated here, are other factors known to impact on sleep quality and somnolence. CMT patients' management must include sleep behavior assessment and evaluation of its correlated factors, including general distress and fatigue.

Distinctive electro-clinical, neuroimaging and histopathological features of temporal encephaloceles associated to epilepsy.

OBJECTIVE: Encephaloceles (ENCs) may cause clinical complications, including drug-resistant epilepsy that can be cured with epilepsy surgery. METHODS: We describe clinical, diagnostic, and neuropathological findings of 12 patients with temporal ENC and epilepsy evaluated for surgery and compare them with a control group of 26 temporal lobe epilepsy (TLE) patients. RESULTS: Six patients had unilateral and 6 bilateral temporal ENCs. Compared to TLEs, ENCs showed i) later epilepsy onset, ii) higher prevalence of psychiatric comorbidities, iii) no history of febrile convulsions, and iv) ictal semiology differences. Seven patients had MRI signs of gliosis, and 9 of intracranial hypertension. Interictal EEG analysis in ENCs demonstrated significant differences with controls: prominent activity in the beta/gamma frequency bands in frontal regions, interictal short sequences of low-voltage fast activity, and less frequent and more localized interictal epileptiform discharges. Ictal EEG patterns analyzed in 9 ENCs showed delayed and slower contralateral spread compared to TLEs. All ENCs that underwent surgery (7 lobectomies and 1 lesionectomy) are in Engel class I. Neuropathological examination revealed 4 patterns: herniated brain fragments, focal layer I distortion, white matter septa extending into the cortex, and altered gyral profile. CONCLUSIONS AND SIGNIFICANCE: The described peculiarities might help clinicians to suspect the presence of largely underdiagnosed ENCs.

Brivaracetam as Early Add-On Treatment in Patients with Focal Seizures: A Retrospective, Multicenter, Real-World Study.

INTRODUCTION: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). METHODS: BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1-2 (early add-on) and ≥ 3 (late add-on) prior antiseizure medications. RESULTS: A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12 months was 125 (100-200) mg in the early add-on group and 200 (100-200) in the late add-on group (p < 0.001). Sustained seizure response was reached by 97/161 (60.3%) of patients in the early add-on group and 286/833 (34.3%) of patients in the late add-on group (p < 0.001). Sustained seizure freedom was achieved by 51/161 (31.7%) of patients in the early add-on group and 91/833 (10.9%) of patients in the late add-on group (p < 0.001). During the 1-year study period, 29 (16.5%) patients in the early add-on group and 241 (28.3%) in the late add-on group discontinued BRV (p = 0.001). Adverse events were reported by 38.7% and 28.5% (p = 0.017) of patients who received BRV as early and late add-on treatment, respectively. CONCLUSION: Brivaracetam was effective and well tolerated both as first add-on and late adjunctive treatment in patients with focal epilepsy.

Adjunctive Brivaracetam in Older Patients with Focal Seizures: Evidence from the BRIVAracetam add­on First Italian netwoRk Study (BRIVAFIRST).

BACKGROUND: The management of epilepsy in older adults has become part of daily practice because of an aging population. Older patients with epilepsy represent a distinct and more vulnerable clinical group as compared with younger patients, and they are generally under-represented in randomized placebo-controlled trials. Real-world studies can therefore be a useful complement to characterize the drug's profile. Brivaracetam is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A and approved as adjunctive therapy for focal seizures in adults with epilepsy. OBJECTIVE: The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive brivaracetam in older patients (≥65 years of age) with epilepsy treated in a real-world setting. METHODS: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a 12-month retrospective multicenter study including adult patients prescribed adjunctive brivaracetam. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events and the incidence of adverse events. Data were compared for patients aged ≥65 years of age ('older') vs those aged <65 years ('younger'). RESULTS: There were 1029 patients with focal epilepsy included in the study, of whom 111 (10.8%) were aged ≥65 years. The median daily dose of brivaracetam at 3 months was 100 [interquartile range, 100-175] mg in the older group and 100 [100-200] mg in the younger group (p = 0.036); it was 150 [100-200] mg in both groups either at 6 months (p = 0.095) or 12 months (p = 0.140). At 12 months, 49 (44.1%) older and 334 (36.4%) younger patients had a reduction in their baseline seizure frequency by at least 50% (p = 0.110), and the seizure freedom rates were 35/111 (31.5%) and 134/918 (14.6%) in older and younger groups, respectively (p < 0.001). During the 1-year study period, 20 (18.0%) patients in the older group and 245 (26.7%) patients in the younger group discontinued brivaracetam (p = 0.048). Treatment withdrawal because of insufficient efficacy was less common in older than younger patients [older: n = 7 (6.3%), younger: n = 152 (16.6%); p = 0.005]. Adverse events were reported by 24.2% of older patients and 30.8% of younger patients (p = 0.185); the most common adverse events were somnolence, nervousness and/or agitation, vertigo, and fatigue in both study groups. CONCLUSIONS: Adjunctive brivaracetam was efficacious, had good tolerability, and no new or unexpected safety signals emerged when used to treat older patients with uncontrolled focal seizures in clinical practice. Adjunctive brivaracetam can be a suitable therapeutic option in this special population.

Sustained seizure freedom with adjunctive brivaracetam in patients with focal onset seizures.

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32-56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12 months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy.

Brivaracetam as add-on treatment in patients with post-stroke epilepsy: real-world data from the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST).

OBJECTIVE: Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy and accounts for about 10-15% of all newly diagnosed epilepsy cases. However, evidence about the clinical profile of antiseizure medications in the PSE setting is currently limited. Brivaracetam (BRV) is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A. The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive BRV in patients with PSE treated in a real-world setting. METHODS: This was a subgroup analysis of patients with PSE included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). The BRIVAFIRST was a 12-month retrospective, multicentre study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure-freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. RESULTS: Patients with PSE included in the BRIVAFIRST were 75 and had a median age of 57 (interquartile range, 42-66) years. The median daily doses of BRV at 3, 6, and 12 months from starting treatment were 100 (100-150) mg, 125 (100-200) mg and 100 (100-200) mg, respectively. At 12 months, 32 (42.7%) patients had a reduction in their baseline seizure frequency by at least 50%, and the seizure freedom rates was 26/75 (34.7%). During the 1-year study period, 10 (13.3%) patients discontinued BRV. The reasons of treatment withdrawal were insufficient efficacy in 6 (8.0%) patients and poor tolerability in 4 (5.3%) patients. Adverse events were reported by 13 (20.3%) patients and were rated as mild in 84.6% and moderate in 15.4% of cases. SIGNIFICANCE: Adjunctive BRV was efficacious and generally well-tolerated when used in patients with PSE in clinical practice. Adjunctive BRV can be a suitable therapeutic option for patients with PSE.

Role of NODDI in the MRI Characterization of Hippocampal Abnormalities in Temporal Lobe Epilepsy: Clinico-histopathologic Correlations.

BACKGROUND AND OBJECTIVES: The identification of possible hippocampal alterations is a crucial point for the diagnosis and therapy of patients with unilateral temporal lobe epilepsy (TLE). This study aims to investigate the role of neurite orientation dispersion and density imaging (NODDI) compared to diffusion tensor imaging (DTI) in the comprehension of hippocampal microstructure in TLE. METHODS: DTI and NODDI metrics were calculated in the hippocampi of adult patients with TLE, with and without histology-confirmed hippocampal sclerosis (HS), and in age/sex-matched healthy controls (HC). Diffusion metrics and hippocampal volumes of the pathologic side were compared within participants and between participants among the HS, non-HS, and HC groups. Diffusion metrics were also correlated with hippocampal volume and patients' clinical features. After surgery, hippocampal specimens were processed for neuropathology examinations. RESULTS: Fifteen patients with TLE (9 with and 6 without HS) and 11 HC were included. Hippocampal analyses resulted in a significant increase in fractional anisotropy (FA) and mean diffusivity (MD; mm2/s × 10-3) and decrease in orientation dispersion index (ODI) comparing the pathologic side of patients with HS and their relative nonpathologic side (0.203 vs 0.183, 0.825 vs 0.724, 0.366 vs 0.443, respectively), the pathologic side of patients without HS (0.203 vs 0.169, 0.825 vs 0.745, 0.366 vs 0.453, respectively), and HC (0.203 vs 0.172, 0.825 vs 0.729, 0.366 vs 0.447, respectively). Moreover, neurite density (ND) was significantly decreased comparing both hippocampi of patients with HS (0.416 vs 0.460). A significant increase in free-water isotropic volume fraction (fiso) was found in the comparison of pathologic hippocampi of patients with HS and nonpathologic hippocampi of patients with HS (0.323 vs 0.258) and HC (0.323 vs 0.226). Hippocampal volume of all patients with TLE negatively correlated with MD (r = -0.746, p = 0.0145) and positively correlated with ODI (r = 0.719, p = 0.0145). Fiso and ND of sclerotic hippocampi positively correlated with disease duration (r = 0.684, p = 0.0424 and r = 0.670, p = 0.0486, respectively). Immunohistochemistry in sclerotic hippocampal specimens revealed neuronal loss in the pyramidal layer and fiber reorganization at the level of stratum lacunosum-moleculare, confirming ODI and ND metrics. DISCUSSION: This study shows the capability of diffusion MRI metrics to detect hippocampal microstructural alterations. Among them, ODI seems to better highlight the fiber reorganization observed by neuropathology in sclerotic hippocampi.

MRI in Late-Onset Rasmussen Encephalitis: A Long-Term Follow-Up Study.

Late-onset Rasmussen encephalitis (LoRE) is a rare unihemispheric progressive inflammatory disorder causing neurological deficits and epilepsy. The long-term radiological evolution has never been fully described. We retrospectively analyzed the MR images of 13 LoRE patients from a total of 136 studies, and searched for focal areas of volume loss or signal intensity abnormality in grey matter or white matter. Each subject had a median of nine MRI studies (IQR 7-13). Frontal and temporal lobes were the most affected regions (13/13 and 8/13, respectively) and showed the greatest worsening over time in terms of atrophic changes (9/13 and 5/8, respectively). A milder cortical atrophy was found in the insular and parietal lobes. The caudate nucleus was affected in seven patients. Hyperintensities of grey matter and white matter on T2-WI and FLAIR images were observed in all patients, and transiently in eight patients. In two cases out of the latter patients, these transient alterations evolved into atrophy of the same region. Disease duration was significantly associated with signal abnormalities in the grey matter at last follow-up. LoRE MRI alterations are milder, and their progression is markedly slower compared to radiological findings described in the childhood form.

Sleep disorders and mental health in hospital workers during the COVID-19 pandemic: a cross-sectional multicenter study in Northern Italy.

INTRODUCTION: From the beginning of the COVID-19 pandemic, healthcare workers had to face unprecedented emergency needs associated with an extraordinary amount of psychological distress. In this cross-sectional multicenter study, we investigated sleep disturbances, and the level of anxiety and depression among the healthcare and non-healthcare staff of three hospitals in Milan (Italy) during the COVID-19 outbreak. Moreover, we explored potential predisposing factors for affective symptoms and poor sleep. METHODS: Between June and July 2020, we administered an online questionnaire to evaluate the presence of sleep disorders (Pittsburgh Sleep Quality Index), insomnia (Sleep Condition Indicator), anxiety (State Trait Anxiety Inventory), and depression (Beck Depression Inventory-II). We used univariate and multivariate analysis to evaluate the association between the personal conditions and sleep and affective disorders. RESULTS: The 964 participants reported high rates of sleep disorders (80.3%)-mainly insomnia (30.5%)-anxiety (69.7%), and depression (32.8%). The multivariate analysis showed a strong association of sleep disorders, especially insomnia, with female gender (p = 0.004), divorced marital status (p = 0.015), self-isolation (p = 0.037), and chronic diseases (p = 0.003). Anxiety was significantly associated with teleworking (p = 0.001), while depressive symptoms were associated with self-isolation (p = 0.028), modified work schedules (p = 0.03), and chronic diseases (p = 0.027). CONCLUSION: In hospital workers, the high prevalence of sleep and psychiatric symptoms during the COVID-19 outbreak appears to be determined mainly by modifications of personal or work habits. Teleworking was associated with increased anxiety. An accurate planning of hospital activities and a psychological support are needed to prevent and manage sleep and mental disorders.

Enhancing Safety in Epilepsy Surgery (EASINESS): Study Protocol for a Retrospective, Multicenter, Open Registry.

Introduction: Optimizing patient safety and quality improvement is increasingly important in surgery. Benchmarks and clinical quality registries are being developed to assess the best achievable results for several surgical procedures and reduce unwarranted variation between different centers. However, there is no clinical database from international centers for establishing standardized reference values of patients undergoing surgery for mesial temporal lobe epilepsy. Design: The Enhancing Safety in Epilepsy Surgery (EASINESS) study is a retrospectively conducted, multicenter, open registry. All patients undergoing mesial temporal lobe epilepsy surgery in participating centers between January 2015 and December 2019 are included in this study. The patient characteristics, preoperative diagnostic tools, surgical data, postoperative complications, and long-term seizure outcomes are recorded. Outcomes: The collected data will be used for establishing standardized reference values ("benchmarks") for this type of surgical procedure. The primary endpoints include seizure outcomes according to the International League Against Epilepsy (ILAE) classification and defined postoperative complications. Discussion: The EASINESS will define robust and standardized outcome references after amygdalohippocampectomy for temporal lobe epilepsy. After the successful definition of benchmarks from an international cohort of renowned centers, these data will serve as reference values for the evaluation of novel surgical techniques and comparisons among centers for future clinical trials. Clinical trial registration: This study is indexed at clinicaltrials.gov (NT 04952298).