Effects of zonisamide as add-on therapy on sleep-wake cycle in focal epilepsy: a polysomnographic study.

PURPOSE: The purpose of this study was to evaluate the effects of zonisamide (ZNS) as adjunctive therapy on sleep-wake cycle and daytime somnolence in adult patients affected by focal epilepsy. METHODS: Thirteen patients affected by focal epilepsy were recruited to undergo a 24-hour ambulatory polysomnography, Multiple Sleep Latency Test (MSLT), and a subjective evaluation of nocturnal sleep by means of the Pittsburgh Sleep Quality Index (PSQI) and daytime somnolence by means of the Epworth Sleepiness Scale (ESS) before and after 3 months of treatment with ZNS as add-on therapy. RESULTS: Twelve patients completed the study. Zonisamide therapy reduced seizures by >50% in 8 out of 12 patients. Zonisamide did not induce any significant changes in nocturnal polysomnographic variables and in PSQI scores. In addition, mean sleep latency and ESS score were unmodified after treatment. CONCLUSION: Zonisamide seems to be effective and safe in focal epilepsy. Both subjective and objective sleep parameters showed no detrimental effects on nocturnal sleep and daytime somnolence in patients with focal epilepsy using ZNS. Since some AEDs induce sleep impairment, which is known to trigger EEG abnormalities and seizures and to worsen quality of life, our findings suggest a positive profile of ZNS.

Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis.

Objectives: Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main objectives of this observational study were to identify the most specific pro-coagulative/vascular factors for multiple sclerosis pathogenesis and to correlate them with brain hemodynamic abnormalities. Methods: We compared i) serum/plasma levels of complement(C)/coagulation/vascular factors, viral/microbiological assays, fat-soluble vitamins and lymphocyte count among people with multiple sclerosis sampled in a clinical remission (n=30; 23F/7M, 40 ± 8.14 years) or a relapse (n=30; 24F/6M, age 41 ± 10.74 years) and age/sex-matched controls (n=30; 23F/7M, 40 ± 8.38 years); ii) brain hemodynamic metrics at dynamic susceptibility contrast-enhanced 3T-MRI during relapse and remission, and iii) laboratory data with MRI perfusion metrics and clinical features of people with multiple sclerosis. Two models by Partial Least Squares Discriminant Analysis were performed using two groups as input: (1) multiple sclerosis vs. controls, and (2) relapsing vs. remitting multiple sclerosis. Results: Compared to controls, multiple sclerosis patients had a higher Body-Mass-Index, Protein-C and activated-C9; and a lower activated-C4. Levels of Tissue-Factor, Tie-2 and P-Selectin/CD62P were lower in relapse compared to remission and HC, whereas Angiopoietin-I was higher in relapsing vs. remitting multiple sclerosis. A lower number of total lymphocytes was found in relapsing multiple sclerosis vs. remitting multiple sclerosis and controls. Cerebral-Blood-Volume was lower in normal-appearing white matter and left caudatum while Cerebral-Blood-Flow was inferior in bilateral putamen in relapsing versus remitting multiple sclerosis. The mean-transit-time of gadolinium-enhancing lesions negatively correlated with Tissue-Factor. The top-5 discriminating variables for model (1) were: EBV-EBNA-1 IgG, Body-Mass-Index, Protein-C, activated-C4 and Tissue-Factor whereas for model (2) were: Tissue-Factor, Angiopoietin-I, MCHC, Vitamin A and T-CD3. Conclusion: Tissue-factor was one of the top-5 variables in the models discriminating either multiple sclerosis from controls or multiple sclerosis relapse from remission and correlated with mean-transit-time of gadolinium-enhancing lesions. Tissue-factor appears a promising pro-coagulative/vascular biomarker and a possible therapeutic target in relapsing-remitting multiple sclerosis. Clinical trial registration: ClinicalTrials.gov, identifier NCT04380220.

Home treatment against fatigue in multiple sclerosis by a personalized, bilateral whole-body somatosensory cortex stimulation.

BACKGROUND: Fatigue in multiple sclerosis (MS) is a highly invalidating symptom with no pharmacological efficacious therapies, which furthermore present frequent severe side effects. In two previous randomized controlled trials we observed the efficacy of a personalized neuromodulation treatment consisting of a personalized transcranial Direct Current Stimulation (tDCS) for 15 min per day for 5 days (Faremus). METHODS: By this medical-device phase II study, we aimed at assessing the feasibility, acceptance, safety and efficacy of Faremus treatment when applied at patients' home. We considered the efficacy as primary outcome assessed by a reduction of fatigue levels measured by Modified Fatigue Impact Scale (mFIS) scored before and after the treatment. Primary outcome determined the sample size estimate. Individual ad-hoc questionnaires quantified the acceptance, safety and side effects during the treatment. RESULTS: All 15 patients completed the treatment, reporting optimal acceptance and safety on using Faremus at their home without side-effects. The treatment ameliorated fatigue symptoms more than 20% of baseline in 10 out of the 15 patients and of 37% on average, with a corresponding effect size 1.21. CONCLUSIONS: Faremus personalized electroceutical intervention, a 5-days anodal tDCS over the bilateral whole-body somatosensory cortex, is well accepted and can be feasibly, safely, and efficaciously applied at patients' home, offering a comfortable treatment by reducing the need to travel when fatigue-related symptoms hamper the quality of life.

Cognitive profile and brain morphological changes in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is accompanied by neurocognitive impairment, likely mediated by injury to various brain regions. We evaluated brain morphological changes in patients with OSA and their relationship to neuropsychological and oximetric data. Sixteen patients affected by moderate-severe OSA (age: 55.8±6.7 years, 13 males) and fourteen control subjects (age: 57.6±5.1 years, 9 males) underwent 3.0 Tesla brain magnetic resonance imaging (MRI) and neuropsychological testing evaluating short- and long-term memory, executive functions, language, attention, praxia and non-verbal learning. Volumetric segmentation of cortical and subcortical structures and voxel-based morphometry (VBM) were performed. Patients and controls differed significantly in Rey Auditory-Verbal Learning test (immediate and delayed recall), Stroop test and Digit span backward scores. Volumes of cortical gray matter (GM), right hippocampus, right and left caudate were smaller in patients compared to controls, with also brain parenchymal fraction (a normalized measure of cerebral atrophy) approaching statistical significance. Differences remained significant after controlling for comorbidities (hypertension, diabetes, smoking, hypercholesterolemia). VBM analysis showed regions of decreased GM volume in right and left hippocampus and within more lateral temporal areas in patients with OSA. Our findings indicate that the significant cognitive impairment seen in patients with moderate-severe OSA is associated with brain tissue damage in regions involved in several cognitive tasks. We conclude that OSA can increase brain susceptibility to the effects of aging and other clinical and pathological occurrences.

Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy.

PURPOSE: The endocannabinoid system is involved in excitatory/inhibitory balance mechanisms within the central nervous system (CNS). Growing evidence shows that its perturbation leads to development of epileptic seizures in experimental models, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. Experimental data also demonstrate that the endocannabinoid anandamide (AEA) can antagonize epileptic discharges in hippocampal tissue. The objective of our study was to measure endocannabinoids levels in the cerebrospinal fluid (CSF) of drug-naive patients affected by temporal lobe epilepsy (TLE). METHODS: We measured the levels of both AEA and the other endocannabinoid, 2-arachidonoylglycerol (2-AG), in the CSF of drug-naive patients with TLE. RESULTS: A significant reduction of AEA was found in the CSF of patients with compared with healthy controls (epileptic patients = 2.55 +/- 1.78 pmol/ml; healthy controls = 11.65 +/- 7.53 pmol/ml; n = 9 for both groups, p < 0.01). 2-AG levels, however, were not affected (epileptic patients = 209.5 +/- 146.56; healthy controls = 159.6 +/- 110.2) (n = 6 for both groups, p = 0.48). DISCUSSION: Our findings seem to be consistent with experimental evidence demonstrating a significant prevention of epileptic seizures induced by endocannabinoids in models of epilepsy. Furthermore, they support the hypothesis that AEA may be involved in its pathogenesis, suggesting a hypothetical primary impairment of the endocannabinoid system in untreated TLE. The actual role of this in vivo dysregulation still remains unclear.

Perampanel in brain tumor-related epilepsy: Observational pilot study.

OBJECTIVE: Possible loss of efficacy and potential interactions between antiepileptic drugs (AEDs) and chemotherapy could complicate the management of patients with brain tumor-related epilepsy (BTRE) that may expose patients to an increased risk of adverse events. Perampanel (PER) is a highly selective, noncompetitive, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptor antagonist. This study evaluates the effectiveness, QoL, cognition, and mood of PER in add-on therapy in BTRE patients. MATERIAL AND METHODS: Observational pilot study on the effectiveness of PER as add-on therapy in BTRE patients with uncontrolled seizures with a 6-month follow-up. RESULTS: We recruited 26 BTRE patients. During the follow-up, 16 underwent chemotherapy and 11 radiotherapy; 11 had disease progression. Five patients dropped out. Mean daily PER dosage was 6.6 mg in the 21 patients who completed the follow-up and 6.4 mg in the ITT population. The mean number of seizures/month decreased from 10.8 ± 15.03 at baseline to 1.7 ± 4.34 in the 21 patients who reached the final follow-up. Responder rate was 88.4%: Eight patients were seizure-free, 15 had ≥50% seizure reduction, and 3 remained stable. Four patients (15.4%) reported AEs: 2 required PER dose reduction, and 2 dropped out. Neuropsychological, mood, and QoL questionnaires were not statistically different compared to baseline. There were no significant differences in seizure control in patients with/without IDH1 mutation and with/without MGMT methylation. CONCLUSIONS: Perampanel proved to be effective on seizure control in BRTE patients and to be well tolerated without negative effects on cognition and QoL. Perampanel could be a valid therapeutic option in BTRE.

Coagulation/Complement Activation and Cerebral Hypoperfusion in Relapsing-Remitting Multiple Sclerosis.

Introduction: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with an underlying immune-mediated and inflammatory pathogenesis. Innate immunity, in addition to the adaptive immune system, plays a relevant role in MS pathogenesis. It represents the immediate non-specific defense against infections through the intrinsic effector mechanism "immunothrombosis" linking inflammation and coagulation. Moreover, decreased cerebral blood volume (CBV), cerebral blood flow (CBF), and prolonged mean transit time (MTT) have been widely demonstrated by MRI in MS patients. We hypothesized that coagulation/complement and platelet activation during MS relapse, likely during viral infections, could be related to CBF decrease. Our specific aims are to evaluate whether there are differences in serum/plasma levels of coagulation/complement factors between relapsing-remitting (RR) MS patients (RRMS) in relapse and those in remission and healthy controls as well as to assess whether brain hemodynamic changes detected by MRI occur in relapse compared with remission. This will allow us to correlate coagulation status with perfusion and demographic/clinical features in MS patients. Materials and Methods: This is a multi-center, prospective, controlled study. RRMS patients (1° group: 30 patients in relapse; 2° group: 30 patients in remission) and age/sex-matched controls (3° group: 30 subjects) will be enrolled in the study. Patients and controls will be tested for either coagulation/complement (C3, C4, C4a, C9, PT, aPTT, fibrinogen, factor II, VIII, and X, D-dimer, antithrombin, protein C, protein S, von-Willebrand factor), soluble markers of endothelial damage (thrombomodulin, Endothelial Protein C Receptor), antiphospholipid antibodies, lupus anticoagulant, complete blood count, viral serological assays, or microRNA microarray. Patients will undergo dynamic susceptibility contrast-enhanced MRI using a 3.0-T scanner to evaluate CBF, CBV, MTT, lesion number, and volume. Statistical Analysis: ANOVA and unpaired t-tests will be used. The level of significance was set at p ≤ 0.05. Discussion: Identifying a link between activation of coagulation/complement system and cerebral hypoperfusion could improve the identification of novel molecular and/or imaging biomarkers and targets, leading to the development of new effective therapeutic strategies in MS. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT04380220.

Exit strategies for "needle fatigue" in multiple sclerosis: a propensity score-matched comparison study.

Patients with multiple sclerosis on long-term injectable therapies may suffer from the so-called "needle fatigue", i.e., a waning commitment to continue with the prescribed injectable treatment. Therefore, alternative treatment strategies to enhance patients' adherence are warranted. In this independent, multicentre post-marketing study, we sought to directly compare switching to either teriflunomide (TFN), dimethyl fumarate (DMF), or pegylated interferon (PEG) on treatment persistence and time to first relapse over a 12-month follow-up. We analyzed a total of 621 patients who were free of relapses and gadolinium-enhancing lesions in the year prior to switching to DMF (n = 265), TFN (n = 160), or PEG (n = 196). Time to discontinuation and time to first relapse were explored in the whole population by Cox regression models adjusted for baseline variables and after a 1:1:1 ratio propensity score (PS)-based matching procedure. Treatment discontinuation was more frequent after switching to PEG (28.6%) than DMF (14.7%; hazard ratio [HR] = 0.25, p < 0.001) and TFN (16.9%; HR = 0.27, p < 0.001). We found similar results even in the re-sampled cohort of 222 patients (74 per group) derived by the PS-based matching procedure. The highest discontinuation rate observed in PEG recipient was mainly due to poor tolerability (p = 0.005) and pregnancy planning (p = 0.04). The low number of patients who relapsed over the 12-month follow-up (25 out of 621, approximately 4%) prevented any analysis on the short-term risk of relapse. This real-world study suggests that oral drugs are a better switching option than low-frequency interferon for promoting the short-term treatment persistence in stable patients who do not tolerate injectable drugs.

Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease.

IMPORTANCE: Nocturnal sleep disruption develops in Alzheimer disease (AD) owing to the derangement of the sleep-wake cycle regulation pathways. Orexin contributes to the regulation of the sleep-wake cycle by increasing arousal levels and maintaining wakefulness. OBJECTIVES: To study cerebrospinal fluid levels of orexin in patients with AD, to evaluate the relationship of orexin cerebrospinal fluid levels with the degree of dementia and the cerebrospinal fluid AD biomarkers (tau proteins and ß-amyloid 1-42), and to analyze potentially related sleep architecture changes measured by polysomnography. DESIGN, SETTING, AND PARTICIPANTS: We conducted a case-control study from August 1, 2012, through May 31, 2013. We included 48 drug-naive AD patients referred to the Neurological Clinic of the University Hospital of Rome Tor Vergata. Based on the Mini-Mental State Examination score, 21 patients were included in mild AD group (score, ≥21), whereas 27 were included in the moderate to severe AD group (score, <21). The control group consisted of 29 nondemented participants of similar age and sex. EXPOSURE: Laboratory assessment of cerebrospinal fluid levels of orexin, tau proteins, and ß-amyloid 1-42 and polysomnographic assessment of sleep variables. MAIN OUTCOMES AND MEASURES: Levels of orexin, tau proteins, and ß-amyloid 1-42; macrostructural variables of nocturnal sleep (total sleep time, sleep efficiency, sleep onset and rapid eye movement [REM] sleep latencies, non-REM and REM sleep stages, and wakefulness after sleep onset); and Mini-Mental State Examination scores. RESULTS: Patients with moderate to severe AD presented with higher mean (SD) orexin levels compared with controls (154.36 [28.16] vs 131.03 [26.55]; P < .01) and with more impaired nocturnal sleep with respect to controls and patients with mild AD. On the other hand, in the global AD group, orexin levels were positively correlated with total tau protein levels (r = 0.32; P = .03) and strictly related to sleep impairment. Finally, cognitive impairment, as measured by the Mini-Mental State Examination, was correlated with sleep structure deterioration. CONCLUSIONS AND RELEVANCE: Our results demonstrate that, in AD, increased cerebrospinal fluid orexin levels are related to a parallel sleep deterioration, which appears to be associated with cognitive decline. Therefore, the orexinergic system seems to be dysregulated in AD, and its output and function appear to be overexpressed along the progression of the neurodegenerative process. This overexpression may result from an imbalance of the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness.

Increased cortical excitability after selective REM sleep deprivation in healthy humans: a transcranial magnetic stimulation study.

BACKGROUND: REM sleep has antiepileptogenic properties whereas, its loss is known to have a proconvulsive role. However, the mechanisms underlying the proepileptogenic effects of REM sleep deprivation are yet not fully understood. The aim of our study was to evaluate the effects of selective REM sleep deprivation (SRD) on cortical excitability in healthy subjects by means of transcranial magnetic stimulation (TMS). METHODS: Ten normal subjects underwent three TMS sessions: (1) in baseline condition (BL), (2) after SRD by awakening them at each REM sleep onset and (3) after non-rapid eye movement sleep awakenings (NREM-A) as control for potential non-specific effects of interruptions. The TMS investigation included two protocols: (a) the evaluation of motor evoked potentials (MEPs) and silent period (SP) parameters, recorded in response to single pulse magnetic stimulation; (b) the evaluation of the time course of intracortical motor activity tested with paired-pulse TMS applied at inter-stimulus intervals of 1-10 ms. RESULTS: After SRD the principal finding observed using single pulse TMS was a significant reduction in the duration of SP whereas, a reduction of intracortical inhibition was found, using the paired-pulse TMS. TMS parameters did not show significant changes after NREM-A with respect to BL. CONCLUSIONS: SRD may influence cortical excitability with a reduction of inhibitory intracortical mechanisms, thus supporting the proconvulsant role of REM loss.