Search

Although international guidelines exist, the clinical heterogeneity of Lennox-Gastaut syndrome (LGS) and the increasing availability of new and repurposed drugs (e.g., fenfluramine and cannabidiol) requires a practical guide to patient management in the clinical context. We report the results of a consensus survey among 42 Italian experts in the diagnosis and treatment of LGS.The consensus procedure followed a modified Delphi approach. Statements were formulated, based on the most recent published evidence and the clinicians' personal experience, then discussed, and agreed upon by the experts through a two-round voting procedure. Approval of a statement was reached with an average score ≥7.Thirteen statements dealing with three main topics (i.e., clinical diagnosis and prognosis, impact on the Quality of Life (QoL), and treatment strategies) were generated. Six statements achieved a level of agreement sufficient for approval on the first voting round. Following the discussion and a few consequent amendments, most of the statements increased their level of agreement and all 13 were approved.Overall, the statements draw a slightly more benign picture of this rare and severe disease, highlighting the possibility of remission - albeit modest -, an apparent trend towards lower mortality, and the availability of several effective drugs, to which greater accessibility would be hoped for. Valproate remains a major therapeutic option in LGS patients although lamotrigine, rufinamide, topiramate, cannabidiol, and clobazam are popular therapeutic options in Italy, allowing for a tailor-made antiseizure therapy.

Introduction Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients’ subgroups based on current drug prescription (drug-naïve patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy). Methods We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study. Results One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms. Conclusion Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 is mostly of central origin but it may coexist with sleep-related breathing disorders. However, there is no consensus on the sleep protocols to be used, assessments vary, and only a minority of patients are regularly tested or are on treatment for EDS. Our study presents data on self-reported and objective EDS in adult-onset myotonic dystrophy type 1. METHODS: Sixty-three patients with adult-onset DM1 were subjected to EDS-sleep assessments (polysomnography, Multiple Sleep Latency Test, Epworth Sleepiness Scale). Correlation coefficients were computed to assess the relationship between sleep and sleepiness test results, fatigue, and quality of life. RESULTS: 33% and 48% of patients had EDS based, respectively, on the Epworth Sleepiness Scale and the Multiple Sleep Latency Test, with a low concordance between these tests (k = 0.19). Thirteen patients (20%) displayed 2 or more sleep-onset rapid eye movement periods on Multiple Sleep Latency Test. Patients having EDS by Multiple Sleep Latency Test had a shorter disease duration (P < .05), higher total sleep time and sleep efficiency and lower wake after sleep onset on polysomnography. Patients with self-reported EDS reported significantly higher fatigue score compared with patients without EDS (P < .05). No other difference was found in demographic, clinical, and respiratory features. CONCLUSIONS: EDS test results are contradictory, making treatment options difficult. Combining quantitative tests and self-reported scales may facilitate physicians in planning EDS care with patients and families. CITATION: Sansone VA, Proserpio P, Mauro L, et al. Assessment of self-reported and objective daytime sleepiness in adult-onset myotonic dystrophy type 1. J Clin Sleep Med. 2021;17(12):2383–2391.

Background: Sleep disturbances are common among athletes. There is recently a growing interest in improving sleep quality by using noninvasive brain stimulation techniques such as transcranial direct current stimulation (tDCS). We hypothesized that bilateral dorsolateral prefrontal cortex anodal tDCS could improve sleep in different sports athletes. A randomized controlled trial is to be conducted to test this hypothesis. Methods: Eighty-four athletes are selected based on specific eligibility criteria and randomly allocated to the intervention or control group. Each participant will receive a 20-min session of bilateral anodal tDCS with an intensity of 1.5 mA (0.057 mA/cm2) in density 3 times a week for 2 weeks. The tDCS current will be delivered only for 30 seconds in the control group. This study’s outcome is a set of subjective and objective sleep parameters. Conclusion: This study assessed the effect of a novel tDCS protocol represented by bilateral anodal stimulation and may result in important advances in sleep management among athletes. Because of the high incidence and impact of athletes’ poor sleep quality, it is particularly important to explore effective interventions. Trial Registration: ClinicalTrials.gov: NCT05318352.

Sleep disorders (SDs) represent an important issue in patients with craniopharyngioma (CP). Nearly 70% of these patients complain of sleep-wake cycle alterations and/or excessive diurnal somnolence due to sleep-related breathing disorders, such as obstructive sleep apnea (OSA) and/or central hypersomnia, including secondary narcolepsy. SDs may severely reduce quality of life, increase disease-related cardiorespiratory and cardiovascular morbidity, and finally play a major role in increased long-term mortality reported on patients with CP. A major risk factor for SDs is represented by the hypothalamic syndrome, which may develop because of direct hypothalamic damage by the tumor itself and/or complications of the treatments, neurosurgery and/or radiotherapy, and typically includes permanent neuroendocrine dysfunctions, morbid obesity, and secondary metabolic disorders. Despite increasing attention to SDs in the general population, and in particular to OSA as a risk factor for cardio-metabolic diseases and excessive daytime somnolence, sleep evaluation is still not routinely proposed to patients with CP. Hence, SDs are often underdiagnosed and undertreated. The aim of this paper is to update current knowledge of the pathogenesis and prevalence of SDs in patients with CP and propose practical algorithms for their evaluation and management in clinical practice. Particular attention is paid to screening and diagnostic tools for appropriate characterization of SDs, identification of risk factors, and potential role of hypothalamic sparing surgery in the prevention of morbid obesity and SDs. Available tools in sleep medicine, including lifestyle interventions, drugs, and respiratory devices, are discussed, as well as the importance of optimal hormone replacement and metabolic interventions. Current limits in the diagnosis and treatment of SDs in patients with CP and possible future avenues for research agenda are also considered.

Nei prossimi giorni saranno due anni dall'inizio della pandemia da COVID-19 in Italia. Una festa di compleanno dove ognuno di noi, togliendosi per un attimo la mascherina, vorrebbe soffiare con tutto il fiato sulle candeline con il desiderio, probabilmente condiviso dalla maggior parte delle persone, di tornare alla normalità. Quella normalità in cui siamo nati e cresciuti, sia nella vita sociale, di relazione che in quella lavorativa. La pandemia ha richiesto a tutti, volenti o nolenti, di intraprendere dei cambiamenti e ogni contesto, dal mondo del lavoro alla scuola, ha avuto ricadute che con molta probabilità richiederanno diversi anni per poter essere assorbite e inserite in una nuova normalità.

Background Perampanel (PER) is a novel antiepileptic drug approved as an add-on therapy for focal onset seizures with or without generalization and primary generalized tonic-clonic seizures. Aim of this study was to evaluate PER efficacy and tolerability as add-on therapy in patients with drug-resistant focal onset seizures and especially temporal lobe epilepsy (TLE). Methods An observational, prospective, multicentre study on adult with drug-resistant focal epilepsy consecutively recruited from six Italian tertiary epilepsy centres. All patients received add-on PER according to indication and clinical judgement. Seizure frequency and adverse events (AEs) were recorded at 6 and 12 months after PER introduction. Results Study sample comprised 246 patients, 77 of which with TLE. Seventy-five (35.9%) out of 209 and 66 (38.8%) out of 170 patients still taking PER resulted to be responders (i.e. ≥50% of seizure frequency or seizure free) after six and 12 months, respectively. In the TLE group, 39 (57.3%) out of 68 subjects on PER after 6 months and 32 (60.4%) out of 53 subjects taking PER after 12 months were responders. Overall reported incidence of AEs was 26.1%. In 28 cases (11.3%) AEs lead/contributed to PER discontinuation. The most frequently reported AE were dizziness (14/84) and somnolence (14/84). Regarding TLE patients, 25.9% of them experienced at least one AE and discontinuation for AEs occurred in eight (10.4%). Conclusions This study confirmed the good efficacy and safety of PER for drug-resistant focal epilepsy in real-life conditions and, above all, for the first time provide its effectiveness in patients with TLE.

Although amyloid pathology plays a role in epilepsy, little is known about the relationship between beta amyloid and progression to Alzheimer's disease (AD) among patients with late-onset epilepsy of unknown origin (LOEU). This multicenter, observational, prospective study enrolled 40 consecutive nondemented adults diagnosed with LOEU, together with 43 age- and sex-matched healthy controls. All patients completed neuropsychological tests, core CSF AD biomarkers assessment (Aβ1-42, total tau, and phosphorylated tau), and follow-up for a mean of 3 years to verify cognitive decline. Despite age and baseline cognitive performance were similar to healthy controls, patients with LOEU had significant prevalence of CSF pathological Aβ1-42 (

Purpose To evaluate sleep disorders and daytime drowsiness in a cohort of patients affected by anorexia nervosa (AN) and their impact on health-related quality of life (HRQoL). Method We evaluated AN patients and healthy controls (C) by the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Beck Depression Index. We also utilized the Short-Form Health Survey (SF-36) questionnaire to assess HRQoL in both AN and C. Results: Twenty-eight out of 34 AN patients (82.3%) had a pathological PSQI score while 10/34 (29.4%) healthy subjects (pConclusion We demonstrated low sleep quality lacking subjective daytime sleepiness in AN. Sleep quality correlated significantly with HRQoL (physical role) and level of education. Level of evidence: level III case-control study

To update the current knowledge concerning sleep complaints and breathing disorders in myotonic dystrophy type 2 (DM2) and to better understand if sleep and breathing symptoms may add a further clinical definition of DM2. Although DM2 has been poorly evaluated, the most relevant sleep disorders are sleep-disordered breathing (SDB) (37.5–66.7%) and restless legs syndrome (RLS) (50–60%). Excessive daytime somnolence (EDS) is not consistent with SDB, and a large percentage of patients with sleep complaints (58–69%) report pain. In addition, respiratory dysfunctions are reported in 6 to 15% of DM2 patients, albeit few data are available regarding pulmonary restriction, hypoventilation, and non-invasive ventilation (NIV). SDB, RLS, and pain may contribute to sleep fragmentation and EDS in DM2. In addition, few studies report hypoventilation and pulmonary restriction, although there are no studies at all on NIV, except for limited clinical experiences. These findings suggest performing a careful pulmonary examination and NIV when required. Furthermore, sleep studies and respiratory evaluation should be recommended if OSA or respiratory muscle dysfunctions are suspected. A large polysomnographic study should be performed to clarify the link between sleep disorders, pain, and sleep disruption in DM2.

Rationale Studies looking at the effect of antiseizure medications (ASMs) on the sleep microstructure of subjects with epilepsy are scarce. This study aims to evaluate the impact of eslicarbazepine (ESL) as add-on therapy on the sleep microstructure in temporal lobe epilepsy (TLE). Methods Twelve patients affected by TLE were recruited to undergo overnight polysomnography and a subjective evaluation of nocturnal sleep utilizing the Pittsburgh Sleep Quality Index (PSQI) and daytime somnolence through the Epworth Sleepiness Scale (ESS) before and after three months of treatment with ESL as add-on therapy. Ten healthy controls (HC) matched for age, sex and BMI were recruited. Scoring and analysis of sleep macrostructure and cyclic alternating pattern (CAP) parameters were performed. Results Ten patients completed the study. The comparison between patients in basal condition (T0) and HC showed a significant lower sleep efficiency (p = 0.049), REM percentage (p = 0.002), higher REM latency (p = 0.02), N2 (p = 0.001) and WASO (p = 0.01). Regarding CAP, patients at T0 showed higher CAP rate in N1 (p = 0.01), lower A1 (%) (p = 0.03), higher A3 (%) (p = 0.01), higher mean duration of A (p = 0.02) and A3 (p = 0.006), A3 index (p = 0.02) than HC. ESL did not induce any significant changes in nocturnal macrostructural polysomnographic variables and PSQI scores. Furthermore, the ESS score showed no modification after treatment. Lower CAP rate in N3 (p = 0.02), phase A2 index (p = 0.02) average number of CAP cycle per sequences and mean duration of CAP sequences (both p = 0.02) was evident after ESL. A trend toward significance was evident for the decrease of CAP rate in N1 (p = 0.09) and N2 (p = 0.09), and for the increase of B phase mean duration (p = 0.07). Conclusion We found significant improvement in sleep continuity as measured by CAP after ESL. These findings suggest that ESL may positively modulate sleep fragmentation in patients with TLE, and hence enhance sleep quality. Our results suggest a favourable sleep profile with the use of ESL.

Poor sleep and daytime sleepiness are common in people with epilepsy. Sleep disorders can disrupt seizure control and in turn sleep and vigilance problems can be exacerbated by seizures and by antiepileptic treatments. Nevertheless, these aspects are frequently overlooked in clinical practice and a clear agreement on the evidence-based guidelines for managing common sleep disorders in people with epilepsy is lacking. Recently, recommendations to standardize the diagnostic pathway for evaluating patients with sleep-related epilepsies and comorbid sleep disorders have been presented. To build on these, we adopted the Delphi method to establish a consensus within a group of experts and we provide practical recommendations for identifying and managing poor night-time sleep and daytime sleepiness in people with epilepsy. We recommend that a comprehensive clinical history of sleep habits and sleep hygiene should be always obtained from all people with epilepsy and their bed partners. A psychoeducational approach to inform patients about habits or practices that may negatively influence their sleep or their vigilance levels should be used, and strategies for avoiding these should be applied. In case of a suspected comorbid sleep disorder an appropriate diagnostic investigation should be performed. Moreover, the possible presence of sleep fragmentation induced by sleep-related seizures should be ruled out. Finally, the dose and timing of antiepileptic medications and other co-medications should be optimized to improve nocturnal sleep and avoid daytime sedation.

The aim of this study was to evaluate the effect of one-year useful continuous positive airway pressure (CPAP) treatment on serum vitamin D levels in middle-aged men affected by obstructive sleep apnea syndrome (OSAS).This is a secondary investigation related to a previously published observational study about the effect of short-term CPAP therapy on serum vitamin D levels in severe OSAS (Apnea-Hypopnea Index - AHI-30/h) patients. In the present study, we included patients participating to the previous investigation who repeated serum vitamin D assessment after one year of useful CPAP treatment, and compared to control a group of OSAS patients with scarce compliance to CPAP treatment. OSAS patients with beneficial use of CPAP treatment were distributed in obese (Body Mass Index - BMI ≥30) and non-obese (BMI 30). Moreover, the mean change between baseline and one-year follow-up (Δ) of serum vitamin D levels was correlated with demographic, polygraphic and clinical data throughout a multiple regression analysis.We documented the significant increase of serum vitamin D levels after one year of CPAP treatment in the OSAS group (n = 39, p 0.001) and in both subgroups of obese (n = 23, p 0.01) and non-obese (n = 16, p 0.01) OSAS patients. Conversely, OSAS patients with a scarce compliance to CPAP therapy did not change serum vitamin D levels after one year (n = 10, p 0.05). OSAS patients with beneficial CPAP treatment showed higher vitamin D serum levels after one year and a more frequent shift from insufficient to sufficient vitamin D status compared to OSAS patients not adequately using CPAP treatment. In particular, the obese OSAS patients subgroup shifted from insufficient (≤20 ng/mL) to sufficient (20 ng/mL) vitamin D status after CPAP therapy more than the non-obese OSAS patients subgroup (p 0.05). We observed higher Δ of vitamin D serum levels, Epworth Sleepiness Scale score, and AHI in obese compared to non-obese OSAS patients. Finally, BMI obtained at baseline positively correlated with Δ of vitamin D serum levels.This study documented that long-term CPAP treatment is a viable therapeutic choice for correcting both sleep apnea condition and vitamin D deficiency in middle-aged male OSAS patients. Significantly, this effect was more evident in obese subjects and possibly represents a valid therapeutic strategy to ensure sufficient vitamin D levels in these patients, which frequently show a deficient vitamin D status.

Generic drugs are increasingly used to treat many diseases including epilepsy. The growing importance of generic antiseizure medications (ASMs) has led the ASMs commission of the Italian League Against Epilepsy (LICE) to review current evidence in the literature about efficacy and safety of these products. Recommendations from other scientific organizations have also been considered to provide an update of the LICE position about their utilization (List of Recommendations). Compared with the previous literature review, randomized controlled trials assessing bioequivalence among branded drugs and generics are currently available. Although some contrasting results have been reported, brand-to-generic switching was effective and tolerable in real-life settings, with similar adverse event ratios. Based on these findings, LICE concluded that, conforming to the rigorous regulation of USA and EU markets, generic ASMs are not inferior to the respective branded, providing a cost advantage for patients starting or replacing monotherapy or add-on, and for those with incomplete seizure control. Branded-to-generic (and vice versa) switching is not recommended (although applicable) during seizure remission, as well as the generic-to-other generic switching. Other recommendations focus on the appropriateness of therapeutic drug monitoring (TDM) when switching is required, paying attention to avoiding the erroneous switch between modified and immediate-release formulations during dispensation. Finally, to support patients' compliance, they should be assured of generics' safety and efficacy and carefully informed with practical advice, particularly when the switching is associated with aspect modifications (e.g. color and shape changes) of the pill or the packaging.

Experimental and clinical observations indicate that amyloid-β1-42 (Aβ1-42) peptide not only represents a major actor in neurodegenerative mechanisms but also induce hyperexcitation in individual neurons and neural circuits. In this abnormal excitability, possibly leading to seizures, the D1 dopamine (DA) receptors may play a role. Cerebrospinal fluid levels of Aβ1-42 were measured in patients with late-onset epilepsy of unknown etiology. Moreover, the effect of amyloid peptide on the hippocampal epileptic threshold and synaptic plasticity and its link to D1 receptor function were tested in experimental mouse model of cerebral amyloidosis and in acute model of Aβ1-42-induced neurotoxicity. Among 272 evaluated epileptic patients, aged >55 years, 35 suffered from late-onset epilepsy of unknown etiology. In these subjects, cerebrospinal fluid Aβ1-42 levels were measured. The effects of Aβ1-42, amyloid oligomers, and D1 receptor modulation on epileptic threshold were analyzed by electrophysiological recordings in the dentate gyrus of mice hippocampal slices. We found that Aβ1-42 levels were significantly decreased in cerebrospinal fluid of patients with late-onset epilepsy of unknown etiology with respect to controls suggesting the cerebral deposition of this peptide in these patients. Aβ1-42 enhanced epileptic activity in mice through a mechanism involving increased surface expression of D1 receptor, and this effect was mimicked by D1 receptor stimulation and blocked by SCH 23390, a D1 receptor antagonist. Aβ1-42 may contribute to the pathophysiology of late-onset epilepsy of unknown origin. Our preclinical findings indicate that the D1 receptor is involved in mediating the epileptic effects of Aβ1-42. This novel link between Aβ1-42 and D1 receptor signaling might represent a potential therapeutic target.

The orexin system has been investigated in patients affected by mild cognitive impairment (MCI) due to Alzheimer's disease (AD) by measuring orexin-A concentrations in the cerebrospinal fluid (CSF), and correlated to subjective and objective sleep parameters, quantified by questionnaires and polysomnography, respectively. Twenty drug-naive patients with MCI due to AD were studied and compared with a population of 26 age and/or sex matched controls, divided into subgroups on the basis of the Pittsburgh Sleep Quality Index (PSQI) score. Increased CSF-orexin levels were detected in patients with MCI due to AD in comparison with controls (p < 0.05). In particular, CSF-orexin concentrations were higher in MCI patients suffering from sleep complaints (PSQI ≥5, n = 10) compared with MCI patients with a regular sleep-wake cycle (PSQI

Summary Objective Although many studies have attempted to describe treatment outcomes in patients with drug‐resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug‐resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria. Methods This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug‐resistant by the investigators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP). Results A seizure‐free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as having a “treatment failure” as compared to the judgment of the investigator (46.7% vs 62.9%, P

Andrea Romigi,1 Giuseppe Vitrani,1 Temistocle Lo Giudice,1 Diego Centonze,1,2 Valentina Franco3 1IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli (IS), Italy; 2Department of System Medicine, University of Rome Tor Vergata Rome, Italy; 3IRCCS Mondino Foundation, Pavia, Italy Abstract: Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and rapid eye movement sleep dysregulation, manifesting as cataplexy and sleep paralysis, as well as hypnagogic and hypnopompic hallucinations. Disease onset may occur at any age, although adolescents and young adults are mainly affected. Currently, the diagnosis delay ranges from 8 to 10 years and drug therapy may only attenuate symptoms. Pitolisant is a first-in-class new drug currently authorized by the European Medicines Agency to treat narcolepsy with or without cataplexy in adults and with an expanded evaluation for the treatment of neurologic diseases such as Parkinson’s disease and epilepsy. This article reviews the pharmacokinetic and pharmacodynamic profile of pitolisant, highlighting its effectiveness and safety in patients with narcolepsy. We performed a systematic review of the literature using PubMed, Embase, and Google Scholar. We report on the efficacy and safety data of pitolisant in narcoleptic patients regarding cataplexy episodes and subjective and objective daytime sleepiness. The development program of pitolisant was characterized by eight Phase II/III studies. One proof-of-concept study followed by two pivotal studies, three randomized controlled trials, and two open studies were evaluated. Our review confirmed the effectiveness of pitolisant in treating major clinically relevant narcolepsy symptoms, including cataplexy, as compared to placebo. In addition, pitolisant revealed a safe profile when compared with placebo and active comparators. Headache, insomnia, and nausea were the prominent side effects. Further long-term randomized controlled trials comparing the efficacy of pitolisant with active comparators (ie, modafinil and sodium oxybate) may clarify its real place in therapy and its possible use as a first-line agent on the basis of its safety and tolerability. Keywords: pitolisant, narcolepsy, cataplexy, histamine, excessive daytime sleepiness

Objective The link between the autonomic nervous system and restless legs syndrome (RLS) has been recently postulated. Since dopaminergic agents are used as first-line treatment for RLS, the purpose of our study is to verify whether chronic pramipexole treatment could influence the autonomic control of cardiovascular reflexes and heart rate variability (HRV) in RLS during wakefulness. Methods Consecutive drug naive RLS patients underwent polysomnography (PSG), subjective scales, and cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, handgrip and cold face before and after 3-month pramipexole therapy. HRV analysis was performed in the frequency domain using both autoregressive and fast Fourier transform algorithms in rest supine condition and during HUTT. Results Twenty RLS patients reported a significant reduction of RLS symptoms after pramipexole treatment, while PSG did not show significant improvements except for periodic limb movement index. Pramipexole induced a trend to a lower systolic blood pressure and a significant higher variation of systolic and diastolic blood pressure at HUTT. Cardiovascular responses to the other tests were unchanged. No significant differences in HRV spectral analysis between drug naive and treated patients were observed. Moreover, the within-group analysis of HRV between orthostatic and supine position did not show any significant change in sympathetic and parasympathetic components both in the drug naive and pramipexole groups. Conclusions Chronic pramipexole treatment does not seem to affect autonomic balance during wakefulness. Considering that neither PSG data nor autonomic parameters are significantly modified by pramipexole, we hypothesize a non-dopaminergic autonomic dysfunction in RLS.

Study Objective:Recent studies report a link between obstructive sleep apnea (OSA) syndrome, low vitamin D levels, and high parathyroid hormone (PTH) concentrations. The aim of the current study is...

Rasmussen's encephalitis (RE) is a rare immune-mediated condition characterized by drug-resistant focal epilepsy, progressive neurological, and cognitive deficits associated to unilateral hemispheric atrophy. The onset is typically reported in childhood, although adult cases (A-RE) have been described. While surgical strategies in childhood RE are well defined, little is known about usefulness of epilepsy surgery in A-RE patients. We describe clinical features, surgical approach, and outcome of five A-RE patients who underwent epilepsy surgery, and we review the literature with regard to surgical A-RE cases. We retrospectively studied five A-RE patients aged 21-38 years (mean age 22.8 years) who were followed after surgery for a period ranging from to 1 to 6 years. Demographic, electroclinical, and neuroimaging data were systematically reviewed. Four out of five subjects underwent invasive EEG monitoring to define epileptogenic zone. Epilepsy outcome was defined according to Engel's classification. Surgery consisted of frontal corticectomy in three patients, temporal lobectomy in one, combined temporal lobectomy plus insular, and frontobasal corticectomy in the remaining case. No permanent neurological deficits were observed after surgery. At the last follow-up observation, one patient was seizure-free, two subjects experienced rare disabling seizures, another had moderate seizure reduction, and one had no clinical improvement. Our experience, although limited to few cases, suggests that resective surgery in A-RE may play a role in the context of multidisciplinary therapeutical approach of this severe condition. Since the lack of specific data about surgical options, this topic seems to deserve further investigations and more targeted studies.

Objective Amyotrophic lateral sclerosis (ALS) is a motor neuron disease whose pathophysiological deficits, causing impairment in motor function, are largely unknown. Here we propose that hydrogen sulfide (H2S), as a glial-released inflammatory factor, contributes to ALS-mediated motor neuron death. Methods H2S concentrations were analyzed in the cerebrospinal fluid of 37 sporadic ALS patients and 14 age- and gender-matched controls, in tissues of a familial ALS (fALS) mouse model, and in spinal cord culture media by means of a specific and innovative high-performance liquid chromatography method. The effects of H2S on motor neurons cultures was analyzed immunohistochemically and by patch clamp recordings and microfluorometry. Results We found a significantly high level of H2S in the spinal fluid of the ALS patients. Consistently, we found increased levels of H2S in the tissues and in the media from mice spinal cord cultures bearing the fALS mutation SOD1G93A. In addition, NaHS, an H2S donor, added to spinal culture, obtained from control C57BL/6J mice, is toxic for motor neurons, and induces an intracellular Ca2+ increase, attenuated by the intracytoplasmatic application of adenosine triphosphate. We further show that H2S is mainly released by astrocytes and microglia. Interpretation This study unravels H2S as an astroglial mediator of motor neuron damage possibly involved in the cellular death characterizing ALS. Ann Neurol 2015;77:697–709

Posterior reversible encephalopathy syndrome (PRES) is a serious adverse event associated with calcineurin inhibitors used for graft-versus-host disease (GVHD) prophylaxis. We compared the incidence of PRES in children with thalassemia (n = 222, 1.4 to 17.8 years old) versus sickle cell disease (SCD; n = 59, 2 to 17 years old) who underwent hematopoietic cell transplantation from HLA-matched siblings or alternative donors and analyzed the risk factors for PRES. Overall, 31 children developed calcineurin inhibitor-related PRES (11%), including 30 patients with seizures and 1 patient without seizures. PRES incidence was significantly higher in SCD patients (22%; 95% confidence interval [CI], 10% to 32%) than in thalassemia patients (8%; 95% CI, 5% to 12%;P = .002). In multivariate analysis, factors associated with PRES were hypertension (hazard ratio [HR], 5.87; 95% CI, 2.57 to 13.43; P = .0001), SCD (HR, 2.49; 95% CI, 1.25 to 4.99; P = .009), and acute GVHD (HR 2.27; 95% CI, 1.06 to 4.85; P = .031). In the entire cohort overall survival (OS) was significantly higher in patients without versus with PRES (90% versus 77%; P = .02). In a subgroup analysis that including matched sibling transplants, OS and disease-free survival (DFS) were similar in thalassemia patients without PRES (92% and 88%, respectively) and with PRES (82% and 73%, respectively), whereas SCD patients with PRES had significantly lower OS (67%) and DFS (67%) than patients without PRES (94% and 94%, respectively; P = .008). Thus, SCD patients had a significantly higher incidence of PRES than thalassemia patients, and hypertension and GVHD were the 2 main risk factors for PRES in patients with hemoglobinopathies. Although PRES did not significantly influence survival in patients with thalassemia, patients with SCD had significantly lower survival after PRES.

Objective Literature proposed the clinical and electrophysiological evidence of optic nerve damage in obstructive sleep apnea (OSA) patients. The aim of this study is to evaluate in patients affected by OSA the effect of continuous positive airway pressure (CPAP) treatment on the functional integrity of the visual system evaluated by means of visual evoked potentials (VEP). Methods We performed the electrophysiological study of visual system in a population of 20 severe OSA patients at baseline and after 1-year of CPAP treatments. We divided OSA patients in two subgroups on the basis of the compliance at the CPAP therapy, measured by analyzing the software ventilator report. To be included in the study, OSA patients should not have visual impairment and systemic disorders with known influence on visual system. VEP were elicited by a reversal pattern generated on a television monitor at low (55′) and high (159) spatial frequencies stimulation. Results Ten patients show a good compliance at CPAP therapy (OSA-CPAP+) and 10 patients present an insufficient compliance at CPAP treatment (OSA-CPAP-). We documented the significant amelioration of latency and amplitude of VEP components in OSA-CPAP+ compared to OSA-CPAP-. Discussion Taking into account that OSA patients are affected by VEP alterations as documented by lower amplitude and longer latency of the P100 component, this study documented that CPAP treatment significantly ameliorate VEP in OSA patients who show good compliance at CPAP treatment with respect to OSA patients who did not adequately treat sleep apneas. Therefore, CPAP treatment may restore the altered electrophysiological findings present in OSA patients if appropriately performed.

Study Objectives We firstly studied cognitive performances, polysomnographic sleep, and CSF β-amyloid, tau proteins and lactate levels in patients affected by subjective cognitive impairment (SCI) divided in three groups: obstructive sleep apnea (OSA) patients (showing an Apnea-Hypopnea Index – AHI ≥15/h), subjects not affected by OSA (nonOSA, AHI Methods We compared results among 25 OSA, 10 OSA-CPAP and 15 nonOSA patients, who underwent a protocol counting neuropsychological testing in the morning, 48-hour polysomnography followed by CSF analysis. Results OSA patients showed lower CSF Aβ 42 andhigher CSF lactate levels, together with higher t-tau/Aβ 42 ratio, when compared to nonOSA and OSA-CPAP patients. OSA patients also showed reduced sleep quality and continuity, and lower performances at memory, intelligence and executive tests than nonOSA and OSA-CPAP patients. We found significant relationships among higher CSF tau proteins levels, sleep impairment and increased CSF lactate levels. Moreover, lower CSF Aβ 42 levels correlate with memory impairment and nocturnal oxygen saturation parameters. Conclusions We hypothesize that OSA reducing sleep quality and producing intermittent hypoxia lowers CSF Aβ 42 levels, increases CSF lactate levels, and alters cognitive performances in SCI patients, thus inducing early AD clinico-neuropathological changes. Notably, nonOSA as well as OSA-CPAP SCI patients did not show clinical and biochemical AD markers. Therefore, OSA may induce early but possibly CPAP-modifiable AD biomarkers changes.

Study Objectives: Obstructive sleep apnea (OSA) is a common sleep disorder. The, literature lacks studies examining sleep, cognition, and Alzheimer's Disease (AD) cerebrospinal fluid (CSF) biomarkers in OSA patients. Therefore, we first studied cognitive performances, polysomnographic sleep, and CSF beta-amyloid 42, tau proteins, and lactate levels in patients affected by subjective cognitive impairment (SCI) divided in three groups: OSA patients (showing an Apnea-Hypopnea Index [AHI] = 15/hr), controls (showing an AHI < 15/hr), and patients with OSA treated by continuous positive airway pressure (CPAP).Methods: We compared results among 25 OSA, 10 OSA-CPAP, and 15 controls who underwent a protocol counting neuropsychological testing in the morning, 48-hr polysomnography followed by CSF analysis.Results: OSA patients showed lower CSF A beta 42 concentrations, higher CSF lactate levels, and higher t-tau/A beta 42 ratio compared to controls and OSA-CPAP patients. OSA patients also showed reduced sleep quality and continuity and lower performances at memory, intelligence, and executive tests than controls and OSA-CPAP patients. We found significant relationships among higher CSF tau proteins levels, sleep impairment, and increased CSF lactate levels in the OSA group. Moreover, lower CSF Aa 42 levels correlate with memory impairment and nocturnal oxygen saturation parameters in OSA patients.Conclusions: We hypothesize that OSA reducing sleep quality and producing intermittent hypoxia lowers CSF A beta 42 levels, increases CSF lactate levels, and alters cognitive performances in SCI patients, thus inducing early AD clinical and neuropathological biomarkers changes. Notably, controls as well as OSA-CPAP SCI patients did not show clinical and biochemical AD markers. Therefore, OSA may induce early but possibly CPAP-modifiable AD biomarkers changes.

The term “Epilepsy” encompasses a broad spectrum of medical and social disorders that affect about 65 million people worldwide and is commonly defined as a tendency to suffer recurrent seizures. In patients with epilepsy, ictal discharges that occur in (or propagate to) the anterior cingulate, insular, posterior orbito-frontal, and the pre-frontal cortices, along with the amygdala and hypothalamus play a key role in influencing the autonomic nervous system (ANS) at the cortical level. In turn, this can result in cardiac effects which are widespread and range from subtle changes in heart rate variability (HRV) to ictal sinus arrest, and from QT-interval shortening to atrial fibrillation. In addition, cardiac events are the main hypothesized mechanisms underlying sudden unexpected death in epilepsy (SUDEP), which occurs in absence of a known structural cause. Patients with epilepsy also experience long-lasting changes in the regulation of the ANS and target organs. Heart rate (HR) and HRV can be easily measured/estimated when compared to other biomarkers that are commonly associated with seizures (i.e., long-term EEG), and are therefore potentially valuable biomarkers when it comes to characterizing seizures. In this context, a number of linear and nonlinear analysis techniques have been applied in order to detect and characterize epilepsy-related ANS changes. While the physiological and clinical applicability of nonlinear analyses like fractal and complexity measures of HR dynamics are not yet completely understood, in view of recent experimental findings it is reasonable to assume that such indices highlight abnormal patterns of RR interval behaviour that are not easily detected by commonly used moment statistics of HR variation. These findings may provide new insight regarding physiological and seizure-induced states of the complex brain-heart network underlying epilepsy and related autonomic modifications. A better understanding of the autonomic manifestations of seizures would provide practical added value to clinical epileptologists dealing with differential diagnosis of epilepsy and related disorders, as well as aiding in designing more sensitive seizure detection and prediction algorithms.

Daytime somnolence and sleep-wake cycle disturbances are commonly encountered symptoms in Frontotemporal Dementia (FTD). Orexin-A (Hypocretin-1) is a hypothalamic neuropeptide regulating the sleep-wake rhythm. We investigated the cerebrospinal-fluid (CSF) orexin levels in a population of FTD patients and evaluated whether there is a relationship between daytime somnolence and CSF orexin concentrations. CSF orexin levels were measured in a sample of FTD patients (n = 11) compared to a population of non-demented controls (n = 13) similar for age and sex. Moreover, CSF orexin concentrations were correlated with daytime somnolence investigated by means of the Epworth Sleepiness Scale (ESS) in both FTD patients and controls. FTD patients showed CSF orexin concentrations (164.3 ± 66.45 vs 170.81 ± 42.73 pg/mL) and ESS scores (7.45 ± 4.36 vs 3.84 ± 1.82) not different from controls. However, three FTD patients showed pathological daytime sleepiness (ESS 10) coupled with the lowest CSF orexin levels. In addition, we found a significant negative correlation between CSF orexin levels and ESS scores in the FTD population (R = -0.91; p 0.0001), which was not evident in the control group (R = 0.16; p 0.05). This is the first study investigating CSF orexin concentrations in FTD. We did not find differences in CSF orexin concentrations between FTD patients and controls. However, a significant negative correlation between daytime somnolence and CSF orexin levels was evident in FTD patients. Moreover, we have found that pathological daytime somnolence was evident in those FTD patients with the lowest CSF orexin levels. Based on these findings, we argued that lower orexin levels may be permissive for increased daytime somnolence in FTD.

Nonconvulsive status epilepticus (NCSE) may have heterogeneous presentations and differential diagnosis may be particularly difficult because clinical signs coupled with periodic EEG pattern are most often subtle or non-specific. Moreover, few cases of NCSE have been previously described as the presenting symptom of sporadic Creutzfeldt–Jakob disease (sCJD) [1,4,5,7]. We describe a patient with a NCSE strongly, but erroneously, suggestive of a probable sCJD.

Myotonic dystrophy is the most common type of muscular dystrophy in adults and is characterized by progressive myopathy, myotonia, and multiorgan involvement. Two genetically distinct entities have been identified, myotonic dystrophy type 1 (DM1 or Steinert’s Disease) and myotonic dystrophy type 2 (DM2). Myotonic dystrophies are strongly associated with sleep dysfunction. Sleep disturbances in DM1 are common and include sleep-disordered breathing (SDB), periodic limb movements (PLMS), central hypersomnia, and REM sleep dysregulation (high REM density and narcoleptic-like phenotype). Interestingly, drowsiness in DM1 seems to be due to a central dysfunction of sleep-wake regulation more than SDB. To date, little is known regarding the occurrence of sleep disorders in DM2. SDB (obstructive and central apnoea), REM sleep without atonia, and restless legs syndrome have been described. Further polysomnographic, controlled studies are strongly needed, particularly in DM2, in order to clarify the role of sleep disorders in the myotonic dystrophies.

We describe the case of a man who presented with spasticity and aphasia related to continuous electroencephalographic epileptic activity in the left frontal-temporal regions. Magnetic resonance imaging (MRI) documented in diffusion-weighted images (DWI) two areas of restricted diffusion in the left frontal and temporal cortex. After starting treatment with levetiracetam 3000 mg/day there was progressive recovery of the clinical picture as well as the gradual disappearance of the electroencephalographic seizure activity and the vanishing of areas of restricted diffusion in brain MRI. Based on the clinical, EEG and MRI data, we hypothesized that both aphasia and spasticity represented ictal signs. To our knowledge, this is the first case report of ictal spasticity.