Elisa Evangelista

Absence of GABA‐A receptor potentiation in central hypersomnolence disorders

The pathophysiology of idiopathic hypersomnia (IH) remains unclear. Recently, cerebrospinal fluid (CSF)‐induced enhancement of γ‐aminobutyric acid (GABA)‐A receptor activity was found in patients with IH compared to controls.

Does the Thalamo-Cortical Synchrony Play a Role in Seizure Termination?

The mechanisms underlying seizure termination are still unclear despite their therapeutic importance. We studied thalamo-cortical connectivity and synchrony in human mesial temporal lobe seizures in order to analyze their role in seizure termination. Twenty-two seizures from 10 patients with drug-resistant mesial temporal lobe epilepsy undergoing pre-surgical evaluation were analyzed using intracerebral recordings [stereoelectroencephalography (SEEG)]. We performed a measure of SEEG signal interdependencies (non-linear correlation), to estimate the functional connectivity between thalamus and cortical regions. Then, we derived synchronization indices, namely global, thalamic, mesio-temporal, and thalamo-mesio temporal index at the onset and the end of seizures. In addition, an estimation of thalamic “outputs and inputs” connectivity was proposed. Thalamus was consistently involved in the last phase of all analyzed seizures and thalamic synchronization index was significantly more elevated at the end of seizure than at the onset. The global synchronization index at the end of seizure negatively correlated with seizure duration (p = 0.045) and in the same way the thalamic synchronization index showed an inverse tendency with seizure duration. Six seizures out of twenty-two displayed a particular thalamo-cortical spike-and-wave pattern at the end. They were associated to higher values of all synchronization indices and outputs from thalamus (p = 0.0079). SWP seizures displayed a higher and sustained increase of cortical and thalamo-cortical synchronization with a stronger participation of thalamic outputs. We suggest that thalamo-cortical oscillations might contribute to seizure termination via modulation of cortical synchronization. In the subgroup of SWP seizures, thalamus may exert a control on temporal lobe structures by inducing a stable hypersynchronization that ultimately leads to seizure termination.

Vitamin D deficiency in type 1 narcolepsy: a reappraisal

OBJECTIVES Narcolepsy type 1 (NT1) is considered to be an immune-mediated disease in which environmental factors, such as vitamin D, might play a major role. The association between NT1 and vitamin D deficiency has previously been reported. The aim of this case-control study was to reassess vitamin D levels in a large clinic-based adult and paediatric population of patients with NT1 by considering several potential confounding factors. METHODS The serum level of 25-hydroxyvitamin D (25OHD) was measured in 174 Caucasian patients with NT1 and 174 controls. Demographic and clinical features, body mass index (BMI), Pandemrix® vaccination, age, and season at the time of blood sampling were recorded. Between-group comparisons were made using univariate and multivariate logistic regression analyses. When appropriate, interaction terms were tested using the Wald Chi-squared test. RESULTS Age, BMI, and season of blood sampling were different between groups. Conversely, the 25OHD level and fraction of subjects with vitamin D deficiency (serum level <75 nmol/L: 46.6% of patients vs 48.3% of controls; <50 nmol/L: 20.7% vs 17.2%) did not differ between patients with NT1 and controls. Overall, vitamin D deficiency was more frequent in men, obese subjects, and in samples collected in winter, without any association with NT1. In the patients group, no significant association was found between vitamin D deficiency, NT1 duration and severity, treatment, and Pandemrix® vaccination. CONCLUSIONS Vitamin D levels were not associated with NT1 in a large case-control population when potential demographic and clinical confounding factors were taken into account.

Test–Retest Reliability of the Multiple Sleep Latency Test in Central Disorders of Hypersomnolence

Study Objectives To assess the test-retest reliability of the polysomnography-multiple sleep latency test (PSG-MSLT) diagnostic classification and measures and to study the determinants of its variability in patients with narcolepsy type 1 (NT1) or with noncataplectic central disorders of hypersomnolence (NCHS): type 2 (NT2), idiopathic hypersomnia (IH), and unspecified hypersomnolence (unspecified excessive daytime sleepiness [UnsEDS]). Methods PSG-MSLT in drug-free conditions was administered twice (median interval of 1.9 years) in 22 patients with NT1 (10 males, median age 31.2 years) and 75 patients with NCHS (32 males, median age 25.7 years). Results At the first PSG-MSLT, patients with NCHS were classified as having NT2 (22.7%), IH (26.7%), or UnsEDS (50.6%). A positive PSG-MSLT was confirmed in 72.7% of NT1. The classification consistency at retesting was significantly lower for the NT2 (47.1%), IH (25.0%), and UnsEDS (42.1%) categories than NT1 (81.3%). The between-test mean sleep latency (MSL) variability was significantly different in NT1 and NCHS, with higher changes in NT2 and lower in NT1. A longer test-retest interval was associated with improved MSL and MSLT normalization. Between-test variations in SOREMP number were associated with changes in nocturnal REM sleep parameters and MSL. No association was found with the clinical decision to repeat the evaluation or the disease clinical course. Conclusion The PSG-MSLT measures and classification are not stable in patients with NCHS, with frequent diagnostic changes, particularly for NT2 and IH, compared with NT1. MSLT needs to be repeated at regular intervals to confirm a stable hypersomnia and provide an accurate diagnosis of NT2 and IH.

Diagnostic criteria for disorders of arousal: A video-polysomnographic assessment: Disorders of Arousal

To assess video‐polysomnographic (vPSG) criteria and their cutoff values for the diagnosis of disorders of arousal (DOAs; sleepwalking, sleep terror).

Depression and Hypersomnia: A Complex Association

Hypersomnolence is a clinically defined syndrome characterized by the association of prolonged nocturnal sleep, impaired arousal quality, and sleep inertia. Hypersomnolence is the major feature of central hypersomnias and is frequently reported in various mood disorders, such as major depressive disorder, bipolar disorder, or seasonal affective disorder. Assessment of hypersomnolence is challenging in depressed patients, with objective tests often in the normal range despite a high level of sleepiness complaint. On the other hand, many patients with central hypersomnias reported depressive symptoms. The self-assessment of mood symptoms in patients with central hypersomnias may overdiagnose depression with an overlap between both conditions.

Update on treatment for idiopathic hypersomnia

ABSTRACT Introduction: Idiopathic hypersomnia (IH) is a poorly characterized orphan central disorder of hypersomnolence responsible for excessive daytime sleepiness (EDS), prolonged nighttime sleep and sleep inertia that often require long-term symptomatic stimulant medication. To date, no drug has currently the authorization for the treatment of IH patients worldwide. Areas covered: The authors reviewed data on pharmacological treatment of IH obtained from published literature (Medline/PubMed/Web of Science) and Clinicaltrial.gov database from 1997 to 2017. Most of data on treatment of IH derived from observational studies and case series with only three well-designed clinical trials available. Expert opinion: In two recent randomized, double-blind, placebo-controlled trials, modafinil improves EDS in IH. Most of other wakefulness-promoting agents labeled for narcolepsy have similar efficacy in cases series of IH patients. Pitolisant and sodium oxybate show promising results in two retrospective studies. The efficacy of γ-aminobutyric acid-A receptor antagonists on objective EDS needs to be clarified. All these medications are used off-label for the management of EDS in IH. Specific clinical instruments and objective tests are required in IH to better evaluate the severity of EDS and responsiveness to medications, but also prolonged sleep and sleep inertia, to optimize the whole management of IH patients.

[18F]Fludeoxyglucose-Positron Emission Tomography Evidence for Cerebral Hypermetabolism in the Awake State in Narcolepsy and Idiopathic Hypersomnia

Background Changes in structural and functional central nervous system have been reported in narcolepsy, with large discrepancies between studies. No study has investigated yet spontaneous brain activity at wake in idiopathic hypersomnia (IH). We compared relative changes in regional brain metabolism in two central hypersomnia conditions with different clinical features, namely narcolepsy type 1 (NT1) and IH, and in healthy controls. Methods Sixteen patients [12 males, median age 30 years (17–78)] with NT1, nine patients [2 males, median age 27 years (20–60)] with IH and 19 healthy controls [16 males, median age 36 years (17–78)] were included. 18F-fludeoxyglucose positron emission tomography (PET) was performed in all drug-free subjects under similar conditions and instructions to stay in a wake resting state. Results We found increased metabolism in the anterior and middle cingulate and the insula in the two pathological conditions as compared to healthy controls. The reverse contrast failed to evidence hypometabolism in patients vs. controls. Comparisons between patient groups were non-significant. At sub-statistical threshold, we found higher right superior occipital gyrus glucose metabolism in narcolepsy and higher middle orbital cortex and supplementary motor area metabolism in IH, findings that require further confirmation. Conclusion There is significant hypermetabolism in narcolepsy and IH in the wake resting state in a set of brain regions constitutive of the salience cortical network that may reflect a compensatory neurocircuitry activity secondary to sleepiness. Metabolic differences between the two disorders within the executive-control network may be a signature of abnormally functioning neural system leading to persistent drowsiness typical of IH.