Difference in background factors between responders to gabapentin enacarbil treatment and responders to placebo: pooled analyses of two randomized,double-blind,placebo-controlled studies in Japanese patients with restless legs syndrome

ObjectiveRestless legs syndrome (RLS) is a sensorimotor disorder that is characterized by uncomfortable and unpleasant sensations mainly in the legs. Two placebo-controlled studies (Phase II/III and post-marketing) in Japanese patients with RLS failed to demonstrate the efficacy of gabapentin enacarbil (GE) 600 mg in the change from baseline in International Restless Legs Syndrome Rating Scale (IRLS) score at the end of the treatment period. The high response to placebo is thought to be a possible reason why the post-marketing study failed. The objectives of these post hoc analyses were to determine potential predictive factors associated with improvement in IRLS score with GE treatment and to identify subgroups with higher placebo responses.MethodsWe combined data from the two Japanese studies and analyzed change from baseline in IRLS score in the pooled population and subgroups defined by several patient characteristics. Moreover, we calculated the variable importance of each factor and performed predictive enrichment analysis to identify an enrichable subpopulation with greater improvement by GE treatment.ResultsThe post hoc analyses suggested that higher baseline IRLS score (≥21) and higher body mass index (≥25 kg/m²) were associated with higher placebo responses. On the other hand, positive family history of RLS, prior use of dopaminergic receptor agonists, and higher baseline ferritin level (≥50 ng/mL) were associated with higher responses to GE.ConclusionsOur results suggest that patients with typical idiopathic RLS characteristics, including positive family history and no low ferritin level, would be expected to derive the greatest benefits from GE treatment.     

Utility of measuring CSF hypocretin-1 level in patients with suspected narcolepsy

ObjectivesThe patho-aetiology of narcolepsy Type I (NT1) is the loss of hypocretin-1 secreting neurons in the hypothalamus. Diagnostic criteria for NT1 include excessive daytime sleepiness (EDS) for at least three months not explained by any other condition, cataplexy and cerebrospinal fluid (CSF) hypocretin-1 concentrations lower than 110 pg/ml. In this study we evaluated the utility of measuring CSF hypocretin-1 levels in patients with suspected narcolepsy (N).MethodsThe study included 29 consecutively recruited patients at a tertiary sleep centre presenting with EDS for exclusion of N. All patients were examined using an extensive clinical interview followed by two weeks of actigraphy and sleep diary recordings, polysomnography (PSG) and multiple sleep latency testing (MSLT). Additionally, HLA-typing, urinary screening for substances of abuse and a lumbar puncture to measure CSF hypocretin-1 expression using radioimmunoassay were carried out.ResultsIn sum, 19 patients (66%) had a CSF hypocretin-1 level <110 pg/ml, of whom two had current severe depression without any features of narcolepsy except EDS. The predictive potential of hypocretin-1 measurement in diagnosing narcolepsy revealed a positive predictive value (PPV) of 89%, a specificity of 83%, with both negative predictive value (NPV) and sensitivity equal to 100%.ConclusionsDespite a high sensitivity and specificity, the MSLT is not always a reliable diagnostic test for narcolepsy and where this uncertainty exits, CSF hypocretin-1 concentrations <110 pg/ml can be useful. However, due to a lower PPV and specificity at this cut-off, it may also not be entirely reliable as a stand-alone diagnostic test, particularly in the context of severe depression.     

Adherence to wakefulness promoting medication in patients with narcolepsy

ObjectiveNarcolepsy management usually requires lifelong pharmacotherapy. However, we know little about adherence to prescribed treatment in narcolepsy. We assessed adherence to wakefulness-promoting agents in narcolepsy patients.Patients and methodsWe retrospectively assessed adherence to wakefulness promoting medication in patients with narcolepsy using the Medicines Possession Ratio (MPR). Three levels of adherence were defined: poor (≤50%), intermediate (51–79%), and good (≥80%). Refractory daytime sleepiness was defined as an Epworth sleepiness scale (ESS) score >12 despite trialling at least three wakefulness-promoting agents. We compared demographic and clinical factors, and prescribed medications between patients, stratified by levels of adherence, as well as by presence or not of refractory sleepiness.ResultsWe included 116 patients with narcolepsy (54.3% female, mean age 39.4 (±14) years). In sum, 93 (80.2%) patients had a diagnosis of narcolepsy type 1 (NT1), and 23 (19.8%) of type 2 (NT2). Suboptimal symptom control was common: 39.8% had refractory sleepiness, and 47.3% of NT1 patients had persistent cataplexy. Good adherence was seen in only 55.2% of patients, while 12.9% were intermediately and 31.9% poorly adherent. Patients with poor adherence were more likely to have a diagnosis of NT2, but adherence did not vary according to gender, age, the presence of psychiatric co-morbidity, or the presence of apparent intractable symptoms. Levels of good adherence to therapy were no better in patients with refractory sleepiness than in those with satisfactory symptom control (56.5% vs 54.3%; p = 0.81).ConclusionSuboptimal adherence to prescribed therapy is common in narcolepsy patients, including those with apparent intractable symptoms, and particularly in patients with NT2.     

Assessing the impact of sodium oxybate treatment on functioning,productivity, and health-related quality of life in patients with narcolepsy: findings from the Nexus Narcolepsy Registry (waves 1–4)

BackgroundThe aim of this study was to evaluate the impact of different therapy regimens, including sodium oxybate (SXB)-containing regimens, on patient-reported outcomes (PROs) in people with narcolepsy.MethodsOnline surveys were used to collect information from persons with narcolepsy in the Nexus Narcolepsy Registry. Surveys contained questionnaires assessing self-reported sleep quality (SQ; via single question), daytime sleepiness and function (Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire), health-related quality of life (HRQoL; 36-Item Short Form Health Survey [SF-36]), work productivity and impairment (Work Productivity and Activity Impairment: Specific Health Problem), and history of injuries or motor vehicle accidents. Treatment with SXB (including monotherapy or combination therapy; SXB group) was compared with non-SXB therapy (No SXB group). The P values presented are nominal, as there are no adjustments for multiplicity.ResultsFrom June 2015 through December 2017, 983 participants completed 1760 surveys. SQ and daytime functioning scores were better in the SXB group compared with the No SXB group (all P < 0.001). HRQoL scores were better for the SXB group compared with the No SXB group for the SF-36 Physical Component (P = 0.016), Mental Component (P < 0.001), and all 8 subscales. Additionally, PROs were better for the SXB group for presenteeism, overall work and activity impairment, and risk of motor vehicle accidents (all P ≤ 0.001).ConclusionBased on participants’ self-assessments, treatment regimens with SXB were associated with better outcomes than regimens not containing SXB across many PROs, including SQ, HRQoL, work and activities, and risk of traffic accidents.Clinicaltrials.gov identifierNCT02769780.     

Burden of disease in pediatric narcolepsy: a claims-based analysis of health care utilization,costs, and comorbidities

BackgroundThis study analyzed a privately insured pediatric population with and without narcolepsy to determine the impact of pediatric narcolepsy on comorbidities, health care utilization, and cost. Additional analyses compared narcolepsy type 1 and type 2.MethodsThis retrospective cross-sectional study identified US patients with narcolepsy <18 years of age with ≥2 claims with a diagnosis code of narcolepsy using Truven MarketScan® data 2011 to 2015. Patients were matched to controls without narcolepsy. Comorbid conditions, health care utilization, and costs were measured by calendar year. P values are nominal, and no adjustments for multiplicity or multiple comparisons were made.ResultsA total of 1427 pediatric patients with narcolepsy were identified and matched with 4281 controls from 2011 to 2015. Patients with narcolepsy had more comorbid conditions (mean 5.8 vs 2.4, nominal P < 0.001). Respiratory diseases and mood disorders were more common in patients with narcolepsy than controls (57% vs 32% and 56% vs 14%, respectively; both nominal P < 0.001). Compared to controls, patients with narcolepsy underwent more diagnostic tests (electroencephalogram, EEG [0.13 vs 0.0053]) and brain computed tomography, CT/magnetic resonance imaging, MRI (0.26 vs 0.022; both nominal P < 0.001). Mean annual inpatient days (0.71 vs 0.15), emergency department visits (0.51 vs 0.15), and outpatient office visits (8.6 vs 2.3) were higher for patients with narcolepsy than controls (all nominal P < 0.001). Annual mean health care costs were higher for patients with narcolepsy versus controls ($15,797 vs $2449, nominal P < 0.001).ConclusionPediatric patients with narcolepsy had greater comorbidity, higher health care utilization, and higher costs than patients without narcolepsy.     

The Nexus Narcolepsy Registry: methodology,study population characteristics,and patterns and predictors of narcolepsy diagnosis

Objective/backgroundThe real-world experience of people with narcolepsy is not well understood.Patients/methodsThe Nexus Narcolepsy Registry (NCT02769780) is a longitudinal, web-based patient registry of self-reported data from adults with physician-diagnosed narcolepsy. Surveys were electronically distributed every 6 months; the current analysis reports registry population demographics, narcolepsy diagnosis journey, and predictors of diagnostic delays.ResultsThe registry population included in this analysis (N = 1024) was predominantly female (85%) and White (92%), with a mean age of 37.7 years. Most participants had education/training beyond high school (93%). Mean (median) reported ages at narcolepsy symptom onset, first consultation for symptoms, and narcolepsy diagnosis were 18.1 (16), 26.4 (24), and 30.1 (28) years, respectively. A majority (59%) of participants reported ≥1 misdiagnosis, and 29% reported consulting ≥5 physicians before narcolepsy diagnosis. More than half (56%) of participants’ first consultations for narcolepsy symptoms were with a general practitioner, whereas the diagnosing clinician was usually a sleep specialist (64%) or neurologist (27%). Pediatric symptom onset was associated with a longer mean interval to first consultation than adult symptom onset (10.7 and 4.6 years, respectively; P < 0.001) and a longer mean interval between first consultation and diagnosis (4.5 and 2.2 years, respectively; P < 0.001). Overall, mean (95% CI) time from symptom onset to diagnosis was 11.8 (11.1–12.5) years.ConclusionsThe Nexus Narcolepsy Registry data indicate that onset of narcolepsy symptoms frequently occurs in childhood or adolescence. In many individuals, the diagnostic process is long and involves multiple physicians and frequent misdiagnosis.     

Association between eveningness preference,socio-behavioral factors,and insomnia symptoms in Korean adolescents

Objective/BackgroundStudies focusing on insomnia in adolescents are relatively scarce compared to those on excessive daytime sleepiness. We aimed to investigate the prevalence of insomnia symptoms and associated factors in Korean high school students.Patients/methodsA total of 8565 students (girls: 4104) were investigated nationwide, across 15 South Korean districts using an online self-report questionnaire. Insomnia symptoms were evaluated using the Global Sleep Assessment Questionnaire. The participants’ mean age was 16.77 ± 0.85 years.ResultsThe prevalence of insomnia symptoms was 39.43% (n = 3377). Logistic regression was used to estimate the odds ratio (OR) of insomnia symptoms associated with sleep characteristics and social behaviors after adjusting for the relevant covariates. Evening preference (OR, 2.51, 95% CI, 2.20–2.86), perception of insufficient sleep (OR, 3.55, 95% CI, 3.11–4.06), snoring usually/always (OR, 1.25; 95% CI, 1.00–1.55), witnessed sleep apnea usually/always (OR, 1.70; 95% CI, 1.17–2.46), increased internet addiction (OR, 1.02; 95% CI, 1.02–1.03), bad sleep environment (OR, 1.77; 95% CI, 1.50–2.10), ≥3 private extra classes (OR, 1.23; 95% CI, 1.01–1.49), often coffee consumption (OR, 1.31; 95% CI, 1.10–1.56), and often nocturnal eating (OR, 1.24; 95% CI, 1.06–1.45) were associated with insomnia symptoms. Evening preference (OR, 3.48; 95% CI, 2.52–4.82) was also associated with insomnia symptoms in the perceived sufficient sleep subgroup.ConclusionInsomnia symptoms were common in Korean high school students. Evening preference was the major factor associated with insomnia symptoms. Various socio-behavioral factors were also associated with insomnia symptoms.     

Sleep time and sleep-related symptoms across two generations – results of the community-based RHINE and RHINESSA studies

Study objectivesTo analyze the association between sleep-related symptoms and sleep length in parents and their children in relation to other risk factors in both generations.MethodThe participants were parents (n = 5,855, age 54.3 ± 6.5 years, 45.2% men) who participated in the community-based Respiratory Health in Northern Europe (RHINE) study and one random member of their adult offspring (n = 5,855, age 30.2 ± 7.7 years, 41.5% men) who participated in the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) study. Both generations responded to identical questionnaires on sleep symptoms, including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), snoring, nocturnal sweating, nocturnal gastroesophageal reflux (nGER), sleep time and excessive daytime sleepiness (EDS). Insomnia was defined as either, or both, DIS and DMS in combination with EDS.ResultsAll sleep variables except nocturnal sweating were more common in offspring whose parents had reported the same symptom. After adjusting for age, gender, BMI, smoking, physical activity, education, center and parents' total number of children, there were independent associations between sleep symptoms in parents and offspring for DIS (adj. OR, 95% CI: 1.52, 1.20–1.93), DMS (1.34, 1.15–1.56), snoring (1.45, 1.15,1.83), nGER (1.65, 1.15–2.37), insomnia (1.39, 1.13–1.73), short sleep time (<6 h/night) (2.51, 1.72–3.68) and EDS (1.48, 1.26,1.72). There were no independent relationships between symptoms in parents and offspring for EMA, nocturnal sweating or long sleep time (>9 h/night).ConclusionThe familiar aggregation of many sleep disturbances was not explained by investigated lifestyle and environmental factors. This supports a heritable factor in sleep problems.     

Long-term health and socioeconomic consequences of childhood and adolescent-onset of narcolepsy

ObjectivesThere is limited information about the long-term consequences of childhood- and adolescent-onset narcolepsy on educational and social factors. Here, we estimate the long-term socioeconomic consequences and health care costs of narcolepsy.MethodsThe prospective cohort study included Danish individuals with narcolepsy onset in childhood or adolescence, diagnosed between 1994 and 2015. Health care costs and socioeconomic data were obtained from nationwide administrative and health registers. One hundred seventy-one patients were compared with 680 controls (mean index age, 15.2 years; SD, 3.4 years) matched for age, gender, and other sociodemographic characteristics.ResultsComparing the narcolepsy patient and control groups at age 20 years we found: (1) no differences in parental educational level; (2) patients had a significantly lower educational level than controls; (3) patients had significantly lower grade-point averages; (4) patients had a lower employment rate and lower-income, even when transfer payments were considered; and (5) patients' initial health care costs were higher. Patients had a higher mortality rate than controls, although the difference was not statistically significant.ConclusionNarcolepsy is associated with a significant influence on educational level, grading, social outcome, and welfare consequences. The development of narcolepsy is independent of parental social level.     

An investigation into an evening intake of a saffron extract (affron®) on sleep quality,cortisol, and melatonin concentrations in adults with poor sleep: a randomised,double-blind,placebo-controlled,multi-dose study

Objective/backgroundTo validate and extend on previous positive findings of the sleep-enhancing effects of saffron supplementation in adults with unsatisfactory sleep.Patients/methodsIn this 28-day, 3-arm, parallel-group, double-blind, randomised controlled trial, 120 adults with unsatisfactory sleep received either a placebo, 14 mg, or 28 mg of a standardised saffron extract (affron®), 1 h before bed. Outcome measures included the Pittsburgh Sleep Diary (with sleep quality ratings as the primary outcome measure), Insomnia Symptom Questionnaire (ISQ), Profile of Mood States, Restorative Sleep Questionnaire, the Functional Outcomes of Sleep Questionnaire, and evening salivary melatonin and cortisol concentrations.ResultsCompared to the placebo, saffron supplementation was associated with greater improvements in sleep quality ratings (primary outcome measure), mood ratings after awakening, the ISQ total score, and ISQ-insomnia classifications. However, there were no significant differences between the saffron and placebo groups in other questionnaire and sleep diary outcome measures. Sleep improvements were similar for the two administered saffron doses. Compared to the placebo, saffron supplementation was associated with increases in evening melatonin concentrations but did not affect evening cortisol. Saffron supplementation was well-tolerated with no reported significant adverse effects.ConclusionsThese results provide further validation of the sleep-enhancing effects of 28-days of saffron supplementation in adults with unsatisfactory sleep. Further research is required to examine the efficacy and safety of saffron supplementation using objective sleep measures, over a longer duration, in people presenting with a diagnosed insomnia disorder and other psychogenic and demographic characteristics, and into its potential sleep-enhancing mechanisms of action.     

Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations).MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards.ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients.ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms.SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.     

Narcolepsy in Slovakia – Epidemiology,clinical and polysomnographic features,comorbid diagnoses: a case-control study

ObjectiveAn increase in the incidence of narcolepsy after the pandemic influenza with the H1N1 vaccination in 2009 resulted in an interest in narcolepsy epidemiology. The aim of the study was to examine the incidence and prevalence rates of narcolepsy and to describe the associated characteristics in Slovakia.MethodsEpidemiology data were calculated for each year from 2000 to 2017 based on records found in specialized centres. In sum, 61 narcoleptic patients were diagnosed, of which 51 (84%) had narcolepsy type 1 (NT1). Clinical data and results of polysomnography (PSG), Human Leukocyte Antigen (HLA)-typing, hypocretin (HCRT)-1 levels and body mass index (BMI) were summarised and evaluated for NT1 and narcolepsy type2 (NT2). Later, 244 sex and age matched controls were chosen to evaluate the comorbid diagnoses.ResultsThe prevalence of narcolepsy in 2017 in Slovakia was 10.47 (CI 95% 8.26–14) cases/million inhabitants, and the mean incidence rate (2000–2017) was 0.57 (CI 95% 0.4–0.74) cases/million inhabitants.Narcoleptic patients were comorbid with arterial hypertension (17%), ischemic heart disease (8%), dyslipidaemia (18%), diabetes mellitus type 2 (10%), cardiac arrhythmia/atrial fibrillation (5%), autoimmune disorders (20%), allergy (11%), malignancy (3%), headache (15%) and mental disorders (20%). Patients with narcolepsy showed double the excess prevalence in mental disorders (OR 2.15, p < 0.05), and dyslipidaemia (OR 2.22, p < 0.05). The presence of autoimmune disorders and allergy showed a mild increase in the narcolepsy group (OR 1.46, resp. 1.63). Hashimoto thyroiditis (HT) was the most frequent autoimmune disorder.ConclusionsNarcolepsy is a rare disorder in Slovakia. From the phenotype, genetic characteristics and comorbidities the disorder does not vary from other European countries.     

Sleep-wake disturbances in supra-and infratentorial stroke: an analysis of post-acute sleep architecture and apnea

Background and purposeSleep-wake disturbances (SWD) are common following stroke, and often extend into the post-acute to chronic periods of recovery. Of particular interest to recovery is a reduction in rapid eye movement (REM) sleep, as we know REM sleep to be important for learning and memory. While there is a breadth of evidence linking SWD and stroke, much less work has been done to identify and determine if differences in sleep architecture and apnea severity are dependent on stroke infarct topographies.MethodsA retrospective chart review was conducted of 48 ischemic stroke patients having underwent a full, overnight polysomnography (PSG). All patients were over 30 days post-injury (post-acute) at the time of the PSG. Patients were divided into supra- and infratentorial infarct topography groups based on available medical and imaging records. In addition to sleep study record review, cognitive and outcome measures were examined.ResultsResults showed that patients with infratentorial stroke had poorer sleep efficiency, decreased REM sleep, and higher apnea hypopnea index (AHI) than those with supratentorial injuries. Longer continuous REM periods were correlated with higher verbal learning/memory scores, higher levels of positive affect, and lower levels of emotional/behavioral dyscontrol. Neither age nor AHI were significantly correlated with the amount or duration of REM. Slow-wave sleep was significantly reduced across both injury topographies.ConclusionsInfratentorial ischemic stroke patients display significant disruptions in sleep architecture and may require close monitoring for SWDs in the post-acute period to maximize outcome potential. REM sleep is particularly affected when compared to supratentorial ischemic stroke.     

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms

BackgroundCOVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity.DesignBlood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies.ResultsUsing cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb.ConclusionThe high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.     

α and θ oscillations in the subthalamic nucleus are potential biomarkers for Parkinson's disease with depressive symptoms

IntroductionAbnormal α oscillations in the bed nucleus of stria terminalis and subgenual cingulate of patients with depression correlate with symptom severity. Some Parkinson's disease (PD) patients also have abnormal θ-α oscillations in the subthalamic nucleus (STN). However, the relationship between abnormal θ-α oscillations and depressive symptoms in PD patients has not been determined. This study explored the correlation between α and θ oscillations of the STN and depressive symptoms in PD patients.MethodsWe conducted a retrospective case-control study on 36 PD patients with (dPD group) or without depressive symptoms (nPD group), analyzing the difference in the average power spectral density (PSD) of α and θ oscillations of the local field potential (LFP) recorded in the STN during deep brain stimulation (DBS), and their correlation with the Hamilton depression rating scale (HAMD) of PD patients during the same period.ResultsThe dPD group had a higher PSD of α oscillations and a lower PSD of θ oscillations in the left ventral STN. The PSD of α oscillations of the left ventral STN were positively correlated with the severity of depressive symptoms, whereas the PSD of θ oscillations of this location was negatively correlated with severity of depressive symptoms. The PSD of α and θ oscillations did not correlate with motor symptoms, sleep quality, or quality of life score.ConclusionAbnormal α and θ oscillations of the left ventral STN could be used as biomarkers of PD with depressive symptoms, which might guide STN-DBS treatment.     

Thalamic deep brain stimulation for Tourette Syndrome: A naturalistic trial with brief randomized,double-blinded sham-controlled periods

BackgroundThere is still a lack of controlled studies to prove efficacy of thalamic deep brain stimulation for Tourette's Syndrome.ObjectivesIn this controlled trial, we investigated the course of tic severity, comorbidities and quality of life during thalamic stimulation and whether changes in tic severity can be assigned to ongoing compared to sham stimulation.MethodsWe included eight adult patients with medically refractory Tourette's syndrome. Bilateral electrodes were implanted in the centromedian-parafascicular-complex and the nucleus ventro-oralis internus. Tic severity, quality of life and comorbidities were assessed before surgery as well as six and twelve months after. Short randomized, double-blinded sham-controlled crossover sequences with either active or sham stimulation were implemented at both six- and twelve-months’ assessments. The primary outcome measurement was the difference in the Yale Global Tic Severity Scale tic score between active and sham stimulation. Adverse events were systematically surveyed for all patients to evaluate safety.ResultsActive stimulation resulted in significantly higher tic reductions than sham stimulation (F = 79.5; p = 0.001). Overall quality of life and comorbidities improved significantly in the open-label-phase. Over the course of the trial two severe adverse events occurred that were resolved without sequelae.ConclusionOur results provide evidence that thalamic stimulation is effective in improving tic severity and overall quality of life. Crucially, the reduction of tic severity was primarily driven by active stimulation. Further research may focus on improving stimulation protocols and refining patient selection to improve efficacy and safety of deep brain stimulation for Tourette's Syndrome.     

Age-associated differences in sleep duration in the US population: potential effects of disease burden

ObjectivesWe contrasted the relative risks (RR) of short [<7 h] and long [>8 h] sleep experienced by middle-aged (45–64 years) and older (≥65 years) adults, compared with young adults (20–44 years).MethodsWe utilized NHANES data (2005–2016), capturing sociodemographic, socioeconomic, and health-related data among US adults.ResultsThe Relative Risk (RR) of short sleep between young and middle-aged adults did not differ [RR = 1.02, NS]. However, the RR of short sleep was significantly reduced among older participants [RR = 0.81, p < 0.01]. Middle-aged adults had significantly lower RR of long sleep [RR = 0.80, p < 0.01], whereas older adults had significantly greater RR of long sleep [RR = 1.41, p < 0.01]. Compared with young adults, older adults with or without increased disease burden had significantly lower RR of short sleep [RR = 0.81, p < 0.01 and RR = 0.80, p < 0.01], respectively. However, for middle-aged adults, the RR of short sleep did not differ whether they reported a greater disease burden. Relative to young adults, older adults with or without disease burden had higher RRs of long sleep [RR = 1.39, p < 0.01] and [RR = 1.45, p < 0.01], respectively. For middle-aged adults without disease burden, the RR of long sleep was lower than among young adults [RR = 0.72, p < 0.01].ConclusionsCompared with young adults, older adults were not at increased risk for short sleep. Rather, they reported longer sleep time regardless of the presence of disease burden. Future studies should investigate longitudinal effects of aging on objective sleep time, with or without common diseases.     

No enhanced (p-) α-synuclein deposition in gastrointestinal tissue of Parkinson's disease patients

BackgroundNeuronal alpha-synuclein (α-Syn) aggregation in the brain is believed to be a central component of the pathogenesis of Parkinson's disease (PD). α-Syn aggregates in the gastrointestinal tract have been suggested as a potential biomarker of PD that may even signal an early event of the Parkinsonian molecular pathology. However, studies further investigating this hypothesis have produced mixed results.ObjectiveTo determine whether the prevalence of α-Syn- and serine 129-phosphorylated α-Syn (Ser129p-α-Syn) depositions detected in intestine from PD patients differed from that of non-Parkinsonian controls.MethodsIn this retrospective study, we examined post-mortem small and large intestine samples of 25 PD patients and 20 age- and sex-matched controls without PD. Specimens were taken from archived paraffin-embedded tissue blocks. Immunohistochemical techniques were applied to detect α-Syn and Ser129p-α-Syn aggregates in situ. Immunoreactivity was quantified by a new approach that employed the detailed assessment of α-Syn- and Ser129p-α-Syn-positive morphological structures of the enteric nervous system (i.e., nerve fibers, myenteric and submucous plexus as well as ganglion cells).Resultsα-Syn immunoreactivity was a common finding in intestinal tissues from PD patients and controls. Importantly, α-Syn and Ser129p-α-Syn immunoreactivity were significantly reduced in PD patients compared to controls in each of the morphological structures examined.ConclusionsImmunohistochemical detection of intestinal α-Syn and Ser129p-α-Syn seems to be a frequent and potentially normal finding. Neither α-Syn nor Ser129p-α-Syn immunoreactivity may, therefore, be regarded as a molecular intestinal biomarker of PD pathology. Reduced intestinal α-Syn and Ser129p-α-Syn immunoreactivity in PD patients rather reflect PD-related neuronal degeneration.     

Effect of exercise training on subjective parameters in patients with obstructive sleep apnea: a systematic review and meta-analysis

Obstructive sleep apnea (OSA) has many effects on subjective parameters of the disease, such as reduction in quality of life (QoL), sleep quality (SQ), and increases in daytime sleepiness. Studies have reported the beneficial effect of exercise training on OSA severity; however, whether it improves subjective parameters remains unclear. The purpose of the present review was to investigate the effect of exercise training on QoL, daytime sleepiness, and SQ in adults with OSA by summarizing the results of clinical trials. The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in PROSPERO. A systematic review of the PubMed, Scopus, and Cochrane (CENTRAL) databases was conducted. Risk of bias analysis was performed using the Cochrane tool, and Review Manager version 5.2 (R Foundation for Statistical Computing, Vienna, Austria) was used to perform the meta-analysis. Of the 1573 studies initially retrieved, 8 relevant studies with 228 participants were included in the analysis. The studies presented moderate risk of bias. Exercise training significantly improved QoL (mean difference, 12.9 [95% confidence interval (CI) 6.4 to 19.5]) and SQ (mean difference, −2.0 [95% CI -3.6 to −0.5]), and reduced daytime sleepiness (mean difference, −3.7 [95% CI -6.1 to −1.2]), and OSA severity (mean difference, −11.4 [95% CI -13.4 to −9.4 events/h]). Thus, physical exercise training was effective in improving subjective parameters and reducing the severity of OSA. Additional randomized clinical trials, however, should be performed to confirm these findings.     

Utility of the sleep stage sequence preceding sleep onset REM periods for the diagnosis of narcolepsy: a study in a Japanese cohort

BackgroundThe minimum narcolepsy criteria “mean sleep latency (MSL) ≤8 min and ≥2 sleep onset rapid eye movement (REM) periods (SOREMPs) on polysomnography (PSG) and the multiple sleep latency test (MSLT),” according to The International Classification of Sleep Disorders, Third Edition (ICSD-3), are not specific to narcolepsy. Recently, the characteristic sleep stage sequences preceding SOREMPs in narcolepsy have received attention, but their diagnostic utility remains unclear.MethodsWe retrospectively reviewed PSG/MSLT records and chart data for 102 Japanese patients with hypersomnia and at least one SOREMP. We examined the sporadic rates of two sleep stage sequences preceding the SOREMPs—wakefulness or stage 1 to REM (W/S1→R) and stage 2 to REM (S2→R)—comparing these between patient groups with narcolepsy type 1 (N = 28), narcolepsy type 2 (N = 19), and other hypersomnia (N = 55). We also examined the utility of three simple indices using the occurrence of W/S1→R SOREMPs for distinguishing between narcolepsy and other hypersomnia in patients who satisfied the minimum narcolepsy criteria.ResultsW/S1→R SOREMPs were significantly more frequent in narcolepsy than in other hypersomnia, and this tendency was also observed even in the patients who satisfied the minimum narcolepsy criteria. The three indices had moderate sensitivities and specificities for distinguishing between narcolepsy and other hypersomnia in patients satisfying the minimum narcolepsy criteria.ConclusionsThe W/S1→R pattern was observed significantly more frequently in narcolepsy than in other hypersomnia, suggesting it may help with differentiating narcolepsy from other hypersomnia in patients demonstrating the narcolepsy criteria, although its ability to do so may be modest.