Rapid Eye Movements during REM Sleep Differentiate PSP from Parkinson's Disease.

BACKGROUND: Little is known about the characteristics and occurrence frequencies of rapid eye movements (REMs) during REM sleep in movement disorders. OBJECTIVES: The aim of this study was to detect and characterize REMs during polysomnographically defined REM sleep as recorded by electro-oculography (EOG) in 12 patients with progressive supranuclear palsy (PSP), 13 patients with Parkinson's disease (PD) and 12 healthy controls. METHODS: Using a modified EOG montage, we developed an algorithm that automatically detects and characterizes REMs during REM sleep based on their presumptive saccadic kinematics. RESULTS: Compared to PD and healthy controls, REM densities and REM peak velocities were significantly reduced in PSP. These effects were most pronounced in vertical REMs. CONCLUSION: Ocular motor dysfunction, one of the cardinal features of PSP, seems to be equally at play during REM sleep and wakefulness. For future studies, we provide a novel tool for the unbiased analysis of REMs during REM sleep in movement disorders.

Sleep spindle and slow wave activity in Parkinson disease with excessive daytime sleepiness.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a common and devastating symptom in Parkinson disease (PD), but surprisingly most studies showed that EDS is independent from nocturnal sleep disturbance measured with polysomnography. Quantitative electroencephalography (EEG) may reveal additional insights by measuring the EEG hallmarks of non-rapid eye movement (NREM) sleep, namely slow waves and spindles. Here, we tested the hypothesis that EDS in PD is associated with nocturnal sleep disturbance revealed by quantitative NREM sleep EEG markers. METHODS: Patients with PD (n = 130) underwent polysomnography followed by spectral analysis to calculate spindle frequency activity, slow-wave activity (SWA), and overnight SWA decline, which reflects the dissipation of homeostatic sleep pressure. We used the Epworth Sleepiness Scale (ESS) to assess subjective daytime sleepiness and define EDS (ESS > 10). All examinations were part of an evaluation for deep brain stimulation. RESULTS: Patients with EDS (n = 46) showed reduced overnight decline of SWA (p = 0.036) and reduced spindle frequency activity (p = 0.032) compared with patients without EDS. Likewise, more severe daytime sleepiness was associated with reduced SWA decline (ß= -0.24 p = 0.008) and reduced spindle frequency activity (ß= -0.42, p < 0.001) across all patients. Reduced SWA decline, but not daytime sleepiness, was associated with poor sleep quality and continuity at polysomnography. CONCLUSIONS: Our data suggest that daytime sleepiness in PD patients is associated with sleep disturbance revealed by quantitative EEG, namely reduced overnight SWA decline and reduced spindle frequency activity. These findings could indicate that poor sleep quality, with incomplete dissipation of homeostatic sleep pressure, may contribute to EDS in PD.

Slow-wave sleep affects synucleinopathy and regulates proteostatic processes in mouse models of Parkinson's disease.

Slow-wave sleep (SWS) modulation in rodent models of Alzheimer's disease alters extracellular amyloid burden. In Parkinson's disease (PD), SWS appears to be closely linked with disease symptoms and progression. PD is characterized by damaging intracellular α-synuclein (αSyn) deposition that propagates extracellularly, contributing to disease spread. Intracellular αSyn is sensitive to degradation, whereas extracellular αSyn may be eliminated by glymphatic clearance, a process increased during SWS. Here, we explored whether long-term slow-wave modulation in murine models of PD presenting αSyn aggregation alters pathological protein burden and, thus, might constitute a valuable therapeutic target. Sleep-modulating treatments showed that enhancing slow waves in both VMAT2-deficient and A53T mouse models of PD reduced pathological αSyn accumulation compared to control animals. Nonpharmacological sleep deprivation had the opposite effect in VMAT2-deficient mice, severely increasing the pathological burden. We also found that SWS enhancement was associated with increased recruitment of aquaporin-4 to perivascular sites, suggesting a possible increase of glymphatic function. Furthermore, mass spectrometry data revealed differential and specific up-regulation of functional protein clusters linked to proteostasis upon slow wave­enhancing interventions. Overall, the beneficial effect of SWS enhancement on neuropathological outcome in murine synucleinopathy models mirrors findings in models of Alzheimer. Modulating SWS might constitute an effective strategy for modulating PD pathology in patients.

Sleep-wake misperception. A comprehensive analysis of a large sleep lab cohort.

OBJECTIVES: Sleep-wake misperception has mainly been reported in insomnia patients. Conversely, the present study aimed to assess the prevalence and correlates of sleep-wake misperception in a large cohort of patients with various sleep-wake disorders, all diagnosed along the third version of the International Classification of Sleep Disorders. METHODS: We retrospectively included 2738 patients examined by polysomnography, who in addition estimated upon awakening their total sleep time, sleep onset latency and Wake after sleep onset (WASO). We computed subjective-objective mismatch by the formula (subjective - objective value)/objective value ×100; negative and positive values indicated under- and overestimation, respectively. RESULTS: In the entire sample, the magnitude of under- and overestimation of total sleep time was similar, but varied significantly between diagnostic groups, with insomnia and insufficient sleep syndrome showing the most pronounced underestimation and REM parasomnia and circadian rhythm disorders showing the most pronounced overestimation of total sleep time. In all diagnostic categories, a majority tended to overestimate their sleep onset latency and to underestimate the amount of WASO. Younger age was independently correlated with underestimation of total sleep time and WASO, and with overestimation of sleep onset latency. Overestimation of sleep onset latency independently correlated to an increased latency to N3 sleep stage on polysomnography. CONCLUSIONS: While sleep-wake misperception is highly prevalent in all sleep-wake disorders, significant differences exist in magnitude of under- and overestimation between distinct diagnostic groups.

Reduced Regional NREM Sleep Slow-Wave Activity Is Associated With Cognitive Impairment in Parkinson Disease.

Growing evidence implicates a distinct role of disturbed slow-wave sleep in neurodegenerative diseases. Reduced non-rapid eye movement (NREM) sleep slow-wave activity (SWA), a marker of slow-wave sleep intensity, has been linked with age-related cognitive impairment and Alzheimer disease pathology. However, it remains debated if SWA is associated with cognition in Parkinson disease (PD). Here, we investigated the relationship of regional SWA with cognitive performance in PD. In the present study, 140 non-demented PD patients underwent polysomnography and were administered the Montréal Cognitive Assessment (MoCA) to screen for cognitive impairment. We performed spectral analysis of frontal, central, and occipital sleep electroencephalography (EEG) derivations to measure SWA, and spectral power in other frequency bands, which we compared to cognition using linear mixed models. We found that worse MoCA performance was associated with reduced 1-4 Hz SWA in a region-dependent manner (F 2, 687 =11.67, p < 0.001). This effect was driven by reduced regional SWA in the lower delta frequencies, with a strong association of worse MoCA performance with reduced 1-2 Hz SWA (F 2, 687 =18.0, p < 0.001). The association of MoCA with 1-2 Hz SWA (and 1-4 Hz SWA) followed an antero-posterior gradient, with strongest, weaker, and absent associations over frontal (rho = 0.33, p < 0.001), central (rho = 0.28, p < 0.001), and occipital derivations, respectively. Our study shows that cognitive impairment in PD is associated with reduced NREM sleep SWA, predominantly in lower delta frequencies (1-2 Hz) and over frontal regions. This finding suggests a potential role of reduced frontal slow-wave sleep intensity in cognitive impairment in PD.

Narcolepsy type 2: A rare, yet existing entity.

Because of unspecific diagnostic criteria, there is much controversy around narcolepsy type 2, its existence and its frequency. With this retrospective and purely descriptive study, we aimed to compare the frequency of narcolepsy type 2 compared to the well-described narcolepsy type 1, in a large (n = 3,782) retrospective sample from a single tertiary sleep centre. After 2 weeks washout of sleep-wake active medication, all patients with excessive daytime sleepiness (n = 1,392) underwent 2 weeks actigraphy, polysomnography and multiple sleep latency test, and all diagnoses were made along current diagnostic criteria. Narcolepsy type 1 was diagnosed in 91 patients, and 191 patients without cataplexy had multiple sleep latency test (MSLT) results indicating narcolepsy. After exclusion of shift work syndrome (n = 19), suspected insufficient sleep syndrome (n = 128), delayed sleep phase syndrome (n = 4) and obstructive sleep apnea (n = 34), six patients were diagnosed with narcolepsy type 2, of whom two patients later developed narcolepsy type 1. Altogether, our observations suggest that narcolepsy type 2 exists, but its frequency may be much lower compared to narcolepsy type 1. In addition, they emphasize the importance of scrupulously excluding other potential causes of sleepiness, if possible, with 2-week actigraphy and polysomnography.

Extending sleep to confirm insufficient sleep syndrome is challenging.

Insufficient sleep syndrome (ISS) is prevalent, but poorly studied. This descriptive study was performed to determine its diagnostic challenges and clinical characteristics in a large (n = 3,461) retrospective sample from a single sleep laboratory. Based on actigraphy, polysomnography and multiple sleep latency tests, we diagnosed "suspected insufficient sleep syndrome" in patients with chronic sleepiness, short time in bed, longer sleep duration during weekends or vacation, and without evidence of other causes of sleepiness. For the diagnosis of "definite insufficient sleep syndrome", we additionally required objectively confirmed resolution of sleepiness with actigraphy-documented extension of time in bed. We diagnosed "suspected insufficient sleep syndrome" in 300 subjects. In 94 subjects, extension of sleep time with consecutive relief of sleepiness was attempted, but only 37 subjects succeeded, often despite being offered several attempts. "Definite insufficient sleep syndrome" was confirmed in 36 patients. In these subjects, mean time in bed after sleep extension was above 8 hr per night and 84 min longer than at baseline. Narcolepsy-like findings were frequently observed before sleep extension, but no sleep onset rapid eye movement sleep on polysomnography. This study indicates that fulfilling the diagnostic criteria of ISS is challenging in clinical practice. It further corroborates the importance of actigraphy and polysomnography for correct diagnosis.

Fatigue in inflammatory bowel disease and its impact on daily activities.

BACKGROUND: Fatigue is a common symptom of chronic inflammation, including inflammatory bowel disease (IBD), resulting in significant impairment in quality of life. AIMS: To identify the prevalence of fatigue in a large IBD cohort compared to the general population, address risk factors, and evaluate its impact on daily life. METHODS: We evaluated 1208 IBD patients from the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) and 414 healthy controls. Significant fatigue was defined as a visual analogue scale (VAS-F, range 0-10) score ≥ 4. Secondary endpoints were severity of fatigue and its impact on daily activities with the Fatigue Severity Scale (FSS), with a score ≥ 4 indicative of fatigue. Demographic, IBD-related and psychiatric symptoms were assessed with a multivariate analysis of variance (MANOVA) model optimised for prediction of VAS-F (primary outcome) and FSS scores. RESULTS: Overall, 672 IBD patients (55.6%) reported significant fatigue compared to 145 (35%) controls (OR 2.71; 95% CI 2.08-3.54; P < 0.001). In IBD, fatigue also significantly affected daily activities (FSS ≥ 4; 405 (33.5%) IBD patients vs 81 (19.6%) controls, P < 0.001). In the MANOVA model, fatigue levels were associated with female gender (coefficient 0.839; 0.556 - 1.123; P < 0.001), younger age at diagnosis (-0.031 per year; -0.042- -0.019; P < 0.001), shorter disease duration (-0.036 per year; -0.050- -0.022; P < 0.001), nocturnal diarrhoea (0.718; 0.295-1.141; P = 0.001), low educational level (P = 0.034) and symptoms of depression and anxiety. CONCLUSIONS: Fatigue is both more frequent and more severe in patients with IBD than in the general population.

Depression in myasthenia gravis: a heterogeneous and intriguing entity.

BACKGROUND: Depressive symptoms in myasthenia gravis (MG) are common, may mimic other disease features, and contribute to misdiagnosis and diagnostic delay. Nevertheless, the clinical determinants of depressive symptoms in MG remain poorly studied, in particular their overlap with fatigue. Moreover, studies in MG have rarely looked at distinct depression phenotypes. METHODS: In 68 consecutive MG patients, we ascertained cognitive-affective and somatic depression with the Beck Depression Inventory (BDI), and also assessed age at disease onset, education, marital state, work ability, sleepiness, fatigue, and treatment modalities. Disease severity was graded according to the Myasthenia Gravis Foundation of America (MGFA) classification. RESULTS: The prevalence of moderate-severe depression was 20.5%. While depression and fatigue showed large overlap (n = 37, 54.4%), only fatigue increased with disease severity, while BDI scores did not. Thymectomy was independently associated with lower BDI scores, but had no impact on fatigue. Total BDI scores were similar in patients with predominantly cognitive-affective and with predominantly somatic depression. However, ESS correlated only with cognitive-affective BDI, and younger age was independently associated with cognitive-affective BDI. Conversely, female sex and thymectomy were independently associated with somatic BDI. CONCLUSIONS: Depression and fatigue are highly prevalent and largely overlapping comorbidities in MG, but only fatigue increased with disease severity, and only depression was milder in thymectomized patients. Comparative use of BDI subscales in MG reveals distinct depression phenotypes with distinct correlations to other disease features.

The eyes wake up: Screening for benign paroxysmal positional vertigo with polysomnography.

OBJECTIVE: While positional nystagmus of benign paroxysmal positional vertigo (BPPV) has been shown to be detectable in electrooculography (EOG) tracings of polysomnography (PSG), the frequency of undiagnosed BPPV in patients referred for sleep-wake examination has never been investigated. METHODS: Prospective evaluation of positional nystagmus in 129 patients, referred to a neurological sleep laboratory for sleep-wake examination with PSG. Both in the evening and morning, patients had diagnostic positioning maneuvers under ongoing EOG-PSG registration, followed by visual inspection of EOG for positional nystagmus. RESULTS: In 19 patients (14.7%), we found patterns of positional nystagmus, typically appearing few seconds after changes in head position. In 9 of these patients (47%), the nystagmus was also provoked by the positioning maneuvers. Nystagmus only occurred during wakefulness, not during sleep. In a patient with severe cupulolithiasis, we observed disappearance of nystagmus while entering N1 sleep stage. Nocturnal positional nystagmus was independently associated with positive positioning maneuvers. CONCLUSIONS: Inspection of EOG-PSG demonstrated that positional nystagmus is common, occurring only when wake, and independently associated with positive positioning maneuvers. SIGNIFICANCE: By routinely searching for positional nystagmus in PSG, sleep physicians may substantially contribute to the identification of patients with so-far undiagnosed BPPV.

Impact of intravenous thrombolysis on functional outcome in patients with mild ischemic stroke without large vessel occlusion or rapidly improving symptoms.

BACKGROUND: Optimal treatment strategy in patients with mild ischemic stroke remains uncertain. While functional dependency or death has been reported in up to one-third of non-thrombolyzed mild ischemic stroke patients, intravenous thrombolysis is currently not recommended in this patient group. Emerging evidence suggests two risk factors-rapid early improvement and large vessel occlusion-as main associates of unfavorable outcome in mild ischemic stroke patients not undergoing intravenous thrombolysis. AIMS: To analyze natural course as well as safety and three-month outcome of intravenous thrombolysis in mild ischemic stroke without rapid early improvement or large vessel occlusion. METHODS: Mild ischemic stroke was defined by a National Institute of Health Stroke Scale score ≤6. We used the modified Rankin Scale (mRS) to compare three-month functional outcome in 370 consecutive mild ischemic stroke patients without early rapid improvement and without large vessel occlusion, who either underwent intravenous thrombolysis (n = 108) or received best medical treatment (n = 262). RESULTS: Favorable outcome (mRS ≤ 1) was common in both groups (intravenous thrombolysis: 91%; no intravenous thrombolysis: 90%). Although intravenous thrombolysis use was independently associated with a higher risk of asymptomatic hemorrhagic transformation (OR = 4.62, p = 0.002), intravenous thrombolysis appeared as an independent predictor of mRS = 0 at three months (OR = 3.33, p < 0.0001). CONCLUSIONS: Mild ischemic stroke patients without rapidly improving symptoms and without large vessel occlusion have a high chance of favorable three-month outcome, irrespective of treatment type. Patients receiving intravenous thrombolysis, however, more often achieved complete remission of symptoms, which particularly in mild ischemic stroke may constitute a meaningful endpoint.

Distinct Vestibular Evoked Myogenic Potentials in Patients With Parkinson Disease and Progressive Supranuclear Palsy.

Background: Early brainstem neurodegeneration is common in Parkinson's disease (PD) and progressive supranuclear palsy (PSP). While previous work showed abnormalities in vestibular evoked myogenic potentials (VEMPs) in patients with either disorder as compared to healthy humans, it remains unclear whether ocular and cervical VEMPs differ between PD and PSP patients. Methods: We prospectively included 12 PD and 11 PSP patients, performed ocular and cervical VEMPs, and calculated specific VEMP scores (0 = normal, 12 = most pathological) based on latencies, amplitude, and absent responses. In addition, we assessed disease duration, presence of imbalance, motor asymmetry, and motor disability using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III). Moreover, we ascertained various sleep parameters by video-polysomnography. Results: PSP and PD patients had similar oVEMP scores (6 [3-6] vs. 3 [1.3-6], p = 0.06), but PSP patients had higher cVEMP scores (3 [0-6] vs. 0 [0-2.8], p = 0.03) and total VEMP scores (9 [5-12] vs. 4 [2-7.5], p = 0.01). Moreover, total VEMP scores >10 were only observed in PSP patients (45%, p = 0.01). MDS-UPDRS III correlated with cVEMP scores (rho = 0.77, p = 0.01) in PSP, but not in PD. In PD, but not in PSP, polysomnographic markers of disturbed sleep, including decreased rapid eye movement sleep, showed significant correlations with VEMP scores. Conclusions: Our findings suggest that central vestibular pathways are more severely damaged in PSP than in PD, as indicated by higher cervical and total VEMP scores in PSP than PD in a between-groups analysis. Meaningful correlations between VEMPs and motor and non-motor symptoms further encourage its use in neurodegenerative Parkinsonian syndromes.

Slow-wave sleep and motor progression in Parkinson disease.

Growing evidence from Alzheimer disease supports a potentially beneficial role of slow-wave sleep in neurodegeneration. However, the importance of slow-wave sleep in Parkinson disease is unknown. In 129 patients with Parkinson disease, we retrospectively tested whether sleep slow waves, objectively quantified with polysomnography, relate to longitudinal changes in Unified Parkinson's Disease Rating Scale motor scores. We found that higher accumulated power of sleep slow waves was associated with slower motor progression, particularly of axial motor symptoms, over a mean time of 4.6 ± 2.3 years. This preliminary finding suggests that deeper sleep relates to slower motor progression in Parkinson disease. Ann Neurol 2019;85:765-770.

Sleep-Related Rhythmic Movement Disorder in Triplets: Evidence for Genetic Predisposition?

ABSTRACT: Sleep-related rhythmic movement disorder (RMD) is common in very young children but rarely persists beyond childhood. Despite its high frequency, the underlying pathophysiology remains unclear. Familial occurrence is rare. Here we present monozygotic female triplets, all of them being affected by body rolling in terms of RMD. Furthermore, they all present with an additional genetic disease, cystic fibrosis, with the same documented mutation of the cystic fibrosis transmembrane conductance regulator gene (F508del-CFTR). Because all three monozygotic siblings are concordant for RMD, genetic factors may contribute to the time course of the disorder.

In search of cerebrospinal fluid biomarkers of fatigue in multiple sclerosis: A proteomics study.

Fatigue in multiple sclerosis is a very common and cumbersome symptom, but its aetiology is poorly understood. Proteomics is increasingly implemented in multiple sclerosis research, but has not yet been used to study the neurobiological basis of fatigue in multiple sclerosis. To identify potential cerebrospinal fluid biomarkers of fatigue in multiple sclerosis, we collected cerebrospinal fluid of 20 patients with multiple sclerosis with fatigue (MS+), 20 patients with multiple sclerosis without fatigue (MS-), and 20 control subjects without multiple sclerosis and without fatigue (HC). We used a shotgun proteomics approach and label-free quantitative proteomics to analyse the protein content in cerebrospinal fluid. Selected proteins with differential abundance were further validated by immunoblotting. Out of 591 detected cerebrospinal fluid proteins, the abundance of nine proteins differed between the three groups, and seven additional proteins differed between MS+ and MS- patients. Using immunoblot or slot-blot techniques, we confirmed decreased levels of protein kinase C-binding protein NELL2, neural cell adhesion molecule L1-like protein, and reelin in MS+ patients. In conclusion, cerebrospinal fluid proteomics may provide insight into the neurobiological basis of fatigue in multiple sclerosis. The proteins identified to be decreased in MS+ are involved in synaptic plasticity and energy homeostasis, and thus appear as plausible biomarkers of this common symptom.

Validation of the Russian version of the Fatigue Impact Scale and Fatigue Severity Scale in multiple sclerosis patients.

BACKGROUND: Fatigue is a common complaint in patients with multiple sclerosis (MS), and its detection and monitoring are based on self-reported questionnaires. The objective of this study was to validate the Russian translation of the Fatigue Impact Scale (FIS) and the Fatigue Severity Scale (FSS) in MS patients and controls. METHODS: We included 85 MS patients and 250 age-, sex-, and body mass index (BMI)-matched controls. We ascertained in all subjects levels of education, marital status, and comorbidities, such as sleepiness (using the Epworth Sleepiness Scale, ESS), anxiety and depression (using the Hospital Anxiety and Depression Scale, HADS). The expanded disability status scale (EDSS) reflected physical disability in MS. RESULTS: The Russian versions of the three FIS subscales (cognitive, physical, and psychosocial) and FSS had excellent internal consistencies (Cronbach's α coefficients 0.88-0.96), and good test-retest stability with intraclass coefficients between 0.78 and 0.89. Both convergent and discriminant validity of the Russian FIS and FSS appeared to be good, as expressed by strong inter-correlations between FIS subscales and FSS, and by absent associations between fatigue scales and BMI. Principal components analysis and scree plots indicated unidimensional structures of the physical and cognitive FIS subscales and FSS, but a multidimensional structure of the psychosocial subscale. We identified EDSS and anxiety scores as independent predictors of more severe fatigue in MS. SIGNIFICANCE: The Russian FIS and FSS represent reliable and valid tools for efficient quantification and monitoring of fatigue severity and its clinical impact in MS. EDSS and anxiety are important contributors to fatigue severity in MS.

Remitting narcolepsy? Longitudinal observations in a hypocretin-deficient cohort.

Study Objective: Narcolepsy type 1 (NT1) is considered a chronic, incurable disease. Excessive daytime sleepiness (EDS) is typically the most troublesome symptom, and more difficult to control by pharmacologic treatment than cataplexy. Although many NT1 patients are monitored by regular follow-ups, the purported relentless persistence of EDS has rarely been the object of longitudinal studies. Methods: Retrospective analysis of 26 well-defined hypocretin-deficient NT1 patients who underwent longitudinal assessments of Epworth sleepiness scale (ESS) scores under stable pharmacotherapy. We present detailed case reports of four patients with unusual spontaneous improvement. Results: Over a mean observation period of 5 years, changes in ESS scores between first and last examination were ≤4 points in 19 patients (73%). Three patients deteriorated by 5 points, four patients ameliorated by 7-11 points. Among the latter, subjective sleepiness resolved in all four patients, and three of them continued showing ESS scores <11 after cessation of their pharmacotherapy. Without therapy, two patients did not fulfill anymore the ICSD-3 multiple sleep latency test criteria (mean sleep latency >8 minutes), one of whom did not fall asleep during maintenance of wakefulness test. Multiple linear regression analysis identified higher cerebrospinal fluid (CSF) hypocretin level (p < 0.001) and absence of fragmented nighttime sleep (p = 0.001) as independent associates of EDS improvement. Conclusions: The longitudinal course of NT1-related sleepiness is not invariably stable, but included spontaneous deterioration or improvement in 27%. Spontaneous improvement can persist after treatment discontinuation and resemble remission. Milder hypocretin deficiency and good nighttime sleep may predict a more favorable disease course.

Increased Sleep Need and Reduction of Tuberomammillary Histamine Neurons after Rodent Traumatic Brain Injury.

Although sleep-wake disturbances are prevalent and well described after traumatic brain injury, their pathophysiology remains unclear, most likely because human traumatic brain injury is a highly heterogeneous entity that makes the systematic study of sleep-wake disturbances in relation to trauma-induced histological changes a challenging task. Despite increasing interest, specific and effective treatment strategies for post-traumatic sleep-wake disturbances are still missing. With the present work, therefore, we aimed at studying acute and chronic sleep-wake disturbances by electrophysiological means, and at assessing their histological correlates after closed diffuse traumatic brain injury in rats with the ultimate goal of generating a model of post-traumatic sleep-wake disturbances and associated histopathological findings that accurately represents the human condition. We assessed sleep-wake behavior by means of standard electrophysiological recordings before and 1, 7, and 28 days after sham or traumatic brain injury procedures. Sleep-wake findings were then correlated to immunohistochemically labeled and stereologically quantified neuronal arousal systems. Compared with control animals, we found that closed diffuse traumatic brain injury caused increased sleep need one month after trauma, and sleep was more consolidated. As histological correlate, we found a reduced number of histamine immunoreactive cells in the tuberomammillary nucleus, potentially related to increased neuroinflammation. Monoaminergic and hypocretinergic neurotransmitter systems in the hypothalamus and rostral brainstem were not affected, however. These results suggest that our rat traumatic brain injury model reflects human post-traumatic sleep-wake disturbances and associated histopathological findings very accurately, thus providing a study platform for novel treatment strategies for affected patients.

Optimizing MSLT Specificity in Narcolepsy With Cataplexy.

Study Objectives: Multiple sleep onset rapid eye movement (R) periods (SOREMPs) and a mean sleep latency of ≤8 minutes on the multiple sleep latency test (MSLT) are diagnostic criteria of narcolepsy (NC), but also occur in other conditions with increased sleep pressure, including insufficient sleep syndrome (ISS), sleep-disordered breathing (SDB), or Parkinson's disease (PD). These false positives are common, may create diagnostic uncertainty, and highlight the need for complementary MSLT measures with high specificity for NC. Methods: Detailed analysis of MSLT findings in 56 NC, 83 PD, 89 SDB, and 23 ISS patients, using receiver operating characteristic curves. Results: A positive MSLT (mean sleep latency ≤ 8.0 minutes and ≥2 SOREMPs) was found in 53 NC (95%), 1 PD (1%), 8 SDB (9%), and 12 ISS patients (52%). MSLT-based differentiation between NC and non-NC patients was best when applying a mean R latency of ≤5 minutes (sensitivity/specificity/positive predictive value [PPV]: 49%/95%/96%) or a mean percentage of sleep stage R ≥ 40% (sensitivity/specificity/PPV: 60%/100%/100%) as cutoffs. When analyzing all 252 naps with SOREMPs in isolation, the combination of both R latency of ≤5 minutes and R percentage of ≥50% yielded a sensitivity/specificity/PPV of 50%/99%/99%. In addition, a sleep stage sequence with R occurring prior to N2 was more common in NC than in non-NC (71% vs. 32%, p < .001), and in combination with R percentage of ≥50% yielded a sensitivity/specificity/PPV of 53%/96%/97%. Conclusions: A better characterization of R sleep by latency, duration, and sleep stage sequence facilitates detection of false positives and, hence, contributes to a higher MSLT specificity in NC.