Pupillometry to differentiate idiopathic hypersomnia from narcolepsy type 1.

Idiopathic hypersomnia is poorly diagnosed in the absence of biomarkers to distinguish it from other central hypersomnia subtypes. Given that light plays a main role in the regulation of sleep and wake, we explored the retinal melanopsin-based pupil response in patients with idiopathic hypersomnia and narcolepsy type 1, and healthy subjects. Twenty-seven patients with narcolepsy type 1 (women 59%, 36 ± 11.5 years old), 36 patients with idiopathic hypersomnia (women 83%, 27.2 ± 7.2 years old) with long total sleep time (> 11/24 hr), and 43 controls (women 58%, 30.6 ± 9.3 years old) were included in this study. All underwent a pupillometry protocol to assess pupil diameter, and the relative post-illumination pupil response to assess melanopsin-driven pupil responses in the light non-visual input pathway. Differences between groups were assessed using logistic regressions adjusted on age and sex. We found that patients with narcolepsy type 1 had a smaller baseline pupil diameter as compared with idiopathic hypersomnia and controls (p < 0.05). In addition, both narcolepsy type 1 and idiopathic hypersomnia groups had a smaller relative post-illumination pupil response (respectively, 31.6 ± 13.9% and 33.2 ± 9.9%) as compared with controls (38.7 ± 9.7%), suggesting a reduced melanopsin-mediated pupil response in both types of central hypersomnia (p < 0.01). Both narcolepsy type 1 and idiopathic hypersomnia showed a smaller melanopsin-mediated pupil response, and narcolepsy type 1, unlike idiopathic hypersomnia, also displayed a smaller basal pupil diameter. Importantly, we found that the basal pupil size permitted to well discriminate idiopathic hypersomnia from narcolepsy type 1 with a specificity = 66.67% and a sensitivity = 72.22%. Pupillometry may aid to multi-feature differentiation of central hypersomnia subtypes.

A comparison of four methods to estimate dim light melatonin onset: a repeatability and agreement study.

Dim light melatonin onset (DLMO) is considered the most reliable circadian phase marker in humans. However, the methods to calculate it are diverse, which limits the comparability between studies. Given the key role of DLMO to diagnose circadian rhythm sleep-wake disorders and determine the optimal timing of chronotherapies, the establishment of clear and validated guidelines on the methodology to assess DLMO is very important. We performed a repeatability study (n = 31) and an agreement study (n = 62) in healthy young adults with hourly blood samples collected under dim light conditions (<8 lux) during a chronobiological protocol. We assessed the repeatability of DLMO with three different methods (fixed threshold, dynamic threshold and hockey stick) across two nights and assessed agreement of each method with the mean visual estimation made by four chronobiologists. Analyses included Bland-Altman diagrams, intraclass correlation coefficients and equivalence tests. The repeatability of the four methods across two nights ranged from good to perfect. The agreement study highlighted that the hockey stick showed equivalent or superior performance (ICC: 0.95, mean difference with visual estimation: 5 min) in healthy subjects compared to the dynamic and fixed thresholds. Thanks to its objective nature, the hockey stick method may provide better estimates than the mean of the visual estimations of several raters. These findings suggest that the hockey stick method provides the most reliable estimate of DLMO within the tested methods and should be considered for use in future studies.

The melanopsin-mediated pupil response is reduced in idiopathic hypersomnia with long sleep time.

Idiopathic hypersomnia (IH), characterized by an excessive day-time sleepiness, a prolonged total sleep time on 24 h and/or a reduced sleep latency, affects 1 in 2000 individuals from the general population. However, IH remains underdiagnosed and inaccurately treated despite colossal social, professional and personal impacts. The pathogenesis of IH is poorly known, but recent works have suggested possible alterations of phototransduction. In this context, to identify biomarkers of IH, we studied the Post-Illumination Pupil Response (PIPR) using a specific pupillometry protocol reflecting the melanopsin-mediated pupil response in IH patients with prolonged total sleep time (TST > 660 min) and in healthy subjects. Twenty-eight patients with IH (women 86%, 25.4 year-old ± 4.9) and 29 controls (women 52%, 27.1 year-old ± 3.9) were included. After correction on baseline pupil diameter, the PIPR was compared between groups and correlated to sociodemographic and sleep parameters. We found that patients with IH had a lower relative PIPR compared to controls (32.6 ± 9.9% vs 38.5 ± 10.2%, p = 0.037) suggesting a reduced melanopsin response. In addition, the PIPR was not correlated to age, chronotype, TST, nor depressive symptoms. The melanopsin-specific PIPR may be an innovative trait marker of IH and the pupillometry might be a promising tool to better characterize hypersomnia.

Sleep-Disordered Breathing, Quality of Sleep and Chronotype in a Cohort of Adult Patients with Bardet-Biedl Syndrome.

OBJECTIVE/BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare but well-recognized ciliopathy with high genetic and phenotypic heterogeneity. Cardinal features include obesity, diabetes and high blood pressure (HBP), which are often associated with sleep-disordered breathing. Also, the high prevalence of blindness due to retinal dystrophy could affect circadian sleep-wake rhythms. We characterized in this cohort of adult BBS patients sleep-disordered breathing, sleep quality, daytime sleepiness and chronotype. PATIENTS AND METHODS: Thirty-two patients with genetically confirmed BBS were included in this observational single center study. Overnight respiratory polygraphy was performed for sleep apnea syndrome (SAS) in 30 patients. Quality of sleep, daytime sleepiness, fatigue and chronotype were assessed in 25 patients using Pittsburgh sleep quality index (PSQI), 14-day sleep diary (SD), Epworth sleepiness scale (ESS), Pichot fatigue scale (PFS) and Horne and Ostberg morningness-eveningness questionnaire (MEQ). RESULTS: Patients' mean age was 32±11 years and mean BMI 32.6±7.7 kg/m2. Eleven (35%) patients had HBP and 7 (22%) diabetes. Moderate to severe sleep apnea syndrome (SAS) was present in 5 (17%) and was not associated with altered sleep, daytime sleepiness or fatigue. Most of the patients (63%) evaluated their sleep as of good quality (PSQI ≤ 5). Median scores of sleep quality, daytime sleepiness and fatigue were normal (PSQI of 3.0 [2.0-6.0], ESS of 9.0 [6.0-13.0] and PFS of 8.0 [3.0-13.0], respectively). Predominant chronotypes according to MEQ were either "intermediate" (57%) or "moderate morning" (29%). None had a free running sleep-wake cycle. 14-day SD revealed overall few awakenings at night and low daytime napping. CONCLUSIONS: Given the cardiovascular risk factors, systematic screening for SAS should be considered in BBS patients, regardless of sleep and daytime vigilance complaints. None of these highly visually impaired patients had a circadian sleep-wake rhythm disorder. Further objective assessments are needed to better characterize sleep and circadian rhythms in BBS patients.

Investigating racing thoughts in insomnia: A neglected piece of the mood-sleep puzzle?

BACKGROUND: Cognitive arousal is thought to play a key role in insomnia disorder. However, although patients frequently complain about racing thoughts appearing at bedtime, studies have considered 'cognitive arousal' as a synonym of rumination and worry, but not as racing thoughts per se. The latter have been mainly linked to hypomanic/manic episodes of bipolar disorder (BD). Here we aimed at investigating self-reported racing thoughts in insomnia disorder, and their specific contribution to insomnia severity, as compared to worry and rumination. METHODS: 72 adults with insomnia disorder, 49 patients with BD in a hypomanic episode and 99 healthy individuals completed the Racing and Crowded Thoughts Questionnaire (RCTQ). Mood symptoms were assessed in patients with insomnia disorder. RESULTS: RCTQ scores were overall higher in insomnia disorder, especially in sleep-onset insomnia, compared to the hypomanic and healthy groups. Moreover, racing thoughts showed an increase in the evening and at bedtime in sleep-onset insomnia. Importantly, racing thoughts at bedtime, but not rumination and worry, were associated with insomnia severity. DISCUSSION: Our results are the first to show that racing thoughts is a transdiagnostic symptom in mood and sleep disorders. Racing thoughts, not only rumination and worry, might contribute to the maintenance of sleep difficulties in insomnia. Clinical trials' registration number: NCT04752254.

[Diagnosis and comorbidities of Circadian Rhythm Sleep Disorders]. / Diagnostic et comorbidités des troubles du rythme veille-sommeil.

Circadian rhythm sleep disorders (CRSD) result from a disturbed endogenous clock (intrinsic CRSD) or from a misalignment between the biological clock and an imposed environment (extrinsic CRSD). Among intrinsic CRSD, one distinguishes the delayed sleep-wake phase disorder, the advanced sleep-wake phase disorder, the irregular sleep-wake rhythm disorder and the non-24-hour sleep-wake rhythm disorder. Shift work disorder, jet lag disorder and circadian sleep-wake disorder not otherwise specified are extrinsic CRSD. Prevalences of the different CRSD remain largely unknown. Some CRSD are particularly frequent such as sleep delayed phase syndrome in adolescents. Overall, CRSD are probably under-diagnosed. CRSD generate insomnia and excessive daytime somnolence. A biological clock dysfunction has to be evoked in case of insomnia or sleepiness. Furthermore, as CRSD can overlap with other sleep disorders, their diagnosis and treatment are essential. CRSD cause significant mental, physical or socio-professional sufferings. They are frequently associated with comorbidities, mainly neurodevelopmental, psychiatric and neurodegenerative disorders. Regarding neurodevelopmental comorbidities, therapy using a chronobiological approach is complementary to the usual clinical care. It helps to limit the significant impact of CRSD on quality of live, daytime functioning, social interactions and neurocognitive difficulties in the children. In psychiatry, sleep disorders and circadian rhythms sleep-wake disorders are a factor of vulnerability, of suicidal risk, of relapse and pharmacoresistance. Thus, diagnosis of CRSD associated with a psychiatric disorder is of major importance. Treatment using a chronobiological approach reinforcing the entrainment of the sleep-wake cycle is complementary to usual treatments. Sleep disorders and circadian sleep-wake rhythm disorders can be a preclinical sign of Alzheimer's and Parkinson's disease. In the elderly, a beginning neurodegenerative disorder can be associated with a CRSD and complaints of sleepiness, nocturnal awakenings and/or irregular sleep-wake cycles. Patients affected by neurogenerative disorders are particularly vulnerable for having CRSD. Data from different studies suggest that CRSD participate in pathophysiology of Alzheimer's disease. Even though treatment of CRSD associated with neurodegenerative disorders is entirely part of the treatment strategy, it remains uncertain to which extend this treatment may impact disease progression.

Intravenous Immunoglobulin Therapy Administered Early after Narcolepsy Type 1 Onset in Three Patients Evaluated by Clinical and Polysomnographic Follow-Up.

Narcolepsy type 1 is a rare disabling sleep disorder mainly characterized by excessive daytime sleepiness and cataplexy, an emotion-triggered sudden loss of muscle tone. Patients have a selective degeneration of hypocretin-producing neurons in the dorsolateral posterior hypothalamus with growing evidence supporting the hypothesis of an autoimmune mechanism. Few case studies that reported intravenous immunoglobulin therapy (IVIg) suggest the efficacy of IVIg when administered early after disease onset, but the results are controversial. In these retrospective case observations, IVIg cycles were initiated within one to four months after cataplexy onset in a twenty-seven-year-old man, a ten-year-old girl, and a seven-year-old boy, all three with early onset typical narcolepsy type 1. Efficacy of treatment (three IVIg cycles of 1 g/kg administered at four-week intervals) was evaluated based on clinical, polysomnographic, and multiple sleep latency test (mean latency and SOREM) follow-up. Two patients reported decreased cataplexy frequency and ameliorated daytime sleepiness, but no significant amelioration of polysomnographic parameters was observed. Given the possibility of spontaneous improvement of cataplexy frequency with self-behavioral adjustments, these observations would need to be confirmed by larger controlled studies. Based on the present study and current literature, proof of concept is still missing thus prohibiting the consideration of IVIg as an efficient treatment option.

Restless legs syndrome related to hemorrhage of a thoracic spinal cord cavernoma.

CONTEXT: Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the lower limbs often accompanied by unpleasant sensations in the legs, worsened at rest and in the evening. Symptoms are improved by movement. Its pathophysiology remains poorly understood. Lesion-related RLS has been reported, mainly in cases of stroke-related RLS involving the brainstem and lenticulostriate nuclei. Only few data of RLS in a context of spinal cord injury have been reported. FINDINGS: We report the case of a woman with secondary RLS due to hemorrhage of a spinal cord cavernoma located at T9-T10. Following recovery from the acute phase of the hemorrhage, the patient began to complain about restlessness in her legs causing impaired sleep and daytime somnolence. Polysomnographic investigations found a high index of periodic leg movements during sleep (71/hour), but no sleep disordered breathing. Iron stores were normal. Relief of symptom's severity was obtained with gabapentin 600mg in the evening. CONCLUSION/CLINICAL RELEVANCE: We hypothesize a possible involvement of the diencephalospinal pathway in the patient's RLS pathophysiology. A systematic study of focal lesions associated with RLS may contribute to improving our understanding of the pathophysiological mechanisms underlying this condition. The frequency of RLS associated with lesions of the spinal cord might be underestimated. Clinicians should be aware of spinal cord lesion-related RLS, especially as efficient treatments are available.

Hyperdopaminergism in lenticulostriate stroke-related restless legs syndrome: an imaging study.

OBJECTIVE: The pathophysiology of restless legs syndrome (RLS) involves a dopaminergic dysregulation that remains poorly understood, with controversial data from the literature. Stroke-related RLS is a rare condition that involves primarily the basal ganglia, the paramedian pons, and the thalamus. Given these elements, we studied dopaminergic metabolism in patients with RLS secondary to lenticulostriate infarction using structural and nuclear imaging in the striatum ipsilateral to the infarction area, as compared to the contralateral side. We hypothesized that dopaminergic metabolism would be impaired in the striatum ipsilateral to stroke. METHODS: In this observational case-control study, we aimed to prospectively include patients with RLS secondary to lenticulo-striate infarction, for analyses of dopamine dysfunction ipsilateral to stroke as compared to the contralateral striatum and to a control population. Four patients fulfilled inclusion criteria with either de novo RLS or major exacerbation of RLS existing prior to stroke, and all four patients were included. Structural imaging was performed using brain magnetic resonance imaging, and the stroke-induced metabolic modifications were assessed by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). Dopamine reuptake via DAT was explored using 123I-FP-CIT SPECT. PET with 18F-FDOPA was used to evaluate the functional integrity of the presynaptic dopaminergic synthesis. RESULTS: The only structure damaged in all patients was the body of the caudate nucleus, right-sided for three and left-sided for one, as illustrated by magnetic resonance imaging. 18F-FDG PET showed a hypometabolism in the infarcted area, the ipsilateral thalamus, and the contralateral cerebellum. All patients displayed, in the ipsilateral putamen, increased dopaminergic tone. CONCLUSION: The present findings suggest that increased dopaminergic tone in the striatum may participate in the pathogenesis of RLS. These observations should encourage further research on RLS symptomatic with well-defined lesions as a promising way to further improve our understanding of its pathophysiology.

Brainstem stroke-related restless legs syndrome: frequency and anatomical considerations.

BACKGROUND: Given the discordant results of studies that have reported cases of RLS associated with brainstem stroke and the absence of RLS in large series describing the clinical spectrum of brainstem infarctions, we decided to assess RLS in all patients admitted for brainstem stroke. METHODS: All patients who were consecutively referred to the Strasbourg stroke unit for brainstem infarction were prospectively evaluated for RLS. The different parameters analyzed were the topography of the ischemic lesions (magnetic resonance imaging), the different symptoms (sensory, motor, cerebellar, cranial nerves and dysarthria) and the NIH stroke scale. Statistical analyses used the Bayesian paradigm. RESULTS: Thirty patients have been included, and RLS was observed in three patients (10%). Two patients suffered from an exacerbation of symptoms anterior to the stroke, and the other patient a de novo, but transient, RLS. Patients with stroke-induced sensory symptoms have a higher risk to develop brainstem stroke-related RLS as compared to patients without sensory symptoms. CONCLUSION: The results suggest that RLS should be systematically screened in patients affected with brainstem stroke, especially in the case of stroke-induced sensory symptoms. Clinicians should be aware of this association, especially as efficient treatments are available and allow improving the management of patients affected with stroke.

Restless legs syndrome as a first manifestation of a cerebral infarct.

The onset of restless legs syndrome (RLS) is usually progressive and the neural substrates underlying its pathophysiology remain to be identified. Here we report on a patient presenting with acute-onset RLS that was symptomatic of a right anteromedial pontine infarction. This case is exceptional because RLS appeared several hours before the occurrence of a regressive dysarthria clumsy-hand syndrome. Additionally, millimetric MRI sections showed that the structures possibly involved in RLS pathogenesis were the corticospinal tract, the pontine nuclei, and the pontocerebellar fibers. Although this is uncommon, clinicians should be aware that RLS characterized by a sudden onset can be a clinical manifestation related to stroke.

Characterization of periodic upper limb movement disorder in a patient with restless arms syndrome.

BACKGROUND: Restless legs syndrome (RLS) and the frequently associated periodic limb movements (PLM) are common neurological disorders whose pathophysiology remains elusive. We report on the case of a 40-year-old patient presenting with severe restlessness in the upper limbs, a poorly known variant of RLS. CASE REPORT: Video-polysomnography was performed because of the associated poor sleep quality and daytime sleepiness evocative of PLM. An electromyogram of the extensor carpi radialis muscle was added. Remarkably, our patient had movements of repeated extension of the small finger that contrasted with the extension of the hallux, characteristic for PLM. Pramipexol was an effective treatment relieving the patient's upper limbs of discomfort and ameliorating her restless sleep. CONCLUSIONS: Involvement of the upper limbs in RLS is relatively common, but restlessness may be located on the upper limbs solely. One should be aware of the upper limb variant, and that treatment by dopaminergic agonists proves to be very efficient.