Biomarkers of neurodegeneration in isolated and antidepressant-related rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: This study compared the features of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and antidepressant-related REM sleep behaviour disorder (RBD) with the aim of highlighting markers that might distinguish the two entities. METHODS: The observational cohort study included RBD patients with and without antidepressant use (antiD+ and antiD- patients, respectively), without cognitive impairment and parkinsonism. Clinical features of RBD, subtle motor and non-motor symptoms of parkinsonism, sleep architecture, REM atonia index, dopamine transporter-single photon emission computed tomography (DAT-SPECT) and skin biopsies for the intraneuronal alpha-synuclein (α-syn), were evaluated in the baseline work-up. RESULTS: Thirty-nine patients, 10 antiD+ and 29 antiD-, were included. AntiD+ patients (more frequently female) reported more psychiatric symptoms, less violent dream enactment, and less frequent hyposmia. Dermal α-syn was detected in 93.1% of antiD- versus 30% of antiD+ patients (p = 0.00024). No differences appeared in other motor and non-motor symptoms, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score, DAT-SPECT, or polysomnographic features. CONCLUSIONS: Patients with antidepressant-related RBD have clinical and neuropathological features suggesting a lower risk of evolution than those with iRBD.

Role of Daytime Continuous Polysomnography in the Diagnosis of Pediatric Narcolepsy Type 1.

BACKGROUND AND OBJECTIVES: Narcolepsy type 1 (NT1) is still largely underdiagnosed or diagnosed too late in children. Difficulties in obtaining rapid and reliable diagnostic evaluations of the condition in clinical practice partially explain this problem. Predictors of NT1 include cataplexy and sleep-onset REM periods (SOREMPs), documented during nocturnal polysomnography (N-PSG) or through the multiple sleep latency test (MSLT), although low CSF hypocretin-1 (CSF hcrt-1) is the definitive biological disease marker. Obtaining reliable MSLT results is not always feasible in children; therefore, this study aimed to validate daytime continuous polysomnography (D-PSG) as an alternative diagnostic tool. METHODS: Two hundred consecutive patients aged younger than 18 years (112 with NT1; 25 with other hypersomnias, including narcolepsy type 2 and idiopathic hypersomnia; and 63 with subjective excessive daytime sleepiness) were randomly split into 2 groups: group 1 (n = 133) for the identification of diagnostic markers and group 2 (n = 67) for the validation of the detected markers. The D-PSG data collected included the number of spontaneous naps, total sleep time, and the number of daytime SOREMPs (d-SOREMP). D-PSG data were tested against CSF hcrt-1 deficiency (NT1 diagnosis) as the gold standard using receiver operating characteristic (ROC) curve analysis in group 1. ROC diagnostic performances of single and combined D-PSG parameters were tested in group 1 and validated in group 2. RESULTS: In group 1, the areas under the ROC curve (AUCs) were 0.91 (95% CI 0.86-0.96) for d-SOREMPs, 0.81 (95% CI 0.74-0.89) for the number of spontaneous naps, and 0.70 (95% CI 0.60-0.79) for total sleep time. A d-SOREMP count ≥1 (sensitivity of 95% and specificity of 72%), coupled with a diurnal total sleep time above 60 minutes (sensitivity of 89% and specificity of 91%), identified NT1 in group 1 with high reliability (area under the ROC curve of 0.93, 95% CI 0.88-0.97). These results were confirmed in the validation group with an AUC of 0.88 (95% CI 0.79-0.97). DISCUSSION: D-PSG recording is an easily performed, cost-effective, and reliable tool for identifying NT1 in children. Further studies should confirm its validity with home D-PSG monitoring. These alternative procedures could be used to confirm NT1 diagnosis and curtail diagnostic delay.

Exploring the emotional and behavioural profile in paediatric narcolepsy type 1: A case-control study.

Narcolepsy type 1 (NT1) is a central disorder of hypersomnolence often arising in childhood and adolescence. NT1 has a significant, but poorly defined, psychological impact. We aimed to investigate the psycho-social functioning of children and adolescents with NT1. We performed a cross-sectional, child and parent-reported questionnaire survey in 37 children and adolescents (6-17 years) with NT1, compared with age- and sex-matched controls. Questionnaires (SSHS, ESS-CHAD, CDI, MASC, CBCL, CRS-R, and SNAP-IV) evaluated various aspects of behavioural and emotional profiles, sleep habits, and daytime sleepiness. Subsequently, NT1 intra-group analysis was performed to investigate the effect of sex (males vs females) and pharmacological treatment (treated vs non-treated) on psychological features. The NT1 questionnaires total scores were then correlated with the clinical characteristics (age, body mass index [BMI], ESS-CHAD score, cerebrospinal hypocretin-1 [Hcrt-1] levels, and diagnostic delay). Patients with NT1 showed a higher tendency to depressive symptoms, anxiety, somatisation, inattention, hyperactivity, oppositional/defiant problems, and other maladaptive behaviours compared with controls. Among NT1 patients, females showed a higher propensity to anxiety, and non-treated patients displayed higher depressive symptoms. Psychological symptoms increased with age, BMI, and daytime sleepiness in patients with NT1, while a younger age was associated with more frequent somatisation symptoms. Lower cerebrospinal Hcrt-1 levels correlated with poorer social competencies, daily activities, and inattention. Diagnostic delay was associated with a higher impact of depressive symptoms and behavioural problems. NT1 in children and adolescents is associated with poorer functioning in multiple psychological domains calling for a multidisciplinary approach and monitoring to reduce disease burden and to prevent psychiatric consequences.

Phenomenology and psychiatric correlates of pseudocataplexy.

STUDY OBJECTIVES: Pseudocataplexy is a rare functional neurological disorder that mimics cataplexy, pathognomonic for narcolepsy type 1 (NT1). We describe the psychiatric comorbidity and personality traits of patients with pseudocataplexy versus NT1 cases. METHODS: The case-control observational study enrolled consecutive patients with pseudocataplexy and a control group of age-matched consecutive NT1 patients. The diagnostic work-up included a structured interview, 48-hour polysomnography, multiple sleep latency test, cataplexy provoking test, and hypocretin-1 measurement in cerebrospinal fluid.All participants were administered Beck Depression Inventory, State-Trait Anxiety Inventory, Patient Health Questionnaire-15 (PHQ-15), Personality Inventory for DSM-5 brief form, and quality of life (QoL) measurement by 36-item Short Form health survey (SF-36). RESULTS: Fifteen patients with pseudocataplexy and 30 with NT1 were included. Despite the suspicion of possible cataplexy, none of the pseudocataplexy participants fulfilled international diagnostic criteria for NT1. Pseudocataplexy patients presented higher rates of moderate state anxiety (40% vs. 10%, p=0.018), medium level of somatic symptoms, defined by PHQ-15 score >10 (66.7% vs. 16.7%, p=0.003), and a trend towards moderate-to-severe depressive symptoms (33.3% vs. 10%, p=0.054) compared to NT1. No significant differences in personality traits emerged. Pseudocataplexy patients had worse QoL profile in almost all SF-36 domains including physical (mean±SD: 37.7±9.88 vs. 51.13±7.81, p<0.001) and mental (mean±SD: 33.36±12.69 vs.42.76±11.34, p=0.02) summary scores. CONCLUSIONS: Patients with pseudocataplexy present more severe psychiatric symptoms and a lower QoL profile in comparison with patients with NT1. The severe somatoform and affection impairment in pseudocataplexy may explain the poorer QoL and should require a tailored therapeutic approach.

Sleep Bruxism and Orofacial Pain in Patients with Sleep Disorders: A Controlled Cohort Study.

BACKGROUND: The gold standard for the diagnosis of sleep bruxism (SB) is laboratory polysomnography (L-PSG) recording. However, many clinicians still define SB using patients' self-assessment and/or clinical tooth wear (TW). The purpose of this cross-sectional controlled study was to compare the prevalence of TW, head-neck muscles sensitivity and Temporomandibular Disorders (TMD) between SB and non-SB patients diagnosed with L-PSG in a cohort of patient with sleep disorders (SD). METHODS: 102 adult subjects with suspected SD underwent L-PSG recording to assess the presence of sleep disorder and SB. TW was clinically analyzed using TWES 2.0. The pressure pain threshold (PPT) of masticatory muscles were assessed using a Fisher algometer. Diagnostic criteria for TMD (DC/TMD) were used to evaluate the presence of TMD. SB self-assessment questionnaires were administered. TWES score, PPT, TMD prevalence and questionnaire results were compared between SB and non-SB patients. RESULTS: 22 SB patients and 66 non-SB patients with SD were included. No significant differences emerged between groups in regards to TW, the PPT values, or SB's self-assessment questionnaires as well the prevalence of TMD. CONCLUSION: in a SD population, TW is not pathognomonic of active SB and SB self-assessment is not reliable. There seems to be no correlation between SB, TMD and head/neck muscle sensitivity.

Real-world treatment of pediatric narcolepsy with pitolisant: A retrospective, multicenter study.

BACKGROUND: First symptoms of narcolepsy mostly present during childhood. Pharmacological management options in children are limited, also due to approval status. Pitolisant is an inverse histamine 3 receptor agonist and has been approved for the treatment of adult narcolepsy with or without cataplexy by EMA and FDA. Clinical experience indicates for a beneficial use also in children and adolescents. Our goal was to evaluate the effects and tolerability of pitolisant in narcolepsy children/adolescents in a real-world setting. METHODS: This multicentre retrospective observational study included 55 patients with narcolepsy from three international narcolepsy centers (Germany, France and Italy) who were treated with pitolisant. Patients were eligible if they were at least 6 years old and diagnosed with narcolepsy type 1 or 2. Demographic and clinical characteristics, questionnaires, sleep medicine and laboratory data were collected. RESULTS: 55 children/adolescents (25 girls, 45.45%, 30 boys, 54.55%) aged 6-18 years, with narcolepsy (type 1 = 92.7%, type 2 = 7.3%), were treated with pitolisant. The mean pitolisant dose was 34.1 mg/d. Treatment was effective for excessive daytime sleepiness (EDS) and cataplexy: the pediatric Epworth Sleepiness Scale (ESS) score decreased from 19 to 13.5 (p < 0.001) and the weekly cataplexy frequency improved from 7.9 at baseline to 5.2 (p < 0.001). Treatment with pitolisant was well tolerated. Side effects were mild and mostly short-term. Insomnia was reported most frequently (5.5%). CONCLUSION: First real-world results suggest that pitolisant treatment is effective in improving EDS and cataplexy in children with narcolepsy, and also is well tolerated.

Multidisciplinary care of patients with narcolepsy during coronavirus disease 2019 pandemic in Italy via televisit: the TElemedicine for NARcolepsy feasibility study.

STUDY OBJECTIVES: Narcolepsy is a rare chronic central disorder of hypersomnolence with frequent endocrine-metabolic comorbidities. To address the complex care needs of patients during the COVID-19 emergency, we carried out a feasibility study of the TElemedicine for NARcolepsy (TENAR) protocol with the aim of assessing the feasibility of a multidisciplinary care approach via televisit for patients with narcolepsy. METHODS: A feasibility single open-arm study on the multidisciplinary care of children (>7 y.o.) and adults with narcolepsy who required a follow-up visit was realized during the COVID-19 pandemic emergency period in Italy. The study included a sleep, metabolic, and psychosocial assessment via televisit at baseline, at 6, and at 12 months from the study inclusion period (15th May-26th June 2020). RESULTS: In total 39 out of 44 eligible patients (89%) entered the study (30 adults, nine children); 37 patients (95%) ended the 12-month follow-up. At baseline, the median Epworth sleepiness scale score (ESS) was 10 (IQR 8-14), and the median body mass index (BMI) was 25.6 (IQR 22.1-30.9). During the follow-up period, the ESS score decreased from the 6th month onward (p = 0.003), and BMI decreased at the 1-year follow-up (p = 0.047), while there were no differences in depressive and anxiety symptoms, quality of life, compliance with treatment, adverse drug reactions, or accidents. CONCLUSIONS: High response and retention rates, stability of ESS, and lack of side effects indicate that telemedicine is a feasible and safe approach for adults and children with narcolepsy.

Child Neurology: A Case Series of Heterogeneous Neuropsychiatric Symptoms and Outcome in Very Early-Onset Narcolepsy Type 1.

Narcolepsy type 1 is a central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy (i.e., sudden loss of muscle tone during wakefulness triggered by emotions), and REM sleep-related manifestations that can present with a peculiar phenotype when arising at a pediatric age. Several features of childhood-onset narcolepsy type 1 are also common in neuropsychiatric conditions; discrete neuropsychiatric comorbidity has also been demonstrated. Here, we report on 3 children with very early narcolepsy type 1. All 3 patients had psychiatric features at the time of symptom onset coupled with peculiar motor disturbances. The course of narcolepsy symptoms also paralleled neuropsychiatric symptoms, suggesting a possible intrinsic link between sleep and psychological features. Multidisciplinary management is mandatory for pediatric narcolepsy type 1 since prompt disease management addressing neuropsychiatric symptoms could lead to better clinical outcomes and quality of life.

REM sleep behavior disorder with predominant nightmares in a patient with ischemic pontine lesions.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia typically associated with synucleinopathy and evolving to neurodegenerative disorders. RBD is caused by impairment of brainstem nuclei controlling REM sleep muscle atonia. Rarely, focal lesions of the brainstem can cause secondary RBD. We present the case of a 74-year-old patient, previously evaluated at age 70 years for insomnia and periodic limb movements during sleep, who then rapidly developed unpleasant dreams with minor motor behavior, affecting his sleep quality. Polysomnography recorded REM sleep without atonia and motor behaviors in REM sleep. Ischemic lesions in the pons were detected by magnetic resonance imaging. Clinical, biological, and instrumental biomarkers of neurodegeneration were repeatedly negative at 2 years' follow-up. Although rare, a lesional cause of RBD must be considered in cases of atypical presentation and without evidence of neurodegeneration. The complaint of unpleasant dreams suggests a possible role of brainstem nuclei controlling REM sleep atonia in affecting oneiric content. CITATION: Biscarini F, Montini A, Antelmi E, Vandi S, Pizza F, Plazzi G. REM sleep behavior disorder with predominant nightmares in a patient with ischemic pontine lesions. J Clin Sleep Med. 2022;18(3):945-948.

Narcolepsy with intermediate cerebrospinal level of hypocretin-1.

STUDY OBJECTIVES: To describe the phenotype of narcolepsy with intermediate cerebrospinal fluid hypocretin-1 levels (CSF hcrt-1). METHODS: From 1600 consecutive patients with narcolepsy from Bologna and Montpellier sleep centers, we selected patients with intermediate CSF hcrt-1 levels (110-200 pg/mL). Clinical, neurophysiological, and biological data were contrasted for the presence of cataplexy, human leukocyte haplotype (HLA)-DQB1*06:02, and median CSF hcrt-1 levels (149.34 pg/mL). RESULTS: Forty-five (55% males, aged 35 ± 17 years) patients (2.8% of all cases) were included. Thirty-three (73%) were HLA-DQB1*06:02, 29 (64%) reported cataplexy (21, 72.4% with typical features), and 5 (11%) had presumed secondary etiology. Cataplexy was associated with other core narcolepsy symptoms, increased sleep onset rapid eye movement periods, and nocturnal sleep disruption. Cataplexy and irrepressible daytime sleep were more frequent in HLA-DQB1*06:02 positive patients. Lower CSF hcrt-1 levels were associated with hallucinations. CONCLUSIONS: Narcolepsy with intermediate CSF hcrt-1 level is a rare condition with heterogeneous phenotype. HLA-DQB1*06:02 and lower CSF hcrt-1 were associated with typical narcolepsy features, calling for future research to distinguish incomplete from secondary narcolepsy forms.

Case Report: Burden of Illness in Narcolepsy Type 1: Hikikomori in a Teenage Girl.

Narcolepsy type 1 (NT1) deeply impacts on quality of life, especially during adolescence, with NT1 children and adolescents that frequently report difficulties in integration with peers and decreased participation in after-school activities. Here we describe the case of NT1 teenager girl presenting with severe physical and social withdrawal, fulfilling the proposed diagnostic criteria for hikikomori, together with the classic NT1 symptoms. Social withdrawal is an overlooked phenomenon among NT1 children and adolescents that, if present, require a multidisciplinary approach and personalized interventions, but patients can benefit from NT1 pharmacological treatment.

Narcolepsy type 1 features across the life span: age impact on clinical and polysomnographic phenotype.

STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is a chronic neurological disorder typically arising during adolescence and young adulthood. Recent studies demonstrated that NT1 presents with age-specific features, especially in children. With this study we aimed to describe and to compare the clinical pictures of NT1 in different age groups. METHODS: In this cross-sectional, multicenter study, 106 untreated patients with NT1 enrolled at the time of diagnosis underwent clinical evaluation, a semistructured interview (including the Epworth Sleepiness Scale), nocturnal video-polysomnography, and the Multiple Sleep Latency Test. Patients were enrolled in order to establish 5 age-balanced groups (childhood, adolescence, adulthood, middle age, and senior). RESULTS: The Epworth Sleepiness Scale score showed a significant increase with age, while self-reported diurnal total sleep time was lower in older and young adults, with the latter also complaining of automatic behaviors in more than 90% of patients. Children reported the cataplexy attacks to be more frequent (> 1/d in 95% of patients). "Recalling an emotional event," "meeting someone unexpectedly," "stress," and "anger" were more frequently reported in adult and older adult patients as possible triggers of cataplexy. Neurophysiological data showed a higher number of sleep-onset rapid eye movement periods on the Multiple Sleep Latency Test in adolescent compared to senior patients and an age-progressive decline in sleep efficiency. CONCLUSIONS: Daytime sleepiness, cataplexy features and triggers, and nocturnal sleep structure showed age-related difference in patients with NT1; this variability may contribute to diagnostic delay and misdiagnosis.

REM Sleep Behavior Disorder in Children With Type 1 Narcolepsy Treated With Sodium Oxybate.

OBJECTIVE: To study the effect of stable treatment with sodium oxybate (SO) on nocturnal REM sleep behavior disorder (RBD) and REM sleep without atonia (RSWA) that severely affected children with type 1 narcolepsy (NT1). METHODS: Nineteen children and adolescents with NT1 (9 female, mean age 12.5 ± 2.7 years, mean disease duration 3.4 ± 1.6 years) underwent neurologic investigations and video-polysomnography (v-PSG) at baseline and after 3 months of stable treatment with SO. v-PSG was independently analyzed by 2 sleep experts to rate RBD episodes. RSWA was automatically computed by means of the validated REM sleep atonia index (RAI). RESULTS: Compared to baseline, RAI significantly improved (p < 0.05) and complex movements during REM sleep were remarkably reduced after stable treatment with SO. Compared to baseline, children also reported improvement in clinical complaints and showed a different nighttime sleep-stage architecture. CONCLUSIONS: RBD and RSWA improved after treatment with SO, pointing to a direct role of the drug in modulating motor control during REM sleep. CLASSIFICATION OF EVIDENCE: This study offers Class IV evidence of the positive effect of SO on modulation of muscle atonia during REM sleep in children with NT1 because of the absence of a control group.

Combining information on nocturnal rapid eye movement sleep latency and atonia to facilitate diagnosis of pediatric narcolepsy type 1.

STUDY OBJECTIVES: The diagnosis of narcolepsy type 1 (NT1) at its onset in children and adolescents is often difficult, with substantial diagnostic delay. We aimed to test and validate the effectiveness of rapid eye movement (REM) sleep latency (REML), the REM sleep atonia index (RAI), and their combination for the automatic identification of pediatric patients with NT1 based on the standard scoring of nocturnal polysomnograms. METHODS: A retrospective cohort of 71 pediatric patients with NT1 and 42 controls was subdivided in test and validation cohorts. A novel index (COM) was developed as a nonlinear function of REML and RAI. The effectiveness of REML, RAI, and COM in identifying patients with NT1 was assessed with receiver operating characteristic (ROC) curves. RESULTS: REML, RAI, and COM significantly identified patients with NT1 both in the test and validation cohorts. Optimal thresholds that maximized identification accuracy were estimated in the test cohort (REML, 49.5 min; RAI, 0.91; COM, 4.57 AU) and validated in the other cohort. COM performed significantly better in identifying patients with NT1 than either REML or RAI, with ROC area under the curve of 94%-100%, sensitivity 85%-96%, and specificity 92%-100%, and with good night-to-night agreement (Cohen's k = 0.69). CONCLUSIONS: The analysis of REML, RAI, and particularly their combination in the COM index may help shorten diagnostic delay of NT1 in children and adolescents based on the standard scoring of nocturnal polysomnography.

Dream Generation and Recall in Daytime NREM Sleep of Patients With Narcolepsy Type 1.

The less rigid architecture of sleep in patients with narcolepsy type 1 (NT1) compared with healthy subjects may provide new insights into some unresolved issues of dream experience (DE), under the assumption that their DE frequencies are comparable. The multiple transition from wakefulness to REM sleep (sleep onset REM period: SOREMP) during the five trials of the Multiple Sleep Latency Test (MSLT) appears of particular interest. In MSLT studies, NT1 patients reported a DE after about 80% of SOREMP naps (as often as after nighttime REM sleep of themselves and healthy subjects), but only after about 30% of NREM naps compared to 60% of daytime and nighttime NREM sleep of healthy subjects. To estimate accurately the "real" DE frequency, we asked participants to report DE ("dream") after each MSLT nap and, in case of failure, to specify if they were unable to retrieve any content ("white dream") or DE did not occur ("no-dream"). The proportions of dreams, white dreams, and no dreams and the indicators of structural organization of DEs reported after NREM naps by 17 adult NT1 patients were compared with those reported by 25 subjects with subjective complaints of excessive daytime sleepiness (sc-EDS), who take multiple daytime NREM naps. Findings were consistent with the hypothesis of a failure in recall after awakening rather than in generation during sleep: white dreams were more frequent in NT1 patients than in sc-EDS subjects (42.86 vs 17.64%), while their frequency of dreams plus white dreams were similar (67.86 and 61.78%) and comparable with that of NREM-DEs in healthy subjects. The longer and more complex NREM-DEs of NT1 patients compared with sc-EDS subjects suggest that the difficulty in DE reporting depends on their negative attitude toward recall of contents less vivid and bizarre than those they usually retrieve after daytime SOREMP and nighttime REM sleep. As this attitude may be reversed by some recall training before MSLT, collecting wider amounts of DE reports after NREM naps would cast light on both the across-stage continuity in the functioning of cognitive processes underlying DE and the difference in content and structural organization of SOREM-DEs preceded by N1 or also N2 sleep.

Protocols of a diagnostic study and a randomized controlled non-inferiority trial comparing televisits vs standard in-person outpatient visits for narcolepsy diagnosis and care: TElemedicine for NARcolepsy (TENAR).

BACKGROUND: Narcolepsy is a rare chronic sleep disorder that typically begins in youth. Excessive daytime sleepiness is the main disabling symptom, but the disease is often associated with severe endocrine-metabolic and psychosocial issues, worsened by a long diagnostic delay, requiring a multidisciplinary approach. The scarcity of reference Sleep Centres forces the patient and family to travel for seeking medical consultations, increasing the economic and psychosocial burden of the disease. Growing evidence suggests that Telemedicine may facilitate patient access to sleep consultations and its non-inferiority in terms of patient satisfaction, adherence to treatment, and symptom improvement for sleep disorders. However, Telemedicine clinical and economic benefits for patients with narcolepsy are still unknown. METHODS: TENAR is a two-part project, including: 1. a cross-sectional study (involving 250 children and adults with suspected narcolepsy) evaluating the accuracy of Teletriage (i.e., a synchronous live interactive sleep assessment through a Televisit) for narcolepsy diagnosis compared to the reference standard; and 2. a two-arm, parallel, open randomized controlled trial (RCT) to demonstrate the non-inferiority of the multidisciplinary care of narcolepsy through Televisits versus standard care. In this RCT, 202 adolescents (> 14 y.o.) and adults with narcolepsy will be randomly allocated (1:1 ratio) either to Televisits via videoconference or to standard in-person outpatient follow-up visits (control arm). The primary outcome is sleepiness control (according to the Epworth Sleepiness Scale). Secondary outcomes are other symptoms control, compliance with treatment, metabolic control, quality of life, feasibility, patient and family satisfaction with care, safety, and disease-related costs. At baseline and at 12 months, patients will undergo neurologic, metabolic, and psychosocial assessments and we will measure primary and secondary outcomes. Primary outcomes will be also measured at 6 months (remotely or in person, according to the arm). DISCUSSION: TENAR project will assess, for the first time, the feasibility, accuracy, efficacy and safety of Telemedicine procedures applied to the diagnosis and the multidisciplinary care of children and adults with narcolepsy. The study may be a model for the remote management of other rare disorders, offering care access for patients living in areas lacking medical centres with specific expertise. TRIAL REGISTRATION: Number of the Tele-multidisciplinary care study NCT04316286. Registered 20 March 2020.

Defining disrupted nighttime sleep and assessing its diagnostic utility for pediatric narcolepsy type 1.

STUDY OBJECTIVES: Disrupted nighttime sleep (DNS) is a core narcolepsy symptom of unconsolidated sleep resulting from hypocretin neuron loss. In this study, we define a DNS objective measure and evaluate its diagnostic utility for pediatric narcolepsy type 1 (NT1). METHODS: This was a retrospective, multisite, cross-sectional study of polysomnograms (PSGs) in 316 patients, ages 6-18 years (n = 150 NT1, n = 22 narcolepsy type 2, n = 27 idiopathic hypersomnia, and n = 117 subjectively sleepy subjects). We assessed sleep continuity PSG measures for (1) their associations with subjective and objective daytime sleepiness, daytime sleep onset REM periods (SOREMPs), self-reported disrupted nocturnal sleep and CSF hypocretin levels and (2) their predictive value for NT1 diagnosis. We then combined the best performing DNS measure with nocturnal SOREMP (nSOREMP) to assess the added value to the logistic regression model and the predictive accuracy for NT1 compared with nSOREMP alone. RESULTS: The Wake/N1 Index (the number of transitions from any sleep stage to wake or NREM stage 1 normalized by total sleep time) was associated with objective daytime sleepiness, daytime SOREMPs, self-reported disrupted sleep, and CSF hypocretin levels (p's < 0.003) and held highest area under the receiver operator characteristic curves (AUC) for NT1 diagnosis. When combined with nSOREMP, the DNS index had greater accuracy for diagnosing NT1 (AUC = 0.91 [0.02]) than nSOREMP alone (AUC = 0.84 [0.02], likelihood ratio [LR] test p < 0.0001). CONCLUSIONS: The Wake/N1 Index is an objective DNS measure that can quantify DNS severity in pediatric NT1. The Wake/N1 Index in combination with or without nSOREMP is a useful sleep biomarker that improves recognition of pediatric NT1 using only the nocturnal PSG.

Structural organization of dream experience during daytime sleep-onset rapid eye movement period sleep of patients with narcolepsy type 1.

STUDY OBJECTIVE: To assess the frequency of dream experience (DE) developed during naps at Multiple Sleep Latency Test (MSLT) by patients with narcolepsy type 1 (NT1) and establish, using story-grammar analysis, the structural organization of DEs developed during naps with sleep onset rapid eye movement (REM) period (SOREMP) sleep compared with their DEs during early- and late-night REM sleep. METHODS: Thirty drug-free cognitively intact adult NT1 patients were asked to report DE developed during each MSLT nap. Ten NT1 patients also spent voluntarily a supplementary night being awakened during the first-cycle and third-cycle REM sleep. Patients provided dream reports, white dreams, and no dreams, whose frequencies were matched in naps with SOREMP versus non-REM (NREM) sleep. All dream reports were then analyzed using story-grammar rules. RESULTS: DE was recalled in detail (dream report) by NT1 patients after 75% of naps with SOREMP sleep and after 25% of naps with NREM sleep. Dream reports were provided by 8 out of 10 NT1 patients after both awakenings from nighttime REM sleep. Story-grammar analysis of dream reports showed that SOREMP-DEs are organized as hierarchically ordered sequences of events (so-called dream-stories), which are longer and more complex in the first and fourth SOREMP naps and are comparable with nighttime REM-DEs. CONCLUSIONS: The similar structural organization of SOREMP-DEs with nighttime REM-DEs indicates that their underlying cognitive processes are highly, albeit not uniformly, effective during daytime SOREMP sleep. Given the peculiar neurophysiology of SOREMP sleep, investigating SOREMP-DEs may cast further light on the relationships between the neurophysiological and psychological processes involved in REM-dreaming.

Cataplexy and ataxia: red flags for the diagnosis of DNA methyltransferase 1 mutation.

None: Mutations in exons 21 and 20 of the DMNT1 gene have been associated with two multisystem neurodegenerative diseases that involve central and peripheral nervous system ADCADN (Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy) and HSAN 1E (Hereditary Sensory and Autonomic Neuropathy IE). We describe a new case of ADCADN that was referred to us in the suspicion of secondary narcolepsy. A 44-year-old female with personal and familiar longstanding history of progressive bilateral sensorineural deafness, and sensitive cerebellar ataxia, presenting with brief episodes of falls while laughing and excessive diurnal somnolence. Clinical and neurophysiological evaluations reveled signs of cerebellar, pyramidal, peripheral, cognitive involvement, and optical atrophy. A 48-hour continuous polysomnography (PSG) and Multiple Sleep Latency Test at first evaluation revealed a normal sleep structure with frequent diurnal sleep episodes and a pathological sleep latency without sleep onset REM periods (SOREMPs). Normal level of cerebrospinal fluid (CSF) hypocretine 1 was detected. Given the reminiscence with DNMT 1 spectrum a direct sequencing of exons 20 and 21 of the DNMT1 gene was performed revealing the p.Glu575Lys mutation in exon 21 in the proband and her mother. During the 4 years of follow-up her walking ability declined, she became more somnolent and repeated PSG documented REM sleep latency shortening, and finally the evidence of de novo spontaneous SOREMPs, although normal CSF hrct-1 at second revaluation. This case highlights the progressive course of disease although a full-blown picture of classical narcolepsy type 1 was never reached.

Excessive daytime sleepiness in narcolepsy and central nervous system hypersomnias.

PURPOSE: Excessive daytime sleepiness (EDS) is the core complaint of central nervous system (CNS) hypersomnias. In this mini-review, we summarized EDS features in CNS hypersomnias to provide a guide for differential diagnosis purposes. METHODS: A review of recent literature was performed to provide an update in CNS hypersomnias. RESULTS: At clinical evaluation, narcolepsy patients report a good restorative potential of sleep together with the frequent occurrence of dreaming even during short-lasting naps. These features are mirrored by the neurophysiological evidence of REM sleep at sleep onset (SOREMP) during the Multiple Sleep Latency Test (MSLT), a specific marker. Conversely, patients with idiopathic hypersomnia (IH) complain sleep inertia and prolonged nocturnal sleep. Polysomnographic studies show high sleep propensity on the MSLT or high 24-h total sleep time during continuous monitoring. Patients with insufficient sleep syndrome (ISS) can present with variable clinical EDS features in between narcolepsy and IH. ISS diagnosis is based on the clinical evidence of nocturnal sleep curtailment (weekdays versus vacations) associated with the disappearance of EDS complaint after sleep extension. Polysomnographic data are not required, but when the MSLT is performed, ISS patients can present with SOREMP arising from non-REM stage 2 sleep (vs narcolepsy patients entering into SOREM most frequently from wakefulness). Kleine-Levin Syndrome is characterized by recurrent episodes of enormously prolonged sleep time lasting days associated with abnormal cognition and behavior intermixed by asymptomatic periods, a sleep pattern that can be well documented by actigraphy. CONCLUSIONS: Different CNS hypersomnias present with specific features of EDS are useful to guide the clinician to apply and interpret appropriate neurophysiological investigations.