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Background and ObjectivesReal-time quaking-induced conversion (RT-QuIC) assay detects misfolded α-synuclein (AS) in the skin and CSF of patients with the synucleinopathies Parkinson disease and dementia with Lewy bodies. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of these synucleinopathies. We aimed to compare the ability of RT-QuIC to identify AS in the skin and CSF of patients with IRBD.MethodsThis was a cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. Three-millimeter skin punch biopsies were obtained bilaterally in the cervical region from dorsal C7 and C8 dermatomes and in distal legs. RT-QuIC assessed AS in these 6 skin sites and the CSF.ResultsWe recruited 91 patients with IRBD and 41 controls. In the skin, sensitivity to detect AS was 76.9% (95% CI 66.9–85.1), specificity 97.6% (95% CI 87.1–99.9) positive predictive value 98.6% (95% CI 91.0–99.8), negative predictive value 65.6% (95% CI 56.6–73.6), and accuracy 83.3% (95% CI 75.9–89.3). In the CSF, the sensitivity was 75.0% (95% CI 64.6–83.6), the specificity was 97.5% (95% CI 86.8–99.9), the positive predictive value was 98.5% (95% CI 90.5–99.8), the negative predictive value was 63.9% (95% CI 55.2–71.9), and the accuracy was 82.0% (95% CI 74.3–88.3). Results in the skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC AS-positive patients had a higher likelihood ratio of prodromal Parkinson disease (p< 0.001) and showed more frequently hyposmia (p< 0.001), dopamine transporter imaging single-photon emission CT deficit (p= 0.002), and orthostatic hypotension (p= 0.014). No severe or moderate adverse effects were reported. There was no difference between the percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% vs 17.2%;p= 0.053). One hundred and ten (83%) and 104 (80%) participants, respectively, stated they would accept to undergo skin biopsy and lumbar puncture again for research purposes.DiscussionOur study in IRBD shows that (1) RT-QuIC detects AS in the skin and CSF with similar high sensitivity, specificity, and agreement, (2) AS RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and (3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. RT-QuIC in the skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting AS in IRBD.Classification of EvidenceThis study provides Class III evidence that RT-QuIC–detected AS in the skin and CSF distinguishes patients with IRBD from controls.

Objective:To report the presentation, main syndromes, human leukocyte antigen (HLA) association, and immunoglobulin G (IgG) subclass in the anti-IgLON5 disease: a disorder with parasomnias, sleep apnea, and IgLON5 antibodies.Methods:This was a retrospective clinical analysis of 22 patients. The IgG subclass was determined using reported techniques.Results:Patients' median age was 64 years (range 46–83). Symptoms that led to initial consultation included sleep problems (8 patients; 36%), gait abnormalities (8; 36%), bulbar dysfunction (3; 14%), chorea (2; 9%), and cognitive decline (1; 5%). By the time of diagnosis of the disorder, 4 syndromes were identified: (1) a sleep disorder with parasomnia and sleep breathing difficulty in 8 (36%) patients; (2) a bulbar syndrome including dysphagia, sialorrhea, stridor, or acute respiratory insufficiency in 6 (27%); (3) a syndrome resembling progressive supranuclear palsy (PSP-like) in 5 (23%); and (4) cognitive decline with or without chorea in 3 (14%). All patients eventually developed parasomnia, sleep apnea, insomnia, or excessive daytime sleepiness. HLA-DRB1*10:01 and HLA-DQB1*05:01 were positive in 13/15 (87%) patients; the DRB1*10:01 allele was 36 times more prevalent than in the general population. Among 16 patients with paired serum and CSF samples, 14 had IgLON5 antibodies in both, and 2 only in serum (both had a PSP-like syndrome). Twenty of 21 patients had IgG1 and IgG4 antibodies; the latter predominated in 16.Conclusions:Patients with IgLON5 antibodies develop a characteristic sleep disorder preceded or accompanied by bulbar symptoms, gait abnormalities, oculomotor problems, and, less frequently, cognitive decline. IgG4 subclass antibodies predominate over IgG1; we confirm a strong association with the HLA-DRB1*10:01 allele.

Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder.Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors.A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008).Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

Objective:To evaluate the presence of prodromal markers of Parkinson disease (PD) in patients with longstanding idiopathic REM sleep behavior disorder (IRBD), a small subgroup of individuals with IRBD with long-term follow-up thought not to be at risk of developing PD.Methods:Demographic, clinical, and neuroimaging markers of PD were evaluated in 20 patients with polysomnographic-confirmed longstanding IRBD and in 32 matched controls.Results:Patients were 16 men and 4 women with mean age of 72.9 ± 8.6 years and mean follow-up from IRBD diagnosis of 12.1 ± 2.6 years. Patients more often had objective smell loss (35% vs 3.4%, p = 0.003), constipation (50% vs 15.6%, p = 0.008), and mild parkinsonian signs (45% vs 18.8%, p = 0.042) than controls. Unified Parkinson's Disease Rating Scale motor score was higher in patients than in controls (5.6 ± 3.5 vs 2.0 ± 2.1, p < 0.0001). Dopamine transporter imaging showed decreased striatal uptake in 82.4% of the patients and transcranial sonography found substantia nigra hyperechogenicity in 35.3%. α-Synuclein aggregates were found in 3 of 6 patients who underwent colon or submandibular gland biopsies. All 20 patients showed clinical, neuroimaging, or histologic markers of PD. Probability of prodromal PD (according to recent Movement Disorders Society research criteria) was higher in patients than in controls (Conclusions:Prodromal PD markers are common in individuals with longstanding IRBD, suggesting that they are affected by an underlying neurodegenerative process. This observation may be useful for the design of disease-modifying trials to prevent PD onset in IRBD.

Objective: This controlled study investigated associations between comorbidity and medication in patients with polysomnographically confirmed idiopathic REM sleep behavior disorder (iRBD), using a large multicenter clinic-based cohort. Methods: Data of a self-administered questionnaire on comorbidity and medication use of 318 patients with iRBD and 318 matched controls were analyzed. Comparisons between cases and controls were made using logistic regression analysis. Results: Patients with iRBD were more likely to report depression (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.3–2.9) and concomitant antidepressant use (OR 2.2, 95% CI 1.4–3.6). Subanalysis of antidepressant agents revealed that the increased use of antidepressants in iRBD was due to selective serotoninergic reuptake inhibitors (OR 3.6, 95% CI 1.8–7.0) and not due to other antidepressant classes. Patients with iRBD reported more lifetime antidepressant use than comorbid depression (antidepressant use: OR 1.9, 95% CI 1.1–3.3; depression: OR 1.6, 95% CI 1.0–2.5). Patients with iRBD reported more ischemic heart disease (OR 1.9, 95% CI 1.1–3.1). This association did not change substantially when adjusting for cardiovascular risk factors (OR 2.3, 95% CI 1.3–3.9). The use of inhaled glucocorticoids was higher in patients with iRBD compared to controls (OR 5.3, 95% CI 1.8–15.8), likely reflecting the higher smoking rate in iRBD (smoking: OR 15.3, 95% CI 2.0–118.8; nonsmoking: OR 2.4, 95% CI 0.4–13.2) and consequent pulmonary disease. Conclusions: This large study confirms the association between comorbid depression and antidepressant use in iRBD. In addition, there was an unexpected association of iRBD with ischemic heart disease that was not explained by cardiovascular risk factors.

To investigate the expression of α-synuclein in colonic biopsies of patients with idiopathic REM sleep behavior disorder (iRBD) and address if α-synuclein immunostaining of tissue obtained via colonic biopsies holds promise as a diagnostic biomarker for prodromal Parkinson disease (PD).Patients with iRBD, patients with PD, and healthy controls were prospectively recruited to undergo colonic biopsies for comparison of α-synuclein immunoreactivity patterns between the groups by using 2 different antibodies.There was no difference in colonic mucosal and submucosal immunostaining between groups using the 15G7 α-synuclein antibody, which was found in almost all participants enrolled in this study. By contrast, immunostaining for serine 129-phosphorylated α-synuclein (pSyn) in submucosal nerve fibers or ganglia was found in none of 14 controls but was observed in 4 of 17 participants with iRBD and 1 out of 19 patients with PD.The present findings of pSyn immunostaining of colonic biopsies in a substantial proportion of iRBD participants raise the possibility that this tissue marker may be a suitable candidate to study further as a prodromal PD marker in at-risk cohorts.

Objective: The aim of the present study was to determine the predictive value of olfactory dysfunction for the early development of a synuclein-mediated neurodegenerative disease in subjects with idiopathic REM sleep behavior disorder (iRBD) over an observational period of 5 years. Methods: Thirty-four patients with polysomnography-confirmed iRBD underwent olfactory testing using the entire Sniffin9 Sticks test assessing odor identification, odor discrimination, and olfactory threshold. Patients with iRBD were prospectively followed up over a period of 4.9 ± 0.3 years (mean ± SD). The diagnosis of neurodegenerative diseases was based on current clinical diagnostic criteria. Results: After 2.4 ± 1.7 years (mean ± SD), 9 patients (26.5%) with iRBD developed a Lewy body disease (6 Parkinson disease and 3 dementia with Lewy bodies). The entire Sniffin9 Sticks test and the identification subtest had the same overall diagnostic accuracy of 82.4% (95% confidence interval: 66.1%–92.0%) in predicting conversion. The relative risk for a Lewy body disease in the lowest tertile of olfactory function was 7.3 (95% confidence interval: 1.8–29.6) compared with the top 2 tertiles. Conclusions: Assessment of olfactory function, particularly odor identification, may help to predict the development of a Lewy body disease in patients with iRBD over a relatively short time period and thus to identify patients suitable for future disease modification trials.

Most patients with idiopathic REM sleep behavior disorder (IRBD) are diagnosed with the synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies. Conversion rates have been estimated to be 35% at 5 years, 73% at 10 years, and 92% at 14 years after IRBD diagnosis.1 Accordingly, IRBD is considered as a marker of the prodromal stage of synucleinopathies. In PD, RBD occurs in about 50% of the patients and in 18% of them, RBD symptoms precede the onset of parkinsonism.2 Most cases of PD are sporadic, but approximately 5% to 10% of cases encompass monogenic forms caused by mutations in PD-associated genes. Mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene represent the most common genetic cause of both familial PD and sporadic PD (sPD). Indeed, the G2019S mutation has been detected in up to 6% of familial and 3% of sPD cases in Europeans.3 Moreover, the LRRK2-associated PD form (LRRK2-PD) is clinical and neuropathologically similar to sPD lacking LRRK2 mutations.3 Acknowledgment: The authors thank the patients who have kindly participated in this study.

Background and Objective: A diagnosis of restless legs syndrome (RLS) requires an urge to move the legs in combination with sensory leg discomfort. Localization of the symptoms to other body areas in the absence of leg involvement is not recognized as part of the phenotypic spectrum of RLS. We describe 3 patients who presented with sensorimotor symptoms confined to the abdominal wall and, with the exception of not involving the legs, satisfied the primary and secondary diagnostic criteria for RLS. Methods: Patients underwent detailed clinical history, video-polysomnography, abdominal imaging, and serologic and genotyping assessment. Results: Unpleasant abdominal symptoms emerged at night during periods of rest and were accompanied by an urge to move and temporized by movement. Patients reported sleep onset and sleep maintenance insomnia due to their abdominal symptomatology. Abdominal imaging was normal. Secondary features included periodic leg movements of sleep (PLMS), and dramatic symptom amelioration with the D 2 -D 3 dopaminergic agonist pramipexole. Two subjects were anemic. Conventional RLS emerged in one subject and resolved after dose escalation. Each subject was homozygous for the most common RLS/PLMS–associated risk allele in the BTBD9 gene. Conclusions: Our observations indicate that the restricted abdominal symptomatology manifest in our subjects represents a phenotypic variant of RLS. Physicians should be vigilant to the existence of this unique phenotype when encountering subjects who present with insomnia and abnormal abdominal sensations. Our experience emphasizes the importance of supportive clinical features in rendering a correct diagnosis such that the most cost-effective workups and treatment can be realized.

A large number of patients with Parkinson's disease (PD) experience nocturnal problems that impair their sleep quality. Among them, motor disorders such as tremor, rigidity, akinesia, akathisia, periodic leg movements, painful dystonia, dyskinesias, restless legs syndrome, and rapid eye movement sleep behavior disorder are common. This article reviews the clinical characteristics of some nocturnal motor problems that often induce sleep disruption in PD patients.

The authors found that continuous positive airway pressure (CPAP) eliminated video-polysomnographic documented stridor in 13 multiple system atrophy (MSA) subjects with vocal cord abnormalities. Long-term follow-up showed high CPAP tolerance, no recurrence of stridor, no major side effects, subjective improvement in sleep quality, and that median survival time was similar to a group of 26 MSA patients without stridor. This study shows that in MSA, CPAP is an effective noninvasive long-term therapy for nocturnal stridor.