Factors associated with injury in REM sleep behavior disorder

ObjectiveAs factors associated with injury in rapid eye movement (REM) sleep behavior disorder (RBD) remain largely unknown, we aimed to identify such factors.MethodsWe surveyed consecutive idiopathic (iRBD) or symptomatic RBD patients seen between 2008 and 2010 regarding RBD-related injuries. Associations between injuries and clinical variables were determined with odds ratios (OR) and multiple logistic regression analyses. The primary outcome variables were injury and injury severity.ResultsFifty-three patients (40%) responded. Median age was 69 years, and 35 (73.5%) were men. Twenty-eight (55%) had iRBD. Twenty-nine (55%) reported injury, with 37.8% to self and 16.7% to the bed partner. 11.3% had marked injuries requiring medical intervention or hospitalization, including two (4%) subdural hematomas. iRBD diagnosis (OR = 6.8, p = 0.016) and dream recall (OR = 7.5, p = 0.03) were associated with injury; and iRBD diagnosis was independently associated with injury and injury severity adjusting for age, gender, DEB frequency, and duration. Falls (p = 0.03) were also associated with injury severity. DEB frequency was not associated with injury, injury severity, or falls.ConclusionsInjuries appear to be a frequent complication of RBD, although the relatively low response rate in our survey could have biased results. iRBD patients are more likely to suffer injury – and more severe injuries – than symptomatic RBD patients. In addition, recall of dreams was also associated with injury, and dream enactment behavior (DEB)-related falls were associated with more severe injuries. One in nine patients suffered injury requiring medical intervention. The frequency of DEB did not predict RBD-related injuries, highlighting the importance of timely initiation of treatment for RBD in patients having even rare DEB episodes. Future prospective studies will be necessary to define predictors of injury in RBD.     

The effects of pramipexole in REM sleep behavior disorder

The authors evaluated the effects of pramipexole, a dopaminergic D2-D3 receptor agonist, on eight patients with idiopathic REM sleep behavior disorder. Five patients reported a sustained reduction in the frequency or intensity of sleep motor behaviors, which was confirmed by video recording, although no change was observed for the percentage of phasic EMG activity during REM sleep. Surprisingly, a decrease in the percentage of time spent with REM sleep muscle atonia was observed with treatment. The treatment did not modify the indexes of periodic leg movements.     

Polysomnographic diagnosis of idiopathic REM sleep behavior disorder

The presence of either excessive tonic chin EMG activity during REM sleep, or excessive phasic submental or limb EMG twitching is required to diagnose REM sleep behavior disorder (RBD). The aim was to identify cut‐off values and to assess the sensitivity and specificity of these values taken separately or combined to diagnose idiopathic RBD patients. Eighty patients presenting with a clinical diagnosis of idiopathic RBD and 80 age‐ and gender‐matched normal controls were studied in the sleep laboratory. Receiver operating characteristic curves were drawn to find optimal cut‐off values for three REM sleep EMG parameters. Tonic and phasic EMG activity were measured in the chin, but not in the limbs. Videos were examined during the recording but were not systematically reviewed by the authors. Total correct classification of 81.9% was found for tonic chin EMG density ≥30%; 83.8% for phasic chin EMG density ≥15% and 75.6% for ≥24 leg movements per hour of REM sleep. Five patients did not fulfill any of these three polysomnographic (PSG) criteria. Conversely, one subject of the control group met the PSG criteria for RBD. This study estimates the diagnostic value of a visual scoring method for the diagnosis of idiopathic RBD and establishes cut‐off values to be used in clinical and research set‐ups. For the five RBD patients who did not show chin EMG abnormalities, it cannot be excluded that they had increased phasic EMG activity in the upper limbs and presented visible motor activity. © 2010 Movement Disorder Society     

Midbrain hyperechogenicity in idiopathic REM sleep behavior disorder

Recent studies have reported an increased risk to develop Parkinson's disease (PD) in patients with idiopathic RBD (iRBD). Midbrain hyperechogenicity is a common transcranial sonography (TCS) finding in PD and has been suggested as a PD risk‐marker in nonparkinsonian subjects. The objective of this study is to assess midbrain echogenicity by TCS in patients with iRBD and compare the findings with the healthy controls. TCS was performed in 55 iRBD patients and in 165 age and sex‐matched controls. The area of echogenicity in the SN region in the iRBD group was significantly increased compared with the control group (P < 0.001). About 19 (37.3%) of patients with iRBD were found to have SN hyperechogenicity when compared with 16 (10.7%) of the controls (P < 0.001). This is the first case‐control study assessing midbrain echogenicity in a large iRBD cohort compared to age‐ and sex‐matched healthy individuals. The finding of an increased prevalence of hyperechogenicity in a subgroup of individuals with a priori increased risk for PD supports the potential role of hyperechogenicity as a risk marker for PD. The prospective follow‐up of this iRBD cohort is needed to establish if those with midbrain hyperechogenicity will go on to develop clinically defined PD or not. © 2009 Movement Disorder Society     

Olfactory dysfunction in idiopathic REM sleep behavior disorder

BackgroundOlfactory dysfunction is frequently observed in patients with idiopathic REM sleep behavior disorder (iRBD) such as Parkinson’s disease or dementia with Lewy bodies.MethodsOlfactory function tests using Sniffin’ Sticks and Odor Stick Identification Test for Japanese (OSIT-J) were performed in 73 consecutive middle-aged (range, 50–69 years) patients with iRBD, 33 consecutive older-aged (71–82 years) patients with iRBD, and 28 control subjects (55–70 years).ResultsOdor identification was more frequently impaired than odor threshold or discrimination among the iRBD group and allowed better discrimination between the middle-aged iRBD group and age-adjusted control subjects. The area under the curve for threshold, discrimination, identification, TDI score and OSIT-J score determined from receiver operating characteristic curves were 0.831 (0.753–0.909), 0.761 (0.666–0.855), 0.938 (0.894–0.982), 0.939 (0.897–0.981), and 0.965 (0.931–0.999), respectively. Discrimination and identification scores were significantly lower in the older-aged iRBD group than in the middle-aged iRBD group. A significant correlation was observed between the identification score on Sniffin’ Sticks and OSIT-J score (r = 0.5910, P < 0.0001, n = 106, Spearman’s rank).ConclusionAnosmia/hyposmia may be a feature of iRBD. Olfactory dysfunction in iRBD is a consistent, widespread central nervous abnormality of different olfactory modalities with different cognitive complexity.     

Impaired decision-making in idiopathic REM sleep behavior disorder

BackgroundPatients with REM sleep behavior disorder (RBD) frequently develop Parkinson’s disease (PD), which can impair decision-making ability. This study was undertaken to investigate decision-making ability and its relation to olfactory function in patients with idiopathic RBD.MethodsThis study used the Iowa Gambling Task (IGT) and the Sniffin’ Stick Test for examination of 38 patients with idiopathic RBD (iRBD) and 34 age-matched healthy control subjects (HC). Associations between these test results and other clinical RBD variables were also assessed.ResultsTotal IGT score and Sniffin’ Stick Test scores were significantly lower in the iRBD group than in the HC group. The iRBD group IGT scores in the first, third, and final blocks were significantly lower than those of the HC group. In the iRBD group, no association was found between the total IGT score and the Sniffin’ Stick Test score or any clinical RBD variable.ConclusionsImpaired decision-making associated with iRBD can herald PD. However, decision-making disability is thought to appear irrespective of olfactory dysfunction and progression of RBD pathology.     

Neuroimaging-evident lesional pathology associated with REM sleep behavior disorder

Background/RationaleRapid eye movement (REM) sleep behavior disorder (RBD) is a potentially injurious parasomnia characterized by dream enactment behavior and polysomnographic REM sleep without atonia (RSWA). Recently, RBD not only has been shown to be strongly associated with synucleinopathy neurodegeneration but has also been rarely reported to be associated with structural lesions involving the brainstem or limbic system. The aim of this study was to describe the clinical, neuroimaging, and outcome characteristics in a case series of patients with lesional RBD.MethodsThis is a retrospective case series from a tertiary care referral center.ResultsA total of 10 patients with lesional RBD were identified. Seven (70%) were men, with an average age of sleep symptom onset of 53.7 ± 17.0 years. Structural pathology evident on neuroimaging included four extraaxial (three meningiomas and one basilar fusiform aneurysm with brainstem compression) and six intraaxial (encephalomalacia, multiple sclerosis, vasculitis, autoimmune limbic encephalitis, and leukodystrophy) lesions. No patient developed parkinsonian features or cognitive impairment suggestive of synucleinopathy over an average of 45.4 ± 35.2 months of follow-up.ConclusionsRBD is rarely associated with non-synuclein structural lesions affecting the pons, medulla, or limbic system. The spectrum of lesional RBD comprises tumors, aneurysms, leukodystrophy, and autoimmune/inflammatory/demyelinating brain lesions.     

The prospective memory of patients with idiopathic REM sleep behavior disorder

BackgroundIdiopathic rapid eye movement sleep behavior disorder (iRBD) likely represents the prodromal stage of synucleinopathy. The present study was to investigate if there was prospective memory (PM) impairment and the relationship between different PM tasks and traditional cognitive tests in patients with iRBD.MethodsA total of 28 patients with iRBD, 25 with Parkinson's disease (PD) and 21 healthy controls were included. The Cambridge Prospective Memory Test (CAMPROMPT) was used to measure the PM including time-based (TBPM) and event-based PM (EBPM). Standard cognitive tests were administered to all participants.ResultsEBPM scores were lower only in patients with iRBD, while the obvious PM abnormalities were found in patients with PD. The patients with iRBD and PD performed worse on delayed recall of the Rey Auditory Verbal Learning Test (RAVLT) and copy of the Rey–Osterrieth complex figure (ROCF). The EBPM correlated with attention, executive function, and immediate memory besides working memory in patients with iRBD. The PM tasks involved in more memory functions in PD patients.ConclusionsThe patients with iRBD were impaired on both episodic memory and EBPM tasks that correlated with attention, executive function, and immediate memory. The PM abnormality was an early cognitive change in iRBD to which more attention should be paid more attention.     

Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder

More than 50% of persons with idiopathic REM sleep behavior disorder (RBD) will develop Parkinson's disease or Lewy body dementia. Symptom screens and metaiodobenzylguanine (MIBG)‐scintigraphy suggest autonomic abnormalities in idiopathic RBD, but it is unclear whether autonomic abnormalities can predict neurodegenerative disease. From a cohort of 99 patients with idiopathic RBD, we selected those who developed parkinsonism or dementia. These were matched by age, sex, and follow‐up duration to patients with RBD who remained disease free and to matched controls. From the polysomnographic trace performed at baseline evaluation, measures of beat‐to‐beat RR variability including time domains (mean RR‐interval and RR‐standard deviation) and frequency domains (low and high frequency components) were retrospectively assessed. Twenty‐one patients with idiopathic RBD who developed neurodegenerative disease were included (Parkinson's disease‐11, multiple system atrophy‐1, and dementia‐9). Age at PSG was 66 years, and 86% were male. PSG was performed on average 6.7 years before defined neurodegenerative disease. Comparing all patients with idiopathic RBD to controls, there were significant reductions in RR‐standard deviation (24.6 ± 2.2 ms vs. 35.2 ± 3.5 ms, P = 0.006), very low frequency components (238.6 ± 99.6 ms² vs. 840.1 ± 188.3 ms², P < 0.001), and low frequency components (127.8 ± 26.3 ms² vs. 288.7 ± 66.2 ms², P = 0.032). However, despite clear differences between patients with idiopathic RBD and controls, there were no differences in any measure between those who did or did not develop disease. RR‐variability analysis demonstrates substantial autonomic dysfunction in idiopathic RBD. However, this dysfunction is identical in patients who will or will not develop defined neurodegenerative disease. This suggests that autonomic dysfunction is linked with RBD independent of associated Parkinson's disease or Lewy body dementia. © 2010 Movement Disorder Society     

Rhythmic movements in idiopathic REM sleep behavior disorder.

Reported are two cases of video-PSG captured head-rolling occurring, in the context of REM Sleep Behavior Disorder (RBD) episodes, in two patients affected with idiopathic RBD and without past personal or familiar history of Rhythmic Movement Disorder during sleep. It has been speculated that the activation of neuronal pathways which underlie REM-related loss of motor control in RBD, may involve the Central Pattern Generator neuronal networks leading to the induction of Rhythmic Movements during RBD episodes, thereby allowing the re-emergence, in pathological conditions in later life, of a motor behavior typically seen in the early stage of life.     

Non-rapid eye movement sleep characteristics in idiopathic REM sleep behavior disorder

This study investigated slow waves (SW; >75μV and <4Hz) characteristics in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). Thirty patients with iRBD and 30 age- and sex-matched healthy subjects underwent one polysomnographic (PSG) nocturnal sleep recording. SW automatic detection was performed on F3, C3, P3, and O1 leads and SW characteristics were derived (SW density, amplitude, frequency, slope, and duration of negative and positive phases). We also compared iRBD patients and control subjects on PSG variables and delta (0.25-4.0Hz) spectral power. No between-group differences were found on PSG variables, delta spectral power, or SW characteristics. Results show no SW abnormalities in iRBD patients compared to healthy participants, which suggests similar level of synchronization of thalamo-cortical neurons during N-REM sleep.     

Investigation of autonomic function in idiopathic REM sleep behavior disorder

Idiopathic REM sleep behavior disorder (iRBD) has been suggested as an early "pre-motor" stage of Parkinson's disease (PD) in a significant proportion of cases. We investigated autonomic function in 15 consecutive iRBD patients and compared these findings to PD patients and healthy controls. All participants underwent cardiovascular autonomic function testing, and were rated on the COMPASS scale. Symptomatic orthostatic hypotension was present in two iRBD patients, two PD patients and none of the healthy controls. In the tilt table examination, blood pressure changes were similar between iRBD patients and healthy controls. In the PD group, blood pressure drops were more pronounced. In the orthostatic standing test, iRBD patients had higher blood pressure changes than healthy controls. Highest drops were found in PD. Valsalva ratio was lower in iRBD and PD compared to healthy controls. Total COMPASS score was higher in iRBD compared to healthy controls. Highest scores were found in PD. These results support the presence of autonomic dysfunction in iRBD. On several measures, dysfunction was intermediate between healthy controls and PD consistent with the concept that iRBD can be manifestation of synuclein-associated neurodegenerative disorders. Follow-up studies are needed to determine whether iRBD patients with dysfunction on several autonomic domains are at particular risk for developing one of these diseases.     

HLA Class II genes associated with REM sleep behavior disorder

Twenty-five white men with rapid eye movement (REM) sleep behavior disorder, but without narcolepsy, under-went HLA class II antigen typing; 84% (N = 21) were DQw1 (DQB1*05,06) positive (28% [N = 7] were DR2 positive); DQB1*0501 (N = 9) and DQB1*0602 (N = 7) were the most common phenotypes. The 84% DQwl rate in men with REM sleep behavior disorder was significantly greater (p = 0.015) than the 56% DQwl rate found in a local white comparison group (N = 66), and was greater than the 39 to 66% DQw1 rates published for 12 white groups (N = 40–418/group). Thus, another disorder of REM sleep dysregulation (besides narcolepsy) appears to be strongly associated with specific HLA class I1 genes.     

Autonomic dysfunction and phenoconversion in idiopathic REM sleep behavior disorder

Clinical Autonomic Research - REM sleep behavior disorder (RBD) is a common finding among patients with synucleinopathies. We aimed to determine the degree of autonomic dysfunction in patients...     

Use of pramipexole in REM sleep behavior disorder: results from a case series

BACKGROUND AND PURPOSE: Rapid eye movement (REM) sleep behavior disorder (RBD) has a known association with other medical conditions, including narcolepsy and neurodegenerative diseases such as synuclienopathies. RBD is currently treated with clonazepam as a first-line therapy. Recent research suggests that the pathophysiology underlying RBD may involve a dopaminergic deficiency, given its association with Parkinson syndromes and restless legs syndrome (RLS). We report on the efficacy of pramipexole, a dopaminergic D2-3 receptor agonist, in the treatment of RBD. PATIENTS AND METHODS: The first 10 consecutive patients presenting with a history and polysomnographically confirmed RBD were given pramipexole as either a single dose before bedtime or as a divided dose regimen with the first dose given in the early evening and the second dose at bedtime. Medication was titrated to control RBD symptoms and the clinical response was monitored through interviews with the patient, spouse, and close family members during the course of the study at regularly scheduled follow-up visits. RESULTS: The mean length of treatment was 13.1 months, and the average total evening dose of pramipexole at the end of the study was 0.89+/-0.31 mg. A divided dose regimen of pramipexole was used in 56% of patients remaining on pramipexole. We found that 89% of patients experienced either a moderate reduction or complete resolution in the frequency of RBD symptoms throughout the duration of the study. Moreover, 67% reported at least a moderate reduction in the severity of remaining symptoms. CONCLUSIONS: Pramipexole markedly reduced the frequency and severity of RBD symptoms and appeared to maintain efficacy for up to 25 months as assessed at follow-up visits. Clonazepam may have numerous unwanted side effects in the elderly or narcoleptics with RBD, such as prominent sedation and the potential exacerbation of underlying obstructive breathing in sleep. The potential role of pramipexole in improving RBD and its associated dopamine deficient syndromes warrants further research in the use of dopaminergic agonists as a potential first-line alternative therapy for RBD.     

Longitudinal assessment of olfactory function in idiopathic REM sleep behavior disorder

ObjectiveIdiopathic REM sleep behavior disorder (IRBD) is an early marker of Lewy body disorders and is linked to olfactory loss. We evaluated whether olfactory function deteriorates with time in IRBD. Progressive smell loss could be a useful way in which to monitor the effect of disease-modifying interventions in subjects with IRBD.MethodsWe conducted a prospective study in which 19 IRBD patients and 19 healthy age and sex matched controls underwent serial clinical evaluations and olfactory identification testing. We used the 40-item University of Pennsylvania Smell Identification Test (UPSIT) at baseline and after 1.5, 3 and 4 years, and olfactory detection testing with the Smell Threshold Test (STT) at baseline and after 1.5 and 4 years.ResultsMean UPSIT score was lower (poorer smell identification) in patients than in controls at baseline, 1.5-, 3-, and 4-year assessments. Mean STT score was higher (poorer smell detection ability) in patients than in controls at 1.5- and 4-year evaluations. At 4 years, there were no differences between patients and controls in the rate of change of UPSIT (P = 0.093) and STT (P = 0.964) scores from baseline. Three patients were diagnosed with Parkinson's disease at 3-year evaluation and one with multiple system atrophy at 4-year assessment. At 4 years, UPSIT and STT scores did not change from baseline in these four patients.ConclusionsIn IRBD, olfactory identification and detection deficits do not worsen over time. Serial olfactory tests may not serve as an outcome measure in future disease-modifying trials in IRBD.     

Plasma immune markers in an idiopathic REM sleep behavior disorder cohort

IntroductionIncreasing evidence shows a strong association between idiopathic REM sleep behavior disorder (iRBD) and α-synucleinopathies. Recent studies have indicated an inflammatory mechanism in the pathogenesis of α-synucleinopathies. Whether peripheral inflammatory cytokines are altered in iRBD and can be biomarkers for predicting phenoconversion remains unclear.MethodsWe collected baseline plasma samples from 77 consecutive iRBD patients and 64 age- and sex-matched healthy controls. Ten cytokines were measured: Interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-α. All iRBD patients underwent clinical assessment tests at baseline, and 75 were prospectively followed and received assessments for parkinsonism or dementia. Cox regression analyses were used to evaluate the predictive value of plasma cytokines in a follow-up period of 6.0 years.ResultsTNF-α and IL-10 were significantly elevated in iRBD compared with controls (both p < 0.001). IL-6/IL-10 and IL-8/IL-10 were significantly reduced in iRBD than in controls (p = 0.001, p < 0.001, respectively). After a median follow-up of 3.7 years, 16 iRBD patients developed neurodegenerative synucleinopathies. iRBD patients with higher TNF-α/IL-10 levels were more likely to develop neurodegenerative diseases (adjusted HR 1.07, 95% CI 1.01–1.14). The coexistence of elevated TNF-α/IL-10 and possible mild cognitive impairment predicted an early conversion of iRBD to neurodegenerative synucleinopathies (adjusted HR 4.17, 95% CI 1.47–11.81).ConclusionsOur study supported the early involvement of peripheral inflammation in prodromal α-synucleinopathy. Plasma cytokines may be predictive of disease conversion in iRBD, while large-scale longitudinal studies are warranted to validate the assumption.