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1.  Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder 
Sleep medicine  2013;14(8):754-762.
Objective
To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder.
Methods
The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria.
Results
172 cases were identified, of whom 143 (83%) were men. The mean ± SD age of onset in years for the core features were as follows – RBD, 62 ± 14 (range, 20–93), cognitive impairment (n = 147); 69 ± 10 (range, 22–90), parkinsonism (n = 151); 68 ± 9 (range, 20–92), and autonomic dysfunction (n = 42); 62 ± 12 (range, 23–81). Death age was 75 ± 9 years (range, 24–96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10 ± 12 (range, 1–61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n = 97), Parkinson’s disease with or without mild cognitive impairment or dementia (n = 32), multiple system atrophy (MSA) (n = 19), Alzheimer’s disease (AD)(n = 9) and other various disorders including secondary narcolepsy (n = 2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD)(n = 77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n = 59), MSA (n = 19), AD (n = 6), progressive supranulear palsy (PSP) (n = 2), other mixed neurodegenerative pathologies (n = 6), NBIA-1/LBD/tauopathy (n = 1), and hypothalamic structural lesions (n = 2). Among the neurodegenerative disorders associated with RBD (n = 170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features.
Conclusions
In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.
doi:10.1016/j.sleep.2012.10.015
PMCID: PMC3745815  PMID: 23474058
REM sleep behavior disorder; Parasomnia; Lewy body disease; Dementia with Lewy bodies; Parkinson’s disease; Multiple system atrophy; Synuclein; Synucleinopathy
2.  Diagnostic Tools for REM Sleep Behavior Disorder 
Sleep medicine reviews  2011;16(5):415-429.
Background
REM sleep behavior disorder (RBD) is a parasomnia characterized by loss of muscle atonia during REM sleep that results in motor behaviors. Diagnosis of RBD involves a clinical interview in which history of dream enactment behaviors is elicited and a subsequent overnight polysomnography (PSG) evaluation to assess for REM sleep without atonia (RWA) and/or observe motor behaviors during REM sleep. Therefore, the nature of RBD diagnosis involves both subjective and objective measurements that attempt to qualify and quantify the different diagnostic sub-criteria.
Objectives
The primary aim of the current study was to identify and summarize the available clinical measurements that have been used for RBD assessment.
Methods
Two major online databases (MEDLINE and PsycInfo) were searched for articles developing, validating, or evaluating psychometric properties of the RBD diagnostic criteria or methods used for diagnosis. Studies of adult subjects (18+) that included sufficient psychometric data for validation were included.
Results
Fifty-eight studies were found to meet review criteria. The objective measurements for assessment of RBD reviewed included visual electromygraphic (EMG) scoring methods, computerized EMG scoring methods, cardiac 123I-MIBG scintigraphy, actigraphy, behavioral classification and video analysis. Subjective measurements of RBD included interviews and questionnaires.
Conclusion
Sleep history may be sufficient for diagnosis of RBD in some populations. However, PSG is necessary for a definitive diagnosis. EMG scoring methods vary in definition used and there is no single accepted approach to scoring muscle activity. Additional validation studies are required for establishing cutoff scores for the different methods. Questionnaires were shown to be appropriate screening tools, yet further validation in different population is necessary.
doi:10.1016/j.smrv.2011.08.004
PMCID: PMC3327886  PMID: 22169258
3.  Probable REM Sleep Behavior Disorder Increases Risk for Mild Cognitive Impairment and Parkinson’s Disease: A Population-Based Study 
Annals of Neurology  2012;71(1):49-56.
Objective
REM sleep behavior disorder (RBD) is associated with neurodegenerative disease and particularly with the synucleinopathies. Convenience samples involving subjects with idiopathic RBD have suggested an increased risk of incident mild cognitive impairment (MCI), dementia (usually dementia with Lewy bodies) or Parkinson’s disease (PD). There is no data on such risk in a population-based sample.
Methods
Cognitively normal subjects aged 70–89 in a population-based study of aging who screened positive for probable RBD using the Mayo Sleep Questionnaire were followed at 15 month intervals. In a Cox Proportional Hazards Model, we measured the risk of developing MCI, dementia, PD among the exposed (pRBD+) and unexposed (pRBD−) cohorts.
Results
Forty-four subjects with pRBD+ at enrollment (median duration of pRBD features was 7.5 years), and 607 pRBD− subjects, were followed prospectively for a median of 3.8 years. Fourteen of the pRBD+ subjects developed MCI and one developed PD (15/44=34% developed MCI / PD); none developed dementia. After adjustment for age, sex, education, and medical comorbidity, pRBD+ subjects were at increased risk of MCI / PD [Hazard Ratio (HR) 2.2, 95% Confidence Interval (95%CI) 1.3 – 3.9; p=0.005]. Inclusion of subjects who withdrew from the study produced similar results, as did exclusion of subjects with medication-associated RBD. Duration of pRBD symptoms did not predict the development of MCI / PD (HR 1.05 per 10 years, 95%CI 0.84 – 1.3; p=0.68).
Interpretation
In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI / PD over four years.
doi:10.1002/ana.22655
PMCID: PMC3270692  PMID: 22275251
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism; synuclein
4.  Polysomnographic Findings in Dementia With Lewy Bodies 
The neurologist  2013;19(1):1-6.
Introduction
The clinical features of dementia with Lewy bodies (DLB) during wakefulness are well known. Other than REM sleep behavior disorder (RBD), only limited data exists on other sleep disturbances and disorders in DLB. We sought to characterize the polysomnographic (PSG) findings in a series of DLB patients with sleep-related complaints.
Methods
Retrospective study of patients with DLB who underwent clinical PSG at Mayo Clinic Rochester or Mayo Clinic Jacksonville over an almost 11 year span for evaluation of dream enactment behavior, excessive nocturnal movements, sleep apnea, hypersomnolence, or insomnia. The following variables were analyzed: respiratory disturbance index (RDI) in disordered breathing events/hour, periodic limb movement arousal index (PLMAI), arousals for no apparent reason (AFNAR), total arousal index (TAI), presence of REM sleep without atonia (RSWA), and percent sleep efficiency (SE).
Results
Data on 78 patients (71M, 7F) were analyzed. The mean age was 71 ± 8 years. Seventy-five (96%) patients had histories of recurrent dream enactment during sleep with 83% showing confirmation of RSWA +/- dream enactment during PSG. Mean RDI = 11.9 ± 5.8, PLMAI = 5.9 ± 8.5, AFNARI = 10.7 ± 12.0, and TAI = 26.6 ± 17.4. SE was <80% in 72% of the sample, <70% in 49%, and <60% in 24%. In patients who did not show evidence of significant disordered breathing (23 with RDI<5), 62% of arousals were AFNARs. In those patients who had significant disordered breathing (55 with RDI ≥ 5), 36% of arousals were AFNARs. Six patients underwent evaluations with PSG plus MSLT. Two patients had mean initial sleep latencies less than five minutes, and both had RDI<5. No patient had any sleep onset rapid eye movement periods. Nineteen patients have undergone neuropathologic examination, and 18 have had limbic- or neocortical-predominant Lewy body pathology. One had progressive supranuclear palsy, but no REM sleep was recorded in prior PSG.
Conclusions
In patients with DLB and sleep-related complaints, several sleep disturbances in addition to RBD are frequently present. In this sample, about three quarters had a significant number of arousals not accounted for by a movement or breathing disturbance, and the primary sleep disorders do not appear to entirely account for the poor sleep efficiency in DLB, especially in those without a significant breathing disorder. Further studies are warranted to better understand the relationship between disturbed sleep, arousal and DLB; such characterization may provide insights into potential avenues of treatment of symptoms which could impact quality of life.
doi:10.1097/NRL.0b013e31827c6bdd
PMCID: PMC3587292  PMID: 23269098
Sleep disorders; REM sleep behavior disorder; dementia with Lewy bodies; synucleinopathy
5.  REM Sleep Behavior Disorder and REM Sleep Without Atonia as an Early Manifestation of Degenerative Neurological Disease 
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by repeated episodes of dream enactment behavior and REM sleep without atonia (RSWA) during polysomnography recording. RSWA is characterized by increased phasic or tonic muscle activity seen on polysomnographic electromyogram channels. RSWA is a requisite diagnostic feature of RBD, but may also be seen in patients without clinical symptoms or signs of dream enactment as an incidental finding in neurologically normal individuals, especially in patients receiving antidepressant therapy. RBD may be idiopathic or symptomatic. Patients with idiopathic RBD often later develop other neurological features including parkinsonism, orthostatic hypotension, anosmia, or cognitive impairment. RSWA without clinical symptoms as well as clinically overt RBD also often occurs concomitantly with the α-synucleinopathy family of neurodegenerative disorders, which includes idiopathic Parkinson disease, Lewy body dementia, and multiple system atrophy. This review article considers the epidemiology of RBD, clinical and polysomnographic diagnostic standards for both RBD and RSWA, previously reported associations of RSWA and RBD with neurodegenerative disorders and other potential causes, the pathophysiology of which brain structures and networks mediate dysregulation of REM sleep muscle atonia, and considerations for the effective and safe management of RBD.
doi:10.1007/s11910-012-0253-z
PMCID: PMC3656587  PMID: 22328094
REM sleep behavior disorder; REM sleep without atonia; Parasomnia; α-synucleinopathy; Parkinsonism; Neurodegeneration; Braak staging; Melatonin; Clonazepam; Treatment; Neuropsychological testing; Neurological disease
6.  Family history of idiopathic REM behavior disorder 
Neurology  2013;80(24):2233-2235.
Objective:
To compare the frequency of proxy-reported REM sleep behavior disorder (RBD) among relatives of patients with polysomnogram-diagnosed idiopathic RBD (iRBD) in comparison to controls using a large multicenter clinic-based cohort.
Methods:
A total of 316 patients with polysomnography-confirmed iRBD were recruited from 12 RBD study group centers, along with 316 controls matched on sex and age group. All subjects completed a self-administered questionnaire that collected proxy-reported information on family history of tremor, gait trouble, balance trouble, Parkinson disease, memory loss, and Alzheimer disease. The questionnaire also included a single question that asked about possible symptoms of RBD among first-degree relatives (siblings, parents, and children).
Results:
A positive family history of dream enactment was reported in 13.8% of iRBD cases compared to 4.8% of controls (odds ratio [OR] = 3.9, 95% confidence interval [CI] 2.0–7.7). ORs were increased for both siblings (OR = 6.1, 95% CI 2.1–18.1) and parents (OR = 3.2, 95% CI 1.4–7.8). We found no significant difference in sex, current age (65.3 ± 10.2 vs 66.9 ± 10.2 years), or age at self-reported RBD onset (55.2 ± 11.7 vs 56.6 ± 15.1 years) in possible familial vs sporadic iRBD. No differences were found in family history of tremor, walking and balance troubles, Parkinson disease, memory loss, or Alzheimer disease.
Conclusion:
We found increased odds of proxy-reported family history of presumed RBD among individuals with confirmed iRBD. This suggests the possibility of a genetic contribution to RBD.
doi:10.1212/WNL.0b013e318296e967
PMCID: PMC3721098  PMID: 23658378
7.  Actigraphy as a diagnostic aid for REM sleep behavior disorder in Parkinson’s disease 
BMC Neurology  2014;14:76.
Background
Rapid eye movement (REM) sleep behavior disorder (RBD) is a common parasomnia in Parkinson’s disease (PD) patients. The current International Classification of Sleep Disorders (ICSD-II) requires a clinical interview combined with video polysomnography (video-PSG) to diagnose. The latter is time consuming and expensive and not always feasible in clinical practice. Here we studied the use of actigraphy as a diagnostic tool for RBD in PD patients.
Methods
We studied 45 consecutive PD patients (66.7% men) with and without complaints of RBD. All patients underwent one night of video-PSG and eight consecutive nights of actigraphy. Based on previous studies, the main outcome measure was the total number of bouts classified as “wake”, compared between patients with (PD + RBD) and without RBD (PD- RBD).
Results
23 (51.1%) patients had RBD according to the ICSD-II criteria. The total number of wake bouts was significantly higher in RBD patients (PD + RBD 73.2 ± 40.2 vs. PD-RBD 48.4 ± 23.3, p = .016). A cut off of 95 wake bouts per night resulted in a specificity of 95.5%, a sensitivity of 20.1% and a positive predictive value of 85.7%. Seven patients were suspected of RBD based on the interview alone, but not confirmed on PSG; six of whom scored below 95 wake bouts per night on actigraphy.
Conclusion
PD patients with RBD showed a significantly higher number of bouts scored as “wake” using actigraphy, compared to patients without RBD. In clinical practice, actigraphy has a high specificity, but low sensitivity in the diagnosis of RBD. The combination of actigraphy and previously reported RBD questionnaires may be a promising method to diagnose RBD in patients with PD.
doi:10.1186/1471-2377-14-76
PMCID: PMC3986453  PMID: 24708629
Parkinson’s disease; Actigraphy; REM sleep behavior disorder; Polysomnography
8.  Brainstem infarcts predict REM sleep behavior disorder in acute ischemic stroke 
BMC Neurology  2014;14:88.
Background
Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disturbance in which patients enact their dreams while in REM sleep. The behavior is typically violent in association with violent dream content, so serious harm can be done to the patient or the bed partner. The prevalence of RBD is well-known in Parkinson’s disease, Lewy body dementia, and multiple systems atrophy. However, its prevalence and causes in stroke remained unclear. The aim of this study was to determine factors influencing the appearance of RBD in a prospective cohort of patients with acute ischemic stroke.
Methods
A total of 2,024 patients with first-ever or recurrent acute ischemic stroke were admitted to the Acute Stroke Unit at the Prince of Wales Hospital between January 2010 and November 2011; 775 of them received an MRI scan. Within 2 days of admission, a research nurse collected demographic and clinical data and assessed the severity of each stroke using the National Institute of Health Stroke Scale (NIHSS). One hundred and nineteen of the 775 patients meeting study entry criteria formed the study sample. All eligible participants were invited to attend a research clinic 3 months after the onset of the index stroke. In the attendance, a research assistant administered the MMSE and the 13-item RBD questionnaire (RBDQ).
Results
Among 119 stroke patients, 10.9% were exhibited RBD, defined as an REM sleep behavior disorder questionnaire score of 19 or above. The proportion of patients with acute brainstem infarct was significantly higher in RBD patients than those without RBD. Compared with patients without RBD, RBD patients were more likely to have brainstem infarcts and had smaller infarct volumes. In a multivariate analysis, in which stroke location and infarct volume were inserted, brainstem infarcts were an independent predictor of RBD (odds ratio = 3.686; P = 0.032).
Conclusions
The results support the notion of a predominant role of brainstem injury in the development of RBD and suggest that patients with brainstem infarcts RBD should be evaluated by a clinical neurologist.
doi:10.1186/1471-2377-14-88
PMCID: PMC4004510  PMID: 24758223
Sleep; Acute ischemic stroke; Ischemia; Brainstem; Infarcts
9.  Probable rapid eye movement sleep behavior disorder, nocturnal disturbances and quality of life in patients with Parkinson’s disease: a case-controlled study using the rapid eye movement sleep behavior disorder screening questionnaire 
BMC Neurology  2013;13:18.
Background
Increasing evidence provides a clear association between rapid eye movement sleep behavior disorders (RBD) and Parkinson’s disease (PD), but the clinical features that determine the co-morbidity of RBD and PD are not yet fully understood.
Methods
We evaluated the characteristics of nocturnal disturbances and other motor and non-motor features related to RBD in patients with PD and the impact of RBD on their quality of life. Probable RBD (pRBD) was evaluated using the Japanese version of the RBD screening questionnaire (RBDSQ-J).
Results
A significantly higher frequency of pRBD was observed in PD patients than in the controls (RBDSQ-J ≥ 5 or ≥ 6: 29.0% vs. 8.6%; 17.2% vs. 2.2%, respectively). After excluding restless legs syndrome and snorers in the PD patients, the pRBD group (RBDSQ-J≥5) showed higher scores compared with the non-pRBD group on the Parkinson’s disease sleep scale-2 (PDSS-2) total and three-domain scores. Early morning dystonia was more frequent in the pRBD group. The Parkinson’s Disease Questionnaire (PDQ-39) domain scores for cognition and emotional well-being were higher in the patients with pRBD than in the patients without pRBD. There were no differences between these two groups with respect to the clinical subtype, disease severity or motor function. When using a cut-off of RBDSQ-J = 6, a similar trend was observed for the PDSS-2 and PDQ-39 scores. Patients with PD and pRBD had frequent sleep onset insomnia, distressing dreams and hallucinations. The stepwise linear regression analysis showed that the PDSS-2 domain “motor symptoms at night”, particularly the PDSS sub-item 6 “distressing dreams”, was the only predictor of RBDSQ-J in PD.
Conclusion
Our results indicate a significant impact of RBD co-morbidity on night-time disturbances and quality of life in PD, particularly on cognition and emotional well-being. RBDSQ may be a useful tool for not only screening RBD in PD patients but also predicting diffuse and complex clinical PD phenotypes associated with RBD, cognitive impairment and hallucinations.
doi:10.1186/1471-2377-13-18
PMCID: PMC3575252  PMID: 23394437
Parkinson’s disease; Rapid eye movement sleep behavior disorder; Cognition; Quality of life; Nocturnal problems
10.  Symptoms of Rapid Eye Movement Sleep Behavior Disorder are Associated with Cholinergic Denervation in Parkinson Disease 
Annals of neurology  2012;71(4):560-568.
Objective
Rapid eye movement sleep behavior disorder (RBD) is common in Parkinson disease (PD), but its relationship to the varied neurotransmitter deficits of PD and prognostic significance remain incompletely understood. RBD and cholinergic system degeneration are identified independently as risk factors for cognitive impairment in PD. We aimed to assess the association between cholinergic denervation and symptoms of RBD in PD patients without dementia.
Methods
Eighty subjects with PD without dementia (age, 64.6 ± 7.0 years; range, 50–82 years; 60 males, 20 females; mean Montreal Cognitive Assessment Test [MoCA] score, 26.2 ± 2.1; range 21–30) underwent clinical assessment, neuropsychological testing, and [11C]methylpiperidyl propionate acetylcholinesterase and [11C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 positron emission tomography (PET) imaging. 11C3-Amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) serotonin transporter PET imaging was performed in a subset of 35 subjects. The presence of RBD symptoms was determined using the Mayo Sleep Questionnaire.
Results
Twenty-seven of 80 subjects (33.8%) indicated a history of RBD symptoms. Subjects with and without RBD symptoms showed no significant differences in age, motor disease duration, MoCA, Unified Parkinson Disease Rating Scale motor scores, or striatal DTBZ binding. Subjects with RBD symptoms, in comparison to those without, exhibited decreased neocortical, limbic cortical, and thalamic cholinergic innervation (0.0213 ± 0.0018 vs 0.0236 ± 0.0022, t = 4.55, p < 0.0001; 0.0388 ± 0.0029 vs 0.0423 ± 0.0058, t = 2.85, p = 0.0056; 0.0388 ± 0.0025 vs 0.0427 ± 0.0042, t = 4.49, p < 0.0001, respectively). Brainstem and striatal DASB binding showed no significant differences between groups.
Interpretation
The presence of RBD symptoms in PD is associated with relative neocortical, limbic cortical, and thalamic cholinergic denervation although not with differential serotoninergic or nigrostriatal dopaminergic denervation. The presence of RBD symptoms may signal cholinergic system degeneration.
doi:10.1002/ana.22691
PMCID: PMC3727906  PMID: 22522445
11.  Prevalence of REM sleep behavior disorder in multiple system atrophy: a multicenter study and meta-analysis 
Objectivey
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia frequently affecting patients with synucleinopathies but its exact prevalence in multiple system atrophy (MSA) is unclear. Whether questionnaires alone are sufficient to diagnose RBD is also unknown.
Methods
Cross-sectional study of patients with probable MSA from six academic centers in the US and Europe. RBD was ascertained clinically and with polysomnography; and meta-analysis according to PRISMA guidelines for studies published before September 2014 that reported the prevalence of RBD in MSA. A random-effects model was constructed using weighted prevalence proportions. Only articles in English were included. Studies were classified into those that ascertained the presence of RBD in MSA clinically and with polysomnography. Case reports or case series (≤5 patients) were not included.
Results
Forty-two patients completed questionnaires and underwent polysomnography. Of those, 32 (76.1%) had clinically-suspected RBD and 34 (81%) had polysomnography-confirmed RBD. Two patients reported no symptoms of RBD but had polysomnography-confirmed RBD.
The primary search strategy yielded 374 articles of which 12 met the inclusion criteria The summary prevalence of clinically suspected RBD was 73% (95% CI, 62%-84%) in a combined sample of 324 MSA patients. The summary prevalence of polysomnography-confirmed RBD was 88% (95% CI, 79%-94%) in a combined sample of 217 MSA patients.
Interpretation
Polysomnography-confirmed RBD is present in up to 88% of patients with MSA. RBD was present in some patients that reported no symptoms. More than half of MSA patients report symptoms of RBD before the onset of motor deficits.
doi:10.1007/s10286-015-0279-9
PMCID: PMC4406814  PMID: 25739474
α-synuclein; sleep disorders; parasomnias; polysomnography; parkinsonism
12.  A Single-Question Screen for REM Sleep Behavior Disorder: A Multicenter Validation Study 
Background
Idiopathic REM sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for PD and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large-scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single-Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response.
Methods
Four hundred and eighty-four sleep-clinic– based participants (242 idiopathic RBD patients and 242 controls) completed the screen during a multicenter case-control study. All participants underwent a polysomnogram to define gold-standard diagnosis according to standard criteria.
Results
We found a sensitivity of 93.8% and a specificity of 87.2%. Sensitivity and specificity were similar in healthy volunteers, compared to controls or patients, with other sleep diagnoses.
Conclusions
A single-question screen for RBD may reliably detect disease, with psychometric properties favorably comparable to those reported for longer questionnaires.
doi:10.1002/mds.25037
PMCID: PMC4043389  PMID: 22729987
REM sleep behavior disorder; screening; diagnosis
13.  REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century(e–Pub ahead of print)(CME) 
Neurology  2010;75(6):494-499.
Background:
Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]).
Methods:
We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome.
Results:
Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients.
Conclusions:
These cases illustrate that the α-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.
GLOSSARY
= dementia with Lewy bodies;
= mild cognitive impairment;
= multiple system atrophy;
= Parkinson disease;
= PD with associated mild cognitive impairment;
= Parkinson disease dementia;
= polysomnogram;
= REM sleep behavior disorder.
doi:10.1212/WNL.0b013e3181ec7fac
PMCID: PMC2918473  PMID: 20668263
14.  Cognition in Rapid Eye Movement Sleep Behavior Disorder 
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by excessive muscle activity and undesirable motor events during REM sleep. RBD occurs in approximately 0.5% of the general population, with a higher prevalence in older men. RBD is a frequent feature of dementia with Lewy bodies (DLB), but is only rarely reported in Alzheimer’s disease. RBD is also a risk factor for α-synuclein-related diseases, such as DLB, Parkinson’s disease (PD), and multiple system atrophy. Therefore, RBD has major implications for the diagnosis and treatment of neurodegenerative disorders and for understanding specific neurodegeneration patterns. Several markers of neurodegeneration have been identified in RBD, including cognitive impairments such as deficits in attention, executive functions, learning capacities, and visuospatial abilities. Approximately 50% of RBD patients present mild cognitive impairment. Moreover, RBD is also associated with cognitive decline in PD.
doi:10.3389/fneur.2012.00082
PMCID: PMC3354332  PMID: 22629254
sleep; cognition; elderly; REM sleep behavior disorder; mild cognitive impairment; Parkinson’s disease; dementia with Lewy bodies
15.  Treatment Outcomes in REM Sleep Behavior Disorder 
Sleep medicine  2013;14(3):237-242.
Objective
REM sleep behavior disorder (RBD) is usually characterized by potentially injurious dream enactment behaviors (DEB). RBD treatment aims to reduce DEBs and prevent injury, but outcomes require further elucidation. We surveyed RBD patients to describe longitudinal treatment outcomes with melatonin and clonazepam.
Methods
We surveyed and reviewed records of consecutive RBD patients seen at Mayo Clinic between 2008–2010 to describe RBD-related injury frequency/severity as well as RBD Visual Analog Scale (VAS) ratings, medication dosage, and side effects. Statistical analyses were performed with appropriate non-parametric matched pairs tests before and after treatment, and with comparative group analyses for continuous and categorical variables between treatment groups. The primary outcome variables were RBD VAS ratings and injury frequency.
Results
Forty-five (84.9%) of 53 respondent surveys were analyzed. Mean age was 65.8 years and 35 (77.8%) patients were men. Neurodegenerative disorders were seen in 24 (53%) patients, and 25 (56%) received antidepressants. Twenty-five patients received melatonin, 18 received clonazepam, and 2 received both as initial treatment. Before treatment, 27 patients (60%) reported an RBD associated injury. Median dosages were melatonin 6 mg and clonazepam 0.5 mg. RBD VAS ratings were significantly improved following both treatments (pm=.0001, pc=.0005). Melatonin-treated patients reported significantly reduced injuries (pm=.001, pc=.06) and fewer adverse effects (p=0.07). Mean durations of treatment were no different between groups (for clonazepam 53.9 +/− 29.5 months, and for melatonin 27.4 +/− 24 months, p=0.13) and there were no differences in treatment retention, with 28% of melatonin and 22% of clonazepam-treated patients discontinuing treatment (p=0.43).
Conclusions
Melatonin and clonazepam were each reported to reduce RBD behaviors and injuries and appeared comparably effective in our naturalistic practice experience. Melatonin-treated patients reported less frequent adverse effects than those treated with clonazepam. More effective treatments that would eliminate injury potential and evidence-based treatment outcomes from prospective clinical trials for RBD are needed.
doi:10.1016/j.sleep.2012.09.018
PMCID: PMC3617579  PMID: 23352028
REM sleep behavior disorder; parasomnia; melatonin; clonazepam; treatment; side effects; tolerability; retention; injury; falls; synucleinopathy
16.  REM Sleep Behavior Disorder: Updated Review of the Core Features, the RBD-Neurodegenerative Disease Association, Evolving Concepts, Controversies, and Future Directions 
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams associated with simple or complex motor behavior during REM sleep. Patients appear to “act out their dreams,” in which the exhibited behaviors mirror the content of the dreams, and the dream content often involves a chasing or attacking theme. The polysomnographic features of RBD include increased electromyographic tone +/- dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straight-forward and effective.
In this review, the terminology, clinical and polysomnographic features, demographic and epidemiologic features, diagnostic criteria, differential diagnosis, and management strategies are discussed. Recent data on the suspected pathophysiologic mechanisms of RBD are also reviewed. The literature and our institutional experience on RBD are next discussed, with an emphasis on the RBD-neurodegenerative disease association and particularly the RBD-synucleinopathy association. Several issues relating to evolving concepts, controversies, and future directions are then reviewed, with an emphasis on idiopathic RBD representing an early feature of a neurodegenerative disease and particularly an evolving synucleinopathy. Planning for future therapies that impact patients with idiopathic RBD is reviewed in detail.
doi:10.1111/j.1749-6632.2009.05115.x
PMCID: PMC2902006  PMID: 20146689
REM sleep behavior disorder; parasomnia; synucleinopathy; neurodegenerative disease
17.  REM sleep behaviour disorder is associated with worse quality of life and other non-motor features in early Parkinson's disease 
Background
Concomitant REM sleep behaviour disorder (RBD) is commonly observed in patients with Parkinson's disease (PD). Although the brainstem structures responsible for the symptoms of RBD correspond to the premotor stages of PD, the association of RBD with motor and non-motor features in early PD remains unclear.
Methods
The study evaluated 475 patients with PD within 3.5 years of diagnosis for the presence of probable RBD (pRBD) using the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A neurologist and a trained research nurse carried out evaluation of each participant blinded to the results of the RBDSQ. Standardised rating scales for motor and non-motor features of PD, as well as health-related quality of life measures, were assessed. Multiple linear and logistic regression analyses were used to determine the relationship between pRBD and a variety of outcomes, controlling for confounding factors.
Results
The overall frequency of pRBD was 47.2% (95% CI 42.7% to 51.9%). None of the patients had a previous diagnosis of RBD. Patients with PD and concomitant pRBD did not differ on motor phenotype and scored comparably on the objective motor scales, but reported problems with motor aspects of daily living more frequently. Adjusted for age, sex, disease duration and smoking history, pRBD was associated with greater sleepiness (p=0.001), depression (p=0.001) and cognitive impairment (p=0.006).
Conclusions
pRBD is common and under-recognised in early PD. It is associated with increased severity and frequency of non-motor features, poorer subjective motor performance and a greater impact on health-related quality of life.
doi:10.1136/jnnp-2013-306104
PMCID: PMC3995329  PMID: 24187013
PARKINSON'S DISEASE; SLEEP DISORDERS; QUALITY OF LIFE
18.  Sleep-Related Declarative Memory Consolidation and Verbal Replay during Sleep Talking in Patients with REM Sleep Behavior Disorder 
PLoS ONE  2013;8(12):e83352.
Objective
To determine if sleep talkers with REM sleep behavior disorder (RBD) would utter during REM sleep sentences learned before sleep, and to evaluate their verbal memory consolidation during sleep.
Methods
Eighteen patients with RBD and 10 controls performed two verbal memory tasks (16 words from the Free and Cued Selective Reminding Test and a 220-263 word long modified Story Recall Test) in the evening, followed by nocturnal video-polysomnography and morning recall (night-time consolidation). In 9 patients with RBD, daytime consolidation (morning learning/recall, evening recall) was also evaluated with the modified Story Recall Test in a cross-over order. Two RBD patients with dementia were studied separately. Sleep talking was recorded using video-polysomnography, and the utterances were compared to the studied texts by two external judges.
Results
Sleep-related verbal memory consolidation was maintained in patients with RBD (+24±36% words) as in controls (+9±18%, p=0.3). The two demented patients with RBD also exhibited excellent nighttime consolidation. The post-sleep performance was unrelated to the sleep measures (including continuity, stages, fragmentation and apnea-hypopnea index). Daytime consolidation (-9±19%) was worse than night-time consolidation (+29±45%, p=0.03) in the subgroup of 9 patients with RBD. Eleven patients with RBD spoke during REM sleep and pronounced a median of 20 words, which represented 0.0003% of sleep with spoken language. A single patient uttered a sentence that was judged to be semantically (but not literally) related to the text learned before sleep.
Conclusion
Verbal declarative memory normally consolidates during sleep in patients with RBD. The incorporation of learned material within REM sleep-associated sleep talking in one patient (unbeknownst to himself) at the semantic level suggests a replay at a highly cognitive creative level.
doi:10.1371/journal.pone.0083352
PMCID: PMC3862769  PMID: 24349492
19.  Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers 
PLoS ONE  2015;10(7):e0132368.
Objective
In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC).
Methods
A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD.
Results
Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC.
Conclusions
Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.
doi:10.1371/journal.pone.0132368
PMCID: PMC4503402  PMID: 26177462
20.  Management of REM sleep behavior disorder: An evidence based review 
Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream enactment behavior resulting from a loss of REM skeletal muscle atonia. The neurobiology of REM sleep and the characteristic features of REM atonia have an important basis for understanding the aggravating etiologies the proposed pharmacological interventions in its management. This review outlines the evidence for behavioral and therapeutic measures along with evidence-based guidelines for their implementation, impact on falls, and effect on polysomnography (PSG) while highlighting the non-motor, autonomic, and cognitive impact of this entity. PubMed databases were reviewed upto May 2013 in peer-reviewed scientific literature regarding the pathophysiology and management of RBD in adults. The literature was graded according to the Oxford centre of evidence-based Medicine Levels. An early intervention that helps prevent consequences such as falls and provides a base for intervention with neuroprotective mechanisms and allocates a unique platform that RBD portrays with its high risk of disease conversion with a sufficiently long latency. RBD provides a unique platform with its high risk of disease conversion with a sufficiently long latency, providing an opportunity for early intervention both to prevent consequences such as falls and provide a base for intervention with neuroprotective mechanisms.
doi:10.4103/0972-2327.150927
PMCID: PMC4350192  PMID: 25745301
Behavioral modification; drug therapy including key pharmacological names; medication; RBD OR; REM Sleep behavior disorder and treatment
21.  Surface EMG activity during REM sleep in Parkinson’s disease correlates with disease severity 
Parkinsonism & related disorders  2014;20(7):766-771.
Objectives
Over 40% of individuals with Parkinson’s disease (PD) have rapid eye movement sleep behavior disorder (RBD). This is associated with excessive sustained (tonic) or intermittent (phasic) muscle activity instead of the muscle atonia normally seen during REM sleep. We examined characteristics of manually-quantitated surface EMG activity in PD to ascertain whether the extent of muscle activity during REM sleep is associated with specific clinical features and measures of disease severity.
Methods
In a convenience sample of outpatients with idiopathic PD, REM sleep behavior disorder was diagnosed based on clinical history and polysomnogram, and severity was measured using the RBD sleep questionnaire. Surface EMG activity in the mentalis, extensor muscle group of the forearms, and anterior tibialis was manually quantitated. Percentage of REM time with excessive tonic or phasic muscle activity was calculated and compared across PD and RBD characteristics.
Results
Among 65 patients, 31 had confirmed RBD. In univariate analyses, higher amounts of surface EMG activity were associated with longer PD disease duration (srho = 0.34; p = 0.006) and greater disease severity (p < 0.001). In a multivariate regression model, surface EMG activity was significantly associated with RBD severity (p < 0.001) after adjustment for age, PD disease duration, PD severity and co-morbid sleep abnormalities.
Conclusion
Surface EMG activity during REM sleep was associated with severity of both PD and RBD. This measure may be useful as a PD biomarker and, if confirmed, may aid in determining which PD patients warrant treatment for their dream enactment to reduce risk of injury.
doi:10.1016/j.parkreldis.2014.04.011
PMCID: PMC4407824  PMID: 24787758
Parkinson’s disease; REM sleep behavior disorder; REM sleep without atonia; Surface EMG activity
22.  Parasomnias: An Updated Review 
Neurotherapeutics  2012;9(4):753-775.
Parasomnias are abnormal behaviors emanating from or associated with sleep. Sleepwalking and related disorders result from an incomplete dissociation of wakefulness from nonrapid eye movement (NREM) sleep. Conditions that provoke repeated cortical arousals, or promote sleep inertia lead to NREM parasomnias by impairing normal arousal mechanisms. Changes in the cyclic alternating pattern, a biomarker of arousal instability in NREM sleep, are noted in sleepwalking disorders. Sleep-related eating disorder (SRED) is characterized by a disruption of the nocturnal fast with episodes of feeding after an arousal from sleep. SRED is often associated with the use of sedative-hypnotic medications; in particular, the widely prescribed benzodiazepine receptor agonists. Recently, compelling evidence suggests that nocturnal eating may in some cases be a nonmotor manifestation of Restless Legs Syndrome (RLS). rapid eye movement (REM) Sleep Behavior Disorder (RBD) is characterized by a loss of REM paralysis leading to potentially injurious dream enactment. The loss of atonia in RBD often predates the development of Parkinson’s disease and other disorders of synuclein pathology. Parasomnia behaviors are related to an activation (in NREM parasomnias) or a disinhibition (in RBD) of central pattern generators (CPGs). Initial management should focus on decreasing the potential for sleep-related injury followed by treating comorbid sleep disorders. Clonazepam and melatonin appear to be effective therapies in RBD, whereas paroxetine has been reported effective in some cases of sleep terrors. At this point, pharmacotherapy for other parasomnias is less certain, and further investigations are necessary.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0143-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-012-0143-8
PMCID: PMC3480572  PMID: 22965264
Parasomnia; Sleepwalking; Sleep terrors; REM sleep behavior disorder; Restless legs syndrome
23.  Increased Corticomuscular Coherence in Idiopathic REM Sleep Behavior Disorder 
The authors hypothesized that if locomotor drive increases along with rapid eye movement (REM) sleep without atonia in idiopathic REM sleep behavior disorder (RBD), then RBD patients would have greater corticomuscular coherence (CMC) values during REM sleep than at other sleep stages and than in healthy control subjects during REM sleep. To explore this hypothesis, we analyzed beta frequency range CMC between sensorimotor cortex electroencephalography (EEG) and chin/limb muscle EMG in idiopathic RBD patients. Eleven drug naive idiopathic RBD patients and 11 age-matched healthy control subjects were included in the present study. All participants completed subjective sleep questionnaires and underwent polysomnography for one night. The CMC value between EEGs recorded at central electrodes and EMGs acquired at leg and chin muscles were computed and compared by repeated measures analysis of variance (ANOVA). Sleep stages and muscle (i.e., chin vs. leg) served as within-subject factors, and group served as the between-subject factor. Repeated measures ANOVA revealed no significant main effect of group (F1,20 = 0.571, p = 0.458) or muscle (F1,20 = 1.283, p = 0.271). However, sleep stage was found to have a significant main effect (F2.067,41.332 = 20.912, p < 0.001). The interaction between group and sleep stage was significant (F2.067,41.332 = 3.438, p = 0.040). RBD patients had a significantly higher CMC value than controls during REM sleep (0.047 ± 0.00 vs. 0.052 ± 0.00, respectively, p = 0.007). This study reveals increased CMC during REM sleep in patients with RBD, which indicates increased cortical locomotor drive. Furthermore, this study supports the hypothesis that sufficient locomotor drive plays a role in the pathophysiology of RBD in addition to REM sleep without atonia.
doi:10.3389/fneur.2012.00060
PMCID: PMC3332227  PMID: 22536195
REM sleep behavior disorder; pathophysiology; corticomuscular coherence; REM sleep without atonia
24.  Abnormal metabolic network activity in REM sleep behavior disorder 
Neurology  2014;82(7):620-627.
Objective:
To determine whether the Parkinson disease–related covariance pattern (PDRP) expression is abnormally increased in idiopathic REM sleep behavior disorder (RBD) and whether increased baseline activity is associated with greater individual risk of subsequent phenoconversion.
Methods:
For this cohort study, we recruited 2 groups of RBD and control subjects. Cohort 1 comprised 10 subjects with RBD (63.5 ± 9.4 years old) and 10 healthy volunteers (62.7 ± 8.6 years old) who underwent resting-state metabolic brain imaging with 18F-fluorodeoxyglucose PET. Cohort 2 comprised 17 subjects with RBD (68.9 ± 4.8 years old) and 17 healthy volunteers (66.6 ± 6.0 years old) who underwent resting brain perfusion imaging with ethylcysteinate dimer SPECT. The latter group was followed clinically for 4.6 ± 2.5 years by investigators blinded to the imaging results. PDRP expression was measured in both RBD groups and compared with corresponding control values.
Results:
PDRP expression was elevated in both groups of subjects with RBD (cohort 1: p < 0.04; cohort 2: p < 0.005). Of the 17 subjects with long-term follow-up, 8 were diagnosed with Parkinson disease or dementia with Lewy bodies; the others did not phenoconvert. For individual subjects with RBD, final phenoconversion status was predicted using a logistical regression model based on PDRP expression and subject age at the time of imaging (r2 = 0.64, p < 0.0001).
Conclusions:
Latent network abnormalities in subjects with idiopathic RBD are associated with a greater likelihood of subsequent phenoconversion to a progressive neurodegenerative syndrome.
doi:10.1212/WNL.0000000000000130
PMCID: PMC3963420  PMID: 24453082
25.  MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies 
Neurology  2013;81(19):1681-1689.
Objective:
To determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.
Methods:
Patients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.
Results:
pRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.
Conclusion:
Presence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.
doi:10.1212/01.wnl.0000435299.57153.f0
PMCID: PMC3812105  PMID: 24107861

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