ARTICLE IN BRIEF
A new study provides a comprehensive review of the clinical characteristics of REM sleep behavior disorder, indicating the disorder is a non-motor subtype within a common disease process that includes Parkinson's disease, Lewy body dementia, multiple system atrophy, and other disorders.
REM sleep behavior disorder (RBD) appears to represent an early occurring form of synucleinopathy — often with non-motor symptoms as severe or worse than those in early Parkinson's' disease (PD). It is also a risk factor for PD and related disorders, according to a large cohort study in an online edition of Sleep. The study compared patients with RBD to controls and those with untreated PD.
While the relationship between RBD and PD is well established, the author of the paper and those who reviewed it for Neurology Today said the new study provides a comprehensive review of the clinical characteristics of RBD, indicating the disorder is a non-motor subtype within a common disease process that includes PD, Lewy body dementia, multiple system atrophy, and other disorders.
Moreover, the study suggests certain clinical features — body mass index less than 30, use or nonuse of antidepressants, and age over 60 — may be factors useful for risk stratification, though the findings require replication; the study indicates the risk for hyposmia (indicative of risk for conversion to PD) is highest for patients who are not using antidepressants, have a BMI under 30, and are over age 60.
“We don't yet have enough follow-up data to say that all RBD patients have prodromal Parkinson's, but based on other studies, the risk is high, with probably more than 75 percent of RBD patients eventually developing Parkinson's or a related disorder,” said Thomas Barber, MD, a clinical research fellow at the University of Oxford Parkinson's Disease Centre.
Dr. Barber and colleagues assessed 171 RBD patients recruited from sleep disorders clinics at three centers in England, 296 healthy controls, and 119 untreated PD patients. Putative risk measures were assessed as predictors of prodromal neurodegeneration using Movement Disorders Society (MDS) criteria for prodromal PD.
A comprehensive, structured medical history was taken from all participants including comorbidities, demographic information, environmental and occupational exposures, medications, and family history.
The researchers assessed motor features using part III of the Movement Disorders Society-revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS), as well as a battery of other mobility and odor identification tests. And they evaluated cognition using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Participants were also screened for common leucine-rich repeat kinase 2 (LRRK2), and for glucocerebrosidase gene (GBA) gene mutations, both of which are associated with PD.
Results showed that patients with RBD had impairments in a wide range of Parkinsonian non-motor characteristics, performing significantly worse than controls in the MMSE, MoCA, and in measures of olfaction, constipation, and orthostatic hypotension. In all of these tests, RBD participants were at least as impaired as PD participants, according to the report.
“The significance of our study is partly its size — this is the largest study of its kind to date and it replicates many of the findings of other smaller studies,” Dr. Barber said. “The important take-home message is that many non-motor Parkinsonian features are already present in patients with RBD, and these might be useful in risk-stratifying patients for future development of Parkinson's disease. We have looked at various methods for estimating risk, but validation of these will require further long-term follow up.”
Dr. Barber emphasized that psychiatric features — depression, anxiety, and apathy — among patients with RBD are worse than those with early PD, and in other features (such as cognition, constipation, postural hypotension) they are equally impaired. “Since RBD patients are earlier in the neurodegenerative process, this suggests that they may be in the prodromal phase of a subtype of parkinsonism with a more severe neuropsychiatric and non-motor phenotype,” he told Neurology Today.
Additionally, genetic testing indicated that GBA mutations — but not LRRK2 mutations — were more common among RBD patients. “The genetic findings also support the idea that RBD patients are not representative of all prodromal PD but rather a disease subtype,” Dr. Barber said.
Putative risk factors for progression to prodromal PD — BMI under 30, age over 60, and non-use of antidepressants — require further investigation. Dr. Barber explained that RBD can be precipitated by use of antidepressants (potentially indicating cases that may be unrelated to the disease process leading to synucleinopathy).
“Although we excluded patients whose RBD developed in conjunction with starting antidepressants, it may be that in those already taking them, RBD is unmasked at an earlier prodromal stage than it otherwise would have been without the medication,” he told Neurology Today. “This would mean that on average they would be at lower risk of short-term conversion to a Parkinsonian disorder.”
Independent experts agreed the study provides a more comprehensive picture of the clinical picture of the disorder as part of a common disease process that encompasses the synucleinopathies.
Ron Postuma, MD, MSc, assistant professor at McGill University in Montreal, explained that RBD — in which an individual reflexively enacts dreams while sleeping — represents a dysfunction of the neural system that normally paralyzes movement during dreams. “What we believe is going on is that a Parkinson's-like disease process is in fact affecting those areas before the motor system itself becomes measurably abnormal,” he said. “It may be that PD spreads along the nervous system but starts outside the motor system.”
Dr. Postuma praised the methodological rigor of the analysis. “We already knew most of what it finds, but what the study does is put it all together, comprehensively, with an analysis of a large cohort and very clear results,” he said.
For clinicians, he emphasized the preventive potential of early identification of patients with RBD. “Clinicians should be aware of this disorder and the fact that nearly everyone with it is going to get PD or a related disorder,” he said.
“They just haven't yet experienced motor symptoms, because PD doesn't start in the motor system. This is an amazing opportunity for intervention in the earliest stages of the disease.”
Clifford B. Saper, MD, PhD, FAAN, chairman of the department of neurology at Beth Israel Deaconess Medical Center, agreed. “The findings are very strong, and in alignment with previous studies that showed that patients with idiopathic RBD have higher UPDRS scores, hyposmia, decreased visual grating acuity, early aspects of Lewy body dementia, sympathetic denervation, and alpha-synuclein in peripheral nerves — in other words, the full range of non-motor Parkinson spectrum findings,” he told Neurology Today.
He added: “I think that everyone in the field is now in agreement that nearly all patients who start with idiopathic RBD will develop a synucleinopathy — Parkinson disease, Lewy body dementia, or multiple system atrophy — with about half having developed it within about 12-14 years after diagnosis.”
The bottom line? “If a practicing neurologist sees a patient with idiopathic RBD, that patient almost certainly will have PD or LBD within the next 10-20 years,” Dr. Saper said. “They need to be followed for development of other symptoms that can be treated.”
Michael Silber, MBChB, professor of neurology at the Mayo Clinic College of Medicine and Science, who also reviewed the report, urged clinicians treating patients with clear RBD, but no sign of motor or cognitive problems, to look for such ancillary symptoms as hyposmia or constipation, which may represent a more rapid progression to synucleinopathy. “Patients will say, ‘I haven't been able to smell anything in years,’” he said. “It's one of the first manifestations of synucleinopathy. We believe that these disorders may begin in the olfactory bulb or the autonomic neurons of the GI tract before spreading to the nervous system and the brain.”
Dr. Barber added that RBD is likely to be under-reported and under-diagnosed. “The disorder might only come to medical attention because of treatment for other comorbidities such as obstructive sleep apnea and depression,” he said. “We hope that our study will increase awareness of the condition and its importance as a marker of prodromal Parkinson's.”