REM Sleep Behavior Disorder: Predicting Conversion to Synucleinopathy
As a marker of impending neurodegeneration, urgency surrounds efforts to slow or stop the progression of REM sleep behavior disorder.
Erik K. St. Louis, MD, MS
Rapid eye movement (REM) sleep behavior disorder (RBD), in which people act out their dreams, affects an estimated 0.5% of the general population, with the highest prevalence found among elderly individuals and males.1 A sizeable body of research supports a multifaceted link between RBD and certain neurogenerative diseases.
“There is a convincing, consistent, and extremely strong association between RBD and the alpha-synucleinopathies, including Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA),” Erik K. St. Louis, MD, MS, co-director of the Center for Sleep Medicine and associate professor of neurology at Mayo Clinic College of Medicine, told NeurologyLive®. The presence of idiopathic RBD (iRBD) in older adults is likely a prodromal marker of eventual conversion to an alpha-synucleinopathy rather than a truly idiopathic condition.
“The rate of conversion is dependent on the duration of the diagnosis of RBD, with longer duration incurring higher risk,” noted Andrew Varga, MD, PhD, assistant professor in the Division of Pulmonary, Critical Care, and Sleep Medicine at the Icahn School of Medicine at Mount Sinai.Longitudinal studies have reported an 80% to 90% risk of conversion to an alpha-synucleinopathy within 14 to 16 years after RBD symptoms emerge. The prevalence of RBD in patients with MSA, DLB, and PD is 80% to 95%, 50% to 80%, and 30% to 50%, respectively.1
“Time from the diagnosis of RBD to the diagnosis of neurodegenerative disease is 6 years on average, but for some individuals it can be 10 years or longer,” according to Emmanuel During, MD, director of the Stanford Parasomnia Clinic and clinical assistant professor in the Department of Psychiatry, Division of Sleep Medicine, and in the Department of Neurology at Stanford University.2 In patients with PD, studies have observed faster motor progression, reduced treatment response, and greater postural instability in those who converted from RBD.3
Secondary RBD
RBD can also occur secondary to other neurologic or sleep disorders and certain other conditions, and as an adverse effect of some medications, including antidepressants.3 Some evidence indicates that these cases may foretell the development of neuro-degeneration, albeit to a lesser extent than iRBD.
In a 2013 study, for example, patients with RBD who were taking antidepressants showed abnormalities in 12 neurodegenerative markers compared with matched controls: olfaction (P = .007), color vision (P = .004), Unified Parkinson Disease Rating Scale II and III (P<.001 and P <.007), Timed Up and Go (P = .003), alternate-tap test (P= .002), Purdue Pegboard (P = .007), systolic blood pressure drop (P = .029), erectile dysfunction (P = .002), constipation (P = .003), depres-sion indices (P <.001), and prevalence of mild cognitive impairment (13% vs 60%; P <.001).4
Overall, these patients had a lower 5-year risk of developing neuro-degenerative disease versus patients with RBD not taking antidepres-sants (22% vs 59%; risk ratio 0.22; 95% CI, 0.06-0.74). While the connection with possible neurodegenerative risk in this group needs to be further studied, RBD “due to other known conditions such as multiple sclerosis or narcolepsy is not associated with risk of developing a synucleinopathy,” During said in an interview with NeurologyLive®.
RBD affects up to 60% of patients with narcolepsy,5 although “RBD is not predictive of narcolepsy or vice versa,” said Meena Khan, MD, assistant professor in the Division of Pulmonary, Critical Care, and Sleep Medicine at the Ohio State University Wexner Medical Center. In addition, “iRBD tends to occur around age 55 years or older and mostly in males, while narcolepsy tends to manifest in the second and third decades of life.” It is possible that, in some cases, RBD may result from medications used to treat narcolepsy that can lead to loss of REM atonia.
“In the setting of narcolepsy, RBD may manifest as a breakdown in the normal boundaries across states, with intrusion of REM sleep without atonia (RSWA) and clinical dream enactment behaviors into REM sleep,” explained St. Louis. “There has been evidence in children and adults with narcolepsy that the presence of RSWA during polysomnography may help to discriminate narcolepsy type 1, in which RSWA is more likely to be present, from type 2, in which RSWA is less prominent or absent.”6
During advised that other nondegenerative disorders—such as RBD associated with posttraumatic stress disorder (PTSD), which is increasingly reported in veterans—should also be considered.7 In study results recently published in Sleep, researchers at the VA Portland Health Care System and Oregon Health & Science University found overall prevalence rates of 9% for RBD, 7% for RSWA, and 31% for other parasomnias in a sample of 394 veterans (94% male; mean age, 54.4 years).7 The prevalence of RBD was even higher in participants with PTSD (15%) and those with both PTSD and traumatic brain injury (21%). It is unclear whether RBD associated with these disor-ders increases the risk of synucleinopathy, as observed in iRBD.
“Importantly, among the non-synucleinopathies, patients tend to develop RBD concurrently or after the onset of the disorder, whereas in alpha-synucleinopathies, RBD typically presents as a prodromal condition years or decades before the symptomatic onset of the core diagnostic features of PD, DLB, and MSA,” wrote Suescun et al.1 “The fact that RBD regularly occurs in alpha-synucleinopathies and rarely in other neurodegenerative diseases is supported by the concept of early involvement of the brainstem neuronal networks that control REM sleep, with a temporal sequence that begins in the medulla and eventually ascends to more rostral structures, compromising the sublaterodorsal nucleus and leading to RSWA and RBD.”
Diagnosing RBD
“When a patient complains about abnormal behavior in sleep, it is important to distinguish whether it sounds consistent with RBD versus non-REM parasomnia, which involves behaviors that the patient is not aware of, [such as] if they are awakened, they are disoriented and cannot describe a vivid dream they were acting out,” Khan said. “If the history sounds consistent with RBD, a sleep study should be done to look for loss of REM atonia. Also, the sleep study will diagnose if the patient has obstructive sleep apnea (OSA), as untreated OSA can increase the frequency of RBD by fragmenting sleep, and there are case reports of RBD resolving by treating OSA.”
In cases in which RBD behaviors are frequent or dangerous, treatment initially involves educating patients about good sleep hygiene, treating the underlying etiology such as OSA, followed by medication—typically clonazepam or melatonin—if the behaviors persist. “All patients with RBD should be counseled on the association with development of Parkinson and Parkinson-like diseases,” advised Khan.
Along with the opportunity to identify a synucleinopathy as the likely cause of disease in patients with parkinsonism or neurocognitive disorder if RBD and/or RSWA are present, St. Louis said that other benefits of “considering polysomnography in these patients can include the opportunity to diagnose and treat other sleep comorbidities such as sleep-disordered breathing, periodic leg movements of sleep with significant associated arousal and sleep comfragmentation, or discovery of sleep-related stridor (implying underlying multiple system atrophy),” thus improving their sleep quality, cognition, and quality of life (FIGURE)
Predictors of Conversion From iRBD to Synucleinopathy
“Once RBD is diagnosed, there are certain symptoms, such as loss of sense of smell and constipation, that predict more likely conversion to a synucleinopathy,” said Varga. In a large prospective multicenter study published in Brain, Postuma et al examined risk factors and rates of conversion to primary dementia or parkinsonism among 1280 patients with iRBD from 24 centers of the International RBD Study Group.8The overall conversion rate was 6.3% annually, with a median time to conversion of 8.0 years. The risk of conversion was 73.5% after 12 years.
They identified the following predictors of conversion: abnormal quantitative motor testing (HR, 3.16), objective motor examination (HR, 3.03), olfactory deficit (HR, 2.62), mild cognitive impairment (HR, 1.91-2.37), erectile dysfunction (HR, 2.13), motor symptoms (HR, 2.11), an abnormal dopamine transporter scan (HR, 1.98), color vision abnormalities (HR, 1.69), constipation (HR, 1.67), REM atonia loss (HR, 1.54), and age (HR, 1.54). These prodromal markers can be used to stratify patients for future trials investigating potential neuroprotection in patients with iRBD.
St. Louis and colleagues recently demonstrated that quantitative RSWA is a biomarker for synucleinopathies such as PD even in the absence of clinically overt dream enactment of RBD.9 Among 77 patients with parkinsonism, elevated submentalis muscle activity distinguished synucleinopathy from tauopathy with high sensitivity (70%-77%) and specificity (95%-100%). In another study, they found that increased RSWA during polysomnography was predictive of more rapid phenoconversion to parkinsonism in patients with iRBDs.10
As an early predictor of underlying synucleinopathy, “the most promising diagnostic marker is cutaneous deposition of alpha-synuclein, which can be detected with high sensitivity in about two-thirds of patients with iRBD, and with total specificity, meaning that synuclein deposition in the skin is not found in other neurolog-ical diseases or with ‘normal’ aging,” During said.11 “Furthermore, if a skin biopsy does not detect synuclein in an individual with RBD, it may be positive if repeated 1 to 2 years later, and then becomes diagnostic.” The skin biopsy could have 100% predictive value, based on the current evidence; however, this test is not yet widely accessible, as it is available at only 4 medical centers worldwide, including Stanford University and Harvard University—Beth Israel Deaconess Medical Center.
“Other tests to support a diagnosis of RBD due to an underlying alpha-synucleinopathy include tests of heart rate and blood pressure, to detect early specific patterns of autonomic dysfunction, as well as smell tests, since loss of smell is another early sign of neurode-generation,” During added. A 2015 study reported that results of the Sniffin’ Sticks test (both the entire test and the identification subtest) predicted conversion from iRBD to Lewy body disease with 82.4% accuracy (95% CI, 66.1%-92.0%) over a period of 5 years in a sample of 34 patients. Compared with the top 2 tertiles of olfactory function, the relative risk for a Lewy body disease was 7.3 in the lowest tertile (95% CI, 1.8-29.6).12 Additionally, smartphone apps are available that can detect subtle motor impairments indicative of parkinsonism that cannot be detected on standard examination by a physician. “These various biomarkers may be used individually or in combination to estimate the likelihood that someone has RBD due to synucleinopathy versus RBD due to another cause such as PTSD,” noted During.
Future Directions
“There are many remaining research needs, starting with an expan-sion of treatment options for RBD, as well as tools to validate the efficacy of those treatments, since often subjects are not good about recalling dream enactment event frequency or vigor,” Varga told NeurologyLive®. “There are also ample research opportunities to evaluate interventions that could potentially slow or eliminate the progression of idiopathic RBD to a synucleinopathy.”
During and colleagues are currently pursuing this avenue in research, with support by the National Institutes of Health. He noted that many patients with RBD are aware of the conversion risk since the topic and supporting evidence are widely discussed online. “The next question is, ‘What can be done to prevent this progression, and [when] is it too late?’ We believe that these patients would most benefit from neuroprotective drugs, as they typically have several years until their neurological disease becomes manifest,” said During. However, current drug research focuses solely on patients at later disease stages—that is , those with a formal diagnosis of PD or DLB.
During and colleagues at Stanford and several other large academic centers in the United States and Canada are collaborating in preparation for the first neuroprotective trial in patients diagnosed with RBD. “This effort is called the North American Prodromal SynucleinopathyConsortium, and this study, the first of its kind, should soon lead to the enrollment of patients in clinical trials of drugs that could slow down or reverse disease progression,” During explained.
St. Louis pointed to the need for further prospective studies to “confirm the utility of polysomnography as a diagnostic tool for parkinsonism and cognition impairment in adults without dream enactment behavior symptoms.” He also noted that some patients in the general population show RSWA on polysomnography without having yet developed RBD. This represents a “research frontier during the course of future prospective cohort studies to determine whether such patients are at risk of conversion to clinical RBD or alternative overt synucleinopathy/Lewy body disease phenotype.”
Another promising focus of research involves the use of wearable technology or devices to measure RBD activity in the home environment. Even simple measures of movement—via actigraphy or accelerometers, for example—have shown approximately 80% accuracy in distinguishing between RBD and other movements during sleep, according to During. “Other technologies to stage sleep and [to track] abnormal muscle activity need to be explored outside the laboratory setting, using [tools like] video or motion sensors, electroencephalography, eye movement signals, and muscle sensors,” he said. “These technologies, used individ-ually or in combination in patients’ homes and over several nights or weeks, could allow for early diagnosis and large-scale population screening. [But] until such technologies are validated, the in-lab poly-somnography will remain the gold standard procedure.”
