Clinical Context

Rapid eye movement (REM) sleep is an important part of healthy sleep, and it is the phase of sleep during which most dreams occur. The brain usually creates muscle atony during REM sleep, which protects humans from acting out our dreams. However, approximately 1% of the population has rapid eye movement sleep behavior disorder (RBD), in which this protective atonia is lost during REM sleep. The authors of the current study describe that dysfunction of GABA-based neuronal mechanisms contributes to RBD, and therefore antidepressants and benzodiazepines can be used to treat RBD. The monoaminergic dorsal and median raphe nuclei are particularly implicated in the pathology of RBD.

RBD may be a precursor for other serious neurologic conditions, including parkinsonism and dementia. The current study analyzes a potential link between RBD and chronic traumatic encephalopathy (CTE).

Study Synopsis and Perspective

RBD is surprisingly common in athletes and may signal CTE caused by brainstem tau and Lewy body pathologies, new research suggests.

CTE is a neurodegenerative disorder linked to years of repetitive head impacts from playing professional football and other contact sports.

"Repetitive head impacts may damage sleep-relevant brainstem nuclei and lead to REM sleep behavior disorder," senior author Thor Stein, MD, PhD, a neuropathologist at VA Boston Healthcare, Massachusetts, said in a webinar hosted by the Concussion Legacy Foundation.

"This is something both athletes and their doctors need to be aware of," added Dr Stein, assistant professor of pathology and laboratory medicine at Boston University School of Medicine.

The findings were published September 17 in Acta Neuropathologica.

Surprising Findings

In RBD, the paralysis that normally occurs during REM sleep is incomplete or absent, causing people to act out their dreams by talking, flailing their arms and legs, punching, kicking, and other behaviors while asleep.

"The disorder often comes to medical attention when there is an injury or potential for injury to the individual or the individual's bed partner," Dr Stein noted.

To investigate ties between CTE and RBD, the researchers analyzed the brains of 247 deceased male contact sports athletes that were donated to the Veterans Affairs-Boston University-Concussion Legacy Foundation (VA-BU-CLF) Brain Bank.

The athletes died at a mean age of 63 years. They all had a neuropathological diagnosis of CTE. Their relatives provided information on sleep.

Nearly one third of these athletes (n=80, 32%) with CTE displayed symptoms characteristic of RBD when they were alive. "That really surprised us," said Dr Stein. "This is about 30 times more than what's reported in the general population, where it has been estimated to be present in about 1% of people," he noted.

In addition, there was a clear dose-response effect. Athletes with CTE and RBD had played contact sports for significantly more years than their peers without RBD (18.3 vs 15.1 years; P=.02).

"The odds of reporting RBD symptoms increased about 4% per year of play," first author Jason Adams, an MD/PhD student now at the University of California, San Diego, said in a statement.

New Insight

The results also point to a potential cause for RBD.

Compared with who have CTE and no RBD, those who have CTE and RBD were nearly 4 times more likely to have tau pathology within brainstem nuclei involved in REM sleep (odds ratio [OR], 3.96; 95% confidence interval [CI], 1.43-10.96; P=.008). Athletes with CTE and RBD were also more likely to have Lewy body pathology (OR, 2.36; 95% CI, 1.18-4.72; P=.02).

"Contrary to our expectations, tau pathology in the raphe nuclei was more strongly associated with RBD than Lewy body pathology, suggesting that tau pathology is more likely to lead to sleep dysfunction in CTE," Dr Stein said.

Christopher John Nowinski, PhD, cofounder and chief executive officer of the Concussion Legacy Foundation, said this study is important because it identifies a potential cause of RBD.

Dr Nowinski, a former professional wrestler, developed RBD after suffering years of concussions and still suffers from the disorder today.

"Living through this, I can tell you, this is not a benign symptom by any stretch of the imagination," said Dr Nowinski, who moderated the webinar. "You are a danger to yourself; you are a danger to others. Hopefully, this study will help us better understand treatment going forward," he said.

Reached for comment on the study, Carmela Tartaglia, MD, Marion and Gerald Soloway Chair in Brain Injury and Concussion Research at the University of Toronto, Canada, said sleep studies are "the most important" factor that needs to be considered when making a diagnosis of probable RBD.

"It is very important to do sleep studies, as it is often difficult to rely on informants, since nightmares and talking in sleep is often misreported as RBD. A polysomnography is the gold standard," Dr Tartaglia told Medscape Medical News.

Another factor is the use of medications. "Although the authors mention antidepressants and benzodiazepines can cause sleep changes, acetylcholinesterase inhibitors (used to treat Alzheimer's disease) are often associated with nightmares and so could be playing an even larger role in misdiagnosis of RBD," Dr Tartaglia said.

In her view, the results of increased brainstem tau pathology associated with RBD should be "pondered in light of recent findings that brainstem tau pathology is an early finding in Alzheimer's disease and that is an illness not associated with RBD."

Summing up, Dr Tartaglia said "changes in sleep are increasingly recognized in concussion and should be studied in prospective studies that include polysomnography so that an accurate diagnosis of RBD can be made. It would be interesting to see the replication of these results in a cohort of such patients."

Support for the study was provided by the Department of Veterans Affairs, the Alzheimer's Association, the National Institutes of Health, Concussion Legacy Foundation, Andlinger Foundation, and World Wrestling Entertainment. Adams and Dr Stein have disclosed no relevant financial relationships.

Acta Neuropathol. Published September 17, 2020.^[1]

Clinical Implications

• RBD is associated with the loss of muscle atony during REM sleep. Dysfunction of GABA-based neuronal mechanisms contributes to RBD, and monoaminergic dorsal and median raphe nuclei are particularly implicated in the pathology of RBD.
• In the current study, 32% of men with a history of repeated head injuries were found to have probable RBD. Probable RBD was not associated with rates of cognitive decline or age at death, but men with RBD were more likely to have NFTs and Lewy body pathology in the dorsal and median raphe nuclei.
• Implications for the Healthcare Team: The healthcare team should obtain a history of head injury among patients with suspected RBD and work to ensure protection against future head trauma. Including discussing any findings at team meetings and educating the individual patient about the risks of RBD.

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