In this video, Carlos H. Schenck, MD, Professor of Psychiatry, University of Minnesota Medical School; Senior Staff Physician, Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, Minneapolis, Minnesota, discusses his recent Tom Roth Lecture of Excellence at the Associated Professional Sleep Societies' Virtual SLEEP 2021 meeting, “REM Sleep Behavior Disorder: Past, Present, and Future.”

Dr. Schenck, Founding President of the International RBD Study Group, and colleagues first reported on REM Sleep Behavior Disorder (RBD) in 1986.

He discusses past and recent findings on the effects on RBD, along with promising upcoming projects. 

Read the transcript: 

Dr. Carlos H. Schenck:  My name is Carlos Schenck. I'm a Professor of Psychiatry at the University of Minnesota Medical School in Minneapolis, and Senior Staff Physician at the Minnesota Regional Sleep Disorders Center, located at Hennepin County Medical Center in Minneapolis.

Now, I was asked to give the Tom Roth Lecture of Excellence, at the recent SLEEP 2021 meeting. The title of my talk was "Rapid Eye Movement Sleep Behavior Disorder: Past, Present, and Future."

Now, the reason I was asked to give this talk is that back in 1982, together with colleagues, we identified the first patient with a new parasomnia, or sleep behavior disorder, that we named REM sleep behavior disorder or (RBD). Then over the next few years, we had gathered a series of five patients with this new parasomnia and we published our findings in the journal SLEEP in 1986.

As a brief background, REM sleep is characterized by a highly energized state, with the cortex being very much activated and that generates our dreaming. However, part of the high energy of REM sleep is also dedicated to an active muscle paralysis called REM atonia.

Basic scientists have identified two key nuclei in the brainstem. In the pons, the sublateral dorsal nucleus in the rat that has a glutamate projection to the medial medulla that then is activated and sends inhibitory descending projections to the alpha spinal motor neurons, or the spinal cord, and that generates the act of paralysis of REM sleep, which is a protective paralysis. So, people can dream and not have to act out their dreams and they are protected.

Well, RBD is the syndrome where that muscle paralysis of REM sleep has been compromised. We now know that a major cause of that compromise of REM atonia is the attack of alpha-synuclein, the pathological basis of the alpha-synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.

As it turns out, RBD is the earliest and most powerful predictor of future alpha- synucleinopathies and that's why the field of neurology is greatly interested in RBD is it’s the sentinel symptom and sign of a future Parkinson's disease.

The race is on to identify newer protective or disease modifying therapies to then slow down or halt the progression from RBD to frank parkinsonism. The identification of RBD, that I will describe in more detail shortly, basically is the first hallmark of alpha-synucleinopathy.

These are sleep physicians who make the diagnosis, and then we refer to neurologists, particularly movement disorder specialists, to monitor these patients because it's a matter not of if, but when.

Meta-analyses have published cases, a case series. These analyses have identified that by 14-year follow-up, 97 percent of idiopathic RBD patients will be phenoconverted generally to dementia with Lewy bodies or Parkinson's disease.

Even the two cases published with neuropathology of idiopathic RBD patients, they showed alpha-synuclein in the brainstem. They had not progressed clinically to have frank alpha-synucleinopathy, but they had the pathological basis in the brainstem despite their clinical diagnosis of idiopathic RBD.

To go backwards, when we had first identified RBD in 1986, four of my five patients actually had diverse neurological disorders that, now we know, had adversely impacted the REM atonia system. One patient was idiopathic.

The next year, in 1987, we published our series of 10 cases in the "Journal of the American Medical Association." In that series of 10 cases, 5 were idiopathic and 5 had diverse neurological disorders. So, RBD actually can be an expression of diverse neurological disorders that have a negative impact on REM atonia in the brainstem.

Generally, about 50 percent of our new cases of RBD are so-called idiopathic. When we followed them over time, we published in the Journal of Neurology in 1996 that 38 percent had converted to Parkinson's disease, dementia with Lewy bodies, and a few to multiple system atrophy.

When we extended our follow up in 2013, we had converted 81 percent of our idiopathic patients to frank synucleinopathy. The Barcelona group published similar findings in Lancet Neurology, shortly afterwards, that 82 percent of their series of patients with idiopathic RBD had converted to an alpha-synucleinopathy.

As I said already, it's not a matter of if but when patients will phenoconvert from idiopathic RBD to frank Parkinson's disease or dementia with Lewy bodies, generally.

There is screening questionnaire, a validated screening question published in Movement Disorders, 2012. Ron Postuma was the first author. It's a very simple screening questionnaire that can be used in a variety of clinics, particularly general medical clinics, neurology clinics, and geriatric clinics.

The question is, "Have you ever been told or suspected yourself that you seem to be acting at your dreams such as throwing punches, flaring your arms or making running movements?" This is a very good initial screen for a possible REM sleep behavior disorder.

I should point out that in the international classification of sleep disorders 3rd edition published by the American Academy of Sleep Medicine, RBD is the only parasomnia or sleep behavior disorder that requires a sleep lab study called video-polysomnography.

The reason is that the objective hallmark of RBD is loss of REM atonia. At least a quarter of REM sleep should have loss of REM atonia to be confident in the diagnosis of RBD together with the clinical history of patients repeatedly acting out their dreams, injuring themselves or bed partners.

All the other parasomnias do not necessarily require a sleep lab study such as sleep walking or night terrors, but RBD requires that. The reason is because of the objective hallmark of loss of REM atonia. Now, if you look at the situation the other way around, up to 50 percent of patients of Parkinson's disease have RBD.

Now we know that 75 percent of patients of dementia Lewy bodies which is the alpha-synucleiopathy causing dementia, the second most common cause of dementia after Alzheimer's disease, one of the core diagnostic criterion now, the current diagnostic criteria for dementia with Lewy bodies requires RBD as one of the core criteria. That tells you how common RBD is with dementia Lewy bodies.

We now have an international RBD study group. I was the founding president in 2009-2010 comprised of basic scientists and clinicians. We have yearly symposia to really understand more and more about RBD at the basic level and also at the clinical level. Furthermore, we now have an NIH funded NAPS Consortium, N-A-P-S, which signifies North American Prodromal Synucleinopathy Consortium.

10 of the leading centers in the country including our center at the University of Minnesota are enrolling patients with idiopathic RBD and going through a battery of tests to identify a whole variety of prodromal markers. For example, loss of smell, color vision discrimination, a variety of imaging defects, and many prodromal markers for future Parkinson's disease which patients of idiopathic RBD have.

These patients are being enrolled and it's critical to have them prepared for when promising neuroprotective therapy is available. I've been told that on the horizon, maybe within three to five years, there will be promising neuroprotection available to test, in a double blind fashion, patients with idiopathic RBD who are at high risk for phenoconversion.

To obtain funding for such studies, we need to identify the cluster of biomarkers affecting these patients with idiopathic RBD for imminent phenoconversions meaning within one to three years. We're also never get funding if we say while we can predict that 50 percent will convert in 5 to 10 years. That's too much of a long timeline.

We are identifying the cluster of biomarkers for Parkinsonian disorders that patients of idiopathic RBD have, to enroll them in neuroprotection studies. There's a study that was approved by the journal of The Lancet Neurology that will be coming out.

Many members of our international RBD study group were authors of this paper and it's on the biomarkers in RBD for predicting phenoconversion to Parkinsonian disorders and an emphasis is on the cluster biomarkers that can predict imminent phenoconversion that can be used for enrolling patients in these studies.

The NAPS Consortium is really a very important effort to have these patients enrolled. They're highly motivated because they know they're such at high risks for converting the Parkinson's disease and dementia Lewy bodies.

Quite honestly, if you have anybody that you suspect to have RBD and it's confirmed in a certified sleep lab then you can contact one of the members of our consortium. There's a website for the NAPS Consortium, N-A-P-S, and they can be enrolled. There's something that neurologists can do to help patients with newly diagnosed RBD.

I do also want to point out the good news. RBD can be clinically treated in the vast majority of cases. These patients come in basically saying, "I'm hurting myself or my bed partner acting out dreams." There's about 90 percent efficacy rate with bedtime clonazepam 0.5mg, 1.0mg and/or melatonin up to 18mg at bedtime.

That's the good news. You can control the clinical complaint in RBD patients. Unfortunately, that does not translate into any neuroprotection. It protects people from injury and from sleep disruption, but it does not slow down or halt the progression to frank Parkinson's.

The initial case series involved middle-aged and older men, because it's the men with RBD that have the more aggressive and violent episodes. That generates the clinical referral, but we now know through epidemiologic studies that just as many women suffer from RBD compared to men, but they have milder cases of RBD. They fall under the radar screen.

These were two community-based studies, one in Switzerland, one in Japan. They went out into the community to do an epidemiological study. That's why the equal male-female ratio was identified. These were not clinical patients.

Clinical patients are male predominant because of the more aggressive and violent RBD, but women are just as much at risk for future conversion to Parkinsonian disorders regardless of the clinical severity of their RBD. That's why it's important to do that screening questionnaire in clinics, because the questionnaire is about acting out dreams, not about becoming injured.

When neuroprotection becomes available, we need to find women with milder cases of RBD, also the men with mild cases of RBD who do not present to a sleep center because there's not any or very minimal sleep-related injury.

The worldwide prevalence now is one percent of RBD. That equals the one percent prevalence of schizophrenia. So, RBD is really not that rare. People like to say it's a rare disorder, but the reality is, it's not that rare.

Some questionnaire studies have even found a prevalence in older adults of seven percent RBD. Clearly, the older the age of the person, the higher the risk for RBD. That coincides with the risk of Parkinsonian disorders.

Parkinson's disease is a very slowly evolving neurodegenerative disorder. You reach a point where you cross the threshold to satisfy the diagnostic criteria for Parkinson's disease or dementia Lewy bodies.

All neurologists know that you identify patients early on with some bradykinesia. You refer to their face as being a Parky face, a Parkinsonian face with diminished facial mobility. It's a gradually evolving process. Then you reach a threshold point.

What's important is that RBD is a sentinel feature. Even before there's mild Parkinsonian signs, RBD is the earliest and the strongest indicator for future Parkinson's disease. I think neurologists need to be aware of the entity of RBD.

They should be aware of sleep centers that are not just sleep apnea sleep centers but full-service sleep centers for diagnosing a whole range of sleep disorders, including the parasomnia as particularly RBD, so that you can work closely with the sleep physicians and start following these patients with newly diagnosed RBD, and to hopefully enroll them in the NAPS Consortium for neuroprotection.

I should also point out for neurologists that up to 16 percent of narcolepsy with cataplexy patients, which is narcolepsy type 1, also have RBD. It's a milder form of RBD. It's a different phenotype. Follow-up studies have indicated that patients of narcolepsy and RBD are not at increased risk for any future Parkinson's disease.

That's important, because as soon as a patient is diagnosed with RBD, that patient and/or family or friends are going to look up RBD on the Internet, and they will quickly find the association with Parkinsonian disorders.

You have to allay any fears in newly diagnosed patients with narcolepsy type 1 and RBD that they are not at increased risk of future Parkinson's disease. It's a different phenotype of RBD.

I should also point out that RBD can be triggered by virtually all antidepressant medications, except for bupropion, which is a very unique and also a very effective antidepressant that's noradrenergic and dopaminergic.

If you have a patient with RBD who also has a clinical depression that needs pharmacotherapy, then unless otherwise clinically contraindicated, that patient should be treated with bupropion because you know that antidepressant will not aggravate the RBD.

It's interesting that virtually all antidepressants can trigger RBD. There is obviously a very small subset of all treated patients with antidepressant medicines.

Studies have already shown that the subset of patients who develop RBD triggered by antidepressant medicines already have the biomarkers of Parkinsonian disorders, such as loss of sense of smell, color vision discrimination problems, and all the other biomarkers that are contained in that Lancet Neurology article that will be published in a matter of months.

You have to keep that in mind as well in terms of antidepressant-induced RBD. RBD can also emerge in children with brain stem tumors, the treatment of cataplexy with antidepressant medications and is also a parasomnia overlap disorder, in which RBD is combined with a non-REM parasomnia such as sleepwalking and sleep terrors.

RBD can be part of a more generalized sleep motor dyscontrol disorder. The younger adults with RBD generally have milder forms of RBD in contrast to the middle-aged and older men that have the most aggressive and violent cases of RBD.

In RBD, the dream enactment is not enactment of typical dreams but much more confrontational and aggressive dreams. RBD is a dream disorder as much as or nearly as much as a behavior disorder of sleep. This has generated a lot of research interest on dreams in RBD, since these are very atypical dreams that are being enacted.

The basic scientists are doing a lot of great research. They have introduced alpha-synuclein into the brain stem in mice and also in rats and replicates clinical RBD. This is a very nice animal model for alpha-synuclein in the brain stem triggering classic RBD. This mimics the progression for the idiopathic RBD in humans to frank Parkinsonian RBD.

This is clearly a very hot topic in the field of movement disorders and also in sleep medicine, parasomnia research, and dream research. As I said before, the good news is that RBD can be treated clinically with melatonin and/or clonazepam at bedtime. However, that does not slow down or halt the progression to frank Parkinsonian disorders.

That's why we have started the NAPS Consortium to get everyone ready to be enrolled in future neuroprotective studies. Hopefully, that will start taking place within maybe two to three years.

Thank you very much.