Interview questions

	[01:50]	As a medical student, resident and later on as a psychiatrist, how did you become interested in Sleep Medicine?
	[10:08]	It was known since antiquity that some individuals act out their dreams (for instance Don Quixote), but despite Jouvet’s experiments in the cat in the 1960's, the medical establishment failed to pay notice until your and your colleagues’ description in the medical literature 30 years later. In your book Paradox Lost you describe dramatically the discovery in 1982 of RBD in conjunction with Mark Mahowald and Andrea Patterson. Please tell us about the book.
	[12:30]	Would you comment on the neurological nature of RBD?
	[14:00]	Would you comment on parasomnia overlap disorder?
	[15:56]	You are also interested in narcolepsy, a disabling condition that is more prevalent than multiple sclerosis. What is the association with RBD?
	[18:07]	What is the current consensus on the clinical significance of RBD and future research?
	[21:44]	These important developments should be known not only to neurologists but to all physicians who care for patients, yes?
	[22:38]	Personal question: When you go to Barcelona, do you lecture in English or Spanish?

Overview

The discovery of RBD and its strong association with alpha-synuclein neurodegenerative disorders and narcolepsy-cataplexy

Rapid eye movement sleep behavior disorder is a parasomnia that consists of abnormal behavioral release during REM sleep, emerging with loss of the mammalian skeletal muscle paralysis of REM sleep, "REM-atonia" (01). REM sleep behavior disorder (RBD) is the only parasomnia that requires objective polysomnographic confirmation. The polysomnographic hallmark of RBD is the electromyographic abnormality “REM without atonia,” with increased muscle tone or increased phasic muscle twitching. RBD represents how one of the defining features of mammalian REM sleep, ie, REM-atonia, can become impaired, permitting abnormal behavioral release during REM sleep. A person with RBD moves with eyes closed while attending to the inner dream environment and being completely unaware of the actual bedside surroundings, a highly vulnerable state that poses a risk for serious and even potentially lethal injury (22). The enacted dreams usually involve confrontations with unfamiliar people and animals, and the dreamer is rarely the primary aggressor but, rather, is usually defending himself or his parnter. The reported dream action closely matches the behaviors observed by the spouse and, during video-polysomnography evaluation, a phenomenon called “isomorphism.” The recurrent, disruptive, and aggressive sleep behaviors are what usually prompt clinical evaluation and treatment (23).

The traditional clinical profile of RBD involves predominantly middle-aged and older men with aggressive, dream-enacting behaviors, with more than 80% of them eventually developing an overt alpha-synucleinopathy (23). This profile now needs to be modified, given a recent population-based study of middle-aged to older adults with polysomnography-confirmed RBD that found a 1.06% prevalence of RBD--and with gender parity (08). Because women generally have less aggressive and injurious RBD, they present for medical attention much less frequently than men. Therefore, the traditional RBD profile has reflected a clinical referral bias on account of more aggressive and injurious RBD behaviors in men compared to women. However, because both male and female middle-aged and older patients with RBD are equally at risk for eventually developing alpha-synucleinopathies, once a promising neuroprotective (disease-modifying) agent becomes available, a concerted effort must be initiated to find the women with RBD who had not sought medical attention (along with men having mild RBD); it is the presence of REM without atonia or RBD, and not its severity, that carries the strong risk for future parkinsonism.

Historical background

The first description of REM sleep behavior disorder was the fictional account written by Cervantes in Don Quixote:

“…he was thrusting his sword in all directions, speaking out loud as if he were actually fighting a giant. And the strange thing was that he did not have his eyes open, because he was asleep and dreaming that he was battling the giant…He had stabbed the wine skins so many times, believing that he was stabbing the giant, that the entire room was filled with wine…” Don Quijote de la Mancha, I, Cap. XXXV (“Aventura De Los Cueros De Vino”) [1605]

The first clinical description of REM sleep behavior disorder was provided by James Parkinson in An Essay on the Shaking Palsy (1817), the treatise on the disease that bears his name. Case VI:

“His attendants observed, that of late the trembling would sometimes begin in his sleep, and increase until it awakened him: when he always was in a state of agitation and alarm…when exhausted nature seizures a small portion of sleep, the motion becomes so violent as not only to shake the bed-hangings, but even the floor and sashes of the room…” [underlining added] (Credit herein is given to Michael J Howell MD, my former sleep medicine fellow, and now my colleague at the University of Minnesota, for finding James Parkinson’s description of RBD. Dr. Howell is currently Associate Editor of the sleep disorders section of Medlink Neurology.)

The first experimental animal (cat) model of RBD, which closely resembles human RBD, was developed in 1965 by Michel Jouvet and colleagues in Lyon, France (23). This model involved bilateral dorsolateral pontine lesions during unequivocal paradoxical sleep (the basic science term for REM sleep, with the paradox being generalized skeletal muscle atonia during an otherwise highly activated brain state). Subsequent experimental animal models of RBD have been developed in mice and rats.

In humans, various polysomnographic and clinical aspects of chronic and acute RBD were described from 1966 to 1985 by investigators from Japan, Europe, and North America, almost exclusively in the settings of neurologic disorders and acute drug intoxication or withdrawal states (23). However, RBD was not formally identified as a distinct clinical disorder emerging from unequivocal REM sleep until 1986, when our group at the Minnesota Regional Sleep Disorders Center published a series of five cases in Sleep, and the next year we expanded our series to 10 cases and named rapid eye movement sleep behavior disorder in JAMA (18; 21; 19). Our initial series of 10 cases included five cases with idiopathic RBD. After increasing our series and following our first 29 patients with idiopathic RBD, we eventually found a 38% conversion rate from idiopathic RBD to an overt synucleinopathy in 1996 (20); with further follow-up, we found an 81% conversion rate in 2013 (16). The Barcelona group found a virtually identical 82% conversion rate from idiopathic RBD to overt synucleinopathy (11). Parkinson disease and dementia with Lewy bodies were equally represented, with multiple system atrophy comprising a much smaller group. The mean interval from idiopathic RBD onset to overt synucleinopathy in the two series was 11.5 years and 14.2 years, respectively (range, 5 to 29 years). These findings set off a major international clinical and basic science research effort on RBD and alpha-synucleinopathies, to be described below.

Personal background

I was primed for discovering RBD by a memorable experience during my neurophysiology class as a first-year medical student in 1973 at the State University of New York at Buffalo. As I wrote in my book about the discovery of RBD (pages 15 to 17):

Emeritus Professor Sir John Carew Eccles delivered a special lecture… The general opinion was that Dr. Eccles would summarize the research for which he was awarded the Nobel Prize in Physiology or Medicine in 1963 [for identifying the electrochemical transformations across the synaptic cleft]. As it turned out, the lean Australian [from Melbourne—where my daughter now practices medicine] stood in front of our class…and launched into a declaration that the brain is very active during sleep…Dr. Eccles turned on an audio cassette player, and we heard amplified recordings of cat brain electrical activity during REM sleep. It sounded like relentless machine-gun fire or the bursting of metallic popcorn. Dr. Eccles emphasized that there is not one instance of the brain shutting down during sleep…The brain does not hibernate while we sleep; the brain directs our sleep as we sleep…Dr. Eccles’ message had a lasting impact for at least one medical student in attendance (14).

I subsequently wrote to Professor Eccles about our discovery of RBD and my clear memory of his lecture, and he responded by hand on December 8, 1987 from his home in Contra, Ticino, Switzerland, with this letter later being scanned into my book. He finished his letter by stating that “I still go on working after 12 years of retirement and have just completed another book—my 8th in retirement—on the evolution of the human brain with, of course, the coming-to-be of self-consciousness.”

So that early medical school experience with the Eccles lecture and the fascinating revelation about the dynamic neurophysiology of sleep was tucked in my memory bank when I had just become a member of the Minnesota Regional Sleep Disorders Center, 1 year after completing my psychiatry residency at the University of Minnesota in 1981. At one of our psychiatry staff meetings at the Hennepin County Medical Center in Minneapolis, my Chief of Psychiatry asked if anyone was interested in joining the recently formed sleep center run by the Deptartment of Neurology that was establishing a multidisciplinary sleep center. I was the only volunteer.

On my first day at the sleep clinic, September 11, 1982, the second patient on my schedule was a 67-year-old married man who complained of "physical moving dreams" and "violent moving nightmares." As described by Michael Long at the start of his story in the December 1987 issue of National Geographic magazine ("What Is This Thing Called Sleep?"):

The crowd roared as running back Donald Dorff, age 67, took the pitch from his quarterback and accelerated smoothly across the artificial turf. As Dorff braked and pivoted to cut back over tackle, a huge defensive lineman loomed in his path. One hundred twenty pounds of pluck, Dorff did not hesitate. But let the retired grocery merchandiser from Golden Valley, Minnesota, tell it: “There was a 280-pound tackle waiting for me, so I decided to give him my shoulder. When I came to, I was on the floor in my bedroom. I had smashed into the dresser and knocked everything off it and broke the mirror and just made one heck of a mess. It was 1:30 a.m.”

Five nights later, Mr. Dorff was studied in our sleep laboratory, where I spent the night in observation, and he demonstrated REM without atonia along with prominent limb jerking and twitching and a variety of complex behaviors during REM sleep. I initiated therapy with a tricyclic antidepressant, hoping to suppress enough REM sleep to minimize his RBD episodes, but the anticholinergic side effects were prohibitive. So I then turned to clonazepam, as he also had periodic limb movements throughout sleep, and at that time the neurology literature contained reported cases on the benefit of clonazepam for “nocturnal myoclonus” (the original term for periodic limb movements in sleep). Lo and behold, clonazepam (0.5 mg before bed) exerted immediate and sustained nightly benefit—both for the abnormal behaviors and the abnormal dreams of RBD. The subsequent literature has documented 80% to 90% efficacy of clonazepam in RBD, and the American Academy of Sleep Medicine, in its Best Practice Guidelines published in 2010, identifies clonazepam as first-line therapy of RBD, along with medium-high dose melatonin.

So my career with RBD began the same day as my career in sleep medicine. And, of course, I had much more than a little help from my friends, beginning with my esteemed longstanding colleague and friend, the sleep neurologist Mark W Mahowald MD, who was cofounder of our sleep center. His stellar career was summarized in the obituary I wrote, together with his daughter Carrie and the noted basic sleep researcher J Allan Hobson, after his demise in 2019 (24).

Subsequent history of RBD and the close link with alpha-synucleinopathies and narcolepsy

Two key linked brainstem nuclei responsible for generating REM-atonia have been identified from elegant basic science studies in rats by the P-H Luppi group in Lyon: (1) the glutamate sublateral dorsal nucleus in the pontine tegmentum and (2) the GABA-ergic and glycine-ergic ventromedial medulla inhibitory neurons. Genetic inactivation of these nuclei produced RBD in the rats (15). These nuclei and their connecting pathways are now known to be the early targets for attack by alpha-synuclein in the evolution of parkinsonian degeneration (Parkinson disease, dementia with Lewy bodies, multiple system atrophy). In fact, the Movement Disorder Society research criteria for prodromal Parkinson disease declared that idiopathic or isolated REM sleep behavior disorder has a likelihood ratio (LR) of 130 for Parkinson disease conversion, along with a predictive value greater than 10x higher than any other clinical marker (eg, LR=4 for olfactory dysfunction and LR=10 for abnormal motor examination) and a predictive value greater than 3x higher than any biomarker (LR=40 for abnormal dopaminergic PET/SPECT findings) (04). Therefore, idiopathic RBD is the earliest and strongest predictor of future overt Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. Furthermore, the risk of neurodegeneration with idiopathic RBD is extraordinarily high, as found in a recent meta-analysis of longitudinal studies, with conversion rates being 33%, 82%, and 97% at 5-year, 10.5-year, and 14-year follow-ups, respectively (07). Conversely, the RBD prevalence in Parkinson disease is almost 50%, and the presence of RBD in Parkinson disease is associated with widespread increased Parkinson disease morbidity across multiple domains. Also, RBD is present in 90% of reported cases of multiple system atrophy and in 75% of reported cases of dementia with Lewy bodies. Consequently, the 2017 updated dementia with Lewy bodies Diagnostic Criteria published by the DLB Consortium, listed RBD as one of the core features of clinically probable dementia with Lewy bodies (definite dementia with Lewy bodies requires autopsy confirmation) (12).

On account of idiopathic RBD being considered prodromal parkinsonism, the International RBD Study Group (IRBD-SG) was formed in 2007, and I was the founding president. To date, there have been 15 annual international symposia involving more than 150 RBD clinical researchers and basic scientists from more than 20 countries and five continents. More than 20 peer-reviewed journal articles have been published to date by the IRBD-SG. A major focus of the research effort has been to identify the predictors of imminent phenoconversion from idiopathic RBD to parkinsonism within several years, for inclusion of these patients in studies testing promising neuroprotective agents. The eight working groups include: biomarkers, imaging, neurophysiology, genetics, basic science, clinical, treatment and trials, and epidemiology. A recent article by the IRBD-SG published in The Lancet Neurology identified that the level of quantitated REM without atonia is the strongest biomarker for predicting imminent phenoconversion from idiopathic RBD to overt parkinsonism (13). Many clinical and basic science members of the IRBD-SG contributed chapters to the first textbook on RBD that was published in 2018 by Springer (Schenck CH, Hogl B, Videnovic A, editors). RBD has been included in the second (2005) and third (2014) editions of the International Classification of Sleep Disorders (01).

The NIH-funded North American Prodromal Synucleinopathy (NAPS) Consortium for RBD was formed in 2018 (and NAPS2 in 2021), involving nine research centers, including the University of Minnesota (NIH R34AG056639 and U19AG071754) NAPS (2018) and NAPS2 (2021). The primary purpose involves neuroprotective treatment trial planning in RBD, recognizing that idiopathic RBD is a prodromal synucleinopathy. This preparation involves establishing a registry of patients with RBD (300+), developing and performing quantitative biological and functional measures of synucleinopathy burden, and establishing a formal process to evaluate candidate neuroprotective agents. The comprehensive effort includes clinical assessments; clinician diagnosis; fluid biomarkers; quantitative REM without atonia measurements; functional assessments (cognitive, visuospatial, motor, sensory, sleep, pareidolia, psychiatric or neuropsychiatric, and autonomic). With NAPS2, there will be the opportunity to address unmet educational needs in the community by involving the general public, physicians, nurses, and other health care providers.

RBD and narcolepsy

Our group first identified the association of RBD with narcolepsy in 1992 (23), and now RBD is known to be present in up to 60% of patients with narcolepsy type 1 (hypocretin-deficient) and represents a distinct phenotype of RBD, with gender parity, earlier age of onset than with idiopathic REM sleep behavior disorder, lower frequency of RBD episodes, less complex movements during REM sleep, less aggressive and violent RBD behaviors, and more even distribution of RBD episodes across all REM epochs compared to idiopathic RBD (03). However, it is premature to conclude that RBD is an intrinsic feature of narcolepsy because a complete understanding of the RBD-narcolepsy phenotype is still lacking, with some patients having normal CSF HCRT levels; also, RBD may be found in patients with narcolepsy type 2 (without cataplexy) (03). Therefore, other factors probably play a role that needs future identification. Furthermore, optimal therapy of RBD in narcolepsy has not been sufficiently studied, and there is no evidence indicating that patients with RBD-narcolepsy are at increased risk for future neurodegeneration. A recent biomarker study comparing 17 patients with narcolepsy type 1 RBD and 30 with idiopathic RBD found that 87% of patients with idiopathic RBD had positive skin biopsies for phosphorylated alpha-synuclein deposits, whereas 0% of patients with narcolepsy type 1-RBD had positive skin biopsies (02). Therefore, clinicians managing patients with RBD-narcolepsy can be confident about the lack of apparent risk for these patients to develop future neurodegeneration.

Parasomnia overlap disorder: RBD and NREM parasomnias

RBD can emerge as an isolated parasomnia, or it can emerge with an NREM parasomnia, designated as “parasomnia overlap disorder” with generalized motor dyscontrol across REM and NREM sleep. Parasomnia overlap disorder was formally described and named by our sleep center in 1997 with a series of 33 cases that emerged idiopathically or symptomatically with neurologic and other disorders (17). The mean age at presentation was 34 years, and the mean age of parasomnia onset was 15 years (range 1 to 66 yars); 70% were males. An idiopathic subgroup (n=22) had a significantly earlier mean age of parasomnia onset (9 years) than a symptomatic subgroup (n=11) (27 years). Since 1997, the literature on parasomnia overlap disorder has grown considerably and has expanded to include appetitive NREM sleep parasomnias (sleep-related eating disorder; sexsomnia or sleepsex), rhythmic movement disorder, and additional types and CNS locations of symptomatic cases. More than 150 cases of parasomnia overlap disorder have been published to date, with more than half being idiopathic parasomnia overlap disorder cases (15). The risk for future neurodegeneration remains unknown in patients with idiopathic parasomnia overlap disorder who are under age 50 years, just as with idiopathic RBD in the younger adult age group. Additionally, the late-life onset of sleepwalking is now known to be associated with Parkinson disease, and when there is also coexisting RBD, parasomnia overlap disorder is present in Parkinson disease (06).

RBD in children, adolescents, and adults younger than 50 years of age

The phenotype of RBD in patients under 50 years of age has now been recognized to differ from the traditional RBD phenotype of middle-aged or older men with aggressive RBD behaviors. Younger patients with RBD have greater gender parity, less severe RBD, greater association with narcolepsy-cataplexy, greater association with psychiatric disorders and with antidepressant use, greater association with the parasomnia overlap disorder, and, perhaps, also greater association with autoimmune diseases. RBD in children and adolescents, although rare, is usually associated with narcolepsy-cataplexy, parasomnia overlap disorder, brainstem tumors, and antidepressants as therapy for depression and cataplexy. Most antidepressant medications (especially selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants) can trigger or aggravate RBD, but bupropion, a dopaminergic-noradrenergic agent, does not.

Acute RBD typically emerges in the context of acute toxic-metabolic disturbances and acute drug withdrawal states, along with a variety of other emergent conditions. A review article on RBD covers the topics in this section, along with a discussion of the broad range of neurologic and other disorders that can disturb normal REM-atonia with emergence of RBD (15). Three other pertinent review articles on RBD are recommended (05; 10; 09).

In conclusion, RBD is a rapidly expanding clinical and research field, and my career has participated in and witnessed these developments from the time of reporting on our initial series of five patients in 1986 (18; 19).