"REM Behavior Disorder, Past, Present and Future" Carlos Schenck (03/02/2022)

March 06, 2022

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00:15Alright, so good afternoon everyone
00:18and welcome to Yale Sleep Seminar.
00:20So just a couple reminders.
00:22Sleep seminar lectures are available for
00:24CME credit and to receive credit text.
00:27The ID for the lecture to Yale
00:29Cloud CME by 3:15 PM today.
00:31Recordings of the lecture available within
00:33two weeks at the site noted in the chat.
00:35And if you have questions during the talk,
00:37please use the chat and we will
00:40moderate these questions at the end.
00:41So it is my pleasure to introduce
00:43today's sleep seminar speaker today.
00:45Doctor Carlos Shank,
00:46Dr Schenk is professor of psychiatry
00:48at the University of Minnesota
00:50Medical School and is a senior staff
00:52psychiatrist at Minnesota Regional
00:54Sleep Disorder Center and Hennepin
00:56County Medical Center in Minneapolis.
00:58He received his BA from Johns
01:00Hopkins in his MD from State
01:01University of New York at Buffalo.
01:03He completed a residency in psychiatry
01:05at the University of Minnesota.
01:07We stayed on as faculty and is
01:09now Professor of psychiatry.
01:11As many in this audience know in
01:13the mid to late 1980s Doctor Shank,
01:15along with his colleague Scott Lindley,
01:17Andrea Patterson and Mark Mahowald reported
01:20on a new category of parasomnia that
01:23they named REM Sleep Behavior Disorder.
01:25In 1996,
01:26Doctor Shank and his colleagues
01:28first reported that RBD commonly
01:30heralds future parkinsonism,
01:32and in 2009 Doctor Shank was the founding
01:34president of the International REM
01:36Sleep Behavior Disorder Study Group,
01:38which is held yearly research symposia
01:41and today has published more than 15
01:43collaborative monthly central articles.
01:45Doctor Shank himself has authored
01:47a 200 peer reviewed publications,
01:49many chapters in several books.
01:51He's the lead editor of the first
01:53textbook on REM Sleep Behavior disorder.
01:56Published in 2018 over his career,
01:59Doctor Shank has been active in
02:00that in our CAN Academy of Sleep
02:02Medicine and other organizations.
02:04He was Co chair of the Parasomnias
02:06Committee for the ICS.
02:07D2 was a member of the Parasomnias
02:09Committee for the ICS D3 and is
02:11currently a member of the ASM Parasomnias
02:13Task Force for the ICS D3 revision.
02:15He served as an associate editor for
02:18the journal Sleep in 2010 to 2021.
02:20He's he's on the editorial board of the
02:22journal Sleep Science and has served
02:24as the North America representative.
02:26For the World Sleep society,
02:29Doctor Schenk is currently chair
02:30of the World Sleep Society,
02:31Parasomnias taskforce reevaluating
02:33guidelines for video.
02:35Polysomnographic procedures in
02:37diagnosing REM behavior disorder.
02:39Doctor Shank and Doctor Mckell together
02:41received the William C Dement Academic
02:43Achievement Award from the American
02:44Academy of Sleep Medicine in 2007 for
02:47their research on RBD and other Paris.
02:49Obvious,
02:49he's also the recipient of the
02:51Sleep Research Society outstanding
02:53Scientific Achievement Award and
02:54the Sleep Science Award for the
02:57American Academy of Neurology,
02:58so we are truly honored to have
03:00Doctor Shank with us today to
03:02discuss when behavior disorder,
03:04past,
03:04present and future to welcome.
03:08Thank you very much. I'm really honored
03:10to be invited to participate in and
03:13talk at the Yale Medicine Seminar,
03:15and I want to salute Mayor Krieger,
03:17who I go way back with and I had a recent
03:19chat with when I was in Santa Rosa,
03:21CA visiting an old colleague John
03:23Sasson and then a number of years ago,
03:26shortly before he came to Yale,
03:28we participated in the CME Symposium
03:30in his hometown of Winnipeg.
03:32So anyway, hello mayor.
03:33And it's wonderful for me to talk
03:36to members of your sleep center.
03:38And here's my disclosure.
03:41Really nothing to disclose.
03:43As it turns out,
03:44RBD was first described in the
03:46literature by Cervantes, Denver, 1605.
03:50And here's the passage.
03:52He was thrusting his sword in all directions,
03:54speaking out loud as if he
03:56were actually fighting a giant.
03:58And the strange thing was that
03:59he did not have his eyes open
04:01because he was asleep and dreaming
04:03that he was battling the giant.
04:05He had stabbed the wineskin so many times,
04:07believing that he was stabbing the giant,
04:09that the entire room was filled with wine.
04:12Very impressive. Sequence of events.
04:16There's actually an early scientific
04:18history for a various bits and
04:20pieces of RBD from 1965 and to 1985,
04:23including rent without a Tonio in Europe,
04:26Japan, and the United States.
04:28But really that no one was
04:29definitive in saying this was true.
04:31REM sleep, the Japanese,
04:33for example,
04:34talked about it quite a peculiar
04:37stage of sleep,
04:38and even Christian gammino at Stanford.
04:40He wrote about Stage 7 sleep I I never
04:42got to talk to Christian about how
04:44he came up with Stage 7 sleep, but.
04:46Anyway,
04:47there was a 20 year history of early
04:49identification of bits and pieces,
04:51almost like the fable of touching
04:53the elephant in the dark,
04:54and I'm getting to know certain parts
04:56of the elephant without understanding
04:58the entirety of the elephant.
05:00So we first reported an RBD in 1986.
05:05And then, as you just heard,
05:07we identified 10 years later
05:09that 38% of 29 older men,
05:12initially diagnosed with idiopathic
05:13when sleep behavior disorder had
05:15converted to Parkinson's Parkinsonism.
05:17And I will discuss this further
05:20later in my presentation.
05:22However,
05:23I want to give credit to my former
05:24Sleep Medicine fellow and now
05:26colleague and sleep neurology at the
05:28University of Minnesota, Mike Howell.
05:30He read the original descriptions
05:32of patients by.
05:35By James Parkinson disease that bears
05:37his name on an essay of the shaking
05:40pause the 1817 and lo and behold,
05:42Mike identified the first clinical
05:45description of RBD with case number 6 quote.
05:49His attendance observed that of late,
05:51the trembling with sometimes begin
05:53in his sleep and increased until
05:55it awakened him when he was always
05:56in a state of agitation and alarm.
05:59When exhausted,
06:00nature seizures a small portion of sleep,
06:02the motion becomes so violent
06:04as not only to shake.
06:05With bed hangings,
06:06but even the floor and the
06:08sashes of the room,
06:10very great description of RBD in a
06:13patient with Parkinson's disease now
06:15Fast forward we now know that RBD
06:17is present in 50% of patients with
06:20PD and we also know that isolated,
06:22which is a term we use now instead
06:24of at the opathic isolated RBD is the
06:26earliest and the strongest predictor
06:28of future Parkinson's disease,
06:30which I will discuss later in my talk.
06:33So I found in my archives.
06:36A patient that would have been
06:39described by James Parkinson.
06:41Look what this man does with his
06:42legs in this crescendo sequenced.
07:12Imagine this man's wife sleeping
07:14with him as she did many years.
07:16She woke up, exhausted in the morning.
07:23And he remained in REM sleep.
07:24This is from our sleep lab back in 1987,
07:27and he remained in REM sleep,
07:29so this is really the closest example
07:31I could come up with for what James
07:34Parkinson had described in patient #6.
07:38Now I wrote a book about our discovery
07:41of RBD and I named it paradox loss for
07:43the reason I'm now going to explain and
07:45this is a our first patient who was in a
07:48sequence of throwing 12 consecutive punches.
07:51REM sleep actually has a number of synonyms.
07:53First of all, active sleep and
07:55this is from the basic scientist.
07:57There's an activated, e.g.,
07:58increased use of oxygen and glucose increase.
08:02Cerebral blood flow is paradoxical.
08:04Sleep is actually the favorite term for
08:06REM sleep among the basic scientists,
08:08because the paradox is that you haven't.
08:10Activated brain state.
08:11But there's generalized muscle paralysis.
08:14We call REM Atonia and a major share
08:16of the brain activation in REM sleep
08:19is actually devoted to establishing
08:21and maintaining REM Antonia,
08:23which is generated in the brain stem.
08:25So R.E.M.
08:26Sleep behavior disorder involves the
08:28loss of REM atonia due to abnormal brain
08:31activity from disease and also medications.
08:33And that's why I called REM
08:35sleep behavior disorder.
08:35Paradox lost because you actually have
08:38active rated rent sleep brain state.
08:40With the loss of paralysis, eyes closed,
08:43behavior release and dream enactment.
08:45And obviously there's major vulnerability
08:46in a great risk for injury.
08:49This is our original patient Mr.
08:50Donald door from Golden Valley, MN.
08:52Very nice gentleman,
08:54as most of these patients are.
08:57He was married 41 years.
08:58He described his RPD beautifully
09:00as physical moving dreams,
09:02violent moving nightmares,
09:03and he had this American football dream
09:06which triggered his referral to our
09:08sleep center. He dreamt that he was.
09:11A halfback carrying the ball
09:13through the line of scrimmage and
09:15he ran into the enormous defensive
09:17back and smashed into the ground.
09:19And when he woke up he was on
09:21the other side of the room after
09:22smashing into the dresser and he
09:23drew blood and that's why he came to
09:25our sleep center and he was shocked
09:27when he woke up in his bedroom.
09:28He was shocked because he was
09:30not on a football field.
09:31This is how real the dreams are.
09:33He he was amazed he was
09:35actually in his bedroom.
09:36Now he was interviewed by Michael
09:38Long and at December 1987 National
09:40Geographic Magazine article which
09:42is really a great article covering.
09:44The whole field of hours and sleep.
09:46What is this thing called sleep quote
09:48the route the crowd roared is running
09:51back Donald Dorf age 67 took the pitch
09:53from his quarterback and accelerated
09:55smoothly across the artificial turf,
09:57as Dorf braked and pivoted
09:59to cut back over tackle.
10:00A huge defensive lineman loomed in his path.
10:04120 pounds of pluck dwarf did not hesitate,
10:07but let the retired grocer grocery
10:10merchandiser from Golden Valley,
10:11MN tell a quote.
10:12There was a 280 pound tackle waiting for me,
10:16so I decided to give him my
10:17shoulder when I came to.
10:18I was on the floor in my bedroom.
10:20I had smashed into the dresser and
10:22knocked everything off it and broke
10:24the mirror and just made one heck
10:26of a mess. It was 1:30 AM so this
10:29is a very dramatic case of RBD.
10:32And now we want to give credit to my
10:34longstanding colleague and friend,
10:35Mark Mahowald, director of our
10:37Sleep Center from 1982 to 2010,
10:39and he passed away two years ago.
10:41But he was just the best colleague.
10:44Great educator,
10:45researcher and also a really
10:47distinguished himself in public
10:49service in the field of Sleep Medicine.
10:52This is our second patient who had
10:54to tether himself to bed every night
10:56to protect himself from leaping
10:58out of bed and injuring himself.
11:00So this is a montage that I
11:02created in 1990 of a vigorous
11:04and aggressive RBD behaviors.
11:09Let me ask you, the viewer,
11:11how you would react upon hearing
11:12that a man was regularly punching
11:14and kicking his wife at night in bed
11:16while dreaming that he was being
11:18attacked and fighting to save his life.
11:20Suppose you are a physician and
11:22a patient reports that he is tide
11:24himself by a rope to the bedpost
11:26every night for eight years to keep
11:29him from leaping out of bed and
11:31becoming injured during violent
11:33nightmares and what have other
11:35patients mentioned that they usually
11:36retire at night to a sleeping bag?
11:38Or to a padded waterbed in order to
11:41protect themselves and bed partners from
11:43their wild dream and acting behaviors.
11:45What explanations come to mind to account
11:48for such bizarre nocturnal events?
11:51As it turns out,
11:52there is a medical cause and a simple
11:55and safe medical treatment for this type
11:57of striking dangerous sleep problem.
12:00Since 1982,
12:01for the past five years,
12:03during the course of routine
12:05clinical practice as physicians,
12:07we have evaluated 30 patients
12:09afflicted with the rapid eye
12:11movement sleep behavior disorder.
12:13This condition has received official
12:15recognition by the Association
12:17of Sleep disorder centers.
12:19These three patients,
12:20usually very calm and pleasant,
12:22middle age or older men
12:25without psychiatric disorder,
12:26presented for help on account of violent
12:29dream enacting behaviors during sleep,
12:31which resulted in numerous injuries
12:34to themselves and their spouses
12:36for up to 20 years before their
12:38sleep problem was understood
12:39and proper treatment initiated.
12:41Their injuries included bone fractures,
12:45lacerations requiring stitches,
12:46and deep bruises.
12:49So now you see the most common
12:51reason why patients have RBD.
12:52I refer to the sleep center.
12:54It's not a subtle problem,
12:55however, I'm going to address
12:57the issue of mild RBD later,
12:58which has great clinical importance as well.
13:02So here's the nice example of the contrast
13:05between normal REM sleep you have the
13:08REMS and look at the emgs the legs.
13:11Arms, the chin.
13:13They all show the the normal,
13:15a Tony of REM sleep and then the the
13:18lower panel with RBD you see tremendous
13:20increase in tone and phasic activity.
13:23So this is the contrast between normal
13:26REM atonia and increased muscle
13:28tone and facial twitching with RBD.
13:31I just wanted to go over the diagnostic
13:33criteria and I should point out
13:35that RBD is the only parasomnia
13:36for which video polysomnography is
13:38required and I make a very important
13:40point when I review articles.
13:42A lot of authors still call
13:45BBD BBD without video.
13:46Polysomnographic documentation,
13:47which is not proper.
13:49You have to call it possible or
13:51probable RBD and based on the
13:53ICS D3 you have to have video
13:56Poly sonography documentation.
13:58So you need repeated episodes
14:00of sleep related vocalization
14:01and or complex motor behaviors.
14:03Second,
14:03these behaviors are documented by
14:05V PSG to occur during REM sleep or
14:07based on clinical history of agreement.
14:09Act meant are presumed to occur
14:12during REM sleep.
14:13And PSG recording demonstrates
14:14REM sleep without a Tonia.
14:17And of course,
14:17the disturbance is not better
14:18explained by another sleep disorder,
14:20mental disorder, medication, or substance.
14:22Use the observed vocalizations
14:24or behaviors often correlate with
14:27simultaneously occurring dream mentation,
14:29leading to the frequent report
14:31of acting out ones dreams.
14:33Now the next point is something
14:34that people always ask,
14:35and this is a very important question.
14:36Basically,
14:37how much loss of REM atonia
14:39do you need to diagnose RBD?
14:41There's no absolute cut off.
14:43But based on the current scoring guidelines,
14:46you need more than 20% loss of
14:48REM atonia to feel confident that
14:51there's enough documentation to
14:53justify the diagnosis of RBD.
14:56Now our baby and dream enactment
14:58are not universally connected and
14:59that's why I dream enacting behavior
15:01is not a required diagnostic
15:02criterion in the ICS D3,
15:04because a comprehensive literature
15:06search revealed that up to 35%
15:08percent of patients RBD we're not
15:10aware of dreaming acting behaviors.
15:12And that's the main reason why it's
15:14not a requirement for the diagnosis.
15:16Also,
15:16there's a differential diagnosis of
15:19dreaming acting behaviors besides RV
15:21that I will be discussing in a few minutes.
15:24The loss of me Tony is a
15:26core universal feature.
15:27You have a full range of behaviors that
15:29you can see here from minimal to complex,
15:31vigorous with a whole range of vocalizations.
15:34So there's a whole complexity of
15:37the behavioral spectrum of RBD.
15:40Also, you have altered dreams of our needy.
15:43They typically are much more vivid,
15:44intense, full of action, unpleasant.
15:46We call that dream process change.
15:49Also the Dreamers being threatened
15:50or attacked by unfamiliar people,
15:52animals or insects.
15:53We call that dream content change and the
15:56dreamer is rarely the primary aggressor.
15:58You have these unusual and
16:00unfortunately scenarios in the
16:02marital bed where in the dream,
16:04the man with RBD is dreaming that he's
16:06protecting his wife from an aggressor.
16:08But in reality he's punching his
16:09wife or kicking his wife in bed.
16:11And when she wakes up,
16:12she's wondering why he's attacking
16:13her and he's telling her, well,
16:15I'm protecting you in my dream.
16:17So they have to sort that one out.
16:20Now this is an important study
16:22from from Italy that you can have
16:25aggressive green dream content
16:26without daytime aggressiveness.
16:28In RDD and they use formal
16:30rating skills to come over,
16:32come up with their findings so men
16:34with RVD have significantly more
16:36aggressive dreams than control men.
16:38Men with RBD are not more aggressive
16:40in wakefulness in control man,
16:42so it's really state dependent
16:44aggression with dreams and behaviors
16:46and REM sleep that are not mirrored
16:48with any waking type of increase.
16:50Aggressiveness Isabel Arno from
16:52Paris documented a whole range of
16:55nonviolent elaborate behaviors
16:57in sleep behavior disorder.
16:59Apart from the vigorous and
17:01violent behaviors.
17:03Now this is a traditional RBD profile
17:05that was documented in our series
17:07in Minneapolis and the series of
17:08Mayo Clinic that are virtually
17:10identical Series A 96 patients,
17:1293 patients,
17:12and it's basically middle age
17:14and older men with violent and
17:16dreaming acting behaviors.
17:17That is the traditional profile that is
17:20still true for middle age and older men,
17:23but for younger adults and
17:25females is a different profile.
17:27But I just want to share with you and
17:29you saw that in the video as well.
17:30The traditional RBD profile.
17:32You can have inadvertent murder,
17:34attempted murder,
17:36the parasomnia pseudo suicide that
17:38my colleague Mark Mahowald first
17:41identified as well as unfortunate
17:44consequences of vigorous and violent RBD.
17:46Now there's some interesting
17:48findings on on the prevalence of
17:51RBD using community based video.
17:53Polysomnographic studies,
17:54at least that's the one in
17:56Japan and Switzerland,
17:57was just PSG but it was still PSG.
17:59Studies in the community and basically
18:02both studies found a 1% prevalence rate,
18:05so I mean that's the same prevalence
18:07rate of schizophrenia for example,
18:09so our belief is surprisingly common,
18:12although many of the patients
18:13or IBD have mild IBD and don't
18:15present to a sleep center.
18:17Also,
18:17I should point out right here in the
18:20Swiss study there was an equal male
18:22to female ratio for RBD and so the
18:25male predominance in the published
18:26studies is B because of the referral
18:28bias due to aggressive and violent
18:30behaviors triggering the clinical referral.
18:32But going out into the community,
18:34at least in the Swiss study,
18:35they found an equal male female
18:37ratio because of loss of RAM atonia
18:40and the women had the more mild RBD.
18:43Now this is very important in terms
18:45of the implications because when
18:47neuroprotection trials become available.
18:49To slow down or halt the
18:50progression from idiopathic,
18:51where now we call it isolated
18:54RBD to parkinsonism.
18:55Then the females of RBD who generally
18:57have milder RBD along with the
18:59males of mild RBD need to be found
19:01in primary care and geriatric
19:02clinics since they also have an
19:05increased risk for parkinsonism.
19:07So here's an example of a mild
19:09RBD behaviors in this woman,
19:11and she was referred to us
19:12for rule out sleep apnea,
19:14and that's how we identified
19:15actually her already.
19:17But we look at these behaviors.
19:19You can see why they don't trigger
19:22a clinical referral because it
19:24doesn't disturb the patient
19:25doesn't disturb the bad partner.
19:27She happened to present to us because
19:30of sleep disordered breathing.
19:32OK, now there is a single question
19:35validated screen now for RBD.
19:38And this is very simple question.
19:39Have you ever been told or
19:41suspected yourself?
19:41You seem to act out your dreams while asleep?
19:44For example, punching,
19:44flailing your arms in the air,
19:46making running boots.
19:49So this questionnaire can be
19:52used in primary care settings,
19:54geriatric clinics, neurology clinics
19:55as a good way to screen for people.
19:58Because you can pick up the the patients,
20:00including the women with mild RVD.
20:02This is not a screen for vigorous
20:05in violent behaviors necessarily.
20:07Now, as already you already heard,
20:08we had our first textbook published in
20:102018 and in the preface that I wrote,
20:14this is a figure I want to spend
20:15some time on it 'cause I think it
20:17has some number of important points.
20:19First of all,
20:20the starting point has to be and
20:22this is a schematic has to be.
20:24Loss of Remy Tony,
20:25I already showed you a a PSG
20:26example of loss of Roma Tony with
20:29increased tonic and phasic twitching.
20:30But when you look at the situation from
20:33the perspective of loss or Remington,
20:34yeah look at all the conditions.
20:37That can result in loss of Rhema Tony.
20:40You can have acute RBD related to
20:43talk to toxic metabolic factors.
20:46Brainstem tumors stroke neuro
20:49developmental factors which I'll
20:50discuss in the context of childhood.
20:52RBD you have narcolepsy.
20:54With cataplexy,
20:56you have antidepressant and other
20:58medications neurodegenerative.
20:59Other neurological disorders,
21:01autoimmune paraneoplastic disorders and
21:03a new frontier that is fascinating.
21:06At least to me as a psychiatrist.
21:07Are severe stress disorders involving
21:10post traumatic stress disorder and
21:12the more newly identified trauma
21:14associated sleep disorder that can
21:16ultimately result in loss of RAM atonia?
21:19There was a paper just published online
21:20and sleep by the Mayo Clinic group.
21:22Chronic PTSD patients,
21:24and they compared these patients
21:26with patients with idiopathic RBD
21:28or isolated RBD and normal controls
21:30and the results are so interesting.
21:33The patients with chronic PTSD
21:35had intermediate loster. Ma tonia.
21:37Halfway in between the lack of
21:39loss of remedy,
21:41tonium normal controls and the more
21:43substantial loss of remnant Tonia.
21:45In idiopathic or isolated RBD.
21:47So patients with chronic PTSD are
21:51halfway to having clinical RBD.
21:53So this is an area of really new research
21:56that's going to be further evaluated.
21:59So going back to that figure,
22:02a broader array of clinical insults can
22:04disturb the integrity of REM atonia,
22:06either singly or in combination.
22:08At one point in time where
22:09with the course of a lifetime,
22:11the results in room without
22:12atonia and RBD and this puts a
22:14spotlight on how RBD can emerge.
22:16If I don't want either one big hit,
22:18a major clinical insults such as
22:20a stroke or from a succession of
22:22multiple smaller hits from various
22:24types of insults over a lifetime
22:26that eventually will overwhelm the
22:28normal REM atonia and triggered
22:30REM without atonia and RBD.
22:33So it's a lifelong process for some patients.
22:36Michelle duvet from the young.
22:38He was the responsible for the first
22:40experimental animal model of RVD that
22:43involved pontine lesions and cats
22:45that release a spectrum of behaviors
22:47during unequivocal REM sleep and of
22:49course the basic scientists called
22:51it paradoxical sleep and he used a
22:54beautiful term called oneiric behaviors.
22:56In other words, dream enacting
22:58behaviors now his successor in Lyon
23:01appear loopy 2 elegant studies that
23:06basically genetically inactivated the.
23:08Glutamate, so lateral dorsal nucleus.
23:12And that recapitulated REM sleep
23:14behavior disorder in rats.
23:15And then there's the same thing with
23:18the ventral medial medulla inhibitory
23:20neurons that also released the
23:23rent own and RBD behaviors in rats.
23:26So these elegant studies really
23:29identified 2 critical nuclei.
23:31First of all,
23:32in the sub lateral dorsal nucleus,
23:35the glutamate neurons that activate
23:38the the medullary inhibitory neurons.
23:41And then you have.
23:42The message sent to the spinal alpha
23:45motor neurons to result in Renmei Tonia.
23:48So lesions to either the subway
23:50or some nucleus,
23:51the connecting pathways or the medulla?
23:54Medial medulla inhibitory neurons can
23:57result in loss of RAM atonia and RBD.
24:01Now if we look at early onset RBD in
24:03patients under the age of 50 years,
24:05we see much more much more gender parity.
24:08Milder forms of RBD.
24:10It really strong association with
24:12narcolepsy type one with cataplexy up
24:14to 60% of patients with narcolepsy type
24:16one have RBD the parasomnia overlap
24:18disorder that I will be discussing,
24:21which is RBD plus a non REM
24:23parasomnia association of psychiatric
24:25disorders antidepressant use and
24:27the intriguing possible association
24:29with autoimmune diseases.
24:31And this is from Chapter 15
24:33and RRBD textbook.
24:35In children and adolescents,
24:37by far the strongest association
24:39with is with narcolepsy type one
24:41and sometimes the ARB can precede
24:43the onset of the classic narcolepsy
24:46type one symptoms by months.
24:48Also, cataplexy therapy with SSR eyes,
24:51then the vaccine tricyclics
24:52can trigger RBD the same thing
24:54with major depression therapy.
24:56With these medications,
24:57and here's another new frontier in
25:00pediatric RBD association with autism,
25:03ADHD and other neurodevelopmental disorders.
25:06I mentioned and I'll mention again
25:08the parasomnia overlap disorder
25:10and not surprisingly,
25:11brainstem tumors can result in RBD in
25:15children and adolescents and also in adults.
25:18This study from Harvard showing
25:20that RBD was found in 25% of both
25:23narcolepsy type one and narcolepsy
25:25Type 2 pediatric patients which
25:27is really fascinating.
25:28It's not just narcolepsy with
25:31cataplexy and they found that
25:33nocturnal REM without atonia
25:34index is a very good diagnostic
25:37biomarker for pediatric narcolepsy.
25:39Now for acute RBD, as I mentioned before,
25:43before 1985 it was mainly drug and alcohol.
25:46Withdrawal states.
25:47Now we know that a cute RBD can
25:50emerge with vascular insults, tumors,
25:52particularly brainstem tumors,
25:55autoimmune paraneoplastic disorders,
25:57inflammatory disorders such as with
25:59Ms encephalitis and vasculitis,
26:02and actually post surgical
26:03with deep brain stimulation.
26:04Implantation for the treatment
26:07of Parkinson's disease.
26:09Now,
26:09in terms of the Association of Neurological
26:12Disorders by far neurodegenerative disorders,
26:14especially parkinsonian disorders
26:15that I will talk about next.
26:18But as I already mentioned,
26:19the preponderance of patients of narcolepsy
26:22type one through vascular disorders,
26:24but virtually any type of neurological
26:26disorder can cause RBD because of
26:28the critical location of the lesion.
26:30In the context of the neurons and
26:34pathways subserving REM atonia.
26:37Focusing now on narcolepsy.
26:38Type one with RBD.
26:40It appears to be a distinct phenotype
26:42of RBD with greater gender parity.
26:45Earlier age of onset,
26:46lower frequency of RBD episodes less.
26:49Complex movements in REM sleep.
26:51Also less aggressive and violent RBD
26:54behaviors and its associated with the
26:56hypocretin deficiency characteristic
26:58of characteristic of narcolepsy type
27:00one and this is very important for you,
27:02it's clinicians.
27:03There is absolutely no evidence
27:04right now that narcolepsy.
27:06Cataplexy of RBD is carries an increased
27:09risk for future neurodegeneration.
27:12It's a different phenotype
27:14from the idiopathic RBD.
27:15So you may have patients with narcolepsy.
27:17Knew diagnosed with RBD and they
27:19may look up on the Internet.
27:21While I have RBD and then they
27:22get really very worried because
27:24of the association of parkinsonism
27:26but the data are very strong.
27:28There is no increased risk for a future
27:31parkinsonism with DRBD associated
27:32with narcolepsy and cataplexy which
27:35is a different different phenotype.
27:37We should be aware that virtually all
27:39ended up Preston's except for bupropion,
27:41a dopaminergic noradrenergic
27:43agonist can trigger RVD,
27:45and So what that means clinically
27:47is that you have North PD patient
27:49with clinical depression,
27:50unless otherwise contraindicated.
27:51European should be the medication
27:54of choice to manage that depression.
27:56Also,
27:57at least two of the beta blockers
27:59have been documented to produce RBD,
28:02along with selegiline, anticholinergics,
28:04and river stigma.
28:07A pair of Samik overlap disorder.
28:08We first identified that in 1997
28:11with sleepwalking and sleep terrors
28:13being the original non REM parasomnia
28:15associated with our DD and it's now
28:18recognized as a variant of RBD in the ICS.
28:20In three you have both an idiopathic
28:23subtype of parasomnia overlap
28:25disorder but also symptomatic subtype
28:27associated with neurological disorders,
28:29particularly Parkinson's disease,
28:31medical disorders, psychiatric disorders,
28:33medication triggers,
28:34alcohol and drug abuse.
28:37And various combined disorders and triggers.
28:40Since 1997,
28:41there's been a growing number of
28:43publications on parasomnia overlap disorder,
28:46with more than 150 reported cases
28:48and also an expanded list of non REM.
28:51Parasomnia is length of RBD besides
28:53sleepwalking and sleep terrors and
28:55these include sex somnia which is
28:57sexual sexual behaviors during sleep,
28:59sleep,
28:59related eating disorder and
29:02rhythmic movement disorder.
29:04Now I'm going to show you a video
29:06fascinating case from Italy from Torino,
29:07Italy.
29:08Sexual behaviors during sleep
29:10associated with Polly.
29:11Graphically confirmed power personality
29:13overlap disorder in two cases,
29:15these patients had five non REM and
29:18REM sleep motor parasomnias each.
29:21Now the first case is a 60 year old
29:23woman who actually presented with
29:25RBD as her presenting complaint.
29:27'cause her husband complained for four years.
29:29She had been violent towards him
29:31during dream enacting behaviors
29:32during sleep so it was not her
29:33non REM parasomnia that triggered
29:35her referral to the Sleep Center
29:36but it was her RBD.
29:38She had childhood onset,
29:40lifelong sleepwalking and sleep talking.
29:42And also sleep related eating
29:44episodes and the V PSG documented
29:46RBD and non REM parasomnias and I'm
29:48going to show you an example and
29:50I got the video from Alessandra,
29:52Chico lean,
29:53a Saxony episode in this woman coming
29:56from N3 sleep.
30:01And you're gonna see a classic disorder,
30:03arousal, behavior.
30:04She has the arousal and immediately the
30:07behavior of touching herself begins.
30:09There's no interlude of
30:10wondering what am I going to do,
30:12and we see this with patients sleep related,
30:14eating disorder, sleepwalking, sleep terrors,
30:17with the arousal comes the abnormal behavior,
30:20and this is very impressive,
30:21and this example is sleep related.
30:22************ emerging from N3 sleep in the
30:25context of parasomnia overlap this order.
30:28This order in this patient.
30:30Now I want to give you an
30:31example of how complex.
30:32Scenarios can be.
30:34Here's A6 non R.E.M., R.E.M.
30:36Parasomnias and superimposed
30:38obstructive sleep apnea.
30:40This is a case from St.
30:41Paul, MN parasomnia overlap disorder
30:43with sexual behaviors during sleep and
30:46a patient with obstructive sleep apnea.
30:4842 year old man with the non REM and R.E.M.
30:51Des Parasomnias and obstructive sleep apnea.
30:54He had sleepwalking, sleep related,
30:56eating confusional, arousal,
30:57sex omnia sleeptalking RBD,
31:00video polysomnography,
31:01confirmed confusion,
31:02confusional arousals and RBD behaviors.
31:06The added complexity was OSA
31:07playing a role in generating the
31:10sleepwalking and sleep related eating.
31:12They all they both responded to nasal
31:14see PAP therapy that controlled
31:16the obstructive sleep apnea.
31:17So it isn't that interesting.
31:19Nasal CPAP treats successfully.
31:20The obstructive sleep apnea treats
31:23successfully the sleepwalking
31:24and the sleep related eating,
31:26but the sex omnia did not respond
31:28to nasal see PAP therapy.
31:30Fortunately,
31:30bedtime clonazepam did control the sex omnia.
31:33I had to tell you there's no
31:35way in the world we could have
31:37predicted this beforehand.
31:38I mean,
31:38I would have said six Omni would have
31:39been controlled also by the nasal CPAP,
31:41but it is what it is and you know,
31:44we live in a complex world,
31:45especially as clinicians, right?
31:48Now the differential diagnosis of RBD non REM
31:52parasomnia's severe obstructive sleep apnea.
31:54The group from Barcelona came up with
31:57their really well documented series 2005.
32:00Publishing sleep on OSA,
32:02pseudo RBD and these are older
32:04men of aggressive dream.
32:05Enacting behaviors.
32:06Typical RBD scenario right wrong in
32:09this case because it was a obstructive
32:12sleep apnea suit to BBD the mean hi
32:15with 67 per hour extending up to 105.
32:18They had aggressive dream enacting
32:20behaviors and fortunately treatment of
32:23the OSA also control the pseudo RBD.
32:26Besides the obstructive sleep
32:28apnea and they studied these
32:30patients baseline after treatment,
32:32REM atonia was reserved both PSG studies.
32:36Now my next slide is going to go
32:38into more detail on the current hot
32:40topic of the OS, HBD relationships.
32:42It's really fascinating,
32:44new field of research,
32:45the other differential diagnosis
32:47for our dreaming Acton behaviors.
32:49Again,
32:49it's the Barcelona Group that documented
32:51severe periodic limb movement disorder,
32:53pseudo RVD.
32:54These patients,
32:55again were older men with aggressive
32:57dream enacting behaviors.
32:59Their median PMI index with 61 per
33:02hour treatment of Prema Pixel control,
33:04the pseudo RBD and this.
33:07Again,
33:07the baseline and the follow up PSG's
33:10documented preserved REM atonia.
33:13Finally,
33:13nocturnal seizures can occur
33:15sometimes during REM sleep with
33:17dreaming acting behaviors as a mimic
33:20of dreaming acting behaviors for RBD.
33:22And we recommend a seizure montage during the
33:25initial valuation of RBD in the Sleep lab.
33:28So here are three of now,
33:29probably seven articles in the
33:32literature on the BBD OSA relationships.
33:35It's really a fascinating 1.
33:37In this paper was just
33:39accepted a few days ago.
33:41Anyway, I'm not going to go into that,
33:42but for those of you who
33:44are pulmonary sleep doctors,
33:45there is a relationship between OSA
33:47and RBD that you may want to become
33:50informed about the treatment of RBD
33:53best practice guide for treatment.
33:55American Academy of Sleep Medicine.
33:57First of all, of course,
33:58protect the bedside environment and then
34:00the the two two Co Firstline medications
34:03with really tremendous efficacy,
34:05clonazepam and melatonin.
34:07Alone or in combination and there's
34:10a long list of tertiary treatments.
34:13I should also mention that there is
34:15a task force American Academy of
34:16Sleep Medicine devoted to an updated
34:19guidelines for the treatment of
34:20robbed my colleague Michael Howell,
34:22who discovered remember the original
34:24description of our baby by James Parkinson.
34:26He is on that committee.
34:27I don't know when it's going to come out,
34:28but it's been a very labor intensive project.
34:32So good for you,
34:34Mike.
34:34OK so our BD at the time of the
34:37diagnosis can be associated with
34:39neurological disorder or be unassociated
34:41with any neurological disorder
34:43which we now call isolated RBD.
34:45And that brings up the question of
34:47what happens to these idiopathic or
34:49isolated RBD patients over time.
34:51As you already know we found a 38%
34:53conversion rate in 1996 and then we
34:56extended our study and then in 2013
35:00it became an 81% conversion rate
35:02with a mean interval from the time.
35:05Of RBD onset to the time of
35:07the diagnosis of parkinsonism.
35:08Where the dementia parkinsonism of 14 years,
35:12the breakdown was 13 with
35:14Parkinson's disease.
35:15For the dementia Lewy bodies,
35:17two of multiple system atrophy with prominent
35:20autonomic nervous system dysfunction,
35:22and this is very interesting.
35:23These two patients with Lewy body
35:25variant of Alzheimer's disease
35:27confirmed at autopsy clinically.
35:29They had Alzheimer's disease and RVD
35:31without any evidence of parkinsonism,
35:33but at autopsy they also had.
35:35Evidence of Lewy body disease and
35:37I really don't think there's any
35:39pure case of Alzheimer's disease
35:41confirmed at autopsy with clinical RBD.
35:43That would be a mega case report.
35:46I predict this not going to happen.
35:47I don't mind being proven wrong by any means,
35:49but I think if you have someone
35:52with clinical Alzheimer's disease
35:54and RBD that person ply has mixed
35:56telepathy with Lewy body pathology
35:58to Barcelona groups the same data.
36:00We had an 81% conversion rate,
36:02they had an 82% conversion rate.
36:05And they found more of a breakdown,
36:07equal breakdown of Parkinson's
36:08disease and dementia.
36:09Lewy bodies, multiple system atrophy,
36:12and then the the more newly
36:15recognized mild cognitive impairment.
36:16So the rate of conversion, identical,
36:18the mean,
36:19latency period including the
36:21group from Montreal
36:22is a very tight 11.5 years to 14
36:25year latency period from the time
36:28of RBD onset to the diagnosis of
36:30Parkinsonian disorder and this is the
36:33opportunity interval for intervening
36:35with neuroprotective therapy.
36:36Once that type of therapy can
36:39be identified and look at this,
36:41this is a meta analysis under risk
36:44of neurodegeneration in BBD at five
36:46year follow up. 33% conversion rate.
36:4910.5 year follow up 82% conversion
36:51rate at 14 year follow-up.
36:5497% conversion rate.
36:55So as I already mentioned,
36:57it's not a matter of if but when
37:00these patients will convert.
37:01And this is the relentless progression
37:04that you can see in this graph.
37:06The movement to sort of society said
37:10that idiopathic RBD is should be
37:13considered prodromal parkinsonism.
37:14It has a likelihood ratio of 130
37:16repeated conversion and a predictive
37:18value of greater than 10 times higher
37:21than any other clinical marker.
37:23As I mentioned.
37:24With that first slide related
37:25to James Parkinson,
37:26we now know that idiopathic or
37:28isolated BBT is the strongest predictor
37:31of future Parkinson's disease.
37:33Mark McClellan,
37:34I wrote an editorial and basically
37:36stated that RBD is the clinical
37:38sign of Synuclein attack on the
37:40REM atonia generating nuclei and
37:42pathways in the brain stem that are
37:44already showed you in this talk.
37:46And here is an example of Lewy body.
37:48This is what attacks the neural
37:51center is generating on rent a Tony.
37:54So the emergence of excessive muscle
37:56tone during REM sleep reflects damage
37:58that the Alpha's nuclear pathology of
38:01PD has done to the pantina medullary
38:03centers and pathways subserving remedy,
38:05Tonia.
38:07So do you have to gravity?
38:09Is this a nuclear apathy and it's
38:11a premier early biomarker of Alpha
38:14Synuclein opathy neurodegeneration.
38:16Just the pathology patients have
38:18isolated RBD have alfacon nuclear
38:20deposition of both the central
38:22nervous system and amazingly also
38:24in the peripheral nervous system.
38:26Then two published idiopathic RBD
38:29cases of postmortem histopathology
38:31and have been six published
38:33idiopathic RBD case series with
38:35antemortem histopathology showing.
38:38The Lewy body,
38:39the theology the first case was when Japan.
38:42This is a 86 year old man,
38:4522 year history of isolated RVD,
38:47confirmed by video polysomnography without
38:49any clinical evidence of parkinsonism.
38:51He died incidentally,
38:53of pneumonia and the postal
38:55postmortem histopathology revealed
38:56Lewy body disease in the brain stem,
38:58particularly in the locus,
39:00are loose and substantial Niagara
39:02second case from the Mayo Clinic.
39:0472 year old Man who had a long
39:06history of idiopathic RBD.
39:08Confirmed by video, probably sonography.
39:09He also died in pneumonia and the
39:12post mortem histopathology revealed,
39:14Alphas,
39:14nuclear pathology and the ventral
39:16medial medulla.
39:17Inhibitory neurons in the medullary
39:20reticular formation so the same
39:22same clinical history in these
39:23two patients went from Japan.
39:25Wants the United States and the
39:27same histopathology and here's the
39:29peripheral nervous system in the gut.
39:31The skin subliminal are gland labial,
39:34salivary gland parotid gland,
39:36all infiltrated with alpha
39:38Synuclein and Musa.
39:39The the slides showing what
39:41alfacon nuclei and Lewy body
39:43pathology looks like.
39:44When you look at the association
39:46the other way around,
39:47almost 50% of patients with
39:49Parkinson disease also have RDD.
39:51Also, the presence of RBD in PD is associated
39:55with widespread increased PD morbidity.
39:57Furthermore, multiple system
39:59atrophy which is a Parkinson's plus
40:01disorder 90% have RBD and dementia.
40:04Lewy bodies, which is the second most common
40:06cause of dementia after Alzheimer's disease.
40:08Basically, 3/4 of these patients have RBD.
40:12In fact, this dissociation is so strong that.
40:14In the 2017 updated diagnostic
40:16criteria for dementia of Lewy bodies,
40:19RBD was one of the core features along the.
40:23As you can see fluctuating attention
40:25and concentration recurrent,
40:26well formed visual hallucinations,
40:28spontaneous parkinsonian motor
40:29signs along with the dementia.
40:31So RBD is a core feature of
40:34dementia of Lewy bodies.
40:36The critical indicator in Parkinson's
40:38disease because it's an error.
40:39Early Herald of Future PD.
40:42It's also a marker of increased
40:44global morbidity and disease burden.
40:46There's greater motor cognitive
40:48autonomic psychiatric dysfunction,
40:49greater disease, burden to self and
40:52caretaker compared to a PD of RBD.
40:54So obviously,
40:55if you are patient with PD,
40:57you don't want to have RBD
40:58along with your PD.
40:59You're better off compared to
41:01a patient with PD and RVD.
41:05And this is Michelle,
41:07who and her colleague from uh
41:09Oxford University basically calling
41:12RBD a malignant subtype of PD.
41:15So here's an important management question.
41:17How do you discuss the risk
41:19of future parkinsonism?
41:20Dementia with a newly diagnosed middle
41:22age or older patient, and spouse of RBD?
41:25This is an important delicate matter.
41:28If you don't mention it,
41:30there's a great likelihood that the patient,
41:32the wife, the other family or
41:33friends are going to look on the
41:35Internet and find the association,
41:37and then no wonder,
41:38why didn't this doctor mention it to me.
41:40So I think you have to mention
41:42it one way or another.
41:43There have been at least five
41:44articles published on this.
41:46This is 1 specialist approaches
41:47to the prognostic counseling and
41:49isolated REM sleep behavior disorder,
41:52and I welcome you to read this
41:53and the other articles you have
41:55to formulate your own game plan.
41:56You have to really use your clinical
41:58sensitivity to share the information
42:00with the patients depending on their
42:02personality type and other factors as well,
42:04but you really do have to mention
42:06it in this article.
42:08I was one of the Co authors I threw in.
42:09Another option that I think is very
42:11appealing to a lot of non neurologist
42:13sleep doctors and that is have the
42:16primary care doctors share the
42:17information with the patient you
42:19feed all the relevant information to
42:21their primary care Doctor Who done
42:23presumably knows the patient quite
42:25well and that primary care doctor can.
42:27Then bring up the issue of increased
42:29risk of future Parkinson's disease
42:30and dementia of Lewy bodies with the
42:33patient with newly newly diagnosed,
42:35isolated RBD.
42:35That way you are being responsible
42:37ensuring the information without
42:39sharing it directly yourself and
42:41then have the primary care doctor
42:43share that information.
42:44So that's a third option for you to consider.
42:46We now have, as you already heard,
42:48an international RBD study group.
42:51We have yearly symposia,
42:53basically clinical researchers
42:54and basic scientists from many
42:57countries 5 continents.
42:58We publish quite a number of
43:00peer reviewed journal articles,
43:01is a very active group and in
43:03range of 4th focus of the research
43:05effort is identifying predictors of
43:07imminent conversion from idiopathic
43:09or isolated RBD parkinsonism within
43:11several years for inclusion of
43:13these patients in studies testing
43:15promising neuroprotective agents,
43:17we need much more biomarker research.
43:21We want to extend the time of.
43:24Non clinical symptoms with
43:26neuroprotective therapy.
43:28Basically,
43:28we have eight working groups
43:31involving biomarkers imaging.
43:33A clinical.
43:34Treatment in trials neurophysiology,
43:37epidemiology,
43:37genetics.
43:38Basic scientists really very
43:40comprehensive set of working groups.
43:43This is a paper we recently
43:45published in Lancet Neurology.
43:46Biomarkers are conversion to alfacon nuclei,
43:48opathy and isolated rapid eye movement,
43:51sleep behavior disorder and in decreasing
43:54order of strength for predicting
43:57final conversion from isolated RBD.
43:59To avoid parkinsonism,
44:00by far the strongest one is the
44:03extent of loss of REM sleep.
44:05Without a Tony or loss of remedy out a Tony,
44:08that's the most strong predictor.
44:11But you see, you can see all
44:13the others going down the line.
44:15Motor function, cognition, hyposmia,
44:17color vision, discrimination,
44:19all the way down the line.
44:21And what's interesting about the genetic
44:24biomarkers is that they identified
44:26GBA variants robustly present,
44:28will GBA, and codes the lysosome.
44:32So if you have GBA variants that are
44:34less efficient than the original GBA.
44:36With the lysosomal deficiency that
44:38results in reduced breakdown of alphas,
44:41nucleon and increase in accumulation
44:43of alpha synuclein,
44:44so that could be one of the
44:46mechanisms for the increased risk for
44:49Parkinson's disease and dementia.
44:51Lewy bodies that the GBA variants
44:54found of RBD.
44:56Result in less efficient lysosomal function.
45:01We need also combination biomarkers
45:03to predict imminent conversion
45:05within three years,
45:06and that's how you get research funding.
45:08You're not going to get research funding
45:09for saying well within 10 years.
45:11We can predict these patients.
45:12You want three years or more or less
45:14to be able to get research funding to
45:17test promising or protective agents,
45:19and there may be some I've been told
45:21by the neurologist we may have no
45:22protective agents on the horizon
45:24within the next two or three years,
45:25but I would not hold my breath.
45:28And this is this study I mentioned at
45:30the beginning, abnormal REM sleep,
45:32atonia control and chronic post
45:34traumatic stress disorder.
45:35These chronic PTSD patients were
45:37halfway between isolated RBD and
45:40normal controls in terms extent
45:42of run without a Tonia.
45:43And to me it's the psychiatrist.
45:45Fascinating question is how does a
45:48traumatic psychological experience
45:50or series of traumatic psychological
45:52experiences result ultimately in
45:55REM without atonia?
45:56So you have wakeful psychology.
45:59Leading to sleep neurology.
46:01Very interesting question.
46:03Finally,
46:03I'm just going to go quickly
46:04'cause we're running out of time.
46:06We now have the North American prodromal
46:09Synuclein Opathy consortium for RBD.
46:11There's eight centers or nine centers now
46:13around the country in Minnesota we have
46:15our group in the University of Minnesota,
46:17Mayo Clinic.
46:19Mass General, Montreal,
46:21Emory, Washu, Stanford,
46:23UCLA and in Portland,
46:26the VA hospital.
46:29And basically we want to establish
46:31a registry more than 400 patients.
46:33Referrals of newly diagnosed,
46:36isolated RBD patients develop quantitative
46:38biological and functional measures
46:41of alfacon nuclei opathy burden
46:43and establish a formal process to
46:46evaluate candidate neuroprotective agents.
46:48So both clinical assessments,
46:50clinician diagnosis,
46:52would biomarkers.
46:53Again,
46:53the importance of documenting quantitatively
46:56the REM sleep without any Tonia,
46:59along with functional assessments.
47:00I'm not going to go into detail.
47:02You can look at this at your leisure.
47:05But this is this is a very active group
47:07and we also want to educate the public.
47:10Uh, uh, physicians, nurses,
47:11other health care providers,
47:13about RBD,
47:14isolated RBD and the risk of
47:17future parkinsonism.
47:17So we can generate more clinical referrals.
47:21There are three review articles
47:22I call to your attention.
47:24The third one was just to impress.
47:27Now I just proof to the galleys
47:29and that should be coming out.
47:32And this also includes a discussion of the.
47:35OSA RBD complex relationships.
47:36So thank you very much for your
47:39attention and I hope we have
47:41some time for for questions.
47:46Thank you Doctor Shank that was excellent.
47:48Really really enjoyed it.
47:50While people are putting questions
47:51in the chat, I just wanted to ask.
47:53I'm very interested in this.
47:55The referral bias, right?
47:56So we're seeing you know the
47:58classic teaching, of course,
47:59'cause the initial case
48:00descriptions of the men with RBD.
48:01And now of course we do see women
48:03with RBD if we know to look for it is.
48:06Is there any difference?
48:08Do we know yet in the rate of
48:10progression to Parkinson's
48:12Parkinsonism in men versus women?
48:14Do we know if a woman has a subtle case?
48:17Does it make?
48:17Matter, which doesn't matter how
48:18severe the presenting symptoms of RBD,
48:20are in terms of the rate of progression.
48:22That's an excellent question
48:23for the first of all,
48:24there's no correlation between the severity
48:26of RBD and the rate of progression,
48:28and this is, let's say, in men,
48:30but also in women that there's
48:32no correlation at all,
48:34and there's no evidence that women
48:36progress any slower than men.
48:38However, I should point out
48:39something very intriguing.
48:40I'm reviewing an article
48:42manuscript for a journal.
48:43Right now, there are at least three
48:45or four papers published from.
48:47Asia indicating that RBD patients in Japan,
48:52Hong Kong, China and Korea may have a
48:56slower progression to overt parkinsonism.
48:58So, as the authors mentioned,
49:00there could be geographical
49:02and or racial factors involved
49:04with regression and that needs
49:07to be explored extensively.
49:09So I don't know about any gender
49:11difference right now among the Caucasians,
49:13but there may be racial and
49:15geographical differences.
49:16Great, thank you, so we're getting
49:18some questions in the chat.
49:19There is a question what is known
49:21about the risk of neurodegeneration
49:24in antidepressant associated orbed?
49:27That's another great question.
49:28I didn't have time to include a study from
49:31the Montreal Group published in Sleep.
49:33I believe 2005 and this is a group
49:36of patients with antidepressant
49:38medication induced RBD.
49:39And they compared it to a patient
49:43with regular so-called regular,
49:45isolated RBD.
49:47The patients prevented depressant
49:49medication induced RBD.
49:50They had the biomarkers
49:53for neurodegeneration,
49:54but at follow up they did not
49:57feel convert at the same rate as
49:59regular patients of idiopathic RBD
50:01and the authors concluded that the
50:03antidepressant kind of prematurely
50:05kind of reveal the risk for future
50:08final conversion without accelerating
50:10the final conversion rate.
50:12So I think it may be that patients who
50:16develop into depressant medication.
50:17Starved is a selected group of patients
50:20already vulnerable to parkinsonism,
50:23and we don't have any long
50:25term outcome studies.
50:25My colleague MM Howell at University
50:28of Minnesota has submitted NIH
50:29grant looking at this question,
50:31so it's still an open question
50:33and I certainly would recommend.
50:34Even if the RBD subsides.
50:36With discontinuation of the antidepressant,
50:39I would let the primary care physician know.
50:41Or if you follow these patients,
50:43keep an eye out for any early
50:45signs of parkinsonism.
50:47Great, thank you.
50:48So another question again,
50:50thanks for a great talk for
50:52patients refractory to high
50:53dose melatonin and clonazepam.
50:55What other treatment
50:56options do we have for TBP?
50:58Well, I I would recommend
50:59that that article sleep.
51:01It's basically pramipexole,
51:03carbamazepine, gabapentin.
51:05Alone or in combination,
51:06those are the ones that we go to next.
51:10Thank you. What's a typical dose
51:11of melatonin that you use you?
51:13You gave the range of three to 15.
51:15Yeah, I know it. Basically,
51:16most patients who respond need a
51:18minimum of 6 milligrams, but generally
51:20more 9/12/15 or 18 milligrams.
51:24Right, and there's another
51:25question about how quickly do you
51:26titrate up the dose of melatonin
51:28when you're using those kinds of
51:29doses we titrate up.
51:31Depending on another episode of RBD,
51:34basically, you know we wait and we
51:37tell the patient and the spouse.
51:39If you have another kind
51:41of episode other than just
51:42minor handwaving or whatever,
51:44then you need to go up by
51:45another 3 milligrams.
51:47OK, thank you and I'm
51:48gonna wait for a few hours.
51:50So here's another question.
51:51In patients with trauma,
51:53associated sleep disorder and
51:54REM without atonia on PSG,
51:57do you treat as isolated RBD?
52:00Well, that's a great question that's
52:02still very much an open question, though.
52:04This is a new field quite honestly,
52:06and these are complex patients
52:07because many of them are on
52:09antidepressant medicines as well.
52:11You see, between the Mayo Clinic study.
52:13They did address the issue of
52:14antidepressant medicine, and that did
52:16not distinguish between the groups.
52:17So it was really a well done
52:19study from that point of view.
52:21You know, you know one approach and this.
52:23This is my my colleague
52:25Mark Maha my late colleague.
52:26He really was interested in treating
52:29the dream disorder and that would
52:31be something like prazosin or
52:33cyproheptadine or this is what we
52:35use to treat nightmares to post
52:36traumatic stress disorder treat
52:38with those medications and see what
52:40happens to dream and acting behavior.
52:41So I think you really everything is
52:43on the table with these patients.
52:45You have to work with the clinicians,
52:46the psychiatrist, the psychotherapist,
52:48the Alcohol and drug abuse counselors.
52:51With these complex patients.
52:52To come up with a protocol, and I,
52:54I think in a few years we will
52:56have much more clarity about how
52:57to proceed with these patients,
52:59but I would really open up this
53:01table to consider medications for
53:02the nightmares such as prazosin
53:05and cyproheptadine.
53:08Great, thank you. We are also another
53:11question about genetics and RBD.
53:13Any associated genetic traits.
53:16Well, just a GBA variance
53:19that encodes for lysosomes.
53:21But that you know the Montreal
53:22Group are the world leaders in this,
53:24so stay tuned on more information
53:26of the genetics of RVD.
53:28Terrific, thanks a question about Afghan
53:32pharmacotherapy for non aggressive behaviors,
53:35how aggressively do you push pharmacotherapy?
53:37Is there a risk of behaviors becoming
53:39more aggressive with aging and
53:41progression of synucleinopathies?
53:43Well, that's a great question and
53:45basically we you know you treat
53:47the patient and the patient.
53:48Treating the patient means also
53:50taking into account the spouse with
53:53whom that person may may sleep.
53:55And so you really have to discuss
53:57with the patient in spouse if the
53:59spouse is very sensitive sleeper
54:00and even minimal behaviors may
54:02disturb the sleep of the spouse,
54:03then maybe you may want to treat with
54:06low dose clonazepam or melatonin.
54:08In a sense, you're also treating
54:09the spouse that way too,
54:10so it really you have to really consider
54:12the the the marital situation as well.
54:14But I I would not treat mild RBD at all.
54:18You can explain to them that the RBD
54:20may progress or may not progress.
54:22You know I have to tell you something.
54:23I saw one of mark males.
54:25Relatives and this is a relative
54:28of his who had mild urbed.
54:30And lo and behold,
54:32his mild RBD went away over time.
54:34So we don't know how many patients actually
54:37have resolution of the behavioral component.
54:39We did not re study the marks relative
54:41to see the remedy Tony went away.
54:43I doubt it would,
54:44but and we don't know the Natural
54:46History really of mild RBD.
54:48And clinically it could be.
54:50It could go away.
54:50But we don't know about the
54:52risk for future parkinsonism if
54:53that has any effect either.
54:55So there's still a lot of open questions.
54:57Terrific and the questions
54:59are flying in so do do.
55:01Is there any association between RBD
55:04and central sleep apnea syndromes?
55:06No. No, that was an easy one.
55:12Alright, what is the role of the
55:14frequency of RBD every night versus one?
55:16So we does that affect your approach to BBD,
55:18BBD treatment or prognostication?
55:21Well, yes, up to a point.
55:23If you have somebody who has a
55:25violent episode once every two months,
55:27you have to treat that person 'cause the
55:29next one could be the lethal one too.
55:31If it's really frequent and and
55:33disturbs the patient and or the spouse,
55:35then you really should treat,
55:36you know right away if it's infrequent.
55:40You know, but they had one episode
55:42that was somewhat disturbing.
55:43You can discuss with the patient and spouse,
55:45hold off on treatment until they're
55:46convinced that there really is a
55:48regular problem that warrants treatment.
55:50So again, you have to use
55:51your clinical judgment,
55:52working closely with the patient and spouse.
55:55Terrific, thanks another question,
55:57is it true the clonazepam,
55:59even when effective,
56:00does not restore when a Tony
56:02Abbott effects only the dream?
56:05Exactly melatonin apparently
56:06can help restore Rhema Tony.
56:09A couple of studies from Japan army.
56:12I'm sorry Clonazepam appears to
56:13tone down phasic motor activity,
56:15but it has no effect on remedy.
56:18OK, sure. Wait,
56:21so they're starting to speak slower?
56:23OK? Don't see another question yet.
56:26I did so for the participants.
56:28If anyone would like to unmute
56:29themselves to ask your old
56:31question now would be the time.
56:32And if you want to put anything
56:34else in the chat, go ahead.
56:36You have about one minute left.
56:47Right, I think I doctor Shank I just
56:49wanted to say in terms of again the
56:51patients with you know post traumatic
56:53stress disorder who seem to have
56:56trauma associated sleep disorder
56:58but may also have you know RBD.
57:02Do you know if there's any evidence of
57:04psychotherapies you know for nightmares?
57:06For example, improving improving
57:08RBD symptoms?
57:11The no studies that I know of,
57:12but that's a great question that I
57:14think that should be studied absolutely.
57:17You know I have a colleague in Germany who
57:19says that for some of his RBD patients,
57:21hypnosis has worked,
57:22but he hasn't published it and
57:24I keep telling him published.
57:26We need to know more about this.
57:28There's still so many open questions
57:30related TPD and the therapy,
57:31including the effect of
57:33psychotherapy with trauma,
57:34PTSD and acting out dreams.
57:39Thank you, well, I think this has
57:41been really a wonderful talk.
57:43Very, very engaged audience and I really,
57:46really appreciate your coming to speak.
57:47It's my pleasure and thank you
57:48for all your questions and
57:49thank you for inviting me.
57:50I wish you great success with
57:52your Sleep Medicine careers.
57:54Thank you so much. Bye bye
57:56now bye everybody. OK bye.