3rd Congress of the European Academy of Neurology

Amsterdam, The Netherlands, June 24 – 27, 2017

Teaching Course 1

MDS-ES/EAN: Differential diagnosis of sleep related movement disorders - Level 3

REM sleep behavior disorder: Diagnostic

criteria, EMG based accurate quantitative diagnostics, value and limitations of

questionnaires for diagnosis and differential diagnosis

Birgit Högl

Innsbruck, Austria

Email: birgit.ho@i-med.ac.at

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Carlos Schenck, Mark Mahowald and co-workers have been the first to

describe REM sleep behaviour disorder in humans three decades ago, and

they also coined the designation of this disorder.

Prevalence and implications

Although RBD is not a rare disorder, Only few studies have addressed the

prevalence of RBD in the general population. it reported that 0,38 % of the

elderly cohort had PSG confirmed RBD (Chiu HF, Sleep 2000). A more

recent series of Korean elderly reported a prevalence of 1,15 % idiopathic

RBD in the elderly population, and 2,01 % for all types of RBD. Ohayon and

co-workers used the Sleep Eval telephone interview in a large cohort

of almost 5000 and reported a 2 % prevalence of violent or injurious

behaviours during sleep (Ohayon and Schenck, 2010). In a sleep laboratory

series of 703 consecutive patients, 4,8 % had REM sleep behaviour disorder

(Frauscher B., Sleep Med. 2010) and importantly, several of these patients

would not have been diagnosed by sleep history alone, only upon insistent

questioning symptoms of RBD could be retrieved from history.

In a cohort of 110 healthy control patients, the prevalence of idiopathic

RBD was 2 % (Mollenhauer, Neurology 2013). In PD, the prevalence in de

novo patients was 25 % (Mollenhauer B. et al, Neurology 2013), and in

clinically more advanced patients the prevalence ranged between 33 and

46 % (Wetter TC, Wien Klin Wochenschr 2001, Gagnon JF, Neurology 2002,

Sixel-Döring F, Neurology 2011).

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It is well known, that REM sleep behaviour disorder is associated with α-

synuclein disorders, and may precede or follow the onset of α synuclein

disease. The conversion rate of patients with initially idiopathic RBD is

higher than 80 – 90 % to α-synuclein disease within the next one or two

decades, which led to the consequence that patients with idiopathic RBD

are now considered as having prodromal α-synuclein disease (Iranzo A,

Lancet Neurol 2016), and PSG-proven diagnosis of RBD, has an extra-

ordinarily high positive calculated likelihood ratio of > 130 as compared to

a only moderate likelihood ratio of 2.3 for questionnaire based diagnosis

(Berg, Postuma, MDS 2015).

Diagnostic criteria for RBD

The diagnostic criteria for REM sleep behaviour disorder according to the

American Academy of Sleep Medicine comprise repeated episodes of sleep

related vocalizations and/or complex motor behaviours. The behaviours

need to be documented by polysomnography to occur during REM sleep,

or are at least presumed to occur during REM sleep based on clinical

history of dream enactment. In addition, it is required for diagnosis of RBD

according to the ICSD-3 that polysomnographic recording is performed and

demonstrates REM sleep without atonia, and that the disturbance is not

better explained by another sleep disorder, mental disorder, medication

or substance use (AASM ICSD-3, 2014).

Questionnaires to detect probable RBD

Several questionnaires and interview based instruments to detect RBD

have been developed. The first was the RBDSQ developed in Marburg by

Karin Stiasny-Kolster in 2007 (Stiasny-Kolster et al, 2007). In 2010, the

REM sleep behaviour disorder questionnaire Hongkong followed (Li SX,

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Sleep Med 2010). The Mayo sleep questionnaire, published by Brad Boeve

in 2013, has an opening question for RBD and if this is answered positive,

subsequent questions follow. The International RBD Study Group IRBDSG

validated a single question for RBD (RBD1Q), which is worded: Have you

ever been told, or suspected yourself, that you seem to act your dreams,

while asleep (e.g. punching, flailing your arms in the air, making running

movements, etc.)? (Postuma R, et al Movement Disorders 2012).

The Innsbruck REM sleep behaviour disorder inventory RBD-I is a 5-item

questionnaire and also includes an RBD summary question. It was

published in 2012, and systematically asks for violent/aggressive dream

content, multiple vocalisations during sleep, movements and flailing or

more extensive movements out of sleep, injury or near–miss injury of self

or bed partner during sleep, and if behaviours are in line with dream

content at least part of the time (Frauscher B., Movement Disorder 2012).

All those questionnaires have undergone validation studies and had

sensitivities and specificities which looked acceptable, except a lower

specificity in the control group with other sleep and neurologic disorders

in the RBD SQ. However, in the course of the subsequent year, it became

clear, that questionnaires alone for diagnosis of RBD may lead to false

positives and false negatives, and that the application circumstances

influence the outcome (Stiasny-Kolster Sleep Medicine 2015). In addition,

it was shown that different questionnaires will give different prevalences

of probable RBD (Mahlknecht P, Movement Disorders 2015) in the general

population. It has also been shown, that administering an RBD

questionnaire to a healthy population without further instructions can give

up to 16 % false positives in otherwise healthy sleepers, who did not have

RBD confirmed in subsequent sleep expert interview or polysomnography

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(Frauscher B., JCSM, 2014). In addition, a follow-up study in the general

population, were 437 participants aged over 60 years completed the

RBDSQ twice in 2008 and 2010, showed that only 1,8 % of this population

screened positive on both occasions, while 6,6 vs. 4,3 % screened positive

only on one of the two assessments, so the congruence between both

assessments was unexpectedly low. If this is related to fluctuation of RBD

clinical expression over time, or a limitation of the questionnaire needs to

be investigated by further studies (Stefani A., MDCP in press). In addition,

the awareness of RBD my be low by the patients themselves (Fernandez-

Arcos Sleep 2016) and improved if a bed partner participates in the

interview.

Recently, a multistep screening approach to search for iRBD has been

suggested for prodromal PD in the general community. It includes a

newspaper advertisement containing the single question screen for RBD

published by the IRDB SG (Postuma, Sleep Med 2016). In this multistep

approach study, screen-positive subjects underwent an interview based on

the Innsbruck RBD inventory (Frauscher et al, 2012) administered by

telephone interview. Those who passed both screens, wunderwent con-

firmatory polysomnography. With this strategy, the PPV of patients 66 %,

but this was out of 111 RBD screen positive participants, 36 had passed

the secondary screen and 29 underwent full PSG (Postuma R et al, Sleep

Med 2016)

PSG Diagnosis of RBD

While Mahowald and Schenck highlighted since the beginning the

importance of PSG recording including EMG of the upper limbs to detect

RBD, the older ICSD-2 criteria required only a more generic “excessive”

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EMG activity in the submental channel or limbs. Later, the SINBAR group

(Sleep Innsbruck Barcelona) performed a systematic study to access

normative EMG values during REM sleep for the diagnosis of REM sleep

behaviour disorder. For this study, 30 patients with REM behaviour

disorder, and 30 matched controls underwent continuous surface EMG

registration of 11 body muscles during polysomnography. The EMG activity

during REM sleep was classified into tonic, phasic and any EMG activity by

a blind rater and quantified for each muscle. In this study, it was shown

that when a specificity of 100 % was targeted, the cut off for a diagnosis

of RBD in the mentalis muscle alone was 18 %, and 32 % for the

combination of any EMG activity in the mentalis muscle and phasic EMG

activity in the flexor digitorum superficialis muscle. This gave a very high

area under the curve of 0,998 %. Nevertheless, despite these quantitative

EMG criteria, it should be emphasized, that a diagnosis of RBD requires

additionally the presence of the other clinical criteria (behaviors and/or

vocalizations)

A recent study in highlighted impressively the diagnostic advantages of

performing polysomnography with EMG not only from the mental/sub-

mental muscles, but routinely including EMG from the upper limbs (flexor

digitorum superficialis or biceps muscle) for a definite diagnosis of RBD,

and the significant proportion of correct diagnosis who would have been

missed, if submental muscle EMG alone would have been performed. The

addition of arm EMG is technically not a challenge for PSG technicians who

are used to record tibial anterior EMG (Fernandez-Arcos Sleep 2017).

Different other groups have used different approaches to quantify EMG

activity during REM sleep. The original method based on submental EMG

recording and dividing activity into tonic and phasic stems from Lapierre

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and Montplaisir 1992. Zhang and co-workers included extensor of the

forearms for quantified diagnosis of RBD (Zhang 2008). Other authors,

including Bliwise, Consens and Eisensehr, proposed slightly different

methods. The Mayo group recently confirmed the suitability of a SINBAR

approach with a modified montage including “chin any” or tibialis anterior

phasic EMG (Mac Carter Sleep 2014).

Another method that uses mental/submental EMG only is the REM atonia

index RAI, which is somewhat the inverse figure of increased REM chin

EMG activity index. It was first described and calculated by Ferri and

coworkers, and later also used and validated by other groups (Mac Carter

2014). Ferri and co-workers also showed, that this approach has a good

night to night stability (Ferri R, JCSM 2013).

In a recent study including 62 patients with Parkinson Disease, two visual

methods, Montreal and SINBAR, and the automatic REM atonia index were

compared. The REM atonia index had a 94,6 % sensitivity and 72 %

specificity, and the authors concluded that RAI may be used as first line

method to detect REM sleep without atonia in the diagnosis of RBD in

patients with Parkinson Disease, together with visual inspection of video

recorded behaviours, while the visual analysis might be used in doubtful

cases (Figorilli, 2017).

In addition, because the visual and manual analysis of increased motor

activity during REM sleep requires highly specific skills and is time-

consuming and cumbersome, automatic detection several different

approaches to detect REM sleep without atonia based on EOG and EEG has

been proposed (Kempfner, 2012, Sissel Bisgaard 2015).

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At present the only validated automatic analysis system for REM sleep

without atonia that does not only include EMG quantification from the

submental muscle, but also from the flexor digitorum superficialis muscle,

and which is built-in into a commercially available PSG system, is supplied

by OSG Belgium and has been validated (Frauscher B, Sleep 2014).

Implications for Diagnosis of RBD

In a situation, when a good polysomnography is still not readily available

everywhere, has long waiting times, or seems too cumbersome, there may

be a temptation to use a questionnaire based diagnosis of probable RBD

only. However, the following should be kept in mind, at least for future

studies of disease modifying substances to prevent the full clinical onset

of neurodegenerative disease / α-synuclein disease in patients with still

idiopathic RBD: The success of these future studies will depend on the fact

if RBD has been diagnosed accurately and correctly or not. Fals positive

and fale negative diagnosis would confound the outcomes of any future

treatment study. Therefore, a quantified and well ascertained PSG

diagnosis of will help to advance the field of neurodegenerative research

as a whole, and in the future hopefully also for the patients with IRBD.

Disclosure: Dr. Birigt Högl has been a consultant with Mundipharma, Axovant and

Benevolent Bio, was speaker and received honoraria for and from Otsuka,

UCB, Abbvie, Lilly, Lundbeck, Janssen Cilag, and Mundipharma and has

received travel Support from Habel Medizintechnik and Vivisol Austria.

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Further reading:

1. Schenck CH, Hurwitz TD, Mahowald MW. REM sleep behavior

disorder. Am J Psychiatry. 1988; 145(5):652.

2. Chiu HF, Wing YK, Lam LC, Lum CM, Ho CK. Sleep-related injury in

the elderly-an epidemiological study in Hong Kong. Sleep. 2000;

15;23(4):513-7.

3. Kang SH, Yoon IY, Lee SD, Han JW, Kim TH, Kim KW. REM sleep

behavior disorder in the Korean elderly population: prevalence and

clinical characteristics. Sleep. 2013; 36(8):1147-52.

4. Ohayon MM, Caulet M, Priest RG. Violent Behavior During Sleep.

J Clin Psychiatry. 1997; 58(8):369-76.

5. Frauscher B, Gschliesser V, Brandauer E, Marti I, Furtner MT,

Ulmer H, et al. REM sleep behavior disorder in 703 sleep-disorder

patients: the importance of eliciting a comprehensive sleep history.

Sleep Med. 2010; 11(2):167-71.

6. Mollenhauser B, Trautmann E, Sixel-Döring F, Wicke T, Ebenthauer

J, Schaumburg M, et al. Nonmotor and diagnostic findings in

subjects with de novo Parkinson disease of the DeNoPa cohort.

Neurology. 2013; 81(14):1226-34.

7. Wetter TC, Trenkwalder C, Gershanik O, Högl B. Polysomnographic

measures in Parkinson's disease: a comparison between patients

with and without REM sleep disturbances. Wien Klin Wochenschr.

2001; 113(7-8):249-53.

8. Gagnon JF, Bédard MA, Fantini ML, Petit D, Panisset M, Rompré S,

et al. REM sleep behavior disorder and REM sleep without atonia in

Parkinson's disease. Neurology. 2002; 59(4):585-9.

9. Sixel-Döring F, Trautmann E, Mollenhauer B, Trenkwalder C.

Associated factors for REM sleep behavior disorder in Parkinson

disease.Neurology. 2011; 77(11):1048-54.

10. Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F, Serradell

M, et al. Neurodegenerative disease status and post-mortem

pathology in idiopathic rapid-eye-movement sleep behaviour

disorder: an observational cohort study. Lancet Neurol. 2013;

12(5):443-53.

11. Postuma RB, Iranzo A, Högl B, Arnulf I, Ferini-Strambi L, Manni R,

et al. Risk factors for neurodegeneration in idiopathic rapid eye

movement sleep behavior disorder: a multicenter study. Ann

Neurol. 2015; 77(5):830-9.

12. American Academy of Sleep Medicine. International classification

of sleep disorders, 3rd ed. Darien, IL: American Academy of Sleep

Medicine, 2014.

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13. Stiasny-Kolster K, Mayer G, Schäfer S, Möller JC, Heinzel-

Gutenbrunner M, Oertel WH. The REM sleep behavior disorder

screening questionnaire-a new diagnostic instrument. Mov Disord.

2007; 22(16):2386-93.

14. Li SX, WING YK, Lam SP, Zhang J, Yu MW, Ho CK, Tsoh J, Mok V.

Validation of a new REM sleep behavior disorder questionnaire

(RBDQ-HK). Sleep Med. 2010; 11(1):43-8.

15. Boeve BF, Molano JR, Ferman TJ, Smith SC, Lin Siong- Chi, Bieniek

K, Tippmann-Peikert M, et al. Validation of the Mayo Sleep

Questionnaire to screen for REM sleep behavior disorder in a

community-based sample. J Clin Sleep Med 2013; 9(5):475-480.

16. Postuma RB, Arnulf I, Högl B, Iranzo A, Miyamoto T, Dauvilliers Y,

et al. A single-question screen for rapid eye movement sleep

behavior disorder: a multicenter validation study. Mov. Disord.

2012; 27(7):913-6.

17. Frauscher B, Ehrmann L, Zamarian L, Auer F, Mitterling T, Gabelia

D, et al. Validation of the Innsbruck REM sleep behavior disorder

inventory. Mov Disord. 2012; 27(13):1673-8.

18. Stiasny-Kolster K, Sixel-Döring F, Trenkwalder C, Heinzel-

Gutenbrunner M, Seppi K, Poewe W, et al. Diagnostiv value of the

REM sleep behavior disorder screening questionnaire in Parkinson’s

disease. Sleep Med. 2015; 16(1):186-9.

19. Mahlknecht P, Seppi K, Frauscher B, Kiechl S, Willeit J, Stockner H,

et al. Probable RBD and association with neurodegenerative disease

markers: A population-based study. Mov Disord. 2015;

30(10):1417-21.

20. Frauscher B, Mitterling T, Bode A, Ehrmann L, Gabelia D, Biermayr

M, et al. A prospective questionnaire study in 100 healthy sleepers:

non-bothersome forms of recognizable sleep disorders are still

present. J Clin Sleep Med. 2014; 10(6):623-9.

21. Stefani A, Mahlknecht P, Seppi K, Nocker M, Mair KJ, Hotter A, et

al. Consistency of “probable RBD” diagnosis with the RBD screening

questionnaire: A follow-up study. Mov Disord Clin Prct. 2016;

[E-pub ahead of print] doi:10.1002/mdc3.12448.

22. Fernández-Arcos A, Iranzo A, Serradell M, Gaig C, Santamaria J.

The Clinical Phenotype of Idiopathic Rapid Eye Movement Sleep

Behavior Disorder at Presentation: A Study in 203 Consecutive

Patients. Sleep. 2016, 39(1):121-32.

23. Postuma RB, Pelletier A, Berg D, Gagnon JF, Escudier F, Montplaisir

J. Screening for prodromal Parkinson's disease in the general

community: a sleep-based approach. Sleep Med. 2016; 21:101-5.

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24. Mahowald MW, Schenk CH. REM Sleep Parasomnias. In: Kryger MH,

Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine.

3rd ed. St. Louis: Elsevier Saunders; 2000. p 1038-1097.

25. American Association of Sleep Medicine. International classification

of sleep disorders, 2nd ed. Westchester: American Academy of

Sleep Medicine, 2005.

26. Frauscher B, Iranzo A, Gaig C, Gschliesser V, Guaita M, Raffelseder

V. Normative EMG values during REM sleep for the diagnosis of REM

sleep behavior disorder. Sleep. 2012; 35(6):835-47.

27. Fernández-Arcos A, Iranzo A, Serradell M, Gaig C, Guaita M,

Salamero M, et al. Diagnostic Value of Isolated Mentalis Versus

Mentalis Plus Upper Limb Electromyography in Idiopathic REM Sleep

Behavior Disorder Patients Eventually Developing a

Neurodegenerative Syndrome. Sleep. 2017.

https://doi.org/10.1093/sleep/zsx025 [Epub ahead of print].

28. Lapierre O, Montplaisir J. Polysomnographic features of REM sleep

behavior disorder: development of a scoring method. Neurology.

1992; 42(7):1371-4.

29. Zhang J, Lam SP, Ho CK, Li AM, Tsoh J, Mok V, et al. Diagnosis of

REM sleep behavior disorder by video-polysomnographic study: is

one night enough?. Sleep. 2008; (8):1179-85.

30. McCarter SJ, St Louis EK, Duwell EJ, Timm PC, Sandness DJ, Boeve

BF, et al. Diagnostic thresholds for quantitative REM sleep phasic

burst duration, phasic and tonic muscle activity, and REM atonia

index in REM sleep behavior disorder with and without comorbid

obstructive sleep apnea. Sleep. 2014; 37(10):1649-62.

31. Ferri R, Gagnon JF, Postuma RB, Rundo F, Montplaisir JY.

Comparison between an automatic and a visual scoring method of

the chin muscle tone during rapid eye movement sleep. Slep Med.

2014; 15(6):661-5.

32. Ferri R, Marelli S, Cosentino FI, Rundo F, Ferini-Strambi L, Zucconi

M. Night-to-night variability of automatic quantitative parameters

of the chin EMG amplitude (Atonia Index) in REM sleep behavior

disorder. J Clin Sleep Med. 2013; 15;9(3):253-8.

33. Figorilli M, Ferri R, Zibetti M, Beudin P, Puligheddu M, Lopiano L,

et al. Comparison Between Automatic and Visual Scorings of REM

Sleep Without Atonia for the Diagnosis of REM Sleep Behavior

Disorder in Parkinson Disease. Sleep. 2017; 40(2).

34. Kempfner J, Jennum P, Nikolic M, Christensen JAE, Sorensen HBD.

Automatic Detection of REM Sleep in Subjects without Atonia.

Conf Proc IEEE Eng Med Biol Soc. 2012; 2012:4242-5.

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35. Bisgaard S, Duun-Christensen B, Kempfner L, Sorensen HBD,

Jennum P. EEG Recordings as a Source for the Detection of IRDB.

Conf Proc IEEE Eng Med Biol Soc. 2015; 2015:606-9.

36. Frauscher B, Gabelia D, Biermayr M, Stefani A, Hackner H,

Mitterling T, et al. Validation of an integrated software for the

detection of rapid eye movement sleep behavior disorder. Sleep.

2014; 37(10):1663-71.