Accepted Manuscript Title: The role of REM sleep without atonia in the diagnosis of REM sleep behavior disorder: past errors and new challenges Author: Raffaele Ferri, Maria Livia Fantini, Carlos H. Schenck PII: DOI: Reference:
S1389-9457(14)00205-6 http://dx.doi.org/doi:10.1016/j.sleep.2014.05.006 SLEEP 2465
To appear in:
Sleep Medicine
Received date: Accepted date:
23-4-2014 16-5-2014
Please cite this article as: Raffaele Ferri, Maria Livia Fantini, Carlos H. Schenck, The role of REM sleep without atonia in the diagnosis of REM sleep behavior disorder: past errors and new challenges, Sleep Medicine (2014), http://dx.doi.org/doi:10.1016/j.sleep.2014.05.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Editorial
The role of REM sleep without atonia in the diagnosis of REM sleep behavior disorder: past errors and new challenges
In this issue of Sleep Medicine, Sasai et al. [1] have published a retrospective study showing that some subjects without REM sleep behavior disorder (RBD) do have “incidental” REM sleep without atonia (RSWA) that falls within the quantitative EMG parameters established by their group for the diagnosis of RBD (the SINBAR method) [2]. Consequently, the authors suggest that future longitudinal studies should be arranged to assess whether non-RBD subjects with isolated and objectively assessed RSWA have an increased risk of developing fully expressed RBD and/or neurodegenerative disease, or not. First of all, it should be said that this is not the first time that subjects with isolated RSWA have been described, especially with quantitative methods for the assessment of RSWA, but it is the first study specifically arranged for this topic. Montplaisir et al. [3], in the validation study for their chin EMG quantification method (the Montréal method), already reported that a significant number of controls (approximately 10-12%) had elevated values in at least one of their chin EMG derived measures. Similarly, decreased atonia has been reported in some normal controls by means of an automated quantitative analysis of the chin EMG (Atonia Index) [4-6], especially in the oldest subjects [7]. It is also crucial to consider that this new report might generate a lively debate on the “normative” cutoff values provided by the same group for the SINBAR method [2] - a nearly 100% accuracy for the diagnosis of RBD - because it shows that finding subjects without RBD, but with RSWA, might be a more frequent event than reported earlier with this method, as established in a single study of an index group of patients [2]. Thus, a validation study on large groups of patients and controls appears to be needed because, from the methodological point of view, the establishment of cut-off values for a clinical measure in an index group of subjects is almost inevitably followed by lower values of specificity and sensitivity when applied to a separate group of subjects. Moreover, this study did not include the flexor digitorum superficialis muscles that have been indicated to be the most sensitive muscle location for the detection of EMG activity in RBD [8]. Thus, a replication study that includes also these muscles is extremely important because it is essential to know if these muscles really need to be used in the diagnosis of RSWA or not.
Ferri et al. - Editorial - page 1 Page 1 of 5
Besides these unsolved problems, the paper by Sasai et al. [1] has the merit to focus the attention of the reader on the meaning of “isolated” RSWA, which is strictly twisted around the still undefined concept of “subclinical” RBD. Some earlier papers have used the term “subclinical RBD” to indicate the observation of dream enactment behaviors that for different reasons could not be diagnosed as fully expressed RBD in the subjects with “incidental” RSWA [9-11], or in patients who eventually developed fully-declared RBD after demonstrating longstanding subclinical behavioral release during sleep. Concerning this last group, in the consecutive series of 96 patients with RBD reported by Schenck et al. [12], 25% had a behavior usually lasting decades, according to the spouses that was termed “subclinical RBD” by the authors on the basis of chronic and often progressive (in regards to both frequency and intensity) limb jerking and twitching, and sleep talking/shouting during sleep (but without any reported associated dreaming). Nevertheless, we will now focus here on RSWA. Similar to the previous ICSD-2 criteria, the recently published ICSD-3 criteria for the diagnosis of RBD [13] require that polysomnographic (PSG) recordings demonstrate RSWA, but a clarifying note linked with the diagnostic criteria also recognizes that: “On occasion, there may be patients with a typical clinical history of RBD with dream-enacting behaviors, who also exhibit typical RBD behaviors during video-PSG, but do not demonstrate sufficient RSWA, based on the current evidence-based data, to satisfy the PSG criteria for diagnosing RBD. In such patients, RBD may be provisionally diagnosed, based on clinical judgment. The same rule applies when video-PSG is not readily available.” Thus, we have both possibilities, RBD patients who do not show RSWA and non-RBD subjects who do exhibit RSWA. The question to solve now is: what is the role of RSWA in the diagnosis of RBD? There is no doubt that it has a role but, to what extent is this measure reliable and necessary? The current RBD diagnostic criteria in the ICSD-3 [13] present other unresolved aspects. First of all, they state that RSWA should be assessed “as defined by the guidelines for scoring PSG features of RBD in the most recent version of the American Academy of Sleep Medicine (AASM) Manual for the Scoring of Sleep and Associated Events” [14]. However, the most recent AASM Manual [14] only defines qualitatively how each REM sleep epoch should be classified as “tonic” or “phasic,” based on the chin and limb EMG activity level but does not specify how many “tonic” and/or “phasic” epochs define RSWA or normality. The equivocal terms “sustained” and “excessive” are still used, leaving the final decision to a totally subjective judgment. Thus, by
Ferri et al. - Editorial - page 2 Page 2 of 5
applying these criteria we can expect a large overlap between RBD and non-RBD subjects, in terms of the presence of RSWA, and the paper by Sasai et al. [1] shows that this is true. The use of quantitative methods only reduces this overlap and opens new questions related to its possible sources. Future studies need to address the effects of additional factors that are likely to play a role in this overlap: night-to-night variability of the measurement, age of the subjects, and the muscles included in the measurements The night-to-night variability of both clinical manifestations and chin EMG changes of RBD are well known [15-17], and quantitative methods might decrease but not abolish it [18]. Thus, it remains to be determined not only how many nights are needed to confirm RSWA in RBD, but also how many nights are needed for non-RBD subjects who might present with RSWA during a lower number of nights. Also, it has been reported that REM sleep atonia develops continuously through a lifespan, with complex changes and different developmental trajectories for REM atonia and “phasic” EMG activations during REM sleep [7]; particularly, in old age a decline of REM atonia is expected, together with an increase in the number of “phasic” EMG activations, making more probable the detection of RSWA according to preset cut-off values not adjusted for age. Finally, a still unexplored field is that of the effects of REM sleep duration on the measurements of atonia. All these considerations should encourage a careful reevaluation of the steps previously taken, and the approaches selected, to help guide us towards a more accurate and reliable use of RSWA in the future.
References
[1] Sasai T, Frauscher B, Mitterling T, Ehrmann L, Gabelia D, Brandauer E et al. Quantitative assessment of isolated rapid eye movement (REM) sleep without atonia without clinical REM sleep behavior disorder: clinical and research implications. Sleep Med 2014;-DOI: http://dx.doi.org/10.1016/j.sleep.2014.02.010. [2] Frauscher B, Iranzo A, Gaig C, Gschliesser V, Guaita M, Raffelseder V et al. Normative EMG Values during REM Sleep for the Diagnosis of REM Sleep Behavior Disorder. Sleep 2012;35:835-847. [3] Montplaisir J, Gagnon JF, Fantini ML, Postuma RB, Dauvilliers Y, Desautels A et al. Polysomnographic diagnosis of idiopathic REM sleep behavior disorder. Mov Disord 2010;25:2044-2051. [4] Ferri R, Manconi M, Plazzi G, Bruni O, Vandi S, Montagna P et al. A quantitative statistical analysis of the submentalis muscle EMG amplitude during sleep in normal controls and patients with REM sleep behavior disorder. J Sleep Res 2008;17:89-100. [5] Ferri R, Rundo F, Manconi M, Plazzi G, Bruni O, Oldani A et al. Improved computation of the atonia index in normal controls and patients with REM sleep behavior disorder. Sleep Med 2010;11:947-949. Ferri et al. - Editorial - page 3 Page 3 of 5
[6] Ferri R, Fulda S, Cosentino FI, Pizza F, Plazzi G. A preliminary quantitative analysis of REM sleep chin EMG in Parkinson's disease with or without REM sleep behavior disorder. Sleep Med 2012;13:707-713. [7] Ferri R, Bruni O, Fulda S, Zucconi M, Plazzi G. A quantitative analysis of the submentalis muscle electromyographic amplitude during rapid eye movement sleep across the lifespan. J Sleep Res 2012;21:257-263. [8] Iranzo A, Frauscher B, Santos H, Gschliesser V, Ratti L, Falkenstetter T et al. Usefulness of the SINBAR electromyographic montage to detect the motor and vocal manifestations occurring in REM sleep behavior disorder. Sleep Med 2011;12:284-288. [9] Eisensehr I, Linke R, Noachtar S, Schwarz J, Gildehaus FJ, Tatsch K. Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson's disease and controls. Brain 2000;123:1155-1160. [10] Mayer G, Kesper K, Ploch T, Canisius S, Penzel T, Oertel W et al. Quantification of tonic and phasic muscle activity in REM sleep behavior disorder. J Clin Neurophysiol 2008;25:48-55. [11] Nomura T, Inoue Y, Miyake M, Yasui K, Nakashima K. Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson's disease. Mov Disord 2005;.. [12] Schenck CH, Hurwitz TD, Mahowald MW. Normal and abnormal REM sleep regulation: REM sleep behaviour disorder: an update on a series of 96 patients and a review of the world literature. J Sleep Res 1993;2:224-231. [13] American Academy of Sleep Medicine. International classification of sleep disorders, 3rd ed. American Academy of Sleep Medicine. Darien, IL, 2014. [14] Berry, RB, Brooks, R, Gamaldo, CE, Harding, SM, Marcus, CL, Vaughn, BV. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Ver. 2.0. American Academy of Sleep Medicine. Darien, IL, 2012. [15] Frauscher B, Gschliesser V, Brandauer E, Ulmer H, Peralta CM, Muller J et al. Video analysis of motor events in REM sleep behavior disorder. Mov Disord 2007;22:1464-1470. [16] 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;31:1179-1185. [17] Cygan F, Oudiette D, Leclair-Visonneau L, Leu-Semenescu S, Arnulf I. Night-to-night variability of muscle tone, movements, and vocalizations in patients with REM sleep behavior disorder. J Clin Sleep Med 2010;6:551-555. [18] 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;9:253-258.
* Raffaele Ferri Department of Neurology I.C. Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS) Via C. Ruggero 73, 94018 Troina, Italy *Tel. +30-0935-936111, Fax +39-0935-936694 e.mail: [email protected]
Maria Livia Fantini Neurology Service, CHU Clermont-Ferrand Ferri et al. - Editorial - page 4 Page 4 of 5
EA 7280, Faculty of Medicine University Clermont 1, Clermont-Ferrand, France e.mail: [email protected]
Carlos H. Schenck Minnesota Regional Sleep Disorders Center Department of Psychiatry, Hennepin County Medical Center University of Minnesota Medical School Minneapolis, MN, U.S.A e.mail: [email protected]
Ferri et al. - Editorial - page 5 Page 5 of 5
S1389-9457(14)00205-6 http://dx.doi.org/doi:10.1016/j.sleep.2014.05.006 SLEEP 2465
To appear in:
Sleep Medicine
Received date: Accepted date:
23-4-2014 16-5-2014
Please cite this article as: Raffaele Ferri, Maria Livia Fantini, Carlos H. Schenck, The role of REM sleep without atonia in the diagnosis of REM sleep behavior disorder: past errors and new challenges, Sleep Medicine (2014), http://dx.doi.org/doi:10.1016/j.sleep.2014.05.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Editorial
The role of REM sleep without atonia in the diagnosis of REM sleep behavior disorder: past errors and new challenges
In this issue of Sleep Medicine, Sasai et al. [1] have published a retrospective study showing that some subjects without REM sleep behavior disorder (RBD) do have “incidental” REM sleep without atonia (RSWA) that falls within the quantitative EMG parameters established by their group for the diagnosis of RBD (the SINBAR method) [2]. Consequently, the authors suggest that future longitudinal studies should be arranged to assess whether non-RBD subjects with isolated and objectively assessed RSWA have an increased risk of developing fully expressed RBD and/or neurodegenerative disease, or not. First of all, it should be said that this is not the first time that subjects with isolated RSWA have been described, especially with quantitative methods for the assessment of RSWA, but it is the first study specifically arranged for this topic. Montplaisir et al. [3], in the validation study for their chin EMG quantification method (the Montréal method), already reported that a significant number of controls (approximately 10-12%) had elevated values in at least one of their chin EMG derived measures. Similarly, decreased atonia has been reported in some normal controls by means of an automated quantitative analysis of the chin EMG (Atonia Index) [4-6], especially in the oldest subjects [7]. It is also crucial to consider that this new report might generate a lively debate on the “normative” cutoff values provided by the same group for the SINBAR method [2] - a nearly 100% accuracy for the diagnosis of RBD - because it shows that finding subjects without RBD, but with RSWA, might be a more frequent event than reported earlier with this method, as established in a single study of an index group of patients [2]. Thus, a validation study on large groups of patients and controls appears to be needed because, from the methodological point of view, the establishment of cut-off values for a clinical measure in an index group of subjects is almost inevitably followed by lower values of specificity and sensitivity when applied to a separate group of subjects. Moreover, this study did not include the flexor digitorum superficialis muscles that have been indicated to be the most sensitive muscle location for the detection of EMG activity in RBD [8]. Thus, a replication study that includes also these muscles is extremely important because it is essential to know if these muscles really need to be used in the diagnosis of RSWA or not.
Ferri et al. - Editorial - page 1 Page 1 of 5
Besides these unsolved problems, the paper by Sasai et al. [1] has the merit to focus the attention of the reader on the meaning of “isolated” RSWA, which is strictly twisted around the still undefined concept of “subclinical” RBD. Some earlier papers have used the term “subclinical RBD” to indicate the observation of dream enactment behaviors that for different reasons could not be diagnosed as fully expressed RBD in the subjects with “incidental” RSWA [9-11], or in patients who eventually developed fully-declared RBD after demonstrating longstanding subclinical behavioral release during sleep. Concerning this last group, in the consecutive series of 96 patients with RBD reported by Schenck et al. [12], 25% had a behavior usually lasting decades, according to the spouses that was termed “subclinical RBD” by the authors on the basis of chronic and often progressive (in regards to both frequency and intensity) limb jerking and twitching, and sleep talking/shouting during sleep (but without any reported associated dreaming). Nevertheless, we will now focus here on RSWA. Similar to the previous ICSD-2 criteria, the recently published ICSD-3 criteria for the diagnosis of RBD [13] require that polysomnographic (PSG) recordings demonstrate RSWA, but a clarifying note linked with the diagnostic criteria also recognizes that: “On occasion, there may be patients with a typical clinical history of RBD with dream-enacting behaviors, who also exhibit typical RBD behaviors during video-PSG, but do not demonstrate sufficient RSWA, based on the current evidence-based data, to satisfy the PSG criteria for diagnosing RBD. In such patients, RBD may be provisionally diagnosed, based on clinical judgment. The same rule applies when video-PSG is not readily available.” Thus, we have both possibilities, RBD patients who do not show RSWA and non-RBD subjects who do exhibit RSWA. The question to solve now is: what is the role of RSWA in the diagnosis of RBD? There is no doubt that it has a role but, to what extent is this measure reliable and necessary? The current RBD diagnostic criteria in the ICSD-3 [13] present other unresolved aspects. First of all, they state that RSWA should be assessed “as defined by the guidelines for scoring PSG features of RBD in the most recent version of the American Academy of Sleep Medicine (AASM) Manual for the Scoring of Sleep and Associated Events” [14]. However, the most recent AASM Manual [14] only defines qualitatively how each REM sleep epoch should be classified as “tonic” or “phasic,” based on the chin and limb EMG activity level but does not specify how many “tonic” and/or “phasic” epochs define RSWA or normality. The equivocal terms “sustained” and “excessive” are still used, leaving the final decision to a totally subjective judgment. Thus, by
Ferri et al. - Editorial - page 2 Page 2 of 5
applying these criteria we can expect a large overlap between RBD and non-RBD subjects, in terms of the presence of RSWA, and the paper by Sasai et al. [1] shows that this is true. The use of quantitative methods only reduces this overlap and opens new questions related to its possible sources. Future studies need to address the effects of additional factors that are likely to play a role in this overlap: night-to-night variability of the measurement, age of the subjects, and the muscles included in the measurements The night-to-night variability of both clinical manifestations and chin EMG changes of RBD are well known [15-17], and quantitative methods might decrease but not abolish it [18]. Thus, it remains to be determined not only how many nights are needed to confirm RSWA in RBD, but also how many nights are needed for non-RBD subjects who might present with RSWA during a lower number of nights. Also, it has been reported that REM sleep atonia develops continuously through a lifespan, with complex changes and different developmental trajectories for REM atonia and “phasic” EMG activations during REM sleep [7]; particularly, in old age a decline of REM atonia is expected, together with an increase in the number of “phasic” EMG activations, making more probable the detection of RSWA according to preset cut-off values not adjusted for age. Finally, a still unexplored field is that of the effects of REM sleep duration on the measurements of atonia. All these considerations should encourage a careful reevaluation of the steps previously taken, and the approaches selected, to help guide us towards a more accurate and reliable use of RSWA in the future.
References
[1] Sasai T, Frauscher B, Mitterling T, Ehrmann L, Gabelia D, Brandauer E et al. Quantitative assessment of isolated rapid eye movement (REM) sleep without atonia without clinical REM sleep behavior disorder: clinical and research implications. Sleep Med 2014;-DOI: http://dx.doi.org/10.1016/j.sleep.2014.02.010. [2] Frauscher B, Iranzo A, Gaig C, Gschliesser V, Guaita M, Raffelseder V et al. Normative EMG Values during REM Sleep for the Diagnosis of REM Sleep Behavior Disorder. Sleep 2012;35:835-847. [3] Montplaisir J, Gagnon JF, Fantini ML, Postuma RB, Dauvilliers Y, Desautels A et al. Polysomnographic diagnosis of idiopathic REM sleep behavior disorder. Mov Disord 2010;25:2044-2051. [4] Ferri R, Manconi M, Plazzi G, Bruni O, Vandi S, Montagna P et al. A quantitative statistical analysis of the submentalis muscle EMG amplitude during sleep in normal controls and patients with REM sleep behavior disorder. J Sleep Res 2008;17:89-100. [5] Ferri R, Rundo F, Manconi M, Plazzi G, Bruni O, Oldani A et al. Improved computation of the atonia index in normal controls and patients with REM sleep behavior disorder. Sleep Med 2010;11:947-949. Ferri et al. - Editorial - page 3 Page 3 of 5
[6] Ferri R, Fulda S, Cosentino FI, Pizza F, Plazzi G. A preliminary quantitative analysis of REM sleep chin EMG in Parkinson's disease with or without REM sleep behavior disorder. Sleep Med 2012;13:707-713. [7] Ferri R, Bruni O, Fulda S, Zucconi M, Plazzi G. A quantitative analysis of the submentalis muscle electromyographic amplitude during rapid eye movement sleep across the lifespan. J Sleep Res 2012;21:257-263. [8] Iranzo A, Frauscher B, Santos H, Gschliesser V, Ratti L, Falkenstetter T et al. Usefulness of the SINBAR electromyographic montage to detect the motor and vocal manifestations occurring in REM sleep behavior disorder. Sleep Med 2011;12:284-288. [9] Eisensehr I, Linke R, Noachtar S, Schwarz J, Gildehaus FJ, Tatsch K. Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson's disease and controls. Brain 2000;123:1155-1160. [10] Mayer G, Kesper K, Ploch T, Canisius S, Penzel T, Oertel W et al. Quantification of tonic and phasic muscle activity in REM sleep behavior disorder. J Clin Neurophysiol 2008;25:48-55. [11] Nomura T, Inoue Y, Miyake M, Yasui K, Nakashima K. Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson's disease. Mov Disord 2005;.. [12] Schenck CH, Hurwitz TD, Mahowald MW. Normal and abnormal REM sleep regulation: REM sleep behaviour disorder: an update on a series of 96 patients and a review of the world literature. J Sleep Res 1993;2:224-231. [13] American Academy of Sleep Medicine. International classification of sleep disorders, 3rd ed. American Academy of Sleep Medicine. Darien, IL, 2014. [14] Berry, RB, Brooks, R, Gamaldo, CE, Harding, SM, Marcus, CL, Vaughn, BV. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Ver. 2.0. American Academy of Sleep Medicine. Darien, IL, 2012. [15] Frauscher B, Gschliesser V, Brandauer E, Ulmer H, Peralta CM, Muller J et al. Video analysis of motor events in REM sleep behavior disorder. Mov Disord 2007;22:1464-1470. [16] 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;31:1179-1185. [17] Cygan F, Oudiette D, Leclair-Visonneau L, Leu-Semenescu S, Arnulf I. Night-to-night variability of muscle tone, movements, and vocalizations in patients with REM sleep behavior disorder. J Clin Sleep Med 2010;6:551-555. [18] 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;9:253-258.
* Raffaele Ferri Department of Neurology I.C. Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS) Via C. Ruggero 73, 94018 Troina, Italy *Tel. +30-0935-936111, Fax +39-0935-936694 e.mail: [email protected]
Maria Livia Fantini Neurology Service, CHU Clermont-Ferrand Ferri et al. - Editorial - page 4 Page 4 of 5
EA 7280, Faculty of Medicine University Clermont 1, Clermont-Ferrand, France e.mail: [email protected]
Carlos H. Schenck Minnesota Regional Sleep Disorders Center Department of Psychiatry, Hennepin County Medical Center University of Minnesota Medical School Minneapolis, MN, U.S.A e.mail: [email protected]
Ferri et al. - Editorial - page 5 Page 5 of 5
