Accepted Manuscript REM sleep behavior disorder in Parkinson Disease: Association with abnormal ocular motor findings Young Eun Kim, MD Hui June Yang, MD Ji Young Yun, MD Han-Joon Kim, MD JeeYoung Lee, MD Beom S. Jeon, MD, PhD PII:

S1353-8020(13)00436-7

DOI:

10.1016/j.parkreldis.2013.12.003

Reference:

PRD 2213

To appear in:

Parkinsonism and Related Disorders

Received Date: 22 July 2013 Revised Date:

2 December 2013

Accepted Date: 7 December 2013

Please cite this article as: Kim YE, Yang HJ, Yun JY, Kim H-J, Lee J-Y, Jeon BS, REM sleep behavior disorder in Parkinson Disease: Association with abnormal ocular motor findings, Parkinsonism and Related Disorders (2014), doi: 10.1016/j.parkreldis.2013.12.003. 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.

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Title page REM sleep behavior disorder in Parkinson Disease: Association with

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abnormal ocular motor findings

Young Eun Kim, MD1, Hui June Yang, MD2, Ji Young Yun, MD3, Han-Joon Kim, MD2,

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Jee-Young Lee, MD4, Beom S Jeon, MD, PhD*2

University College of Medicine, Korea

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1. Department of Neurology, Seoul National University Bundang Hospital, Seoul National

2. Department of Neurology and Movement disorder center, Parkinson Study Group, Seoul National University Hospital, Korea.

3. Department of Neurology, Ewha Womans University Mokdong Hospital, Korea.

Hospital, Korea

Corresponding author

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4. Department of Neurology, College of Medicine, Seoul National University Boramae

Beom S. Jeon, MD, PhD

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Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea Tel: +82-2-2072-2876, Fax: +82-2-3672-7553, e-mail address: [email protected]

Keywords REM sleep behavior disorder; Parkinson disease; downbeat nystagmus; ocular motor abnormality; videooculography

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Short title

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REM sleep behavior disorder and ocular motor findings in Parkinson Disease

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Abstract Background: The anatomical substrates associated with generalized muscle atonia during

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REM sleep are located on the pontine tegmentum and medial medulla oblongata. We examined whether patients with REM sleep behavior disorder (RBD) have abnormal ocular movements suggesting brainstem or cerebellar dysfunction in Parkinson’s disease (PD).

Methods: Cross-sectional survey for the existence of RBD and abnormal ocular movements.

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Ocular movements were examined by video-oculography (VOG).

Results: A total of 202 patients were included in this study. One hundred and sixteen (57.4%)

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of the 202 patients have clinically probable RBD, and 28 (24.1%) of the 116 with clinically probable RBD patients had abnormal VOG findings suggesting brainstem or cerebellar dysfunction; whereas 86 of the 202 patients did not have clinically probable RBD, and only 7 (8.1%) of the 86 patients had abnormal VOG findings suggesting brainstem or cerebellar

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dysfunction. (P =.001).

Conclusion: This study suggests that the presence of RBD is associated with more severe or

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extensive brainstem pathology or different distribution of pathology in PD.

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Main Text 1. Introduction

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REM sleep behavior disorder (RBD) is a relatively frequent phenomenon occurring in 2560% of patients with Parkinson’s disease (PD) [1]. Several studies have shown that RBD is associated with a decreased response to medication, showing a lack of tremors, more cognitive impairment, higher incidence of hallucination, more falls, and more autonomic

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dysfunction [2]. Current understanding about RBD pathology suggests that several structures in the pontine tegmentum and medial medulla oblongata are responsible for this sleep

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problem [3].

Several abnormal ocular motor findings such as downbeat nystagmus and ocular flutter sometimes reflect brainstem or cerebellar pathology [4]. These oculomotor findings are very rare, but several reports have noted that these ocular motor findings are also found in PD [5,

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6]. Therefore, we investigated whether the existence of RBD is associated with these ocular motor findings suggesting brainstem or cerebellar dysfunction.

Patients

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2. Methods

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Video-oculography (VOG) was conducted to all consecutive patients with PD from March 2007 except the patients who refused the test. The existence of clinical RBD was evaluated in patients who were tested by VOG from March 2007 to September 2012 and who visited the Movement Disorder Clinic of Seoul National University Hospital from January 2012 to September 2012. They were all diagnosed with PD (using the criteria of the UK PD Society Brain Bank) [7]. We collected data on their clinical profiles such as age, sex, disease duration, initial symptoms, Hoehn and Yahr (HY) stage and medications from a review of their medical records. The Institutional Review Board of Seoul National University Hospital approved this

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study. REM sleep behavior disorder A positive diagnosis of clinically probable RBD was obtained by an interview with a clinician

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according to the minimal diagnostic criteria for parasomnias provided in the International Classification of Sleep Disorders-Revised (ICSD-R) [8]. Video-oculographic recording

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Patients underwent the following eye movement recordings; spontaneous nystagmus was recorded both with and without fixation. Head-shaking and positioning test was used as

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previously described [6]. Passive head-shaking was done in a sinusoidal manner at a rate of 2.5 Hz for 10 s, post head-shaking nystagmus was observed immediately after the headshaking. [6] Positioning nystagmus was induced by the Dix-Hallpike and straight headhanging maneuvers. [6] Through above tests, following findings were detected. Spontaneous vertical nystagmus [9], positional downbeat nystagmus [4], perverted headshaking nystagmus

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(vertical nystagmus) [6], direction-changing positional nystagmus [10], and ocular flutter [4] were regarded as VOG findings suggesting brainstem or cerebellar pathology (B-VOG). We did not include square wave jerks, cogwheel pursuit and hypometric saccade as B-VOG

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because they are relatively common in the elderly [4]. The interpretation of VOG findings was confirmed by two neurologists (B.J. and Y.E.K.). Eye movements were recorded with an

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infrared camera (resolution of 640 3 480 pixels, frame rate of 60 Hz) and displayed on a computer monitor (SLMED, Seoul, Korea). Statistical analysis

Comparisons of the occurrence of RBD and the prevalence of other non-continuous variables between patients with and without B-VOG were tested by Pearson’s x2 test. The comparisons of continuous variables such as clinical profiles were tested by One-way analysis of variances and the Kruskal-Wallis test for more than two groups, and Independent t test or Mann-

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Whitney U test for the two groups. The statistical analyses were done using the SPSS software (version 19.0; SPSS, Chicago, IL),

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with the limit of significance set at 0.05.

3. Results

The clinical profiles of all the patients are summarized in Table 1. Among the total of 202

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patients, 116 (57.4%) patients had clinically probable RBD and 35 (17.3%) patients had BVOG. Among the B-VOG findings, perverted headshaking nystagmus was found in 25

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(12.38%) patients, positional downbeat nystagmus in 7 (3.47%), spontaneous vertical nystagmus in 2 (0.99%), direction-changing positional nystagmus in 1 (0.5%), and ocular flutter in 2 (0.99%). Twenty-eight (24.1%) of the 116 patients who had probable RBD presented with B-VOG, while only 7 (8.1%) of the 86 patients who had never experienced RBD had B-VOG. B-VOG was experienced in 7 patients of the non-RBD group. Perverted

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headshaking nystagmus was found in 5 patients and positional downbeat nystagmus was found in 2 patients. B-VOG was experienced in 28 patients of the RBD group. Among them, perverted headshaking nystagmus was found in 20 patients, positional downbeat nystagmus

patients.

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in 5, spontaneous DBN in 2, direction-changing nystagmus in 1, and ocular flutter in 2

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Therefore, the prevalence of B-VOG was associated with the existence of RBD (P = .003, Pearson’s x2 test). B-VOG was 3.59 times as high in patients with RBD as in patients without RBD (Odds Ratio = 3.59, 95% Confidence Interval is 1.48-8.68). Current age and age at PD onset were higher in patients with RBD than in patients without RBD (P = .001). These were especially higher in patients with RBD and B-VOG than in patients without them (P=.003). HY stage was higher in patients with RBD than in patients without RBD (P = .033). However, PD duration and Levodopa equivalent daily dose (LEDD)

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were not different between the groups according to the existence of RBD as well as VOG. Regarding the motor phenotypes, the distribution of akineto-rigid type and the symmetric motor presentation were not different between the groups according to the existence of RBD

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and B-VOG (Table 2).

4. Discussion

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This study suggests that RBD is associated with abnormal ocular motor findings suggesting brainstem or cerebellar dysfunction in PD. Current age and age at onset of PD were higher in

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patients with RBD, especially in the case with abnormal ocular motor findings than in patients without RBD.

The anatomical substrates associated with generalized muscle atonia during REM sleep are located on the pontine tegmentum and medial medulla oblongata [11]. Abnormal ocular motor findings such as positional downbeat nystagmus, perverted headshaking nystagmus

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(vertical nystagmus), direction-changing positional nystagmus, and ocular flutter are caused by brain stem lesions such as in the pons as well as the cerebellum [4]. The common coexistence of RBD and abnormal VOG findings in this study could be explained by the

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closely located anatomical substrates.

Perverted headshaking nystagmus is attributed to lesions in central vestibular connections [4].

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Downbeat nystagmus is mainly caused by lesion of vestibulocerebellum and positional downbeat nystagmus originates from lesions involving the flocculonodular lobes or posterior vermis of the cerebellum [4, 6]. Direction-changing nystagmus can occur with either peripheral or central vestibular lesions or lateral canal variant of BPPV [4]. Finally, ocular flutter can occur due to cerebellar dysfunction or malfunction of omnipause neurons [4]. BVOG except perverted headshaking nystagmus comes largely from the cerebellar dysfunction. However, among the 35 patients with B-VOG, 25 patients had perverted headshaking

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nystagmus. Therefore, B-VOG observed in patients with RBD may be largely attributable to central vestibular connections including cerebellum. Another explanation is that Multiple System Atrophy (MSA) can be mixed in this study

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population. MSA have more brainstem and cerebellar pathology than PD, which results in more frequent RBD and abnormal VOG findings [6, 12]. Several autopsy studies reported misdiagnosis of MSA as PD. It may be argued that some patients with abnormal VOG (B-

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VOG) in our study were in fact MSA but were misdiagnosed as PD. However, our subjects did not show any sign of MSA including cerebellar dysfunction, and the mean disease

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duration in this population of our study was 6.29 years, which is usually adequate to differentiate MSA from PD considering the mean disease duration of MSA [13]. Nevertheless, it’s impossible to exclude MSA completely without autopsy.

RBD is known to be more common in elderly populations [14, 15]. This supports the findings that current age and age at onset of PD were older in patients with RBD than in patients

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without RBD in this study. Even though it is not statistically significant, patients with B-VOG were older than patients without B-VOG in the RBD group. Another possibility is that there is unknown structural lesion in patient with B-VOG because older people have more chance

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to have asymptomatic brain lesion such as small vessel disease. Many clinical studies suggest that RBD is associated with special clinical phenotypes such as

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older age, longer disease duration, male gender, higher doses of dopaminergic drug, showing a lack of tremors, cognitive dysfunction, hallucination, more severe motor disability, and autonomic dysfunction [14, 16-18]. These clinical features may implicate that the presence of RBD is associated with a more extensive and profound pathology in PD. Additionally, Zibetti et al. reported that patients with probable RBD had less prominent improvement in overall motor performances and axial symptoms after subthalamic stimulation, which implies that the presence of RBD might reflect a more severe and extensive brainstem degenerative process

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[19]. Our finding that the patients with RBD have higher frequency of B-VOG means that the patients with RBD have more brainstem or cerebellar pathology. This may be caused by more

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profound or extensive pathology in brainstem or cerebellum or different distribution of pathology in patients with RBD.

This study has a limitation because polysomnographic confirmation was not performed for

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RBD. Therefore, there is possibility to reduced or increase the ability to find the differences between groups.

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This study is in agreement with the suggestion that the presence of RBD is associated with more severe or extensive brainstem pathology or different distribution of pathology in PD.

Acknowledgements.

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This study was supported by grant no. 04-2010-1230 from the SNUH Research Fund.

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Contemporary neurology series 70. 4th ed.

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[11] Avidan AY. Sleep disorders in the older patient. Primary care. 2005;32:563-86. [12] McCarter SJ, St Louis EK, Boeve BF. REM sleep behavior disorder and REM sleep without atonia as an early manifestation of degenerative neurological disease. Current neurology and

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neuroscience reports. 2012;12:182-92. [13] Litvan I, Bhatia KP, Burn DJ, Goetz CG, Lang AE, McKeith I, et al. Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Movement disorders : official journal of the Movement Disorder Society. 2003;18:467-86.

[14] Lee JE, Kim KS, Shin HW, Sohn YH. Factors related to clinically probable REM sleep behavior disorder in Parkinson disease. Parkinsonism & related disorders. 2010;16:105-8. [15] Scaglione C, Vignatelli L, Plazzi G, Marchese R, Negrotti A, Rizzo G, et al. REM sleep behaviour disorder in Parkinson's disease: a questionnaire-based study. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2005;25:316-

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21. [16] Vendette M, Gagnon JF, Decary A, Massicotte-Marquez J, Postuma RB, Doyon J, et al. REM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology. 2007;69:1843-9.

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[17] Postuma RB, Gagnon JF, Vendette M, Charland K, Montplaisir J. Manifestations of Parkinson disease differ in association with REM sleep behavior disorder. Movement disorders : official journal of the Movement Disorder Society. 2008;23:1665-72.

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[19] Zibetti M, Rizzi L, Colloca L, Cinquepalmi A, Angrisano S, Castelli L, et al. Probable REM sleep behaviour disorder and STN-DBS outcome in Parkinson's Disease. Parkinsonism & related disorders.

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2010;16:265-9.

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Table 1. Clinical profiles of all patients Mean ± SD Sex (M/F)

N = 202 (109/93)

Age (yr)

62.97 ± 8.95 (39-82)

age at PD onset

56.76 ± 9.05 (31-74) 6.29 ± 3.15 (1-20)

HY stage LEDD

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PD duration

2.09 ± .57 (1-4) 749.80 ± 350.11 (0-1925)

Abbreviations: PD = Parkinson’s disease; HY = Hoehn and Yahr stage;

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LEDD = Levodopa Equivalent Daily Dose

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Table 2. The comparison of clinical characteristics according to the existence of abnormal ocular motor findings and REM sleep behavior disorder. RBD(+) (n=116) RBD(-) (n=86) B-VOG (n=28)

valuables Current Age (yr)

66.68

N-VOG (n=88)

B-VOG (n=7)

N-VOG (n=79)

P value

64.16

62.29

60.39*

.003

64.8 (8.6) Age at PD onset (yr)

60.96

57.68

56.00

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58.5 (8.4)

PD duration (yr)

5.00

60.6 (8.9)

54.4 (9.4) 5.80

5.67

5.61

HY

2.14

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Initial symptom

(Akineto-rigid type, n (%))

(Symmetric presentation, n (%))

730.00

6.00 5.96

2.13

2.00

2.13

LEDD

54.30*

985.71

784.8 (336.8)

.005 .002 .615 .885

2.01 2.01

802.24

.001

.225 .037

676.57

702.0 (364.1)

.051 .098

9(32.1)

41(46.6)

2(28.6)

24(30.4)

.143

7(25)

16(18.2)

2(28.6)

16(20.3)

.820

Abbreviations: B-VOG = the patients group whose video-oculographic findings suggest brainstem or cerebellar dysfunction; N-VOG = the patients group whose video-oculographic findings are normal; RBD (+) = the patients group with REM sleep behavior disorder; RBD (-) = the patients group without REM sleep behavior disorder; other abbreviations are same as Table 1. Values are expressed as mean or mean (SD) in cases of continuous variables.

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The 2nd rows for each variables mean the mean values for those with RBD (+) and RBD (-) group. HY and PD duration are described as median value, and P-value was calculated by Kruskal-Wallis method or Mann-Whitney U test.

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REM sleep behavior disorder in Parkinson disease: association with abnormal ocular motor findings.

The anatomical substrates associated with generalized muscle atonia during REM sleep are located on the pontine tegmentum and medial medulla oblongata...
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