Reduced cardiac 123I-MIBG scintigraphy in idiopathic ... - Neurology

Reduced cardiac 123 I-MIBG scintigraphy in idiopathic REM sleep behavior disorder

Abstract—Idiopathic REM sleep behavior disorder (RBD) may represent prodromal synucleinopathies. We report markedly reduced cardiac 123Imetaiodobenzylguanidine uptake, consistent with the loss of sympathetic terminals, in idiopathic RBD. We also demonstrate that this reduction is of the same magnitude as that found in patients with Parkinson disease. The results are consistent with the hypothesis that idiopathic RBD in older patients is a forme fruste of Lewy body disease. NEUROLOGY 2006;67:2236–2238

T. Miyamoto, MD, PhD; M. Miyamoto, MD, PhD; Y. Inoue, MD, PhD; Y. Usui, MD; K. Suzuki, MD; and K. Hirata, MD, PhD

According to the results of a survey,1 11 of 29 older men (38%) with diagnosed idiopathic REM sleep behavior disorder (RBD) developed Parkinson disease (PD) within 3.7 years. These data suggest that RBD represents a prodromal phase of neurodegenerative diseases such as PD. To date, idiopathic RBD has not been reported to be associated with any other neurologic findings except for those characteristic of RBD itself. Patients with idiopathic RBD have been shown to perform poorly on tests of color vision, olfactory function, and motor speed, findings also thought to be early makers of PD.1 In this study, we carried out cardiac 123Imetaiodobenzylguanidine (MIBG) scintigraphy in a group of patients with idiopathic RBD and PD and in controls. Our data revealed the presence of sympathetic cardiac denervation in RBD patients who did not exhibit severe movement disorders. Methods. We studied 34 subjects: 10 men and three women with confirmed idiopathic RBD of 5.5 ⫾ 3.7 years’ duration (mean ⫾ SD age 68.4 ⫾ 7.5 years; range 52 to 82), six men and six women who were age-matched idiopathic PD patients (mean ⫾ SD age 68.4 ⫾ 5.3 years; range 61 to 79; mean Hoehn-Yahr stage 2.3 ⫾ 0.8), and four men and four women who were age-matched controls (mean ⫾ SD age 71.9 ⫾ 8.2 years; range 62 to 82). RBD was defined as described in the International Classification of Sleep Disorders, second edition.2 Polysomnography (PSG) and videotape recordings were made simultaneously as the patients slept. Exclusion criteria were an abnormal neurologic examination, alcohol or psychotropic drug use, psychiatric disorders, and moderate or severe obstructive sleep apnea hypopnea syndrome (apneahypopnea index ⬎15/hour).3 All 12 PD patients had clinically defined disease but had not been taking medications that could potentially influence their MIBG; their mean ⫾ SD disease duration was 30.6 ⫾ 21.8 months (range 12 to 72 months). All procedures described in this study were approved by the

From the Department of Neurology (T.M., M.M., K.S., K.H.), Center of Sleep Medicine (T.M., M.M.), Dokkyo Medical University School of Medicine, Tochigi, Japan; Japan Somnology Center (Y.I.), Neuropsychiatry Research Institute, Tokyo, Japan; Second Department of Internal Medicine (Y.U.), Tokyo Medical University, Tokyo, Japan. Disclosure: The authors report no conflicts of interest Received June 7, 2006. Accepted in final form September 13, 2006. Address correspondence and reprint requests to Dr. Tomoyuki Miyamoto, Dokkyo Medical University School of Medicine; 880 Kitakobayashi, Mibu, Shimotuga, Tochigi 321-0293, Japan; e-mail: [email protected] 2236

Copyright © 2006 by AAN Enterprises, Inc.

Ethics Review Committee of Dokkyo Medical University, and informed consent was obtained from each subject. Patients underwent one night (8 hours) of PSG recordings in our sleep laboratory that consisted of the use of the standard montage for scoring sleep stages.4 For the RBD group, REM sleep was scored without the chin EMG criterion, thereby allowing for the maintenance of muscle tone during REM sleep. After the subjects had been in the supine position for 15 minutes, they were injected intravenously with 111 MBq 123I-MIBG. SPECT and planar images of the chest were obtained using a gamma camera 15 minutes (early phase) and 4 hours (delayed phase) after injection. The heart-to-mediastinum (H/M) ratio was calculated by dividing the count density of the left ventricular region of interest (ROI) by that of the mediastinal ROI (figure 1), as previously described.5,6 The eight age-matched subjects who were selected as controls had 1) no clinical findings of RBD, 2) no autonomic nervous system disorders, 3) not been taking medications that could potentially influence the MIBG examination (e.g., tricyclic and tetracyclic antidepressants, sympathomimetics, and sympatholytics), and 4) no history of cardiac or diabetic diseases. Five of these subjects had an essential tremor, one subject exhibited lumbar spondylosis, and two others had no history of morbidity. Even though the presence of an essential tremor is indicative of a nervous system disease, subjects with an essential tremor were included in the control group based on reports that showed that cardiac MIBG uptake in such patients is not reduced.7 Comparisons between groups were made using a one-way analysis of variance that was Bonferroni corrected for multiple comparisons. All values are expressed as the mean ⫾ SD.

Results. Of our 13 patients with RBD, 11 displayed abnormal behavior during REM sleep. The PSG data for these 13 patients with RBD are shown in the table; all these patients displayed reductions in cardiac 123I-MIBG uptake. Uptake was also markedly reduced in the patients with PD (figure 1). The mean ratio of 123I-MIBG uptake in the ROI of the heart to that in the mediastinum (H/M ratio delayed) was reduced in patients with either idiopathic RBD (1.34 ⫾ 0.20) or PD (1.43 ⫾ 0.20) compared to controls (3.01 ⫾ 0.39) (each p ⬍ 0.001) (figure 2).

Discussion. In this study, we found reduced cardiac MIBG uptake in patients with idiopathic RBD or PD; such reductions were reported to be characteristic of patients with ␣-synucleinopathies such as PD and dementia with Lewy bodies (DLB).6-9 Cardiac MIBG scintigraphy allows for the visual and quantitative assessment of adrenergic neuronal function and is a useful tool for the differential diagnosis of neurodegenerative diseases.6-9 Reductions in MIBG uptake were reported in patients with stage 2 or higher PD. Such reductions, as revealed by metaanalysis, occurred in 89.7% (220 of 246) of patients,

Figure 1. Planar cardiac delayed 123 I-metaiodobenzylguanidine (MIBG) imaging in representative control (A) and in patients with idiopathic RBD (B) and PD (C). Regions of interest regarding MIBG uptake in the heart (irregularly shaped region labeled with H) and MIBG uptake in the mediastinum (rectangular region indicated by M) are shown in the figure. Note the markedly reduced MIBG uptake in the patients with RBD and PD. RBD ⫽ REM behavior disorder; PD ⫽ Parkinson disease.

with a specificity of 94.6% in patients with PD.8 Use of this methodology allowed for the differential diagnosis between PD and PD-related neurodegenerative diseases while the patients were still in their early stages of disease6 as well as between two kinds of dementia, i.e., DLB and Alzheimer disease (AD).9 In an attempt to determine why cardiac MIBG uptake decreases in synucleinopathies, researchers reported that tyrosine hydroxylase (TH)–immunoreactive nerve fibers were damaged in the heart but relatively intact in patients with progressive supranuclear palsy and AD; they also found that in most patients with multiple system atrophy, THimmunoreactive nerves are not damaged in the heart.10 The authors inferred that denervation of sympathetic nerve fibers occurred in the cardiac muscle of these patients prior to any pathologic alterations in their ganglia. Reductions in cardiac MIBG uptake were recently reported in patients with pure autonomic failure (PAF) complicated by RBD,1 supporting the notion that ␣-synucleinopathies characterized by the presence of ␣-synuclein–positive Lewy bodies, including PAF, PD, and DLB, represent a clinical and pathologic spectrum.

Interestingly, reductions in heart rate variance during sleep and disruptions in the sympathetic and parasympathetic nervous systems during arousal were also reported in 36% of patients with idiopathic RBD1 and were suggested to represent incipient degenerative changes in the CNS. The magnitude of cardiac activation during periodic leg movements that are associated with RBD was reported to be smaller than those that occur in restless leg syndrome.1 Our results showing reduced cardiac MIBG uptake in all patients with idiopathic RBD suggests that this methodology represents a highly sensitive early marker of this condition. Although the internationally recognized staging system developed by Braak et al., which relies on the identification of changes in ␣-synuclein–immunopositive neurons and Lewy bodies, identified early PD abnormalities in the dorsal motor nucleus of the glossopharyngeal and vagus nerves and the anterior olfactory nucleus, no abnormalities were found in peripheral autonomic ganglia and myocardial sympathetic nerve fibers. A case of incidental LBD was reported in an individual in whom PD did not develop, even 20 years after RBD developed.1 Our data suggest that reduced cardiac 123I-MIBG scintigraphy

Table Characteristics of patients with idiopathic RBD Patient age/sex

Duration, years

Frequency of RBD

ESS

PSG findings

2 times/week

4

Increased EMG tone in REM sleep

52/M

3

72/M

13

Daily

4


62/M

12

3–4 times/week

2


72/M

1

3–4 times/month

3


75/M

3

2–3 times/week

1


65/M

9

1–2 times/month

14


72/M

5

Daily

3


65/M

2

Daily

2


67/F

5

1 time/week

1


64/F

3

2–3 times/week

0


82/M

4

1–3 times/week

2


63/F

5

2–3 times/month

4


75/M

7

1 time/week

2


RBD ⫽ REM sleep behavior disorder; ESS ⫽ Epworth Sleepiness Scale; PSG ⫽ polysomnography. December (2 of 2) 2006

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References

Figure 2. Distribution of the heart-to-mediastium metaiodobenzylguanidine (H/M) uptake ratio in control subjects and patients with idiopathic REM behavior disorder (RBD) and Parkinson disease (PD). The horizontal lines indicate the median values.

may be an additional early premotor manifestation of LBD.6 Acknowledgment The authors thank T. Hashimoto (Department of Radiology, Dokkyo Medical University School of Medicine) for his helpful comments.

1. Gagnon J-F, Postuma RB, Mazza S, Doyon J, Montplaisir J. Rapid-eyemovement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol 2006;5:424–432. 2. American Academy of Sleep Medicine. Internal classification of sleep disorders, 2nd ed. Diagnosis and cording manual. Westchester, IL: American Academy of Sleep Medicine, 2005:148–152. 3. Otsuka N, Ohi M, Chin K, et al. Assessment of cardiac sympathetic function with iodine-123-MIBG imaging in obstructive sleep apnea syndrome. J Nucl Med 1997;38:567–572. 4. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington, DC: US Government Printing Office, Public Health Service, 1968. 5. Kobayashi H, Momose M, Kanaya S, Kondo C, Kusakabe K, Mitsuhashi N. Scatter correction by two-window method standardizes cardiac I-123 MIBG uptake in various gamma camera systems. Ann Nucl Med 2003; 17:309–313. 6. Taki J, Yoshita M, Yamada M, Tonami N. Significance of 123I-MIBG scintigraphy as a pathophysiological indicator in the assessment of Parkinson’s disease and related disorders: it can be a specific marker for Lewy body disease. Ann Nucl Med 2004;18:453–461. 7. Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H. 123I–metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;67:189–194. 8. Braune S. The role of cardiac metaiodobenzylguanidine uptake in the differential diagnosis of parkinsonian syndromes. Clin Auton Res 2001; 11:351–355. 9. Yoshita M, Taki J, Yokoyama K, et al. Value of 123I-MIBG radioactivity in the differential diagnosis of DLB from AD. Neurology 2006;66:1850– 1854. 10. Orimo S, Amino T, Itoh Y, et al. Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease. Acta Neuropathol 2005;109:583–588.

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