J Neurol (2014) 261:45–51 DOI 10.1007/s00415-013-7135-4
ORIGINAL COMMUNICATION
Is reduced myocardial sympathetic innervation associated with clinical symptoms of autonomic impairment in idiopathic Parkinson’s disease? Daniel Guidez • Stefanie Behnke • Ramona Halmer Ulrich Dillmann • Klaus Faßbender • Carl M. Kirsch • Dirk Hellwig • Jo¨rg Spiegel
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Received: 21 August 2013 / Revised: 24 September 2013 / Accepted: 26 September 2013 / Published online: 18 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Patients with idiopathic Parkinson’s disease (IPD) have a reduced myocardial MIBG uptake in MIBG scintigraphy, indicating myocardial sympathetic denervation. We were interested whether this myocardial sympathetic denervation coincides with clinical symptoms of autonomic impairment in IPD patients. We performed MIBG scintigraphy, the SCOPA-AUT scale, a standardized medical history (developed in our clinic) and autonomic nervous system testing in 47 IPD patients (21 female, 26 male patients). We correlated myocardial MIBG uptake with the results of the SCOPA-AUT scale, the standardized medical history and the autonomic nervous system testing through the use of Spearman’s correlation. Myocardial MIBG uptake correlated significantly (p \ 0.05) with several items of the SCOPA-AUT scale (in female patients: perspiration during the night, in male patients: sum score, saliva dribbling of the mouth, difficulty swallowing, fainting, constipation), of the standardized medical history (in male patients: swollen ankles) and of the autonomic nervous system testing (all patients: sum score, Ewing orthostasis test). Remarkably, we found more significant correlations in male than in female patients. Reduced myocardial sympathetic innervation—as revealed by MIBG scintigraphy—is associated with clinical symptoms of autonomic impairment. This association is more
D. Guidez S. Behnke R. Halmer U. Dillmann K. Faßbender J. Spiegel (&) Department of Neurology, Saarland University, Kirrberger Strasse, 66421 Homburg/Saar, Germany e-mail: [email protected] C. M. Kirsch D. Hellwig Department of Nuclear Medicine, Saarland University, Kirrberger Strasse, 66421 Homburg/Saar, Germany
pronounced in male than in female patients. The cause for this gender-specific phenomenon is unclear. Keywords Parkinson’s disease Autonomic nervous system SCOPA-AUT scale MIBG scintigraphy
Introduction The clinical diagnosis of idiopathic Parkinson’s disease (IPD) can be supported using myocardial metaiodobenzylguanidine (MIBG) scintigraphy, which measures the postganglionic sympathetic myocardial innervation. Numerous studies have reported a reduced myocardial MIBG uptake indicating a reduced myocardial sympathetic innervation in IPD patients [1–9]. Some IPD patients, in particular, exhibit a very pronounced myocardial sympathetic denervation (Figs. 1, 2). Such differences in myocardial sympathetic innervation, as illustrated by Figs. 1 and 2, raise the question whether a decreased sympathetic myocardial innervation correlates with clinical symptoms of autonomic impairment (for example orthostatic hypertension, salivation, difficulty swallowing, indigestion or constipation, impaired bladder function, vertigo, increased or reduced sweating, hypo-/hypertension, irregular pulse, swollen ankles). Previous studies report few and inconsistent findings concerning the correlation between myocardial MIBG uptake and clinical symptoms of autonomic impairment. For example, IPD patients with syncope or presyncope exhibit a significantly lower myocardial MIBG uptake than patients without syncope or presyncope [10]. Myocardial MIBG uptake also correlates significantly with the nocturnal fall of mean arterial blood pressure in IPD [11].
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Fig. 2 Strongly decreased myocardial MIBG uptake in a 62-year-old female IPD patient Fig. 1 Slightly decreased myocardial MIBG uptake in a 64-year-old male IPD patient
Myocardial MIBG uptake correlates significantly with the blood pressure overshoot in phase IV of the Valsalva maneuver but not with the systolic blood pressure response on head-up tilt-table testing in de novo IPD patients [12]. IPD patients with a heart-to-mediastinum (H/M) ratio \1.7 showed a significant reduction of the cardiac velocity index, an indicator for cardiac contractility, during exercise compared to IPD patients with an H/M ratio [1.7 [13]. Furthermore, IPD patients with a score C3.3 on the Parkinson fatigue scale (‘‘fatigued’’ IPD patients) reveal a significantly lower myocardial MIBG uptake than patients with a score \3.3 (‘‘non-fatigued’’ IPD patients, [14]). In contrast, the results of other studies argue against a correlation between myocardial MIBG uptake and clinical symptoms of autonomic impairment in IPD patients. Haensch et al. [15] reported that myocardial MIBG uptake did not correlate with the extent of orthostatic hypotension or heart rate variability in IPD patients. Berganzo et al. [16] could not find a significant correlation between myocardial MIBG uptake and any score of the SCOPA-AUT scale in 112 IPD patients. In IPD patients, the myocardial MIBG uptake does not correlate with changes of blood pressure or heart rate during exercise [13].
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In summary, the data of previous studies are inconsistent and incomplete concerning the correlation between sympathetic myocardial innervation (measured by myocardial MIBG scintigraphy) and clinical symptoms of autonomic impairment. In this paper, we applied MIBG scintigraphy, the SCOPA-AUT questionnaire [17], a self-designed standardized interview and autonomic testing to resolve this question.
Patients and methods Patients The study included 47 patients (age 65 ± 8 years, mean ± SD, 21 female, 26 male patients) with IPD. Based on the Hoehn and Yahr (H&Y) staging system, 22 patients were at stage 1, 11 at stage 2, 11 at stage 3, and 3 at stage 4. Nineteen patients belonged to the akinetic rigid type, ten to the tremor dominant type, and 18 to the equivalence type. IPD was diagnosed according to the British Brain Bank criteria [18]. All patients exhibited normal cranial magnetic resonance imaging. No patient had any history of dementia or depression. Depression was excluded by use of the Beck depression inventory. All patients underwent myocardial MIBG scintigraphy, the SCOPA-AUT scale [17], a
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standardized medical history (developed in our department, see below) and testing of autonomic nervous system function. Patients with any present/previous disease or medication, which might affect MIBG uptake, were excluded. Anti-parkinsonian medication was continued during all measurements. All participants gave their informed consent prior to their inclusion in the study. The study protocol was approved by the local ethics committee ¨ rztekammer des Saarlandes). (Ethikkommission der A
47 Table 1 SCOPA-AUT scale 1. In the last month, have you had difficulty swallowing or have you choked? 2. In the last month, has saliva dribbled out of your mouth? 3. In the last month, has food ever become stuck in your throat? 4. In the last month, did you ever have the feeling during a meal that you were full very quickly? 5. Constipation is a blockage of the bowel, a condition in which someone has a bowel movement twice a week or less. In the last month, have you had problems with constipation? 6. In the last month, did you have to strain hard to pass stools?
MIBG scintigraphy Following thyroid gland blocking with sodium perchlorate, intravenous injection of 123I-MIBG (Amersham, Amersham Buchler, Braunschweig, Germany) with a specific activity of 200 MBq/mg was given. Planar whole-body images in anterior and posterior views were obtained 4 h after injection using a dual-head large-field gamma camera (Siemens Multispect, MS2, Siemens, Erlangen, Germany) equipped with medium-energy high-resolution parallelhole collimators. MIBG uptake of myocardium and mediastinum was quantified by drawing a rectangular region of interest over the upper mediastinum and a manually delineated region outlining the left ventricular myocardium of the heart. The heart-to-mediastinum ratio (HMR) was calculated, defined as the average counts/pixel in the myocardium divided by that of the upper mediastinum. Our lower norm value (mean - 2 SD) was 1.79 and was obtained from age-matched healthy controls. MIBG scintigraphy was considered pathological if the HMR was \1.79 and classified as normal if the HMR was C1.79. After MIBG imaging, an additional myocardial rest perfusion SPECT imaging was performed with 99m Tc-Sestamibi (MIBI, Cardiolite, Bristol Myers Squibb, New York, NY, USA) to confirm normal myocardial perfusion and to exclude hampered myocardial MIBG uptake due to cardiac disease. The injected dose of MIBI was 500 MBq.
7. In the last month, have you had involuntary loss of stools? 8. In the last month, have you had difficulty retaining urine? (Extra: use catheter) 9. In the last month, have you had involuntary loss of urine? (Extra: use catheter) 10. In the last month, have you had the feeling that after passing urine your bladder was not completely empty? (Extra: use catheter) 11. In the last month, has the stream of urine been weak? (Extra: use catheter) 12. In the last month, have you had to pass urine again within 2 h of the previous time? (Extra: use catheter) 13. In the last month, have you had to pass urine at night? (Extra: use catheter) 14. In the last month, when standing up have you had the feeling of becoming either light-headed, or no longer being able to see properly or no longer being able to think clearly? 15. In the last month, did you become light-headed after standing for some time? 16. Have you fainted in the last 6 months? 17. In the last month, have you ever perspired excessively during the day? 18. In the last month, have you ever perspired excessively during the night? 19. In the last month, have your eyes ever been oversensitive to bright light? 20. In the last month, how often have you had trouble tolerating cold? 21. In the last month, how often have you had trouble tolerating the heat?
SCOPA-AUT scale
22. In the last month, have you used medication for: (a) constipation? (b) urinary problems? (c) blood pressure? (d) other symptoms (no/yes)
The SCOPA-AUT scale was developed by Visser er al. [17] to assess autonomic dysfunction in IPD. The original version comprises 26 questions. For the purpose of discretion, we did not apply the questions which concern sexual function. The remaining questions are listed in Table 1.
The response options for the questions 1–21 are never (0 points), sometimes (1 point), often (2 points), regularly/nearly always (3 points), always (4 points). Question 22 concerning medications have the response options no (0 points) and yes (1 point). In contrast to the original version of Visser et al. [17], we do not apply the questions concerning sexual dysfunction (question 22–25 in the original version)
Standardized medical history
Autonomic nervous system testing
We developed a questionnaire with ten questions (Table 2) that focused on central and peripheral autonomic and cardiovascular dysfunction and disease.
The autonomic nervous system testing (autonomic testing) was performed in the morning. If applicable, the patients delayed their morning antihypertensive medication until
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48 Table 2 Standardized medical history 1. In the last month, did you feel shortness of breath during slight exercise? 2. In the last month, were your ankles swollen? 3. In the last month, did you remark an irregular pulse? 4. Are/were you suffering from a valvular defect? Have you had prior cardiac surgery? (We did not ask about coronary disease since coronary disease represents an exclusion criterion for this study) 5. Have you ever had problems with too low or too high blood pressure? 6. In the last month, did you feel any pain in the legs during longer walks? 7. Have you ever had a transient ischemic attack, a stroke or a constriction of a brain vessel (at the neck or in the brain)? 8. Have you ever had bleeding in the brain? 9. Do you suffer from diabetes mellitus? 10. Do you take medication besides anti parkinsonian medication? If yes, what medication and since when? The response options for the questions 1, 2, 3, and 6 are never (0 points), sometimes (1 point), often (2 points), regularly/nearly always (3 points), always (4 points). The questions 4, 5, 7, 8, 9 and 10 have the response options no (0 points) and yes (1 point)
after the testing was completed. The autonomic testing was conducted according to standard clinical methods [19] and consisted of three tests: the Ewing orthostasis test (cardiovascular response from lying to upright position), respiratory sinus arrhythmia (cardiac response to deep breathing), and the Valsalva maneuver (cardiovascular response to the Valsalva maneuver). During all tests the electrocardiogram was continuously recorded. The orthostatis test and the Valsalva maneuver included an intermittent automated blood pressure measurement every 60 s. Fifty age-matched healthy volunteers served as the control group. For each test a maximum of two points were given: normal finding (0 points), finding at the threshold (1 point), pathological finding (2 points). The Ewing orthostasis test measures the heart rate (Ewing ratio) and the blood pressure (orthostasis test) after a change from the supine to the upright position. Before the beginning of this test, subjects were in the supine position for at least 10 min. The subjects then stood up taking an upright position. The course of the arterial blood pressure, after upright position is taken, gives evidence for the integrity of the sympathetic noradrenergic function: an impaired sympathetic noradrenergic function results in a pathological orthostatic blood pressure decrease [norm (independent of age): D systolic blood pressure B20 mmHg or D diastolic blood pressure B10 mmHg] after the upright position is taken. The Ewing ratio is calculated as the quotient [longest RR interval (*30th heartbeat) in the upright position]/[shortest RR interval (*15th heartbeat) in the upright position] and quantifies
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the cardiac parasympathetic (vagal) function (norm: age 45–49 years: quotient C 1.09; 50–54 years: C1.08; 55–64 years: C1.07; 65–74 years: C1.05; 75–80 years: C1.04). Respiratory sinus arrhythmia was evaluated in the supine position with the patient breathing slowly and deeply at six breaths a minute for 3 min. The RR difference = longest RR interval—shortest RR interval during deep breathing was determined. Respiratory sinus arrhythmia is based mainly on the parasympathetic (vagal) function [norm: age 45–49 years: C98 ms; age 50–54 years: C92 ms; 55–59 years: C86 ms; 60–64 years: C81 ms; 65–69 years: C76 ms; 70–74 years: C71 ms; 75–80 years: C61 ms]. The Valsalva maneuver was assessed in the supine position. After the subject had breathed normally over 60 s, they had to exhale against a constant pressure of 40 mmHg (via a mouthpiece) over 15 s, which increased the intrathoracic pressure (Valsalva maneuver). Then the subject had to breathe normally over the following 75 s. The Valsalva ratio was calculated by dividing the longest RR interval within 30 s after the Valsalva maneuver by the shortest RR interval during or maximally 5 s after the Valsalva maneuver (norm: age 40–49 years: quotient C 1.19; 50–59 years: C1.18; 60–64 years: C1.17; 65–69 years: C1.15; 70–74 years: C1.15; 75–80 years: C1.14). Five phases of the Valsalva manoeuvre can be differentiated. Each of these five phases is dominated by the sympathetic pathway or the parasympathetic pathway of the autonomic nervous system. The investigator who performed and evaluated the clinical tests (SCOPA-AUT scale, standardized medical history and autonomic testing) was blinded to the results of myocardial MIBG scintigraphy and vice versa. Statistics We used the software GraphPad Prism for Windows (Version 5.04; GraphPad Software, San Diego, CA, USA). Descriptive data are given as mean and standard deviation (SD). Correlations were calculated using the Pearson’s correlation coefficient in case of normally distributed data and Spearman’s correlation coefficient in case of ordinal data. The SCOPA-AUT scale, the standardized medical history, and the autonomic testing deliver ordinal data. Statistical significance was assumed in case of a p value\0.05.
Results Correlation between myocardial MIBG uptake and the SCOPA-AUT scale We performed the SCOPA-AUT scale to determine whether myocardial MIBG uptake correlates with clinical
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autonomic dysfunction (for example salivation, difficulty swallowing, indigestion or constipation, incontinence, problems with urination, vertigo, increased or reduced sweating, hypo-/hypertension). Overall, only the answer to question 18 (‘‘In the last month, have you ever perspired excessively during the night?’’) correlated significantly with myocardial MIBG uptake (r = ?0.37, p \ 0.05; Spearman’s correlation). After we divided the patients into female (n = 21) and male patients (n = 26), we found gender-specific results: in the female patients myocardial MIBG uptake correlated only with the scores of question 18 (‘‘In the last month, have you ever perspired excessively during the night?’’; r = ?0.44; p \ 0.05). Interestingly, in the male patients there were more significant correlations. Myocardial MIBG uptake correlated inversely with the SCOPA-AUT scale sum score (r = -0.41; p \ 0.05), the answer to question 2 (‘‘In the last month, has saliva dribbled out of your mouth?’’; r = -0.53, p \ 0.01), question 1 (‘‘In the last month have you had difficulty swallowing or have you choked?’’; r = -0.47, p \ 0.05), question 16 (‘‘Have you fainted in the last 6 months?’’; r = -0.40, p \ 0.05) and question 6 (‘‘In the last month, did you have to strain hard to pass stools?’’; r = -0.39, p \ 0.05). Correlation between myocardial MIBG uptake and standardized medical history Neither the sum score nor the scoring of any single question of the standardized medical history correlated significantly with myocardial MIBG uptake. In the female patients there was no significant correlation between myocardial MIBG uptake and the scoring of any question. In contrast, there were significant correlations in the male patients: myocardial MIBG uptake correlated inversely with the sum score (r = -0.42; p \ 0.05) and the rating of question 2 (‘‘In the last month, were your ankles swollen?’’; r = -0.40; p \ 0.05).
Correlation between myocardial MIBG uptake and autonomic nervous system testing (autonomous testing) Myocardial MIBG uptake correlated significantly inversely with the sum score of the autonomic testing (r = -0.43; p \ 0.005; Spearman’s correlation), the Ewing orthostasis test (r = -0.38; p \ 0.01) and nearly significantly with respiratory sinus arrhythmia (r = -0.30; p = 0.0504). We did not find any correlation between myocardial MIBG uptake and the findings of the Valsalva maneuver.
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We assume that the age of the patients did not influence or cause the significant correlations, which we presented so far, since the patient’s age did not correlate with myocardial MIBG uptake (r = -0.03; p = 0.82; Pearson’s correlation).
Discussion Numerous studies have reported reduced myocardial sympathetic innervation in IPD patients [1–9]. As yet, it is unclear whether, and in which manner, this impaired sympathetic myocardial innervation interacts with clinical symptoms of autonomic impairment (for example orthostatic hypertension, salivation, difficulty swallowing, indigestion or constipation, impaired bladder function, vertigo, increased or reduced sweating, hypo-/hypertension, irregular pulse, swollen ankles) in IPD patients. In our study, several items of the SCOPA-AUT scale correlated significantly with myocardial MIBG uptake. Remarkably, we detect more significant correlations in the male patients than in the female patients. In addition, the items of the SCOPA-AUT scale, which correlated significantly with myocardial MIBG uptake, differed between male and female patients. Therefore, it seems to be meaningful to differentiate between genders. In the male patients, there were significant correlations between myocardial MIBG uptake and the SCOPA-AUT scale sum score as well as the answers to question 1 (‘‘In the last month have you had difficulty swallowing or have you choked?’’), question 2 (‘‘In the last month, has saliva dribbled out of your mouth?’’), question 6 (‘‘In the last month, did you have to strain hard to pass stools?’’) and question 16 (‘‘Have you fainted in the last 6 months?’’). In our opinion, the significant correlation of the SCOPA-AUT scale ‘sum score—combined with these four single questions—with myocardial MIBG uptake shows that the myocardial sympathetic denervation influences clinical symptoms of autonomic impairment in male IPD patients. It is unclear why there were fewer significant correlations in the female IPD patients. In contrast, Berganzo et al. [16] could not find any significant correlation between the SCOPA-AUT scale and myocardial MIBG uptake in a larger cohort of 112 IPD patients. Berganzo et al. calculated the correlation between myocardial MIBG uptake and the SCOPA-AUT scale only over all patients and did not differentiate between male and female patients. When we considered the whole patient population, not differentiating between female and male patients, we also find little evidence of significant correlations between MIBG scintigraphy and the SCOPA-AUT scale. It might be speculated that Berganzo et al. would
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have found significant correlations as well, if they had divided their patients by gender. Further symptoms beyond those that are screened in the SCOPA-AUT scale and certain diseases may be associated with an impairment of central or peripheral autonomic function. For this reason, we developed a questionnaire with ten questions—which asks for these further symptoms and diseases (Table 2)—called the ‘‘standardized medical history’’. This standardized medical history is designed to supplement the SCOPA-AUT scale. We were interested whether the results of the standardized medical history correlate with myocardial MIBG uptake. In the male patients, myocardial MIBG uptake correlated significantly with the sum score and the rating of question 2 (‘‘In the last month, were your ankles swollen?’’) of the standardized medical history. This small output of significant correlations between MIBG uptake and the standardized medical history might be due to several reasons: (1) the diseases of arterial hyper-/hypotension and diabetes mellitus (question 5 and 9 of the standardized medical history) often do not cause specific clinical symptoms; they are hardly or not noticed by the patient and thus cannot be scored sufficiently by the patient, (2) the other screened diseases (question 4: valvular defect/cardiac surgery, question 7: ischemic cerebrovascular disease; question 8: bleeding in the brain) are not very common, therefore their discriminatory power might be too low, and (3) the screened clinical symptoms (question 1, 3, and 6) are subject to subjective judgment and may, therefore, vary between individuals. Nevertheless, our study showed significant correlations between myocardial sympathetic denervation and some questions of the SCOPA-AUT scale and the standardized medical history. Such correlations have not been described so far. In previous studies myocardial MIBG scintigraphy was correlated with several clinical aspects in IPD patients: IPD patients with cognitive deficits disclose a significantly lower myocardial MIBG uptake than IPD patients without cognitive deficits [20, 21]. IPD patients with visual hallucinations or other psychotic symptoms have a significantly lower myocardial MIBG accumulation than IPD patients without visual hallucinations or other psychotic symptoms [21–23]. Nakamura et al. [14] found a significantly lower myocardial MIBG uptake in IPD patients with fatigue than in IPD patients without fatigue. Nomura et al. [24] reported a significantly lower myocardial MIBG uptake in IPD patients with REM sleep behavior disorders than in IPD patients with normal REM sleep. Myocardial MIBG uptake correlates significantly with the severity of hypokinesia, rigidity, and midline symptoms (such as speech, posture, and gait) but not with the intensity of resting or postural tremor in IPD [7, 25]. IPD patients with the tremor-dominant type disclose a significantly higher myocardial MIBG
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uptake than patients with the akinetic rigid type at the same disease stage [7, 26]. In IPD patients, myocardial MIBG uptake correlates significantly with olfactory function quantified by the odor stick identification test Japan (OSITJ score; [12]). There is a significant correlation between myocardial MIBG uptake with bladder function, but not with constipation or orthostatic hypotension in IPD [15, 27]. Lenska-Mieciek et al. [10] found a significantly lower myocardial MIBG uptake in IPD patients with syncope or presyncope than in IPD patients without syncope or presyncope. Myocardial MIBG uptake correlates significantly with the nocturnal fall of mean arterial blood pressure in IPD [11]. In addition to these previous findings, our study indicates that myocardial MIBG uptake correlates significantly inversely with the frequency of swollen ankles in the last month and the sum score of our standardized medical history. The cited studies and our own study show that this field (of correlations between myocardial MIBG scintigraphy and clinical findings) is still open to new ideas. Furthermore, in our study, myocardial MIBG uptake correlated significantly with the results of the autonomic nervous system testing, primarily with the sum score of autonomic testing and with the Ewing orthostasis test. The Ewing orthostasis test quantifies the cardiac parasympathetic function and the sympathetic noradrenergic function. These significant correlations show that the density of postganglionic noradrenergic myocardial neurons—as visualized by myocardial MIBG scintigraphy—reflects the function of the sympathetic nervous system. This result is in accordance with previous studies [15, 28, 29]. In summary, a reduced myocardial sympathetic innervation—indicated by a reduced myocardial MIBG uptake— is associated with some clinical symptoms of autonomic impairment. This association is more pronounced in male than in female patients. The cause for this gender-specific difference is unclear and requires further investigation. Conflicts of interest of interest.
The authors declare that they have no conflicts
Ethical standard This single case study was performed in accordance with the ethical standard laid down in the 1964 Declaration of Helsinki.
References 1. Braune S (2001) The role of cardiac metaiodobenzylguanidine uptake in the differential diagnosis of parkinsonian syndromes. Clin Auton Res 11:351–355 2. Hirayama M, Hakusui S, Koike Y, Ito K, Kato T, Ikeda M et al (1995) A scintigraphical qualitative analysis of peripheral vascular sympathetic function with meta-[123I]iodobenzylguanidine in neurological patients with autonomic failure. J Auton Nerv Syst 53:230–234
J Neurol (2014) 261:45–51 3. Nagayama H, Hamamoto M, Ueda M, Nagashima J, Katayama Y (2005) Reliability of MIBG myocardial scintigraphy in the diagnosis of Parkinson’s disease. J Neurol Neurosurg Psychiatry 76:249–251 4. Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H (1999) (123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 67:189–194 5. Satoh A, Serita T, Tsujihata M (1997) Total defect of metaiodobenzylguanidine (MIBG) imaging on heart in Parkinson’s disease: assessment of cardiac sympathetic denervation. Nihon Rinsho 55:202–206 6. Sawada H, Oeda T, Yamamoto K, Kitagawa N, Mizuta E, Hosokawa R et al (2009) Diagnostic accuracy of cardiac metaiodobenzylguanidine scintigraphy in Parkinson disease. Eur J Neurol 16:174–182 7. Spiegel J, Hellwig D, Farmakis G, Jost WH, Samnick S, Fassbender K et al (2007) Myocardial sympathetic degeneration correlates with clinical phenotype of Parkinson’s disease. Mov Disord 22:1004–1008 8. Taki J, Nakajima K, Hwang EH, Matsunari I, Komai K, Yoshita M et al (2000) Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 27:566–573 9. Yoshita M (1998) Differentiation of idiopathic Parkinson’s disease from striatonigral degeneration and progressive supranuclear palsy using iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. J Neurol Sci 155:60–67 10. Len´ska-Mieciek M, Derecka-Charzyn´ska I, Fiszer U, Kro´licki L, Kułakowski P (2011) Syncope and autonomic cardiovascular dysfunction in Parkinson disease. Neurol Neurochir Pol 45:335–341 11. Manabe Y, Fujii D, Kono S, Sakai Y, Tanaka T, Narai H (2011) Systemic blood pressure profile correlates with cardiac 123IMIBG uptake in patients with Parkinson’s disease. J Neurol Sci 307:153–156 12. Oka H, Toyoda C, Yogo M, Mochio S (2010) Olfactory dysfunction and cardiovascular dysautonomia in Parkinson’s disease. J Neurol 257:969–976 13. Nakamura T, Hirayama M, Yamashita F, Uchida K, Hama T, Watanabe H, Sobue G (2010) Lowered cardiac sympathetic nerve performance in response to exercise in Parkinson’s disease. Mov Disord 25:1183–1189 14. Nakamura T, Hirayama M, Hara T, Hama T, Watanabe H, Sobue G (2011) Does cardiovascular autonomic dysfunction contribute to fatigue in Parkinson’s disease? Mov Disord 26:1869–1874 15. Haensch CA, Lerch H, Jo¨rg J, Isenmann S (2009) Cardiac denervation occurs independent of orthostatic hypotension and impaired heart rate variability in Parkinson’s disease. Parkinsonism Relat Disord 15:134–137
51 16. Berganzo K, Tijero B, Somme JH, Llorens V, Sa´nchez-Manso JC, Low D et al (2012) SCOPA-AUT scale in different parkinsonism’s and its correlation with (123) I-MIBG cardiac scintigraphy. Parkinsonism Relat Disord 18:45–48 17. Visser M, Marinus J, Stiggelbout AM, van Hilton JJ (2004) Assessment of autonomic dysfunction in Parkinson’s disease: the SCOPA-AUT. Mov Disord 19:1306–1312 18. Hughes A, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinicopathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184 19. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P et al (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33:2285–2293 20. Kim JS, Shim YS, Song IU, Yoo JY, Kim HT, Kim YI et al (2009) Cardiac sympathetic denervation and its association with cognitive deficits in Parkinson’s disease. Parkinsonism Relat Disord 15:706–708 21. Kitayama M, Wada-Isoe K, Irizawa Y, Nakashima K (2008) Association of visual hallucinations with reduction of MIBG cardiac uptake in Parkinson’s disease. J Neurol Sci 264:22–26 22. Kashihara K, Ohno M, Katsu Y (2005) Psychoses in patients with Parkinson’s disease; their frequency, phenomenology, and clinical correlates. Rinsho Shinkeigaku 45:1–5 23. Oka H, Yoshioka M, Onouchi K, Morita M, Mochio S, Suzuki M et al (2007) Impaired cardiovascular autonomic function in Parkinson’s disease with visual hallucinations. Mov Disord 22:1510–1514 24. Nomura T, Inoue Y, Ho¨gl B, Uemura Y, Kitayama M, Abe T et al (2010) Relationship between (123)I-MIBG scintigrams and REM sleep behaviour disorder in Parkinson’s disease. Parkinsonism Relat Disord 16:683–685 25. Kim JS, Lee KS, Song IU, Kim YI, Kim SH, You IR et al (2008) Cardiac sympathetic denervation is correlated with Parkinsonian midline motor symptoms. J Neurol Sci 270:122–126 26. Saiki S, Hirose G, Sakai K, Kataoka S, Hori A, Saiki M et al (2004) Cardiac 123I-MIBG scintigraphy can assess the disease severity and phenotype of PD. J Neurol Sci 220:105–111 27. Matsui H, Nishinaka K, Oda M, Komatsu K, Kubori T, Udaka F (2006) Does cardiac metaiodobenzylguanidine (MIBG) uptake in Parkinson’s disease correlate with major autonomic symptoms? Parkinsonism Relat Disord 12:284–288 28. Oka H, Toyoda C, Yogo M, Mochio S (2011) Reduced cardiac 123I-MIBG uptake reflects cardiac sympathetic dysfunction in de novo Parkinson’s disease. J Neural Transm 118:1323–1327 29. Shibata M, Morita Y, Shimizu T, Takahashi K, Suzuki N (2009) Cardiac parasympathetic dysfunction concurrent with cardiac sympathetic denervation in Parkinson’s disease. J Neurol Sci 276:79–83
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ORIGINAL COMMUNICATION
Is reduced myocardial sympathetic innervation associated with clinical symptoms of autonomic impairment in idiopathic Parkinson’s disease? Daniel Guidez • Stefanie Behnke • Ramona Halmer Ulrich Dillmann • Klaus Faßbender • Carl M. Kirsch • Dirk Hellwig • Jo¨rg Spiegel
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Received: 21 August 2013 / Revised: 24 September 2013 / Accepted: 26 September 2013 / Published online: 18 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Patients with idiopathic Parkinson’s disease (IPD) have a reduced myocardial MIBG uptake in MIBG scintigraphy, indicating myocardial sympathetic denervation. We were interested whether this myocardial sympathetic denervation coincides with clinical symptoms of autonomic impairment in IPD patients. We performed MIBG scintigraphy, the SCOPA-AUT scale, a standardized medical history (developed in our clinic) and autonomic nervous system testing in 47 IPD patients (21 female, 26 male patients). We correlated myocardial MIBG uptake with the results of the SCOPA-AUT scale, the standardized medical history and the autonomic nervous system testing through the use of Spearman’s correlation. Myocardial MIBG uptake correlated significantly (p \ 0.05) with several items of the SCOPA-AUT scale (in female patients: perspiration during the night, in male patients: sum score, saliva dribbling of the mouth, difficulty swallowing, fainting, constipation), of the standardized medical history (in male patients: swollen ankles) and of the autonomic nervous system testing (all patients: sum score, Ewing orthostasis test). Remarkably, we found more significant correlations in male than in female patients. Reduced myocardial sympathetic innervation—as revealed by MIBG scintigraphy—is associated with clinical symptoms of autonomic impairment. This association is more
D. Guidez S. Behnke R. Halmer U. Dillmann K. Faßbender J. Spiegel (&) Department of Neurology, Saarland University, Kirrberger Strasse, 66421 Homburg/Saar, Germany e-mail: [email protected] C. M. Kirsch D. Hellwig Department of Nuclear Medicine, Saarland University, Kirrberger Strasse, 66421 Homburg/Saar, Germany
pronounced in male than in female patients. The cause for this gender-specific phenomenon is unclear. Keywords Parkinson’s disease Autonomic nervous system SCOPA-AUT scale MIBG scintigraphy
Introduction The clinical diagnosis of idiopathic Parkinson’s disease (IPD) can be supported using myocardial metaiodobenzylguanidine (MIBG) scintigraphy, which measures the postganglionic sympathetic myocardial innervation. Numerous studies have reported a reduced myocardial MIBG uptake indicating a reduced myocardial sympathetic innervation in IPD patients [1–9]. Some IPD patients, in particular, exhibit a very pronounced myocardial sympathetic denervation (Figs. 1, 2). Such differences in myocardial sympathetic innervation, as illustrated by Figs. 1 and 2, raise the question whether a decreased sympathetic myocardial innervation correlates with clinical symptoms of autonomic impairment (for example orthostatic hypertension, salivation, difficulty swallowing, indigestion or constipation, impaired bladder function, vertigo, increased or reduced sweating, hypo-/hypertension, irregular pulse, swollen ankles). Previous studies report few and inconsistent findings concerning the correlation between myocardial MIBG uptake and clinical symptoms of autonomic impairment. For example, IPD patients with syncope or presyncope exhibit a significantly lower myocardial MIBG uptake than patients without syncope or presyncope [10]. Myocardial MIBG uptake also correlates significantly with the nocturnal fall of mean arterial blood pressure in IPD [11].
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Fig. 2 Strongly decreased myocardial MIBG uptake in a 62-year-old female IPD patient Fig. 1 Slightly decreased myocardial MIBG uptake in a 64-year-old male IPD patient
Myocardial MIBG uptake correlates significantly with the blood pressure overshoot in phase IV of the Valsalva maneuver but not with the systolic blood pressure response on head-up tilt-table testing in de novo IPD patients [12]. IPD patients with a heart-to-mediastinum (H/M) ratio \1.7 showed a significant reduction of the cardiac velocity index, an indicator for cardiac contractility, during exercise compared to IPD patients with an H/M ratio [1.7 [13]. Furthermore, IPD patients with a score C3.3 on the Parkinson fatigue scale (‘‘fatigued’’ IPD patients) reveal a significantly lower myocardial MIBG uptake than patients with a score \3.3 (‘‘non-fatigued’’ IPD patients, [14]). In contrast, the results of other studies argue against a correlation between myocardial MIBG uptake and clinical symptoms of autonomic impairment in IPD patients. Haensch et al. [15] reported that myocardial MIBG uptake did not correlate with the extent of orthostatic hypotension or heart rate variability in IPD patients. Berganzo et al. [16] could not find a significant correlation between myocardial MIBG uptake and any score of the SCOPA-AUT scale in 112 IPD patients. In IPD patients, the myocardial MIBG uptake does not correlate with changes of blood pressure or heart rate during exercise [13].
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In summary, the data of previous studies are inconsistent and incomplete concerning the correlation between sympathetic myocardial innervation (measured by myocardial MIBG scintigraphy) and clinical symptoms of autonomic impairment. In this paper, we applied MIBG scintigraphy, the SCOPA-AUT questionnaire [17], a self-designed standardized interview and autonomic testing to resolve this question.
Patients and methods Patients The study included 47 patients (age 65 ± 8 years, mean ± SD, 21 female, 26 male patients) with IPD. Based on the Hoehn and Yahr (H&Y) staging system, 22 patients were at stage 1, 11 at stage 2, 11 at stage 3, and 3 at stage 4. Nineteen patients belonged to the akinetic rigid type, ten to the tremor dominant type, and 18 to the equivalence type. IPD was diagnosed according to the British Brain Bank criteria [18]. All patients exhibited normal cranial magnetic resonance imaging. No patient had any history of dementia or depression. Depression was excluded by use of the Beck depression inventory. All patients underwent myocardial MIBG scintigraphy, the SCOPA-AUT scale [17], a
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standardized medical history (developed in our department, see below) and testing of autonomic nervous system function. Patients with any present/previous disease or medication, which might affect MIBG uptake, were excluded. Anti-parkinsonian medication was continued during all measurements. All participants gave their informed consent prior to their inclusion in the study. The study protocol was approved by the local ethics committee ¨ rztekammer des Saarlandes). (Ethikkommission der A
47 Table 1 SCOPA-AUT scale 1. In the last month, have you had difficulty swallowing or have you choked? 2. In the last month, has saliva dribbled out of your mouth? 3. In the last month, has food ever become stuck in your throat? 4. In the last month, did you ever have the feeling during a meal that you were full very quickly? 5. Constipation is a blockage of the bowel, a condition in which someone has a bowel movement twice a week or less. In the last month, have you had problems with constipation? 6. In the last month, did you have to strain hard to pass stools?
MIBG scintigraphy Following thyroid gland blocking with sodium perchlorate, intravenous injection of 123I-MIBG (Amersham, Amersham Buchler, Braunschweig, Germany) with a specific activity of 200 MBq/mg was given. Planar whole-body images in anterior and posterior views were obtained 4 h after injection using a dual-head large-field gamma camera (Siemens Multispect, MS2, Siemens, Erlangen, Germany) equipped with medium-energy high-resolution parallelhole collimators. MIBG uptake of myocardium and mediastinum was quantified by drawing a rectangular region of interest over the upper mediastinum and a manually delineated region outlining the left ventricular myocardium of the heart. The heart-to-mediastinum ratio (HMR) was calculated, defined as the average counts/pixel in the myocardium divided by that of the upper mediastinum. Our lower norm value (mean - 2 SD) was 1.79 and was obtained from age-matched healthy controls. MIBG scintigraphy was considered pathological if the HMR was \1.79 and classified as normal if the HMR was C1.79. After MIBG imaging, an additional myocardial rest perfusion SPECT imaging was performed with 99m Tc-Sestamibi (MIBI, Cardiolite, Bristol Myers Squibb, New York, NY, USA) to confirm normal myocardial perfusion and to exclude hampered myocardial MIBG uptake due to cardiac disease. The injected dose of MIBI was 500 MBq.
7. In the last month, have you had involuntary loss of stools? 8. In the last month, have you had difficulty retaining urine? (Extra: use catheter) 9. In the last month, have you had involuntary loss of urine? (Extra: use catheter) 10. In the last month, have you had the feeling that after passing urine your bladder was not completely empty? (Extra: use catheter) 11. In the last month, has the stream of urine been weak? (Extra: use catheter) 12. In the last month, have you had to pass urine again within 2 h of the previous time? (Extra: use catheter) 13. In the last month, have you had to pass urine at night? (Extra: use catheter) 14. In the last month, when standing up have you had the feeling of becoming either light-headed, or no longer being able to see properly or no longer being able to think clearly? 15. In the last month, did you become light-headed after standing for some time? 16. Have you fainted in the last 6 months? 17. In the last month, have you ever perspired excessively during the day? 18. In the last month, have you ever perspired excessively during the night? 19. In the last month, have your eyes ever been oversensitive to bright light? 20. In the last month, how often have you had trouble tolerating cold? 21. In the last month, how often have you had trouble tolerating the heat?
SCOPA-AUT scale
22. In the last month, have you used medication for: (a) constipation? (b) urinary problems? (c) blood pressure? (d) other symptoms (no/yes)
The SCOPA-AUT scale was developed by Visser er al. [17] to assess autonomic dysfunction in IPD. The original version comprises 26 questions. For the purpose of discretion, we did not apply the questions which concern sexual function. The remaining questions are listed in Table 1.
The response options for the questions 1–21 are never (0 points), sometimes (1 point), often (2 points), regularly/nearly always (3 points), always (4 points). Question 22 concerning medications have the response options no (0 points) and yes (1 point). In contrast to the original version of Visser et al. [17], we do not apply the questions concerning sexual dysfunction (question 22–25 in the original version)
Standardized medical history
Autonomic nervous system testing
We developed a questionnaire with ten questions (Table 2) that focused on central and peripheral autonomic and cardiovascular dysfunction and disease.
The autonomic nervous system testing (autonomic testing) was performed in the morning. If applicable, the patients delayed their morning antihypertensive medication until
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48 Table 2 Standardized medical history 1. In the last month, did you feel shortness of breath during slight exercise? 2. In the last month, were your ankles swollen? 3. In the last month, did you remark an irregular pulse? 4. Are/were you suffering from a valvular defect? Have you had prior cardiac surgery? (We did not ask about coronary disease since coronary disease represents an exclusion criterion for this study) 5. Have you ever had problems with too low or too high blood pressure? 6. In the last month, did you feel any pain in the legs during longer walks? 7. Have you ever had a transient ischemic attack, a stroke or a constriction of a brain vessel (at the neck or in the brain)? 8. Have you ever had bleeding in the brain? 9. Do you suffer from diabetes mellitus? 10. Do you take medication besides anti parkinsonian medication? If yes, what medication and since when? The response options for the questions 1, 2, 3, and 6 are never (0 points), sometimes (1 point), often (2 points), regularly/nearly always (3 points), always (4 points). The questions 4, 5, 7, 8, 9 and 10 have the response options no (0 points) and yes (1 point)
after the testing was completed. The autonomic testing was conducted according to standard clinical methods [19] and consisted of three tests: the Ewing orthostasis test (cardiovascular response from lying to upright position), respiratory sinus arrhythmia (cardiac response to deep breathing), and the Valsalva maneuver (cardiovascular response to the Valsalva maneuver). During all tests the electrocardiogram was continuously recorded. The orthostatis test and the Valsalva maneuver included an intermittent automated blood pressure measurement every 60 s. Fifty age-matched healthy volunteers served as the control group. For each test a maximum of two points were given: normal finding (0 points), finding at the threshold (1 point), pathological finding (2 points). The Ewing orthostasis test measures the heart rate (Ewing ratio) and the blood pressure (orthostasis test) after a change from the supine to the upright position. Before the beginning of this test, subjects were in the supine position for at least 10 min. The subjects then stood up taking an upright position. The course of the arterial blood pressure, after upright position is taken, gives evidence for the integrity of the sympathetic noradrenergic function: an impaired sympathetic noradrenergic function results in a pathological orthostatic blood pressure decrease [norm (independent of age): D systolic blood pressure B20 mmHg or D diastolic blood pressure B10 mmHg] after the upright position is taken. The Ewing ratio is calculated as the quotient [longest RR interval (*30th heartbeat) in the upright position]/[shortest RR interval (*15th heartbeat) in the upright position] and quantifies
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the cardiac parasympathetic (vagal) function (norm: age 45–49 years: quotient C 1.09; 50–54 years: C1.08; 55–64 years: C1.07; 65–74 years: C1.05; 75–80 years: C1.04). Respiratory sinus arrhythmia was evaluated in the supine position with the patient breathing slowly and deeply at six breaths a minute for 3 min. The RR difference = longest RR interval—shortest RR interval during deep breathing was determined. Respiratory sinus arrhythmia is based mainly on the parasympathetic (vagal) function [norm: age 45–49 years: C98 ms; age 50–54 years: C92 ms; 55–59 years: C86 ms; 60–64 years: C81 ms; 65–69 years: C76 ms; 70–74 years: C71 ms; 75–80 years: C61 ms]. The Valsalva maneuver was assessed in the supine position. After the subject had breathed normally over 60 s, they had to exhale against a constant pressure of 40 mmHg (via a mouthpiece) over 15 s, which increased the intrathoracic pressure (Valsalva maneuver). Then the subject had to breathe normally over the following 75 s. The Valsalva ratio was calculated by dividing the longest RR interval within 30 s after the Valsalva maneuver by the shortest RR interval during or maximally 5 s after the Valsalva maneuver (norm: age 40–49 years: quotient C 1.19; 50–59 years: C1.18; 60–64 years: C1.17; 65–69 years: C1.15; 70–74 years: C1.15; 75–80 years: C1.14). Five phases of the Valsalva manoeuvre can be differentiated. Each of these five phases is dominated by the sympathetic pathway or the parasympathetic pathway of the autonomic nervous system. The investigator who performed and evaluated the clinical tests (SCOPA-AUT scale, standardized medical history and autonomic testing) was blinded to the results of myocardial MIBG scintigraphy and vice versa. Statistics We used the software GraphPad Prism for Windows (Version 5.04; GraphPad Software, San Diego, CA, USA). Descriptive data are given as mean and standard deviation (SD). Correlations were calculated using the Pearson’s correlation coefficient in case of normally distributed data and Spearman’s correlation coefficient in case of ordinal data. The SCOPA-AUT scale, the standardized medical history, and the autonomic testing deliver ordinal data. Statistical significance was assumed in case of a p value\0.05.
Results Correlation between myocardial MIBG uptake and the SCOPA-AUT scale We performed the SCOPA-AUT scale to determine whether myocardial MIBG uptake correlates with clinical
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autonomic dysfunction (for example salivation, difficulty swallowing, indigestion or constipation, incontinence, problems with urination, vertigo, increased or reduced sweating, hypo-/hypertension). Overall, only the answer to question 18 (‘‘In the last month, have you ever perspired excessively during the night?’’) correlated significantly with myocardial MIBG uptake (r = ?0.37, p \ 0.05; Spearman’s correlation). After we divided the patients into female (n = 21) and male patients (n = 26), we found gender-specific results: in the female patients myocardial MIBG uptake correlated only with the scores of question 18 (‘‘In the last month, have you ever perspired excessively during the night?’’; r = ?0.44; p \ 0.05). Interestingly, in the male patients there were more significant correlations. Myocardial MIBG uptake correlated inversely with the SCOPA-AUT scale sum score (r = -0.41; p \ 0.05), the answer to question 2 (‘‘In the last month, has saliva dribbled out of your mouth?’’; r = -0.53, p \ 0.01), question 1 (‘‘In the last month have you had difficulty swallowing or have you choked?’’; r = -0.47, p \ 0.05), question 16 (‘‘Have you fainted in the last 6 months?’’; r = -0.40, p \ 0.05) and question 6 (‘‘In the last month, did you have to strain hard to pass stools?’’; r = -0.39, p \ 0.05). Correlation between myocardial MIBG uptake and standardized medical history Neither the sum score nor the scoring of any single question of the standardized medical history correlated significantly with myocardial MIBG uptake. In the female patients there was no significant correlation between myocardial MIBG uptake and the scoring of any question. In contrast, there were significant correlations in the male patients: myocardial MIBG uptake correlated inversely with the sum score (r = -0.42; p \ 0.05) and the rating of question 2 (‘‘In the last month, were your ankles swollen?’’; r = -0.40; p \ 0.05).
Correlation between myocardial MIBG uptake and autonomic nervous system testing (autonomous testing) Myocardial MIBG uptake correlated significantly inversely with the sum score of the autonomic testing (r = -0.43; p \ 0.005; Spearman’s correlation), the Ewing orthostasis test (r = -0.38; p \ 0.01) and nearly significantly with respiratory sinus arrhythmia (r = -0.30; p = 0.0504). We did not find any correlation between myocardial MIBG uptake and the findings of the Valsalva maneuver.
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We assume that the age of the patients did not influence or cause the significant correlations, which we presented so far, since the patient’s age did not correlate with myocardial MIBG uptake (r = -0.03; p = 0.82; Pearson’s correlation).
Discussion Numerous studies have reported reduced myocardial sympathetic innervation in IPD patients [1–9]. As yet, it is unclear whether, and in which manner, this impaired sympathetic myocardial innervation interacts with clinical symptoms of autonomic impairment (for example orthostatic hypertension, salivation, difficulty swallowing, indigestion or constipation, impaired bladder function, vertigo, increased or reduced sweating, hypo-/hypertension, irregular pulse, swollen ankles) in IPD patients. In our study, several items of the SCOPA-AUT scale correlated significantly with myocardial MIBG uptake. Remarkably, we detect more significant correlations in the male patients than in the female patients. In addition, the items of the SCOPA-AUT scale, which correlated significantly with myocardial MIBG uptake, differed between male and female patients. Therefore, it seems to be meaningful to differentiate between genders. In the male patients, there were significant correlations between myocardial MIBG uptake and the SCOPA-AUT scale sum score as well as the answers to question 1 (‘‘In the last month have you had difficulty swallowing or have you choked?’’), question 2 (‘‘In the last month, has saliva dribbled out of your mouth?’’), question 6 (‘‘In the last month, did you have to strain hard to pass stools?’’) and question 16 (‘‘Have you fainted in the last 6 months?’’). In our opinion, the significant correlation of the SCOPA-AUT scale ‘sum score—combined with these four single questions—with myocardial MIBG uptake shows that the myocardial sympathetic denervation influences clinical symptoms of autonomic impairment in male IPD patients. It is unclear why there were fewer significant correlations in the female IPD patients. In contrast, Berganzo et al. [16] could not find any significant correlation between the SCOPA-AUT scale and myocardial MIBG uptake in a larger cohort of 112 IPD patients. Berganzo et al. calculated the correlation between myocardial MIBG uptake and the SCOPA-AUT scale only over all patients and did not differentiate between male and female patients. When we considered the whole patient population, not differentiating between female and male patients, we also find little evidence of significant correlations between MIBG scintigraphy and the SCOPA-AUT scale. It might be speculated that Berganzo et al. would
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have found significant correlations as well, if they had divided their patients by gender. Further symptoms beyond those that are screened in the SCOPA-AUT scale and certain diseases may be associated with an impairment of central or peripheral autonomic function. For this reason, we developed a questionnaire with ten questions—which asks for these further symptoms and diseases (Table 2)—called the ‘‘standardized medical history’’. This standardized medical history is designed to supplement the SCOPA-AUT scale. We were interested whether the results of the standardized medical history correlate with myocardial MIBG uptake. In the male patients, myocardial MIBG uptake correlated significantly with the sum score and the rating of question 2 (‘‘In the last month, were your ankles swollen?’’) of the standardized medical history. This small output of significant correlations between MIBG uptake and the standardized medical history might be due to several reasons: (1) the diseases of arterial hyper-/hypotension and diabetes mellitus (question 5 and 9 of the standardized medical history) often do not cause specific clinical symptoms; they are hardly or not noticed by the patient and thus cannot be scored sufficiently by the patient, (2) the other screened diseases (question 4: valvular defect/cardiac surgery, question 7: ischemic cerebrovascular disease; question 8: bleeding in the brain) are not very common, therefore their discriminatory power might be too low, and (3) the screened clinical symptoms (question 1, 3, and 6) are subject to subjective judgment and may, therefore, vary between individuals. Nevertheless, our study showed significant correlations between myocardial sympathetic denervation and some questions of the SCOPA-AUT scale and the standardized medical history. Such correlations have not been described so far. In previous studies myocardial MIBG scintigraphy was correlated with several clinical aspects in IPD patients: IPD patients with cognitive deficits disclose a significantly lower myocardial MIBG uptake than IPD patients without cognitive deficits [20, 21]. IPD patients with visual hallucinations or other psychotic symptoms have a significantly lower myocardial MIBG accumulation than IPD patients without visual hallucinations or other psychotic symptoms [21–23]. Nakamura et al. [14] found a significantly lower myocardial MIBG uptake in IPD patients with fatigue than in IPD patients without fatigue. Nomura et al. [24] reported a significantly lower myocardial MIBG uptake in IPD patients with REM sleep behavior disorders than in IPD patients with normal REM sleep. Myocardial MIBG uptake correlates significantly with the severity of hypokinesia, rigidity, and midline symptoms (such as speech, posture, and gait) but not with the intensity of resting or postural tremor in IPD [7, 25]. IPD patients with the tremor-dominant type disclose a significantly higher myocardial MIBG
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uptake than patients with the akinetic rigid type at the same disease stage [7, 26]. In IPD patients, myocardial MIBG uptake correlates significantly with olfactory function quantified by the odor stick identification test Japan (OSITJ score; [12]). There is a significant correlation between myocardial MIBG uptake with bladder function, but not with constipation or orthostatic hypotension in IPD [15, 27]. Lenska-Mieciek et al. [10] found a significantly lower myocardial MIBG uptake in IPD patients with syncope or presyncope than in IPD patients without syncope or presyncope. Myocardial MIBG uptake correlates significantly with the nocturnal fall of mean arterial blood pressure in IPD [11]. In addition to these previous findings, our study indicates that myocardial MIBG uptake correlates significantly inversely with the frequency of swollen ankles in the last month and the sum score of our standardized medical history. The cited studies and our own study show that this field (of correlations between myocardial MIBG scintigraphy and clinical findings) is still open to new ideas. Furthermore, in our study, myocardial MIBG uptake correlated significantly with the results of the autonomic nervous system testing, primarily with the sum score of autonomic testing and with the Ewing orthostasis test. The Ewing orthostasis test quantifies the cardiac parasympathetic function and the sympathetic noradrenergic function. These significant correlations show that the density of postganglionic noradrenergic myocardial neurons—as visualized by myocardial MIBG scintigraphy—reflects the function of the sympathetic nervous system. This result is in accordance with previous studies [15, 28, 29]. In summary, a reduced myocardial sympathetic innervation—indicated by a reduced myocardial MIBG uptake— is associated with some clinical symptoms of autonomic impairment. This association is more pronounced in male than in female patients. The cause for this gender-specific difference is unclear and requires further investigation. Conflicts of interest of interest.
The authors declare that they have no conflicts
Ethical standard This single case study was performed in accordance with the ethical standard laid down in the 1964 Declaration of Helsinki.
References 1. Braune S (2001) The role of cardiac metaiodobenzylguanidine uptake in the differential diagnosis of parkinsonian syndromes. Clin Auton Res 11:351–355 2. Hirayama M, Hakusui S, Koike Y, Ito K, Kato T, Ikeda M et al (1995) A scintigraphical qualitative analysis of peripheral vascular sympathetic function with meta-[123I]iodobenzylguanidine in neurological patients with autonomic failure. J Auton Nerv Syst 53:230–234
J Neurol (2014) 261:45–51 3. Nagayama H, Hamamoto M, Ueda M, Nagashima J, Katayama Y (2005) Reliability of MIBG myocardial scintigraphy in the diagnosis of Parkinson’s disease. J Neurol Neurosurg Psychiatry 76:249–251 4. Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H (1999) (123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 67:189–194 5. Satoh A, Serita T, Tsujihata M (1997) Total defect of metaiodobenzylguanidine (MIBG) imaging on heart in Parkinson’s disease: assessment of cardiac sympathetic denervation. Nihon Rinsho 55:202–206 6. Sawada H, Oeda T, Yamamoto K, Kitagawa N, Mizuta E, Hosokawa R et al (2009) Diagnostic accuracy of cardiac metaiodobenzylguanidine scintigraphy in Parkinson disease. Eur J Neurol 16:174–182 7. Spiegel J, Hellwig D, Farmakis G, Jost WH, Samnick S, Fassbender K et al (2007) Myocardial sympathetic degeneration correlates with clinical phenotype of Parkinson’s disease. Mov Disord 22:1004–1008 8. Taki J, Nakajima K, Hwang EH, Matsunari I, Komai K, Yoshita M et al (2000) Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 27:566–573 9. Yoshita M (1998) Differentiation of idiopathic Parkinson’s disease from striatonigral degeneration and progressive supranuclear palsy using iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. J Neurol Sci 155:60–67 10. Len´ska-Mieciek M, Derecka-Charzyn´ska I, Fiszer U, Kro´licki L, Kułakowski P (2011) Syncope and autonomic cardiovascular dysfunction in Parkinson disease. Neurol Neurochir Pol 45:335–341 11. Manabe Y, Fujii D, Kono S, Sakai Y, Tanaka T, Narai H (2011) Systemic blood pressure profile correlates with cardiac 123IMIBG uptake in patients with Parkinson’s disease. J Neurol Sci 307:153–156 12. Oka H, Toyoda C, Yogo M, Mochio S (2010) Olfactory dysfunction and cardiovascular dysautonomia in Parkinson’s disease. J Neurol 257:969–976 13. Nakamura T, Hirayama M, Yamashita F, Uchida K, Hama T, Watanabe H, Sobue G (2010) Lowered cardiac sympathetic nerve performance in response to exercise in Parkinson’s disease. Mov Disord 25:1183–1189 14. Nakamura T, Hirayama M, Hara T, Hama T, Watanabe H, Sobue G (2011) Does cardiovascular autonomic dysfunction contribute to fatigue in Parkinson’s disease? Mov Disord 26:1869–1874 15. Haensch CA, Lerch H, Jo¨rg J, Isenmann S (2009) Cardiac denervation occurs independent of orthostatic hypotension and impaired heart rate variability in Parkinson’s disease. Parkinsonism Relat Disord 15:134–137
51 16. Berganzo K, Tijero B, Somme JH, Llorens V, Sa´nchez-Manso JC, Low D et al (2012) SCOPA-AUT scale in different parkinsonism’s and its correlation with (123) I-MIBG cardiac scintigraphy. Parkinsonism Relat Disord 18:45–48 17. Visser M, Marinus J, Stiggelbout AM, van Hilton JJ (2004) Assessment of autonomic dysfunction in Parkinson’s disease: the SCOPA-AUT. Mov Disord 19:1306–1312 18. Hughes A, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinicopathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184 19. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P et al (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33:2285–2293 20. Kim JS, Shim YS, Song IU, Yoo JY, Kim HT, Kim YI et al (2009) Cardiac sympathetic denervation and its association with cognitive deficits in Parkinson’s disease. Parkinsonism Relat Disord 15:706–708 21. Kitayama M, Wada-Isoe K, Irizawa Y, Nakashima K (2008) Association of visual hallucinations with reduction of MIBG cardiac uptake in Parkinson’s disease. J Neurol Sci 264:22–26 22. Kashihara K, Ohno M, Katsu Y (2005) Psychoses in patients with Parkinson’s disease; their frequency, phenomenology, and clinical correlates. Rinsho Shinkeigaku 45:1–5 23. Oka H, Yoshioka M, Onouchi K, Morita M, Mochio S, Suzuki M et al (2007) Impaired cardiovascular autonomic function in Parkinson’s disease with visual hallucinations. Mov Disord 22:1510–1514 24. Nomura T, Inoue Y, Ho¨gl B, Uemura Y, Kitayama M, Abe T et al (2010) Relationship between (123)I-MIBG scintigrams and REM sleep behaviour disorder in Parkinson’s disease. Parkinsonism Relat Disord 16:683–685 25. Kim JS, Lee KS, Song IU, Kim YI, Kim SH, You IR et al (2008) Cardiac sympathetic denervation is correlated with Parkinsonian midline motor symptoms. J Neurol Sci 270:122–126 26. Saiki S, Hirose G, Sakai K, Kataoka S, Hori A, Saiki M et al (2004) Cardiac 123I-MIBG scintigraphy can assess the disease severity and phenotype of PD. J Neurol Sci 220:105–111 27. Matsui H, Nishinaka K, Oda M, Komatsu K, Kubori T, Udaka F (2006) Does cardiac metaiodobenzylguanidine (MIBG) uptake in Parkinson’s disease correlate with major autonomic symptoms? Parkinsonism Relat Disord 12:284–288 28. Oka H, Toyoda C, Yogo M, Mochio S (2011) Reduced cardiac 123I-MIBG uptake reflects cardiac sympathetic dysfunction in de novo Parkinson’s disease. J Neural Transm 118:1323–1327 29. Shibata M, Morita Y, Shimizu T, Takahashi K, Suzuki N (2009) Cardiac parasympathetic dysfunction concurrent with cardiac sympathetic denervation in Parkinson’s disease. J Neurol Sci 276:79–83
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