ABSTRACT
Background
Autonomic dysfunction forms the diagnostic cornerstone in MSA. Data are limited on autonomic dysfunction differences between the two subtypes, MSA‐C and MSA‐P.
Objectives
To assess autonomic dysfunction in MSA subtypes and Parkinson's disease (PD) and compare it to healthy controls.
Methods
We conducted a cross‐sectional study. A validated questionnaire (Scales for Outcomes in Parkinson's Disease–Autonomic Dysfunction; SCOPA‐AUT) was used for symptom screening. Cardiovascular autonomic testing included deep breathing (change in heart rate, E: I ratio), Valsalva ratio, diastolic blood pressure (BP) rise (hand grip, cold pressor), and postural (tilt, 30:15 ratio) tests. Disease severity was assessed by the Unified MSA Rating Scale (UMSARS), H & Y stage, and International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating scale part III.
Results
MSA‐P (48 subjects; age, 63.6 ± 9.7 years; UMSARS, 45.0 ± 16.5), MSA‐C (52 subjects; age, 58.0 ± 8.1 years; UMSARS, 44.0 ± 12.8), PD (50 subjects; age, 57.6 ± 6.7 years), and healthy controls (50 subjects; age, 58.0 ± 8.0 years) were enrolled. MSA patients had higher SCOPA‐AUT scores in gastrointestinal, urinary, cardiovascular, and sexual domains than controls and in gastrointestinal, urinary, and cardiovascular domains compared to PD. The two MSA subtypes did not differ in autonomic dysfunction. Heart‐rate change on tilt and deep breathing, and diastolic BP rise on cold pressor test, differed significantly between MSA and PD patients.
Conclusions
Autonomic dysfunction symptomatology and cardiovascular autonomic tests were similar between MSA‐P and MSA‐C patients. Autonomic symptoms were more prominent in MSA than PD. Emphasis on these domains may improve likelihood of accurate clinical diagnosis of MSA at earlier stages.
Keywords: multiple system atrophy, autonomic nervous system, dysautonomia, Parkinson's disease
MSA is a rapidly progressive oligodendrioglial synucleinopathy characterized by α‐synuclein deposition in the central and peripheral autonomic nervous system.1, 2, 3, 4 Autonomic dysfunction is a core feature of diagnosis and manifests chiefly as orthostatic hypotension and urogenital dysfunction.5 Both may cause significant disability to MSA patients and are also challenging to treat. Early autonomic dysfunction in MSA may also be associated with poorer prognosis.6
The two subtypes of MSA, MSA‐parkinsonism (MSA‐P) and MSA‐cerebellar (MSA‐C), have dominant initial motor differences based on the neurodegenerative process affecting different anatomical sites within the neuraxis.4, 7 We hypothesize that these subtypes could similarly exhibit differential involvement of the autonomic nervous system that may lead to clinical differences in autonomic dysfunction. Indeed, previous studies have suggested that subtle differences do exist in the pattern of autonomic involvement between the two subtypes that may enable clinicians to focus on troublesome symptoms and alleviate these in an otherwise therapeutically dismal scenario.8 Sudomotor dysfunction may be more severe in MSA‐P.9 MSA‐C may exhibit more‐severe urogenital dysfunction.10 In India, large‐scale studies on epidemiology of MSA are lacking. Studies that have reported imaging features have enrolled small numbers of patients, with varying proportions of MSA‐P and MSA‐C.11, 12
Early MSA‐P may also closely resemble Parkinson's disease (PD), with up to 20% of patients clinically diagnosed to have MSA eventually determined to have dementia with Lewy bodies or PD at autopsy.13, 14, 15 Therefore, a comparison of MSA with PD subgroup also may be clinically relevant to identify features that may help differentiate between the two diseases.
In the absence of clear results from previous studies, as well as certain strong limitations of these studies, including retrospective nature and small patient numbers, we aimed to study patients with MSA using both a clinical autonomic symptomatology questionnaire (Scales for Outcomes in Parkinson's Disease–Autonomic Dysfunction; SCOPA‐AUT) and cardiovascular tests of autonomic dysfunction and to compare these to PD patients and healthy control subjects.
Materials and Methods
Study Design
We conducted a cross‐sectional study among patients with MSA‐P, MSA‐C, and PD attending the movement disorder clinic of a tertiary care, university hospital in North India. Patients who gave informed consent and met the following criteria were included: patients meeting the Gilman Consensus Criteria (for MSA)5 and the UK Parkinson's Disease Society Brain Bank criteria for PD.16 Patients meeting any of the following criteria were excluded: pregnant patients; patients with chronic liver disease/chronic kidney disease; malignancy and other diseases that precluded autonomic function testing; as well as diabetic patients and patients who refused consent. A consensus diagnosis was reached by two movement disorders experts (A.K.S. and R.R.). Healthy control subjects of age ± 2 years of patients were enrolled from spouses of patients or relatives of other neurological inpatients. Control subjects had no significant medical history and were not on any long‐term drug therapy. The study was approved by the institutional ethical committee. After written informed consent, all subjects underwent a standardized neurological history and examination.
Measurements
Disease severity was assessed using H & Y staging, Unified MSA Rating Scale (UMSARS),17 and International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS)18 (permission obtained from the MDS for use of both these scales). We used the clinical autonomic questionnaire, the SCOPA‐AUT (permission obtained from the authors of the scale).19 The SCOPA‐AUT questionnaire covers six different autonomic domains with a total of 23 items: gastrointestinal (seven items); urinary (six items); cardiovascular (three items); thermoregulatory (four items); pupillomotor (one item); and sexual (two items for men and two items for women). The response option for each item ranges from 0 (never) to 3 (often), with higher total scores reflecting more‐severe autonomic dysfunction. The maximal possible score is 69.
Cardiovascular autonomic testing was performed using standard tests.20 Anticholinergics, sympathomimetic and parasympathetic drugs, fludrocortisone, and midodrine were stopped 48 hours before testing. Alpha‐ and beta‐blockers were stopped 24 hours before testing. Levodopa (LD) medication was stopped on the day of testing. Resting heart rate (HR) and blood pressure (BP) were recorded. Continuous electrocardiography (ECG) was taken for calculation of HR‐based parameters, and both systolic and diastolic BP were recorded using sphygmomanometer for pressure‐based parameters. For the head‐up tilt test, the patient/subject was asked to lie down on a head‐up tilt table for 5 minutes, and supine BP was measured. The table was tilted in 15 seconds at 70 degrees and kept in that position for 5 minutes. BP was measured at 0.5, 1, 2, 2.5, and 5 minutes. The maximum fall within 5 minutes of head‐up tilt was noted. For the deep breathing test, the patient/subject was asked to take slow and deep inspiration followed by slow and deep expiration, such that each breathing cycle lasted for 10 seconds. Calculation was done from recorded tracings of respiration and ECG. Changes in HR between inspiration and expiration were averaged over six cycles. The Valsalva test was done in the sitting position. The patient/subject was instructed to blow into a mouthpiece attached to a sphygmomanometer. Expiratory pressure was kept at 40 mm Hg for 15 seconds. At the end of 15 seconds, the subject was asked to release the pressure. The Valsalva ratio was calculated from the longest RR interval during phase IV and the shortest RR interval during phase II. For the hand‐grip test, the patient/subject was asked to press a hand‐grip dynamometer at 30% of maximum voluntary contraction for 4 minutes. BP was recorded at the first, second, and fourth minute of contraction. Rise in diastolic BP above baseline was noted. For cold pressor test, the patient/subject was instructed to immerse one hand in cold water (10°C) for 1 minute up to the wrist, and BP was measured at the end of 1 minute in the contralateral upper limb. Rise in diastolic BP above baseline was noted.
Statistical Analysis
Statistical analysis of the data was performed using IBM SPSS software (IBM SPSS Statistics for Windows, Version 22.0; IBM Corp., Armonk, NY). Categorical data were expressed as frequency and percentage. Quantitative data were expressed as mean ± standard deviation and median/minimum/maximum were followed for normal distribution and skewed deviation respectively. A test of association between categorical variables was done using Pearson's chi‐square/Fisher's exact test. An independent‐samples t test was used to compare the means of quantitative variables between MSA‐P, MSA‐C, and PD groups that were normally distributed, whereas the Mann‐Whitney U test was used to compare the medians of non‐normal quantitative variables. Furthermore, we used the one‐way analysis of variance, followed by Bonferroni's post‐hoc test, to compare the normal quantitative variables between MSA‐P, MSA‐C, PD, and control groups. Finally, the Kruskal‐Wallis test, followed by the Mann‐Whitney U test, was used to compare the non‐normal quantitative variables between MSA‐P, MSA‐C, PD, and control groups. All tests were two‐sided, and level of significance was set at P < 0.05.
Results
We recruited 52 patients with MSA‐P, 48 patients with MSA‐C, 50 patients with PD, and 50 healthy controls, as shown in Table 1. MSA‐P patients were significantly older (mean age: 63.6 ± 9.7 years) compared to patients with MSA‐C (mean age: 58.0 ± 8.1 years). Disease duration was similar among the three groups, being 31.5 ± 20.2 months for MSA‐P, 33.5 ± 18.2 months for MSA‐C, and 32.9 ± 15.6 months for PD patients, enhancing comparative assessment. Age of onset (defined as age of first motor complaint) was similarly higher (60.3 ± 9.8 years) for MSA‐P, 56.2 ± 9.4 years for MSA‐C, and 54.9 ± 7.0 years for PD patients. In all subgroups, sex distribution showed male predominance, with 75.0% of MSA‐P and 61.5% of MSA‐C patients being males. Mean LD dose was higher for PD patients (745.1 ± 430.2 mg). Mean LD dose was 371.9 ± 151.7 and 359.8 ± 147.7 mg for MSA‐P and MSA‐C patients, respectively. Forty‐six percent of MSA‐P and 38% of MSA‐C patients were in H & Y stage 3. In the PD group, 46% of patients belonged to stage 2. MDS‐UPDRS part III score was higher for MSA‐P patients (46.9 ± 16.6) compared to MSA‐C patients (38.3 ± 16.8). UMSARS (total score) was 45.0 ± 16.5 and 44.0 ± 12.8 for MSA‐P and MSA‐C patients, respectively, suggesting comparable overall severity between the two subtypes. UMSARS part II score was comparable, being 23.1 ± 7.9 and 21.4 ± 5.9 for MSA‐P and MSA‐C patients, respectively.
Table 1.
Baseline characteristics of patients with MSA subtype P and C, PD, and healthy controls
| MSA‐P | MSA‐C | PD | Healthy Controls | |
|---|---|---|---|---|
| No. | 48 | 52 | 50 | 50 |
| Sex | ||||
| Male | 36 (75.0) | 32 (61.5) | 31 (62.0) | 32 (64.0) |
| Female | 12 (25.0) | 20 (38.5) | 19 (38.0) | 18 (36.0) |
| Age at presentation (years) | 63.6 ± 9.7 | 58.0 ± 8.1 | 57.6 ± 6.7 | 58.4 ± 8.1 |
| Age at onset (years) | 60.3 ± 9.8 | 56.2 ± 9.4 | 54.9 ± 7.0 | NA |
| Duration of disease (months) | 31.5 ± 20.2 | 33.5 ± 18.2 | 32.9 ± 15.6 | NA |
| 30 (18.5–36.0) | 36 (19.5–36.0) | 33 (21.5–48.0) | NA | |
| LD dose (mg/day) | 371.9 ± 151.7 | 359.8 ± 147.7 | 745.1 ± 430.2 | NA |
| H & Y staging | ||||
| 1 | 1 (2) | 4 (8) | 9 (18) | NA |
| 2 | 4 (8) | 4 (8) | 23 (46) | |
| 3 | 22 (46) | 20 (38) | 15 (30) | |
| 4 | 15 (31) | 14 (27) | 3 (6) | |
| 5 | 6 (13) | 10 (19) | 0 | |
| MDS‐UPDRS III | 46.9 ± 16.6 | 38.3 ± 16.8 | 30.7 ± 12.2 | NA |
| UMSARS | 45.0 ± 16.5 | 44.0 ± 12.8 | NA | NA |
| (total score = Part I + II + IV) | ||||
| UMSARS Part I | 19.3 ± 8.5 | 19.3 ± 6.9 | ||
| UMSARS Part II | 23.1 ± 7.9 | 21.4 ± 5.9 | ||
| UMSARS Part IV | 2.6 ± 1.0 | 2.7 ± 0.9 |
All values expressed as mean ± standard deviation, frequency (%), or median (minimum‐maximum).
NA, not applicable.
In the results of the SCOPA‐AUT questionnaire shown in Table 2, MSA‐P patients had significantly higher scores compared to control subjects in gastrointestinal, urinary, cardiovascular, thermoregulatory, and sexual domains (both male and female; P < 0.05). MSA‐C patients also had significantly higher scores compared to control subjects in the above domains, except the thermoregulatory domain (P < 0.05). MSA‐P and MSA‐C patients had significantly higher scores compared to PD patients in gastrointestinal, urinary, and cardiovascular domains (P < 0.05). In the gastrointestinal domain, MSA‐P patients had a mean score of 5.6 ± 3.4 and MSA‐C patients had a mean score of 7.1 ± 3.4 compared to PD patients who scored only 1.3 ± 3.4. Overall, the scores suggested moderate severity for MSA patients, with the highest possible score being 21 in this domain. Similarly, mean scores for MSA‐P and MSA‐C patients in the urinary domain were 4.8 ± 3.6 and 5.8 ± 3.6 compared to PD patients, with a mean score of 1.9 ± 3.6. Mean scores in the cardiovascular domain were 1.9 ± 1.5 for MSA‐P, 2.2 ± 1.5 for MSA‐C, compared to 0.9 ± 1.7 in the PD group. These scores in the cardiovascular and urinary domains suggested mild severity. We did not find any differences in the scores between MSA‐P and MSA‐C patients in any of the domains.
Table 2.
SCOPA‐AUT scores in MSA‐P, MSA‐C, PD patients, and healthy controls
| Domain | MSA‐P (n = 48) | MSA‐C (n = 52) | PD (n = 50) | Healthy Controls (n = 50) |
|---|---|---|---|---|
| Gastrointestinal | 5.6 ± 3.4a , 4 | 7.1 ± 3.4b , 5 | 1.3 ± 3.4 | 2.8 ± 3.4 |
| Urinary | 4.8 ± 3.6a , 4 | 5.8 ± 3.6b , 5 | 1.9 ± 3.6 | 2.8 ± 3.6 |
| Cardiovascular | 1.9 ± 1.5a , 4 | 2.2 ± 1.5b , 5 | 0.9 ± 1.7 | 1.1 ± 1.5 |
| Thermoregulatory | 1.3 ± 1.6a | 1.5 ± 1.6 | 0.8 ± 1.5 | 0.9 ± 1.5 |
| Pupillomotor | 0.4 ± 0.7 | 0.4 ± 0.8 | 0.2 ± 0.4 | 0.2 ± 0.4 |
| Sexual‐Male | 2.2 ± 1.8a | 2.3 ± 1.8b | 1.5 ± 1.8 | 1.8 ± 1.8 |
| (n = 36) | (n = 32) | (n = 31) | (n = 32) | |
| Sexual‐Female | 1.3 ± 1.4a | 1.6 ± 1.4b | 0.8 ± 1.4 | 0.9 ± 1.4 |
| (n = 12) | (n = 20) | (n = 20) | (n = 17) |
All values are expressed as mean ± standard deviation.
P < 0.05 for MSA‐P versus control.
P < 0.05 for MSA‐C versus control.
3 P < 0.05 for MSA‐P versus MSA‐C.
P < 0.05 for MSA‐P versus PD.
P < 0.05 for MSA‐C versus PD.
In the autonomic symptomatology, dysphagia (69%) and early satiety (62%) were the most frequent gastrointestinal autonomic complaints for MSA‐P patients whereas dysphagia (62%), constipation (62%), and early satiety (81%) were the most frequent complaints in MSA‐C patients (Table 3). In the urinary domain, 77% of MSA‐P patients had urinary urgency, which was the most frequent complaint, followed by urinary incontinence (75%), which was significantly higher than patients with PD (P < 0.001). A similar pattern was observed in MSA‐C patients, with 79% complaining of urinary urgency and 64% complaining of urinary incontinence. In the cardiovascular domain, 77% of MSA‐P and MSA‐C patients complained of presyncopal symptoms on standing for some time. This proportion was significantly higher than PD patients (P < 0.001). In the sexual domain, 100% of male patients with MSA‐P and 98% of patients with MSA‐C complained of erectile dysfunction and 97% of MSA‐P and 91% of MSA‐C patients had ejaculatory difficulty, which was significantly higher than control subjects (P < 0.001).
Table 3.
Autonomic symptoms in MSA‐P, MSA‐C, PD, and healthy controls
| Domain | MSA‐P (n = 48) | MSA‐C (n = 52) | PD (n = 50) | Controls (n = 50) |
|---|---|---|---|---|
| Gastrointestinal | ||||
| Dysphagia | 33 (69)a , c | 32 (62)b | 20 (40) | 7 (14) |
| Hypersalivation | 21 (44)a | 26 (50)b | 15 (30) | 5 (10) |
| Choking | 27 (56)a , c | 22 (42) | 15 (30) | 7 (14) |
| Early satiety | 30 (62.5)a , c | 42 (81)b , d | 13 (26) | 8 (16) |
| Constipation | 26 (54)a , c | 32 (62)b | 25 (50) | 7 (14) |
| Fecal incontinence | 12 (25)a , c | 21 (40)b , d | 1 (2) | 0 |
| Urinary | ||||
| Urgency | 37 (77)a , c | 41 (79)b , d | 16 (32) | 9 (18) |
| Incontinence | 36 (75)c | 33 (64) | 16 (32) | 13 (26) |
| Incomplete | 15 (31) | 23 (44) | 18 (36) | 11 (22) |
| voiding | 18 (38) | 22 (42) | 17 (34) | 10 (20) |
| Poor stream | 28 (58)a , c | 33 (63)b , d | 15 (30) | 10 (20) |
|
Frequency Nocturia |
25 (52)a | 28 (54)b | 15 (30) | 8 (16) |
| Cardiovascular | ||||
| Presyncope‐immediate | 32 (67)a , c | 35 (67)b , d | 15 (30) | 15 (30) |
| Presyncope‐postural | 37 (77)a , c | 40 (77)b , d | 14 (28) | 12 (24) |
| Syncope | 16 (33)a , c | 11 (21),b,e | 1 (2) | 1 (2) |
| Thermoregulatory | ||||
| Daytime perspiration | 18 (38)a , c | 17 (33) | 5 (10) | 4 (8) |
| Nocturnal perspiration | 17 (35)a , c | 12 (23) | 12 (24) | 4 (8) |
| Cold intolerance | 10 (21) | 12 (23) | 10 (20) | 6 (12) |
| Heat intolerance | 11 (22) | 14 (26) | 14 (28) | 7 (14) |
| Pupillomotor | 15 (31) | 13 (25) | 10 (20) | 8 (16) |
| Sexual‐Male | (n = 36) | (n = 32) | (n = 31) | (n = 32) |
| Erectile dysfunction | 36 (100)a | 31 (98)b | 22 (71) | 5 (16) |
| Ejaculation | 35 (97)a | 29 (91)b | 21 (68) | 4 (13) |
| dysfunction | ||||
| Sexual‐Female | (n = 12) | (n = 20) | (n = 20) | (n = 17) |
| Vaginal dryness | 7 (58)a | 7 (35)b | 9 (45) | 3 (18) |
| Orgasmic difficulty | 5 (42)a | 8 (40)b | 9 (45) | 0 |
All values expressed as frequency (%).
P < 0.001 for MSA‐P versus control.
P < 0.001 for MSA‐C versus control.
P < 0.001 for MSA‐P versus MSA‐C.
P < 0.001 for MSA‐P versus PD.
P < 0.001 for MSA‐C versus PD.
In the cardiovascular autonomic function testing, supine systolic BPs were higher for both MSA‐P and MSA‐C patients compared to healthy controls (P < 0.001; Table 4). Differences in supine systolic BP and systolic BP on performing the tilt test were also higher for MSA patients compared to control subjects (P < 0.001). However, there was statistically no significant difference between the two subtypes of MSA or between MSA subtypes and PD patients. We also noted that the mean degree of fall in supine systolic BP on tilting for MSA‐P and MSA‐C was 20.2 ± 10.4 and 22.4 ± 10.5 mm Hg. This was also observed in the mean fall in diastolic BP on tilting, which was 4.5 ± 8.8 mm Hg for MSA‐P and 5.2 ± 8.8 mm Hg for MSA‐C patients. Among these, 13% had a fall in systolic BP of ≥30 mm Hg, and 16% had fall in diastolic BP >15 mm Hg, satisfying the criteria of probable MSA.
Table 4.
Autonomic function testing of the cardiovascular system in MSA‐P, MSA‐C, PD patients, and healthy controls
| Test | Parameter | MSA‐P (n = 48) | MSA‐C (n = 52) | PD (n = 50) | Control (n = 50) |
|---|---|---|---|---|---|
| HUT | |||||
| SBP | Supine | 132.1 ± 11.2a | 133.6 ± 11.2b | 127.5 ± 11.3 | 129.1 ± 11.2 |
| Tilt | 112.5 ± 13.3 | 111.4 ± 13.4 | 119 ± 13.4 | 119.8 ± 13.3 | |
| Difference | 20.2 ± 10.4a | 22.4 ± 10.5b | 7.6 ± 10.6 | 9.3 ± 10.5 | |
| DBP | Supine | 79.3 ± 11.8a | 81.1 ± 11.9b | 74.0 ± 11.9 | 75.8 ± 11.8 |
| Tilt | 75.7 ± 9.8a | 76.8 ± 9.8b | 72.4 ± 9.8 | 73.6 ± 9.8 | |
| Difference | 4.5 ± 8.8 | 5.2 ± 8.8 | 1.9 ± 8.8 | 2.7 ± 8.8 | |
| HR | Supine | 78.7 ± 7.6 | 79.6 ± 7.7b | 75.8 ± 7.7 | 76.8 ± 7.6 |
| Tilt | 82.9 ± 7.9a , c | 84.9 ± 8.0b , d | 76.8 ± 8.0 | 78.8 ± 7.9 | |
| Difference | –4.1 ± 5.4 | –5.2 ± 5.4 | –0.9 ± 5.3 | –2.0 ± 5.4 | |
| 30:15 ratio | 1.74 ± 0.09 | 1.95 ± 0.04 | 1.11 ± 0.09 | 1.3 ± 0.04 | |
| DBT | Change in HR | 10.4 ± 4.4a , c | 9.0 ± 4.4b , d | 14.7 ± ‐4.3 | 13.3 ± 4.4 |
| E/I ratio | 1.15 ± 0.09a | 1.14 ± 0.09b | 1.18 ± 0.09 | 1.17 ± 0.10 | |
| Valsalva | Valsalva ratio | 1.22 ± 0.14a | 1.20 ± 0.15 | 1.26 ± 0.15 | 1.25 ± 0.14 |
| HGT | Rise in DBP | 9.7 ± 5.9a | 8.7 ± 6.0b | 12.7 ± 6.0 | 11.7 ± 5.9 |
| CPT | Rise in DBP | 10.0 ± 4.8a , c | 8.8 ± 4.9b , d | 13.8 ± 4.7 | 12.4 ± 4.8 |
All values in mean ± SE.
P < 0.001 for MSA‐P versus control.
P < 0.001 for MSA‐C versus control.
P < 0.001 for MSA‐P versus MSA‐C.
P < 0.001for MSA‐P versus PD.
P < 0.001 for MSA‐C versus PD.
HUT, head‐up tilt; DBT, deep breathing tests; SBP, systolic BP; DBP, diastolic BP; HGT, hand‐grip test; CPT, cold pressor test.
We observed higher mean HR on head‐up tilt in patients with MSA‐P (82.9 ± 7.9 beats per minute) and MSA‐C (84.9 ± 8.0 beats per minute), which was significantly different from PD patients (mean HR of 76.8 ± 8.0 beats per minute; P < 0.001) as well as control subjects (mean HR of 78.8 ± 7.9 beats per minute; P < 0.001). In the deep breathing test, mean change in HR was significantly lower for MSA‐P (10.4 ± 4.4 beats per minute) and MSA‐C patients (9.0 ± 4.4 beats per minute) compared to both PD patients (14.7 ± –4.3 beats per minute; P < 0.001) as well as healthy controls (13.3 ± 4.4 beats per minute; P < 0.001). In the cold pressor test, mean change in diastolic BP for MSA‐P (10.0 ± 4.8 mm Hg) and MSA‐C (8.8 ± 4.9 mm Hg) was lower as compared to PD (13.8 ± 4.7 mm Hg; P < 0.001) and healthy controls (12.4 ± 4.8 mm Hg; P < 0.001). There was no statistically significant difference in E/I ratio, Valsalva ratio, hand‐grip test, and head‐up tilt tests between the two MSA subtypes or between MSA and PD. However, E/I and Valsalva ratio were lower in MSA‐P patients compared to controls, similar to findings by Schmidt et al.
We also performed statistical comparison between SCOPA‐AUT (total score) and motor severity scores, UMSARS part II, and UPDRS part III motor severity for MSA and PD subgroups, which did not show any statistical correlation. Disease duration also did not show any correlation with SCOPA‐AUT scores.
Discussion
Autonomic dysfunction is an early feature in patients with MSA and worsens with progression of disease.3 It occurs because of cell loss in the dorsal motor nucleus of the vagus as well as catecholaminergic neurons of the ventrolateral medulla.21, 22, 23 The brunt of autonomic dysfunction involves damage to cells in the intermediolateral column.24, 25 In a study by McKay et al., 73% of patients who were eventually diagnosed to have MSA presented with symptoms of autonomic dysfunction, predominantly related to the genitourinary system or to orthostatic intolerance,26 similar to our study. The minority that remained developed complaints of autonomic dysfunction within 5 years of presentation. Identification and knowledge of domain‐specific autonomic dysfunction in these patients may help tailor management and follow‐up.
Mean age of onset of MSA‐P patients in our study was higher compared to other series, which report mean age of onset of 55 to 56 years.27, 28, 29 It was also significantly higher than other subgroups, and further statistical analysis was adjusted for the same. It has been observed that older age at onset may be an unfavorable predictor of survival in patients with MSA.30 This may be attributable to the nature of motor manifestations in patients with MSA‐C, with ataxia and speech abnormalities likely to manifest clinically earlier than extrapyramidal features in MSA‐P. The majority of MSA patients in our cohort were males, similar to previously reported series.27, 28, 29 We also observed that UPDRS part III score was higher for MSA‐P patients (46.9 ± 16.6) compared to MSA‐C patients (38.3 ± 16.8). This is probably because the thrust of part III of the MDS‐UPDRS is on extrapyramidal features rather than ataxia.
To date, there have been scanty data concerning description and comparative analysis of autonomic dysfunction in patients with MSA. One histopathological study with 42 autopsy‐confirmed cases showed no differences regarding symptoms of autonomic dysfunction.31 Another study with 100 MSA cases reported more‐severe clinical autonomic dysfunction in the olivopontocerebellar (MSA‐C) than the striatonigral (MSA‐P) phenotype.32 Both studies were based on retrospective data collection regarding autonomic dysfunction. Another prospective study directly assessed differences in autonomic dysfunction between the two MSA subtypes using a clinical autonomic questionnaire designed by the authors comprising 50 questions.8 In our study, we used the SCOPA‐AUT questionnaire, which is a well‐validated questionnaire for autonomic assessment in MSA.33 In our study, both the SCOPA‐AUT clinical questionnaire as well as objective autonomic function tests assessing cardiovascular function were used to compare autonomic function between the two MSA subtypes. In addition, we used both diseased controls in the form of PD patients as well as healthy controls for comparison. We did not find any significant differences between the two MSA subtypes in the clinical amnestic battery in any of the autonomic domain functions, including gastrointestinal, cardiovascular, urinary, thermoregulatory, pupillomotor, and sexual dysfunction. However, in comparison to control subjects, patients with MSA‐P as well as MSA‐C had higher scores in all domains except pupillomotor. This contrasts with the study by Schmidt et al.,8 in which significant differences between MSA‐P and ‐C patients were observed. MSA‐P patients had symptoms in more autonomic subsystems and more frequently in the vasomotor, secretomotor, and gastrointestinal subsystems. However, the pupillomotor and cardiovascular systems did not demonstrate any significant difference. Our findings were based on a sample of 100 patients with MSA, unlike the Schmidt et al. study which included 26 patients with MSA‐P and 12 patients with MSA‐C. Hence, our study is more representative and negates minor differences that may have acquired statistical significance because of small sample size in the Schmidt et al. study. In addition, we have used a quantitative scale, SCOPA‐AUT, which has been well standardized for MSA. In the study by Schmidt et al., a semiquantitative amnestic battery devised by the authors was used. Also, we did not perform sympathetic skin response in our study, which showed minor differences in the Schmidt et al. study.
Even in the autonomic function battery of the cardiovascular system, our study did not demonstrate significant differences between the two MSA subtypes, although these differed significantly in all tests from controls. Interestingly, the orthostatic fall in BP in our MSA patients showed a mean difference of 20.2 mm Hg systolic BP and 22.4 mm Hg systolic BP for MSA‐P and MSA‐C, respectively, and 4.5 and 5.2 mm Hg for diastolic BP. These values were lower than those required for the definition of probable MSA.5 Our cohort still met the definition of probable MSA because the proportion of urinary and sexual dysfunction was high. It is also possible that our Indian cohort may not have displayed as profound a fall in BP as has been reported from Western literature, which needs to be evaluated in future studies. Another series of MSA patients from India also reported an orthostatic fall in systolic BP >30 mm Hg in only 41.5% of MSA cases. However, the degree of fall in the remaining cases is not mentioned in this study.34 In the largest series of MSA patients worldwide, 59% of MSA patients, an orthostatic drop of systolic BP of ≥20 mm Hg or diastolic BP of ≥10 mm Hg have been reported. In 46% of these cases, the drop was ≥30/15 mm Hg.35
As compared to patients with PD, patients with MSA had significantly higher scores in the gastrointestinal, urinary, and cardiovascular domains. The pupillomotor domain did not exhibit any difference from controls, probably because there is only one question in the SCOPA‐AUT scale that addresses this domain. In a prospective study of 52 MSA patients and 29 PD patients by Lipp et al., Composite Autonomic Symptom Score (COMPASS), Composite Autonomic Severity Score (CASS), Thermoregulatory Sweat Test percent, as well as functional rating scales (UMSARS and H & Y grading) were used to attempt to make this differentiation.36 The authors concluded that it may be possible to distinguish between MSA and PD patients based on the above evaluation, and this would be significantly augmented if evaluation was repeated after 12 months given that MSA is characterized by more‐rapid and ‐severe progression of autonomic dysfunction. A prospective study by Swaminath et al. in 2010 assessed 150 PD patients and 31 MSA‐P patients and compared urinary and genital symptoms, and concluded that these complaints occur with less motor manifestations within 2 years of onset in MSA‐P, whereas in PD these occur along with more‐severe motor manifestations.37 In another study from the same institute, presence of orthostatic abnormalities within 1 year of motor onset favored MSA‐P over PD.38 Our patients of MSA‐P and PD were assessed at similar time points in the disease course. In our study, more‐severe complaints in gastrointestinal, urinary, and cardiovascular domains tend to favor MSA‐P over PD. Similar to our findings, subtle differences in cardiovagal baroreflex sensitivity and cold pressor test in patients with MSA and PD have been reported previously.39, 40
Statistical comparison between SCOPA‐AUT (total score) and motor severity scores, UMSARS part II, and MDS‐UPDRS part III did not show any statistical correlation. SCOPA‐AUT (total score) was also compared with duration and disease, but failed to reveal any correlation. These results suggest that autonomic dysfunction in MSA occurs independent of motor severity and duration of the disease, and therefore should be treated as a separate diagnostic and therapeutic target. However, we used age of first motor complaint as age of onset, given that it is these complaints that bring patients to clinical attention and are definitive. We acknowledge that this may have led to an underestimation of disease duration in patients who may have had autonomic dysfunction as a recognizable early feature predating motor complaint. This may explain the lack of correlation between autonomic symptomatology and disease duration in our study. However, the use of motor onset to define disease onset seems clinically appropriate.
The strength of our study is that it is among the largest studies in patients with MSA addressing this question. We also utilized a validated symptom‐based questionnaire targeting six major autonomic domains. The scale also permitted quantification, enabling an estimation of severity of autonomic symptoms. We also used objective autonomic testing measures.
Limitations of the study were that diagnosis of MSA and PD both were based on clinical criteria and none of these cases had pathological confirmation. We also restricted objective autonomic function testing to the cardiovascular domain. Other domains of autonomic function, including sudomotor testing (thermoregulatory sweat test, quantitative sudomotor axon reflex test distribution, and sympathetic skin response) and pupillography, were not performed. We also used SCOPA‐AUT, which, although validated for MSA, is not as detailed as some other clinical autonomic scales; hence, some symptom data may have been missed. In addition, as aforementioned, we used age of first motor complaint as age of onset, which may have introduced a bias in the assessment of disease duration.
Our study demonstrates that there are no differences in the autonomic symptomatology and cardiovascular autonomic functions between the two subtypes of MSA. This suggests that although different brain regions bear the brunt of motor disease, the autonomic nervous system is affected similarly in both subtypes. Orthostatic BP fall in our study was lower compared to other series and requires further evaluation. There were minor, but significant, differences in cardiovascular, urinary, and gastrointestinal complaints and HR changes in autonomic testing compared to patients with PD. Large patient numbers in our study may have definitively answered the question of differential autonomic involvement in the two subtypes of MSA.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
D.G.: 1A, 1B, 1C, 2A, 2B, 3A, 3B
A.K.S.: 1A, 1B, 2A, 2B, 3B
A.K.J.: 1A, 1B, 2A, 2C, 3B
R.R.: 1B, 2C, 3B
A.S.: 1C, 2A, 2B, 3B
A.K.P.: 1B, 2C, 3B
D.V.: 1B, 2C, 3B
G.S.: 1B, 2C, 3B
A.G.: 1B, 2C, 3B
R.M.P.: 1B, 2A, 2B, 2C, 3B
K.P.: 1A, 2C, 3B
Disclosures
Ethical Compliance Statement
The study was approved by the Ethics Committee of All India Institute of Medical Sciences, New Delhi vide reference number IECPG‐163/23.08.2017, RT‐28/07.09.2017. Informed written consent was obtained from all study participants. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest
The authors report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months
The authors declare that there are no disclosures to report.
Acknowledgements
We thank the participants for their time and effort.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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