Introduction
Methods
Literature search
Study population and data collection
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demographic data (i.e., sex; age at onset, baseline visit, and last available follow-up; disease duration to baseline visit and last available follow-up; and follow-up time);
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initial clinical features (divided into a motor, autonomic, or combined motor and autonomic symptomatic onset);
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presence of MSA motor or non-motor features and their associated treatment, including, among others:
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classic orthostatic hypotension (OH), defined as orthostatic blood pressure (BP) falls of ≥ 20 mmHg systolic BP or ≥ 10 mmHg diastolic BP within 3 min of active or passive orthostatic challenge [15];
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severe OH, defined as history of recurrent syncope and orthostatic BP falls ≥ 30 mmHg systolic BP or ≥ 15 mmHg diastolic BP [15];
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intake of central nervous system (CNS)-active drugs with BP-lowering side effects, including anti-depressants, benzodiazepines, anti-psychotics, opioids, and trazodone [16];
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comorbidities (presence of any cardio- and/or cerebrovascular disease, or diabetes mellitus).
Statistical analysis
Results
Literature review on sex-related differences in the clinical presentation and natural history of MSA
Comparison of the clinical-demographic characteristics of female and male individuals included in the Innsbruck MSA Registry
Sex-related differences in the clinical presentation at baseline visit
Clinical-demographic characteristics | Baseline visit | Last follow-up | ||||
---|---|---|---|---|---|---|
Total MSA cohort (n = 116) | Male MSA cohort (n = 60) | Female MSA cohort (n = 56) | Total MSA cohort (n = 116) | Male MSA cohort (n = 60) | Female MSA cohort (n = 56) | |
Sociodemographic data | ||||||
Age (years) | 60.9 [55.0; 68.5] | 64.0 [55.5; 70.6]* | 59.0 [53.2; 65.6]* | 64.3 [57.1; 71.3] | 66.5 [57.6; 72.9]* | 62.4 [56.8; 69.1]* |
Disease duration (months) | 30.9 [17.2; 48.2] | 29.3 [17.4; 45.8] | 34.8 [14.2; 53.5] | 61.8 [48.7; 83.8] | 54.4 [46.3; 70.4]* | 68.8 [56.1; 87.9]* |
Motor features and associated treatment | ||||||
Parkinsonism (n-BV = 58 M, 55 F; n-FU = 57 M, 56 F) | 86 (76.1) | 46 (79.3) | 40 (72.7) | 104 (92.0) | 50 (87.7) | 54 (96.4) |
Bradykinesia (n-FU = 59 M, 56 F) | 90 (77.6) | 48 (80.0) | 42 (75.0) | 107 (93.0) | 53 (89.8) | 54 (96.4) |
Rigidity (n-BV = 59 M, 55 F; n-FU = 58 M, 56 F) | 85 (74.6) | 45 (76.3) | 40 (72.7) | 101 (88.6) | 48 (82.8)* | 53 (94.6)* |
Tremor, any (n-BV = 59 M, 56 F) | 66 (57.4) | 35 (59.3) | 31 (55.4) | 68 (58.6) | 34 (56.7) | 34 (60.7) |
Postural instability (n-BV = 48 M, 49 F; n-FU = 52 M, 55 F) | 51 (52.6) | 23 (47.9) | 28 (57.1) | 95 (88.8) | 43 (82.7) | 52 (94.5) |
Cerebellar syndrome (n-BV = 58 M, 55 F; n-FU = 56 M; 53 F) | 52 (46.0) | 25 (43.1) | 27 (49.1) | 72 (66.1) | 36 (64.3) | 36 (67.9) |
Gait ataxia (n-BV = 60 M, 55 F; n-FU = 56 M, 53 F) | 57 (49.6) | 29 (48.3) | 28 (50.9) | 74 (67.9) | 38 (67.9) | 36 (67.9) |
Ataxic dysarthria (n-BV = 54 M, 52 F; n-FU = 47 M, 43 F) | 32 (30.2) | 14 (25.9) | 18 (34.6) | 46 (51.1) | 21 (44.7) | 25 (58.1) |
Limb ataxia (n-BV = 59 M, 55 F; n-FU = 59 M, 55 F) | 49 (43.0) | 24 (40.7) | 25 (45.5) | 68 (59.6) | 33 (55.9) | 35 (63.6) |
Cerebellar oculomotor dysfunction | 57 (49.1) | 34 (56.7)* | 23 (41.1)* | 88 (75.9) | 46 (76.7) | 42 (75.0) |
Postural abnormalities (n-BV = 58 M, 56 F; n-FU = 58 M, 56 F) | 28 (24.6) | 17 (29.3) | 11 (19.6) | 61 (53.5) | 31 (53.4) | 30 (53.6) |
Pyramidal tract signs (n-BV = 54 M, 51 F; n-FU = 56 M, 53 F) | 58 (55.2) | 27 (50.0) | 31 (60.8) | 61 (56.0) | 24 (42.9)* | 37 (69.8)* |
Dopaminergic treatment | 77 (66.4) | 42 (70.0) | 35 (62.5) | 89 (76.7) | 43 (71.7) | 46 (82.1) |
LEDD (mg) (n-BV = 41 M, 35 F; n-FU = 42 M, 46 F) | 600 [300; 975] | 583 [300; 947] | 600 [300; 1000] | 849 [481; 1244] | 800 [500; 1169] | 938 [400; 1286] |
Dopaminergic response (n-BV = 38 M, 28 F; n-FU = 48 M, 50 F) | ||||||
- No or poor | 12 (18.2) | 5 (13.2) | 7 (25.0) | 70 (71.4) | 39 (81.3)* | 31 (62.0)* |
- Moderate to good | 15 (22.7) | 9 (23.7) | 6 (21.4) | 1 (1.0) | 0 (0.0)* | 1 (2.0)* |
- Uncertain | 39 (59.1) | 24 (63.2) | 15 (53.6) | 27 (27.6) | 9 (18.7)* | 18 (36.0)* |
Rating scales | ||||||
Hoehn and Yahr stage (n-BV = 49 M, 45 F; n-FU = 56 M, 54 F) | 2.3 [2.0; 3.0] | 2.0 [2.0; 3.0] | 3.0 [2.0; 3.0] | 4.0 [3.0; 5.0] | 4.0 [2.0; 5.0] | 4.0 [4.0; 5.0] |
UMSARS Part IV score (n-BV = 42 M, 37 F) | 2.0 [2.0; 3.0] | 2.0 [2.0; 3.0]* | 2.0 [2.0; 3.0]* | 4.0 [3.0; 4.0] | 4.0 [3.0; 4.0] | 4.0 [3.0; 5.0] |
Non-motor features & associated treatment | ||||||
Classic OH (n-BV = 57 M, 52 F; n-FU = 58 M, 53 F) | 43 (39.4) | 26 (45.6) | 17 (32.7) | 84 (75.7) | 49 (84.5)* | 35 (66.0)* |
- Severe OH (n-BV = 58 M, 51 F; n-FU = 56 M, 53 F) | 34 (31.2) | 23 (39.7)* | 11 (21.6)* | 67 (61.5) | 41 (73.2)* | 26 (49.1)* |
- History of orthostatic syncope (n-BV = 60 M, 53 F; n-FU = 59 M, 54 F) | 26 (23.0) | 17 (28.3) | 9 (17.0) | 47 (41.6) | 30 (50.8)* | 17 (31.5)* |
- OH treatment, pharmacological and/or non-pharmacological | 36 (31.0) | 18 (30.0) | 18 (32.1) | 68 (58.6) | 38 (63.3) | 30 (53.6) |
- OH treatment, pressor agents | 26 (22.4) | 13 (21.7) | 13 (23.2) | 50 (43.1) | 29 (48.3) | 21 (37.5) |
- Supine hypertension (n-BV = 55 M, 49 F; n-FU = 53 M, 54 F) | 21 (20.2) | 12 (21.8) | 9 (18.4) | 45 (42.1) | 28 (52.8)* | 17 (31.5)* |
Neurogenic bladder disturbances (n-BV = 49 M, 46 F; n-FU = 53 M, 49 F) | 51 (53.7) | 26 (53.1) | 25 (54.3) | 93 (91.2) | 49 (92.5) | 44 (89.8) |
- Urinary incontinence (n-BV = 58 M, 56 F; n-FU = 57 M, 55 F) | 58 (50.9) | 31 (53.4) | 27 (48.2) | 93 (83.0) | 48 (84.2) | 45 (81.8) |
- Incomplete bladder emptying (n-BV = 44 M, 43 F; n-FU = 50 M, 42 F) | 37 (42.5) | 20 (45.5) | 17 (39.5) | 68 (73.9) | 39 (78.0) | 29 (69.0) |
- Overactive bladder symptoms (n-FU = 59 M, 55 F) | 78 (67.2) | 44 (73.3) | 34 (60.7) | 109 (95.6) | 58 (98.3) | 51 (92.7) |
- Catheterization (n-FU = 59 M, 56 F) | 16 (13.8) | 9 (15.0) | 7 (12.5) | 48 (41.7) | 29 (49.2)* | 19 (33.9)* |
Sexual dysfunction (n-BV = 30 M, 6 F; n-FU = 43 M, 17 F) | 31 (86.1) | 28 (93.3)* | 3 (50.0)* | 57 (95.0) | 43 (100)* | 14 (82.4)* |
Constipation (n-BV = 47 M, 46 F; n-FU = 50 M, 49 F) | 43 (46.2) | 22 (46.8) | 21 (45.7) | 75 (75.8) | 39 (78.0) | 36 (73.5) |
Stridor (n-BV = 16 M, 22 F; n-FU = 29 M, 25 F) | 8 (21.1) | 2 (12.5) | 6 (27.3) | 29 (53.7) | 15 (51.7) | 14 (56.0) |
Inspiratory sighs (n-BV = 14 M, 14 F; n-FU = 21 M, 21 F) | 8 (28.6) | 4 (28.6) | 4 (28.6) | 25 (59.5) | 12 (57.1) | 13 (61.9) |
Speaking/acting out dreams (n-BV = 44 M, 37 F; n-FU = 55 M, 51 F) | 51 (63.0) | 28 (63.6) | 23 (62.2) | 83 (78.3) | 41 (74.5) | 42 (82.4) |
Depression (n-BV = 57 M, 48 F; n-FU = 58 M, 48 F) | 49 (46.7) | 20 (35.1)* | 29 (60.4)* | 63 (59.4) | 24 (41.4)* | 39 (81.3)* |
Intake of CNS-active drugs with BP lowering side effects | 60 (51.7) | 23 (38.3)* | 37 (66.1)* | 77 (66.4) | 30 (50.0)* | 47 (83.9)* |
Comorbidities | ||||||
Cardiovascular disease | 41 (35.3) | 25 (41.7) | 16 (28.6) | 49 (42.2) | 31 (51.7)* | 18 (32.1)* |
Antihypertensive medication intake | 36 (31.0) | 21 (35.0) | 15 (26.8) | 39 (33.6) | 29 (48.3)* | 10 (17.9)* |
Diabetes mellitus (n-BV = 59 M, 56 F; n-FU = 59 M, 56 F) | 11 (9.6) | 7 (11.9) | 4 (7.1) | 12 (10.4) | 8 (13.6) | 4 (7.1) |
Outcome variable (i.e., clinical characteristic showing an association with female or male sex) | Covariate sex | Other covariates in the multivariable models | ||
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M/F | Odds ratio (95% CI) | p | ||
At baseline visit | ||||
Cerebellar oculomotor dysfunction (yes vs. no) | M | 2.7 (1.2–6.5) | 0.021* | Initial clinical feature: cerebellar symptomsb. At baseline visit: age; disease durationb |
Severe OH (yes vs. no) | M | 5.5 (1.4–21.9) | 0.016* | At baseline visit: age; disease duration; LEDD; intake of CNS-active drugs with BP lowering side effects; antihypertensive medication intakec |
Sexual dysfunction (yes vs. no) | M | 14 (1.6–120.1)a | 0.024* | At baseline visit: age; disease duration; depression; comorbidities (cardiovascular disease; diabetes mellitus) |
Depression (yes vs. no) | F | 4.7 (1.5–14.1) | 0.007* | At baseline visit: age; disease duration; UMSARS Part IV score; comorbidities (cardiovascular disease; diabetes mellitus) |
At last available follow-up | ||||
Pyramidal tract signs (yes vs. no) | F | 2.7 (1.2–6.2) | 0.019* | At last follow-up: age; disease duration; comorbidities (diabetes mellitus) |
Classic OH (yes vs. no) | M | 7.5 (1.5–37.8) | 0.014* | At last follow-up: age; disease duration; LEDD; intake of CNS-active drugs with BP-lowering side effects; antihypertensive medication intakec |
Severe OH (yes vs. no) | M | 11.1 (2.5–50.2) | 0.002* | At last follow-up: age; disease duration; LEDD; intake of CNS-active drugs with BP-lowering side effects; antihypertensive medication intake |
Supine hypertension (yes vs. no) | M | 3.0 (1.2–7.6) | 0.020* | At last follow-up: age; disease duration; OH treatment (pressor agents); antihypertensive medication intake |
Depression (yes vs. no) | F | 6.2 (2.3–16.4) | <0.001* | At last follow-up: age; disease duration; UMSARS Part IV score; comorbidities (cardiovascular disease; diabetes mellitus) |
Intake of CNS-active drugs with BP-lowering side effects (yes vs. no) | F | 4.1 (1.2–14.4) | 0.029* | At last follow-up: age; disease durationc; UMSARS Part IV scoreb; depressionb; speaking/acting out dreams |
Antihypertensive medication intake (yes vs. no) | M | 8.7 (2.4–32.2) | 0.001* | At last follow-up: age; disease duration; severe OH; supine hypertension; comorbidities (cardiovascular diseaseb) |
Change from baseline to last available follow-up | ||||
Antihypertensive medication intake (start yes vs. no) | M | 12.4 (1.5–99.1)a | 0.018* | Age at last follow-up; follow-up time New onset from baseline to follow-up of: severe OHb; supine hypertensionc; comorbidities (cardiovascular diseaseb) |
Sex-related differences in the clinical presentation at last available follow-up
Sex-related differences in the baseline to last follow-up changes in clinical presentation
Clinical presentation | Total MSA cohort (n = 116) | Male MSA cohort (n = 60) | Female MSA cohort (n = 56) | p (M vs. F) |
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Sociodemographic data | ||||
Follow-up time (months) | 27.0 [14.3; 41.8] | 25.5 [11.4; 39.1] | 29.8 [14.9; 47.2] | 0.193 |
Motor features & associated treatment | ||||
New onset of parkinsonism (n = 56 M; 55 F) | 19 (17.1) | 6 (10.7) | 13 (23.6) | 0.071* |
New onset of bradykinesia (n = 59 M; 56 F) | 18 (15.7) | 6 (10.2) | 12 (21.4) | 0.097* |
New onset of rigidity (n = 57 M; 55 F) | 19 (17.0) | 6 (10.5) | 13 (23.6) | 0.065* |
New onset of tremor, any (n = 59 M; 56 F) | 19 (16.5) | 8 (13.6) | 11 (19.6) | 0.380 |
New onset of postural instability (n = 46 M; 48 F) | 32 (34.0) | 15 (32.6) | 17 (35.4) | 0.774 |
New onset of cerebellar syndrome (n = 55 M; 52 F) | 19 (17.8) | 11 (20.0) | 8 (15.4) | 0.532 |
New onset of gait ataxia (n = 56 M; 52 F) | 17 (15.7) | 10 (17.9) | 7 (13.5) | 0.531 |
New onset of ataxic dysarthria (n = 47 M; 42 F) | 14 (15.7) | 8 (17.0) | 6 (14.3) | 0.723 |
New onset of limb ataxia (n = 58 M; 54 F) | 24 (21.4) | 12 (20.7) | 12 (22.2) | 0.843 |
New onset of cerebellar oculomotor dysfunction | 37 (31.9) | 16 (26.7) | 21 (37.5) | 0.211 |
New onset of postural abnormalities (n = 56 M; 56 F) | 32 (28.6) | 12 (21.4) | 20 (35.7) | 0.094* |
New onset of pyramidal tract signs (n = 51 M; 49 F) | 18 (18.0) | 7 (13.7) | 11 (22.4) | 0.256 |
Start of dopaminergic treatment | 17 (14.7) | 6 (10.0) | 11 (19.6) | 0.142 |
- Adjustment of LEDD (mg) (n = 46 M; 46 F) | 290.0 [-33.0; 490.0] | 195.0 [-92.5; 396.3] | 337.5 [1.8; 587.5] | 0.013* |
- Worsening of dopaminergic response (n = 38 M; 28 F) | 45 (68.2) | 29 (76.3) | 16 (57.1) | 0.098* |
Rating scales | ||||
Increase of Hoehn and Yahr, overall (n = 56 M; 54 F) | 89 (80.9) | 42 (75.0) | 47 (87.0) | 0.108 |
Increase of Hoehn and Yahr stage (n = 56 M; 54 F) | 2.0 [1.0; 3.0] | 1.0 [0.0; 3.0] | 2.0 [1.0; 3.0] | 0.120 |
- per year of follow-up (n = 56 M; 54 F) | 0.6 [0.3; 1.0] | 0.6 [0.0; 0.9] | 0.6 [0.4; 1.1] | 0.849 |
Increase of UMSARS Part IV, overall (n = 42 M; 37 F) | 61 (77.2) | 31 (73.8) | 30 (81.1) | 0.442 |
Increase of UMSARS Part IV score (n = 42 M; 37 F) | 1.0 [1.0; 2.0] | 1.0 [0.0; 2.0] | 2.0 [1.0; 2.0] | 0.327 |
- per year of follow-up (n = 42 M; 37 F) | 0.6 [0.3; 1.0] | 0.6 [0.0; 1.1] | 0.7 [0.4; 0.9] | 0.916 |
Non-motor features & associated treatment | ||||
New onset of classic OH (n = 56 M; 51 F) | 38 (35.5) | 21 (37.5) | 17 (33.3) | 0.653 |
- New onset of severe OH (n = 55 M; 49 F) | 29 (27.9) | 17 (30.9) | 12 (24.5) | 0.466 |
- New onset of history of orthostatic syncope (n = 59 M; 52 F) | 20 (18.0) | 13 (22.0) | 7 (13.5) | 0.241 |
- Start of OH treatment, pharmacological and/or non-pharmacological | 36 (31.0) | 20 (33.3) | 16 (28.6) | 0.580 |
- Start of OH treatment, pressor agents | 29 (25.0) | 18 (30.0) | 11 (19.6) | 0.198 |
- New onset of supine hypertension (n = 49 M; 48 F) | 19 (19.6) | 13 (26.5) | 6 (12.5) | 0.082* |
New onset of neurogenic bladder disturbances (n = 46 M; 43 F) | 29 (32.6) | 16 (34.8) | 13 (30.2) | 0.647 |
- New onset of urinary incontinence (n = 56 M; 55 F) | 36 (32.4) | 18 (32.1) | 18 (32.7) | 0.948 |
- New onset of incomplete bladder emptying (n = 40 M; 38 F) | 21 (26.9) | 10 (25.0) | 11 (28.9) | 0.694 |
- New onset of overactive bladder symptoms (n = 59 M; 55 F) | 32 (28.1) | 15 (25.4) | 17 (30.9) | 0.515 |
- Start of catheterization (n = 59 M; 56 F) | 34 (29.6) | 21 (35.6) | 13 (23.2) | 0.146 |
New onset of sexual dysfunction (n = 30 M; 6 F) | 2 (5.6) | 2 (6.7) | 0 (0) | 1.000 |
New onset of constipation (n = 42 M; 41 F) | 23 (27.7) | 13 (31.0) | 10 (24.4) | 0.504 |
New onset of stridor (n = 15 M; 18 F) | 2 (6.1) | 1 (6.7) | 1 (5.6) | 1.000 |
New onset of inspiratory sighs (n = 14 M; 13 F) | 2 (7.4) | 1 (7.1) | 1 (7.7) | 1.000 |
New onset of speaking/acting out dreams (n = 43 M; 37 F) | 11 (13.8) | 4 (9.3) | 7 (18.9) | 0.330 |
New onset of depression (n = 56 M; 43 F) | 15 (15.2) | 7 (12.5) | 8 (18.6) | 0.401 |
Start of CNS-active drugs with BP lowering side effects | 23 (19.8) | 11 (18.3) | 12 (21.4) | 0.676 |
Comorbidities | ||||
New onset of cardiovascular disease | 9 (7.8) | 6 (10.0) | 3 (5.4) | 0.493 |
Start of antihypertensive medication intake | 12 (10.3) | 11 (18.3) | 1 (1.8) | 0.004* |
New onset of diabetes mellitus (n = 59 M; 56 F) | 1 (0.9) | 1 (1.7) | 0 (0) | 1.000 |