ABSTRACT
Introduction
The overall frequency of postural abnormalities (PA) in Parkinson's disease (PD) is unknown. We evaluated the overall prevalence of PA and assessed the association with demographic and clinical variables.
Methods
For this multicenter, cross‐sectional study, consecutive PD outpatients attending 7 tertiary Italian centers were enrolled. Patients were evaluated and compared for the presence of isolated PA such as camptocormia, Pisa syndrome, and anterocollis and for combined forms (ie, camptocormia + Pisa syndrome) together with demographic and clinical variables.
Results
Of the total 811 PD patients enrolled, 174 (21.5%; 95% confidence interval [CI], 18.6%–24.3%) presented PA, 144 of which had isolated PA and 30 had combined PA. The prevalence of camptocormia was 11.2% (95% CI, 9%–13.3%), Pisa syndrome 8% (95% CI, 6.2%–9.9%), and anterocollis 6.5% (95% CI, 4.9%–8.3%). Patients with PA were more often male and older with longer disease duration, more advanced disease stage, more severe PD symptoms, a bradykinetic/rigid phenotype, and poorer quality of life. They were initially treated with levodopa, and more likely to be treated with a combination of levodopa and dopamine agonist, took a higher daily levodopa equivalent daily dose, and had more comorbidities. Falls and back pain were more frequent in PD patients with PA than in those without PA. Multiple logistic regression models confirmed an association between PA and male gender, older age, Hoehn and Yahr stage, and total Unified Parkinson's Disease Rating Scale score.
Conclusions
PA are frequent and disabling complications in PD, especially in the advanced disease stages.
Keywords: Parkinson's disease, camptocormia, Pisa syndrome, anterocollis, postural abnormalities
Postural abnormalities (PA) are disabling motor complications affecting patients with Parkinson's disease (PD) or atypical parkinsonism.1 The most common PAs are camptocormia (CC), Pisa syndrome (PS), and anterocollis (AC). They may occur either isolated (ie, CC, PS) or combined (ie, CC + PS, CC + AC) in different phases of disease; they interfere with activities of daily living and contribute to significant disability and falls.1, 2, 3, 4
The overall frequency of PA in PD is unknown. Previous studies have reported variable prevalence of each isolated PA. For instance, CC has been estimated to range from 3% to 17.7%; the variability results from the diagnosis of CC based on the angle of forward bending with cut‐off values between 15° and 45°.3 Different criteria have been applied to define AC either under the general term of “dropped head syndrome” or 45° of neck flexion.1 Based on a cut‐off of 10° of trunk lateroflexion,1 the prevalence of PS was estimated to be about 8.8% in a large population of PD patients involved in a multicenter observational study.5
A recent consensus study, using the angle and fulcrum of trunk flexion, defined the clinical criteria of lower CC (L1‐sacrum, hip flexion) with a forward‐bending angle ≥30° and for upper CC (C7 to T12‐L1) with a bending angle ≥45°.6 AC was defined as a forward flexion of the head and neck of at least 45°.1 None of these studies has reported the overall prevalence of PA in patients with PD nor compared isolated with combined PA. For the present study, we investigated the overall prevalence of isolated and combined PA using consensus‐based diagnostic criteria and assessed the relationship with demographic and clinical features in a large cohort of consecutive outpatients with PD. Our findings may be useful for identifying at‐risk patients and PA‐associated symptoms that could benefit from earlier therapeutic strategies.
Methods
Study Design and Eligibility Criteria
For this multicenter, cross‐sectional study, consecutive outpatients with PD attending 7 Italian (north and central Italy) tertiary centers for movement disorders were enrolled between March 7, 2018, and October 7, 2018, and underwent standardized clinical assessment; patients with 1 (isolated PA; ie, CC, PS) or more PA (combined; ie, CC + PS, CC + AC) underwent additional evaluations with an ad hoc questionnaire and specific physical assessments (Fig. 1).
Figure 1.
Study design. Flowchart illustrating how PD patients with PA were selected from the whole study population. PD, Parkinson's disease; PA, postural abnormalities; CC, camptocormia; PS, Pisa syndrome; AC, anterocollis.
PD was diagnosed according to the International Parkinson and Movement Disorder Society clinical diagnostic criteria.7 Exclusion criteria were the following: (1) coexistent neurological diseases known to negatively affect posture; (2) previous major spinal surgery, skeletal and/or muscle disease (eg, vertebral fractures, spondylodiscitis, inflammatory myopathy); (3) diagnosis of atypical parkinsonism (ie, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration);8 or (4) treatment with medications possibly leading to PA (neuroleptics other than clozapine or quetiapine and antiemetics, except for domperidone) in the 6 months prior to enrolment.
Patients were assessed on their usual drug treatment during the on phase at each center in a single session by the same neurologist expert in movement disorders and familiar with the assessment of PA, identified prior to study initiation. The following clinical and demographic variables were recorded: gender, age, body mass index, age at PD onset, disease duration (in years since diagnosis), modified Hoehn and Yahr scale to assess stage of disease, and the Unified Parkinson's Disease Rating Scale (UPDRS) parts I to IV to assess disease severity.9 We also evaluated PD phenotype (rigid akinetic, tremor dominant, or mixed type),10 laterality of motor symptoms at PD onset, clinical asymmetry calculated as the difference between the lateralized scores of UPDRS III items 20 to 26 (a difference ≥4 points was considered indicative of motor asymmetry),5 quality of life as measured with the Parkinson Disease Questionnaire 8, latency between PD onset and start of antiparkinsonian therapy, and pharmacological therapy at disease onset and at ongoing visit. First pharmacological therapy was retrospectively recorded from the patients’ charts (first neurological medical records) and the hospital database. Levodopa equivalent daily dose (LEDD) was calculated according to the established criteria.11 We recorded comorbidities (physical trauma, diabetes, heart diseases, hypertension, mental disorders, malignancies, obesity, cerebrovascular diseases, metabolic disorders), associated medical conditions (rheumatic diseases, arthrosis, otovestibular disorders, osteoporosis),5 occurrence of falls in the previous month,12 and the presence of back pain and its intensity quantified by means of the numeric rating scale graded from 0 (“no pain at all”) to 10 (“excruciating pain”).
In keeping with our previous methods,2, 6 trunk misalignment was measured using a wall goniometer and expressed in degrees. The patients underwent physical examination and were evaluated in standing position for at least 5 minutes before the PA was evaluated. CC was diagnosed in patients presenting with involuntary flexion of the spine during standing or walking and resolving in the supine position of at least 30° at the lumbar fulcrum (L1‐sacrum, hip flexion; ie, lower CC) and/or at least 45° at the thoracic fulcrum (C7 to T12‐L1; ie, upper CC).6 PS was diagnosed in patients presenting with lateral flexion of the trunk of at least 10° that could be almost completely reverted by passive mobilization or supine positioning.1, 5 AC was diagnosed in patients presenting with at least 45° of forward neck bending that could be reverted by passive mobilization or supine positioning.1 We also recorded latency to develop PA after PD onset, PA duration, pattern of PA onset (acute <1 month; subchronic ≥1 month <3 months; chronic ≥3 months) and its relationship with changes in drug regimen, awareness of trunk leaning by asking patients if they felt tilted forward and/or sideways, occurrence of sensory trick,5 and presence of head compensation, scoliosis, or striatal hand and foot deformities.4 Also, we recorded the direction and the side of PD symptoms onset and inclination in patients with PS.
The institutional review boards of the participating centers reviewed and approved the study protocol. All patients (or their guardians) were informed about the nature of the study and gave their written consent to participate (consent for research). Authorization has been obtained for disclosure (consent to disclose) of any recognizable persons in photographs. The study was registered at http://clinicaltrials.gov (NCT03573232).
Sample Size
A sample size of 778 patients was calculated using the simple asymptotic formula for confidence interval based on the normal approximation to the binomial. Assuming the highest estimated prevalence of CC in PD (18%),3 a precision of 2.7% and a drop‐out rate of 2%, the number of patients to be enrolled was at least 794.
Statistical Analysis
Missing data were explored. Absolute and relative frequencies were calculated for categorical data and tested by χ2 tests after checking the minimum acceptable number of expected frequencies (≥5). Nonnormality of continuous variables was checked by visual inspection of distribution and confirmed by Kolmogorov‐Smirnov tests. When several continuous variables were not normally distributed, the values were expressed as the means ± standard deviations and compared across groups by nonparametric Mann‐Whitney U tests or otherwise using t tests for independent samples. Unadjusted odds ratio (OR; 95% confidence interval [CI]) between PA and each sociodemographic and clinical characteristic was obtained by estimating a series of univariate logistic regression models with PA as the dependent variable and the sociodemographic and clinical features as the independent variables. An adjusted OR (95% CI) for all possible confounding effects was obtained by estimating a multiple logistic regression model with all sociodemographic and clinical features as the independent variables. Independent variables were chosen according to the results of exploratory analysis and clinical relevance. Sensitivity analyses were performed to check for robustness of results. All tests were bilateral at P < 0.05. Statistical analyses were performed using SPSS statistical software (version 20; IBM‐SPSS, Armonk, NY).
Results
Clinical Features of PD Patients
A total of 811 patients with PD met the eligibility criteria and entered the study (Fig. 1).
Clinical Features of PD Patients With PA
PA was detected in 174 patients (21.5%; 95% CI, 18.6%–24.3%): isolated PA in 144 and combined PA in 30. Among the patients with isolated PA, CC was present in 68, PS in 39, and AC in 37. CC + PS was present in 14, CC + AC in 4, PS + AC in 7, and a combination of all 3 PAs in 5 patients. Among the patients with 1 or more PA, CC was present in 91 (11.2%; 95% CI, 9%–13.3%; 75 upper type, 11 lower type, and 5 with both types), PS in 65 (8%; 95% CI, 6.2%–9.9%), and AC in 53 (6.5%; 95% CI, 4.9%–8.3%). No significant association between centers and PA was found (P = 0.377).
CC ranged from 30° to 45° to 90°, with an average of 52.7 ± 9.3° for the upper subtype, 39.9 ± 5.84° for the lower subtype, and 65 ± 15.81° and 40 ± 7.91° for concomitant upper/lower subtypes. CC appeared 53.4 ± 60.3 months after PD onset, with an average duration of 4.5 ± 4.2 years; the majority of patients (85.7%) developed CC in a chronic fashion.
PS ranged from 10° to 40°, with an average of 15.7 ± 8°. The proportion of patients leaning toward the more‐affected or less‐affected side was similar. PS appeared 80.9 ± 71.8 months after PD onset, with an average duration of 3.8 ± 2.9 years; the majority of patients (81.5%) developed PS in a chronic fashion.
AC ranged from 45° to 100°, with an average of 62.5 ± 14.8. AC appeared 81.5 ± 84.3 months after PD onset, with an average duration of 3.7 ± 5.3 years; the majority of patients (88.7%) developed AC in a chronic fashion.
The remaining clinical characteristics of patients with PA are presented in Table 1 and Table S1 (Figure S1).
Table 1.
Clinical features of PD patients with PA
| Combined PA | |||||||
|---|---|---|---|---|---|---|---|
| Variable | Patients With 1 or More PA | Total of PA | Isolated PA CC/PS/AC | CC + PS | CC + AC | PS + AC | CC + PS + AC |
| Patients, n (%) | 174 (21.5) | 68/39/37 | 14 | 4 | 7 | 5 | |
| Camptocormia, n | 91 | ||||||
| Degrees, mean (SD) | |||||||
| Upper | 52.67 (9.27) | 52.50 (8.37) | 48.33 (4.92) | 48.33 (5.77) | 71.25 (13.15) | ||
| Lower | 39.09 (5.84) | 37.78 (5.07) | 45 (7.07) | – | – | ||
| Upper & Lower | 65 (15.81) | 58.33 (10.41) | – | 90 | 60 | ||
| 40 (7.91) | 41.67 (7.64) | – | 45 | 30 | |||
| Pisa syndrome, n | 65 | ||||||
| Degrees, mean (SD) | 15.69 (7.90) | 13.46 (5.75) | 18.57 (8.86) | 13.57 (3.78) | 28 (11.51) | ||
| Fulcrum, range | T5–L5 | T5–L5 | T5–L3 | T8–L3 | T5–L3 | ||
| PS direction, n (%) | |||||||
| Right | 37 (56.9) | 24 (61.5) | 8 (57.1) | 2 (28.6) | 3 (60) | ||
| Left | 28 (43.1) | 15 (38.5) | 6 (42.9) | 5 (71.4) | 2 (40) | ||
| Side of PD symptoms at onset and PS inclination, n (%) | |||||||
| Ipsilateral | 27 (41.5) | 16 (41) | 3 (21.4) | 4 (57.1) | 4 (80) | ||
| Contralateral | 28 (43.1) | 19 (48.7) | 7 (50) | 1 (14.3) | 1 (20) | ||
| Bilateral onset | 10 (15.4) | 4 (10.3) | 4 (28.6) | 2 (28.6) | – | ||
| Anterocollis, n | 53 | ||||||
| Degrees, mean (SD) | 62.55 (14.86) | 59.32 (12.31) | 63.75 (17.97) | 66.43 (12.82) | 80 (22.64) | ||
The total number of PA is 174 provided by the sum of isolated and combined PA.
PD, Parkinson's disease; PA, postural abnormalities, including CC, PS, and AC; Isolated PA, means patients with only CC or PS or AC; Combined PA, means patients with 2 or more PA; CC, camptocormia; PS, Pisa syndrome; AC, anterocollis; SD, standard deviation; Total, total number of patients with PA.
Comparison of Demographic and Clinical Features Between PD Patients With and Without PA
Patients with PA were more often male, older, with longer disease duration and more severe disease, a bradykinetic/rigid phenotype, with less clinical asymmetry, and worse quality of life when compared with patients without PA. Moreover, patients with PA took mainly levodopa (l‐dopa) as a first pharmacological therapy, a higher LEDD, and more often combined l‐dopa and dopamine‐agonist therapy and were more likely to have comorbidities. The frequency of falls and intense back pain was higher in patients with PA (Table 2).
Table 2.
Comparison of the demographic and clinical features of PD patients without and with PA
| Variable | All Patients | Without PA | With PA | Without vs. With PA P Value* |
|---|---|---|---|---|
| Patients, n | 811 | 637 | 174 | |
| Gender, n (%) | 0.003 | |||
| Male | 445 (54.9) | 332 (52.1) | 113 (64.9) | |
| Female | 366 (45.1) | 305 (47.9) | 61 (35.1) | |
| Age, y, mean (SD) | 69.89 (9.88) | 68.87 (10.20) | 73.61 (7.55) | <0.0005 |
| Body mass index, mean (SD) | 25.79 (4.02)a | 25.83 (4.08) | 25.64 (3.78) | 0.869 |
| Age at PD onset, y, mean (SD) | 62.56 (10.71) | 62.29 (10.86) | 63.56 (10.12) | 0.216 |
| Disease duration, y, mean (SD) | 6.92 (5.46) | 6.22 (4.65) | 9.51 (7.19) | <0.0005 |
| Modified H&Y stage, mean (SD) | 2.24 (0.92) | 2.07 (0.85) | 2.85 (0.91) | <0.0005 |
| Modified H&Y stage, n (%) | <0.0005 | |||
| 1 | 138 (17) | 133 (20.9) | 5 (2.9) | |
| 1.5 | 44 (5.4) | 39 (6.1) | 5 (2.9) | |
| 2 | 362 (44.6) | 306 (48) | 56 (32.2) | |
| 2.5 | 56 (6.9) | 46 (7.2) | 10 (5.7) | |
| 3 | 101 (12.5) | 54 (8.5) | 47 (27) | |
| 4–5 | 110 (13.6) | 59 (9.3) | 51 (29.3) | |
| UPDRS total score on state, mean (SD) | 42.54 (24.73)b | 37.17 (21.74) | 62.18 (25.12) | <0.0005 |
| I | 5.29 (5.67)b | 4.47 (4.98) | 8.27 (6.91) | <0.0005 |
| II | 11 (7.85)b | 9.26 (6.82) | 17.39 (8.09) | <0.0005 |
| III | 24.58 (13.50) | 21.97 (12.21) | 34.11 (13.72) | <0.0005 |
| III, right | 8.04 (5.61) | 7.55 (5.47) | 9.83 (5.77) | <0.0005 |
| III, left | 7.97 (5.52) | 7.25 (5.27) | 10.63 (5.60) | <0.0005 |
| IV | 1.65 (2.77) | 1.48 (2.61) | 2.24 (3.21) | 0.005 |
| Dominant phenotype, n (%) | 0.001 | |||
| Tremor type | 236 (29.1) | 205 (32.2) | 31 (17.8) | |
| Bradykinetic/rigid type | 340 (41.9) | 254 (39.9) | 86 (49.4) | |
| Mixed type | 235 (29) | 178 (27.9) | 57 (32.8) | |
| Laterality of PD symptoms onset, n (%) | 0.389 | |||
| Right | 417 (51.4) | 333 (52.3) | 84 (48.3) | |
| Left | 304 (37.5) | 238 (37.4) | 66 (37.9) | |
| Bilateral | 90 (11.1) | 66 (10.3) | 24 (13.8) | |
| Clinical asymmetry, n (%) | <0.0005 | |||
| Yes | 478 (58.9) | 397 (62.3) | 81 (46.6) | |
| No | 333 (41.1) | 240 (37.7) | 93 (53.4) | |
| PDQ‐8, mean (SD) | 22.83 (18.92)c | 19.47 (17.48) | 34.76 (19.06) | <0.0005 |
| Latency between PD onset and drug introduction, y, mean (SD) | 1.07 (2.05)d | 1.04 (1.94) | 1.17 (2.41) | 0.734 |
| First pharmacological therapy, n (%) | 0.02 | |||
| l‐dopa monotherapy | 347 (43.6)d | 273 (43.4) | 74 (44.3) | |
| DA monotherapy | 241 (30.3) | 189 (30) | 52 (31.1) | |
| l‐dopa + DAs | 29 (3.6) | 17 (2.7) | 12 (7.2) | |
| Other antiparkinsonian drugs | 179 (22.5) | 150 (23.9) | 29 (17.4) | |
| Ongoing pharmacological therapy, n (%) | 0.506 | |||
| l‐dopa monotherapy | 216 (26.7)b | 172 (27) | 44 (25.3) | |
| DA monotherapy | 39 (4.8) | 34 (5.3) | 5 (2.8) | |
| l‐dopa + DAs | 106 (13.1) | 81 (12.8) | 25 (14.4) | |
| Other antiparkinsonian drugs | 449 (55.4) | 349 (54.9) | 100 (57.5) | |
| l‐dopa equivalent daily dose, mg, mean (SD) | 553.91 (325.93)e | 516.32 (303.58) | 693.06 (366.65) | <0.0005 |
| Comorbidities, n (%) | 0.01 | |||
| Yes | 534 (65.9)b | 407 (63.9) | 127 (73.4) | |
| No | 276 (34.1) | 230 (36.1) | 46 (26.6) | |
| Associated medical conditions, n (%) | 0.079 | |||
| Yes | 332 (41)b | 251 (39.4) | 81 (46.8) | |
| No | 478 (59) | 386 (60.6) | 92 (53.2) | |
| Falls, mean (SD) | 0.48 (2.16) | 0.35 (1.97) | 0.95 (2.72) | <0.0005 |
| Back pain, n (%) | <0.0005 | |||
| Yes | 257 (31.7) | 176 (27.6) | 81 (46.6) | |
| No | 554 (68.3) | 461 (72.4) | 93 (53.4) | |
| VAS back pain, mean (SD) | 5.65 (2.18) | 5.32 (2.19) | 6.38 (1.98) | <0.0005 |
Total missing cases are reported as follows: a = 3, b = 1, c = 18, d = 15, e = 7. l‐dopa = l‐dopa + carbidopa, l‐dopa + carbidopa extended release, l‐dopa + benserazide, l‐dopa + benserazide extended release, melevodopa + carbidopa. DA = pramipexole, pramipexole extended release, ropinirole, ropinirole extended release, rotigotine, pergolide, cabergoline, apomorphine. Other antiparkinsonian drugs = anticholinergics, Monoamine oxidase type B (MAO‐B) inhibitors, amantadine, tolcapone; Bold values indicate significant values.
Nonparametric Mann‐Whitney U test for continuous variables; χ2 for categorical variables.
PD, Parkinson's disease; PA, postural abnormalities, including patients with camptocormia, Pisa syndrome, and anterocollis; SD, standard deviation; H&Y, Hoehn and Yahr; UPDRS = Unified Parkinson's Disease Rating Scale; PDQ‐8, Parkinson's Disease Questionnaire–8; l‐dopa, levodopa; DA, dopamine agonist; NRS, Numeric Rating Scale.
Clinical and Demographical Variables Associated With PA
The univariate logistic regression model yielded a significant association of PA with many of the investigated clinical and demographic features (Table 3). After adjusting for all variables in the model, multivariate logistic regression analysis confirmed the previous associations with the following variables: male gender (adjusted OR, 2.05; 95% CI, 1.33–3.16), older age (adjusted OR, 1.05; 95% CI, 1.02–1.07), modified Hoehn and Yahr stage (adjusted OR, 1.41; 95% CI, 1.05–1.90), and UPDRS total score (adjusted OR, 1.03; 95% CI, 1.01–1.04).
Table 3.
Clinical and demographic variables associated with postural abnormalities
| Unadjusted | Adjusted | ||||||
|---|---|---|---|---|---|---|---|
| Independent Variable | Total Sample | OR | 95% CI | P Value | OR | 95% CI | P Value |
| Patients, n | 811 | ||||||
| Sex, males vs. femalesa | 811 | 1.70 | 1.20–2.41 | 0.003 | 2.05 | 1.33–3.16 | 0.001 |
| Body mass index | 808 | 0.99 | 0.95–1.03 | 0.57 | 1.01 | 0.96–1.06 | 0.71 |
| Age, y | 811 | 1.06 | 1.04–1.08 | <0.0005 | 1.05 | 1.02–1.07 | 0.001 |
| Disease duration, y | 811 | 1.10 | 1.07–1.14 | <0.0005 | 0.98 | 0.93–1.03 | 0.36 |
| Modified H&Y stage | 811 | 2.43 | 2.01–2.94 | <0.0005 | 1.41 | 1.05–1.90 | 0.02 |
| UPDRS total during the on state | 810 | 1.04 | 1.03–1.05 | <0.0005 | 1.03 | 1.01–1.04 | <0.0005 |
| Dominant phenotype | 811 | ||||||
| Tremor type vs. bradykinetic/rigid typea | 0.45 | 0.28–0.70 | <0.0005 | 0.65 | 0.37–1.14 | 0.13 | |
| Mixed type vs. bradykinetic/rigid typea | 0.95 | 0.64–1.39 | 0.77 | 1.17 | 0.73–1.89 | 0.51 | |
| Laterality of PD symptoms onset | 811 | ||||||
| Left vs. righta | 1.10 | 0.76–1.58 | 0.61 | 1.12 | 0.71–1.75 | 0.63 | |
| Bilateral vs. righta | 1.44 | 0.85–2.44 | 0.17 | 0.83 | 0.43–1.62 | 0.59 | |
| Clinical asymmetry, yes vs. no | 811 | 0.53 | 0.37–0.74 | <0.0005 | 0.70 | 0.45–1.09 | 0.11 |
| PDQ–8 | 793 | 1.04 | 1.03–1.05 | <0.0005 | 1.01 | 0.99–1.02 | 0.10 |
| Latency between PD symptom onset and drug introduction, y | 796 | 1.03 | 0.95–1.11 | 0.47 | 1.02 | 0.93–1.12 | 0.70 |
| First pharmacological therapy, n (%) | 796 | ||||||
| DA monotherapy vs. l‐dopa monotherapya | 1.01 | 0.68–1.51 | 0.94 | 1.36 | 0.79–2.34 | 0.26 | |
| LD + DAs vs. l‐dopa monotherapya | 2.60 | 1.19–5.69 | 0.016 | 1.75 | 0.67–4.54 | 0.25 | |
| Other antiparkinsonian drugs vs. l‐dopa monotherapya | 0.71 | 0.44–1.14 | 0.16 | 1.02 | 0.56–1.88 | 0.94 | |
| Ongoing pharmacological therapy | 810 | ||||||
| DA monotherapy vs. l‐dopa monotherapya | 0.57 | 0.21–1.56 | 0.27 | 0.91 | 0.27–3.11 | 0.88 | |
| LD + DAs vs. l‐dopa monotherapy^ | 1.21 | 0.69–2.11 | 0.51 | 1.35 | 0.63–2.87 | 0.43 | |
| Other antiparkinsonian drugs vs. l‐dopa monotherapya | 1.12 | 0.75–1.67 | 0.58 | 1.47 | 0.83–2.63 | 0.18 | |
| l‐dopa equivalent daily dose, mean (SD), mg | 804 | 1.01 | 1.01–1.02 | <0.0005 | 1.00 | 1.00–1.00 | 0.17 |
| Comorbidities, yes vs. noa | 810 | 1.56 | 1.07–2.27 | 0.020 | 0.97 | 0.60–1.55 | 0.89 |
| Associated medical conditions, yes vs. noa | 810 | 1.35 | 0.96–1.90 | 0.07 | 0.79 | 0.51–1.23 | 0.31 |
| Back pain, yes vs. noa | 811 | 2.28 | 1.62–3.22 | <0.0005 | 1.35 | 0.87–2.09 | 0.18 |
l‐dopa = l‐dopa + carbidopa, l‐dopa + carbidopa extended release, l‐dopa + benserazide, l‐dopa + benserazide extended release, melevodopa + carbidopa. DA = pramipexole, pramipexole extended release, ropinirole, ropinirole extended release, rotigotine, pergolide, cabergoline, apomorphine. Other antiparkinsonian drugs = anticholinergics, Monoamine oxidase type B (MAO‐B) inhibitors, amantadine, tolcapone. Significant associations at P < 0.05; Bold indicates significant values.
Reference category.
OR, odds ratio; CI, confidence interval; H&Y, Hoehn and Yahr; UPDRS, Unified Parkinson's Disease Rating Scale; PD, Parkinson disease; PDQ‐8 = Parkinson's Disease Questionnaire–8; l‐dopa, levodopa; DA, dopamine agonist; SD, standard deviation.
Comparison of Demographic and Clinical Features of PD Patients With Combined PA and Pure PA
Patients with combined PA had a more advanced stage of disease, more severe symptoms, and an onset of PD symptoms more often affecting the right side (Table 4).
Table 4.
Comparison of the demographic and clinical features of PD patients with combined and isolated PA
| Variable | Combined PA | Isolated PA | Combined vs. Isolated P Value* |
|---|---|---|---|
| Patients, n | 30 | 144 | |
| Gender, n (%) | 0.29 | ||
| Male | 22 (73.3) | 91 (63.2) | |
| Female | 8 (26.7) | 53 (36.8) | |
| Age, y, mean (SD) | 73.40 (7.79) | 73.65 (7.53) | 0.92 |
| Body mass index, mean (SD) | 26.17 (4.59) | 25.52 (3.60) | 0.40 |
| Age at PD onset, y, mean (SD) | 61.50 (10.79) | 63.99 (9.96) | 0.23 |
| Disease duration, y, mean (SD) | 11.43 (7.27) | 9.10 (7.13) | 0.06 |
| Modified H&Y stage, mean (SD) | 3.25 (0.89) | 2.77 (0.89) | 0.01 |
| Modified H&Y stage, n (%) | 0.15 | ||
| 1 | 0 | 5 (3.5) | |
| 1.5 | 1 (3.3) | 4 (2.8) | |
| 2 | 6 (20) | 50 (34.7) | |
| 2.5 | 0 | 10 (6.9) | |
| 3 | 9 (30) | 38 (26.4) | |
| 4‐5 | 14 (46.6) | 37 (25.7) | |
| UPDRS total score on state, mean (SD) | 79.03 (30.63) | 58.67 (22.38) | 0.001 |
| I | 12.10 (8.44) | 7.47 (6.29) | 0.004 |
| II | 22.97 (9.66) | 16.23 (7.25) | <0.0005 |
| III | 40.33 (14.65) | 32.81 (13.21) | 0.008 |
| III, right | 10.93 (5) | 9.59 (5.90) | 0.15 |
| III, left | 12.47 (5.44) | 10.24 (5.58) | 0.03 |
| IV | 3.63 (4.21) | 1.95 (2.89) | 0.04 |
| Dominant phenotype, n (%) | 0.111 | ||
| Tremor type | 4 (13.3) | 27 (18.8) | |
| Bradykinetic/rigid type | 20 (66.7) | 66 (45.8) | |
| Mixed type | 6 (20) | 51 (35.4) | |
| Laterality of PD symptoms onset, n (%) | 0.018 | ||
| Right | 12 (40) | 72 (50) | |
| Left | 9 (30) | 57 (39.6) | |
| Bilateral | 9 (30) | 15 (10.4) | |
| Clinical asymmetry, n (%) | 0.23 | ||
| Yes | 11 (36.7) | 70 (48.6) | |
| No | 19 (63.3) | 74 (51.4) | |
| PDQ‐8, mean (SD) | 40.75 (18.99) | 33.52 (18.90) | 0.05 |
| Latency between PD onset and drug introduction, y, mean (SD) | 1.22 (2.39) | 1.16 (2.42) | 0.69 |
| First pharmacological therapy, n (%) | 0.142 | ||
| l‐dopa monotherapy | 11 (36.7) | 63 (46) | |
| DA monotherapy | 8 (26.7) | 44 (32.1) | |
| l‐dopa + DAs | 5 (16.7) | 7 (5.1) | |
| Other antiparkinsonian drugs | 6 (20) | 23 (16.8) | |
| Ongoing pharmacological therapy, n (%) | 0.65 | ||
| l‐dopa monotherapy | 9 (30) | 35 (24.3) | |
| DA monotherapy | 0 | 5 (3.5) | |
| l‐dopa + DAs | 5 (16.7) | 20 (13.9) | |
| Other antiparkinsonian drugs | 16 (53.3) | 84 (58.3) | |
| l‐dopa equivalent daily dose, mg, mean (SD) | 809.550 (393.09) | 668.272 (357.35) | 0.05 |
| Comorbidities, n (%) | 0.07 | ||
| Yes | 26 (86.7) | 101 (70.6) | |
| No | 4 (13.3) | 42 (29.4) | |
| Associated medical conditions, n (%) | 0.43 | ||
| Yes | 16 (53.3) | 65 (45.5) | |
| No | 14 (46.7) | 78 (54.5( | |
| Falls, mean (SD) | 1.70 (5.54) | 0.80 (1.61) | 0.85 |
| Back pain, n (%) | 0.67 | ||
| Yes | 15 (50) | 66 (45.8) | |
| No | 15 (50) | 78 (54.2) | |
| VAS back pain, mean (SD) | 6.60 (1.80) | 6.33 (2.02) | 0.51 |
l‐dopa = l‐dopa + carbidopa, l‐dopa + carbidopa extended release, l‐dopa + benserazide, l‐dopa + benserazide extended release, melevodopa + carbidopa. DA = pramipexole, pramipexole extended release, ropinirole, ropinirole extended release, rotigotine, pergolide, cabergoline, apomorphine. Other antiparkinsonian drugs = anticholinergics, MAO‐B inhibitors, amantadine, tolcapone. PA includes patients with camptocormia, Pisa syndrome, and anterocollis; Bold indicates significant values.*Nonparametric Mann‐Whitney U test or t test for independent samples for continuous variables; χ2 for categorical variables.
PA, postural abnormalities; PD, Parkinson's disease; H&Y, Hoehn and Yahr; SD, standard deviation; UPDRS = Unified Parkinson's Disease Rating Scale; PDQ‐8, Parkinson's Disease Questionnaire–8; l‐dopa, levodopa; DA, dopamine agonist; NRS, Numeric Rating Scale.
Discussion
In this multicenter, cross‐sectional study involving 811 consecutive outpatients with PD, 174 presented PA (overall prevalence 21.5%). The total PA prevalence was less than the sum of each PA frequency because some individuals had more than 1 PA (isolated in 144 and combined in 30).
Patients with PA were more often male, older, with longer disease duration and more advanced disease stage, more severe symptoms as assessed by UPDRS, a bradykinetic/rigid phenotype, and poorer quality of life. They were more likely to be under l‐dopa as first therapy, take a higher LEDD, and have more comorbidities. Moreover, falls and back pain were more frequent, with greater pain intensity in patients with PA than in those without PA. Finally, the patients with combined PA had a more advanced stage of disease, more severe symptoms, and fewer right‐side symptoms at PD onset than those with isolated PA.
This is the first study to estimate the overall prevalence of isolated and combined PA and to assess the association with demographic and clinical variables using consensus‐based diagnostic criteria. Previous studies exploring the prevalence of isolated PA showed a wide variability especially for CC (from 3% to 17.7%) because of the different criteria used, particularly the cut‐off values for degrees, which were either not reported sometimes or varied from 15° to 45°.3 Furthermore, these studies did not differentiate between upper and lower CC. Using the recent consensus‐based criteria, we found that 91 patients (11.2%) presented CC (75 upper CC, 11 lower CC, and 5 with both types), 68 of which with isolated CC and 23 with combined CC. The higher frequency of upper CC might be related to the progression of thoracic kyphosis, which is often increased in the elderly.13
The PS prevalence of 8% in our study is consistent with a recent multicenter Italian study that reported a prevalence of 8.8%,5 and the prevalence of AC (6.5%) was similar to that reported previously.14
The patients with PA were mainly men, older, with more severe disease by Hoehn and Yahr staging, and more severe parkinsonian symptoms. Multivariate logistic regression confirmed these associations that, although close to 1, suggested that patients with severe symptoms and with more advanced PD stages are more likely to develop PA. These findings extend the results reported in some previous studies that assessed isolated CC and PS5, 15, 16, 17, 18, 19 and reported that PA are associated with male gender and severe PD phenotype, but not directly dependent on dopaminergic therapy. The association of poor quality of life with PA in our cohort supports its clinical effect as a motor manifestation of PD; however, this was not confirmed by multivariate logistic regression analysis, indicating that PA might not be the principal determinant of poor quality of life but, rather, one among other contributing factors.1
Regarding exposure to dopaminergic drugs, patients with PA were treated first with l‐dopa and higher LEDD, more often in a combination of l‐dopa and dopamine agonist, likely because of a more advanced disease stage. Nevertheless, this association did not survive the multivariate logistic regression analysis, which suggests that long‐term treatment with dopaminergic drugs at high dosages is not the only factor that contributes to causing PA despite previous findings for a link between dopaminergic replacement therapy and CC,20, 21 PS,5 , 22, 23, 24, 25 26 and AC.20, 32 27, 28, 29, 30, 31In particular, the discontinuation of the dopamine agonists was associated with resolution of the PA.22, 24, 26, 31
We also found that patients with PA were frequently affected by comorbidities preceding or following PA onset: physical trauma, diabetes, heart diseases, hypertension, and mental disorders among others. Yamane and colleagues33 showed that patients with PD and CC more often have deep venous thrombosis of the lower extremities than those with PD without CC (17% vs. 4%, respectively); we did not explore this association. Associated medical conditions may predispose to PA and increase the likelihood of developing PS,5 according to a previous study, but we found no significant difference.
Back pain was more frequent (46%) and more intense in the PD patients with PA who were also more likely to report falls. This observation is shared by previous studies that reported that PA are associated with increased probability of pain and falling, along with a fall history, greater disease severity, and longer disease duration.2, 34, 35, 36 However, this might point toward an involvement of brainstem structures that have a role in the physiology of axial control, as hypothesized for camptocormia, which has been linked to oculomotor37 and sleep38 impairment as well as atrophic changes in the axial surface of the midbrain.39
The present study has several limitations. Although this was not a population‐based study, we corrected for a bias in case selection by recruiting all consecutive patients with PD who met the eligibility criteria during the study period. Our case population had clinical and demographic features similar to other clinical and population‐based series5 and was representative of the spectrum of PD in the population. As a study conducted in tertiary centers for movement disorders, which tend to have a selected case mix with above‐average phenotypical severity when compared with the spectrum of PD in the population, our survey probably overestimated the frequency of PA. The frequency of patients with PA were, however, comparable with those reported in previous series.1, 2, 3
Because of the cross‐sectional design of our study and the lack of laboratory tests, we were unable to accurately determine the timing of PA onset, the relationship with drug schedule change, or the efficacy of any treatment, and we could not speculate on the pathophysiologic mechanisms underpinning PA in PD. Moreover, we did not include healthy age‐matched controls or patients with PA from other causes. Finally, because of the large study sample, we were unable to perform cognitive assessments or evaluate whether patients with cognitive impairment were more likely to develop PA.
These limitations notwithstanding, our findings indicate that PA are frequent and disabling motor complications in PD, especially in older patients with severe parkinsonian symptoms and advanced disease stages. Our explorative analysis suggests that patients with combined PA (2 or more PA) have a more advanced stage of disease and a more severe impairment than patients with isolated PA (only 1).
Overall, our findings extend in different ways the results reported in previous studies.First, previous studies investigated the prevalence of each isolated PA and reported variable results because of methodological reasons; we used well‐defined consensus criteria for the definition of PA in a large population of PD. Second, we report the overall frequency, prevalence, and associated factors of different PA, either isolated and/or combined. Third, our explorative analysis suggests the importance of combined forms of PA in which motor impairment in the PD population is more severe. Finally, fourth, we report for the first time the prevalence and the association between demographic and clinical variables of 2 different types of camptocormia (upper and lower): the upper type is more frequent (relevant for interventional studies). The results of this study need to be further investigated in longitudinal studies to advance our understanding of the pathophysiologic mechanisms of PA in PD and identify at‐risk patients who may benefit from specific treatment strategies.
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.
M.T.: 1A, 1B, 1C, 2A, 2B, 2C, 3A
C.G.: 1A, 1B, 1C, 2A, 2B, 2C, 3A
M.G.: 1A, 1B, 1C, 2A, 2C, 3B
R.C.: 1A, 1B, 1C, 2A, 2C, 3B
A.F.: 1A, 1B, 1C, 2A, 2C, 3B
M.C.: 1B, 1C, 2C, 3B
E.A.: 1B, 1C, 2C, 3B
M.G.C.: 1B, 1C, 2C, 3B
L.B.: 1B, 1C, 2C, 3B
M.O.: 1B, 1C, 2C, 3B
M.V.: 1B, 1C, 2C, 3B
M.C.: 1B, 1C, 2C, 3B
P.P.: 1B, 1C, 2C, 3B
C.B.: 1B, 1C, 2C, 3B
S.M.: 1B, 1C, 2C, 3B
S.G.: 1B, 1C, 2C, 3B
N.S.: 1B, 1C, 2C, 3B
S.T.: 1B, 1C, 2C, 3B
L.V.: 1B, 1C, 2C, 3B
F.S.: 1B, 1C, 2C, 3B
F.G.R.: 1B, 1C, 2C, 3B
C.A.A.: 1B, 1C, 2C, 3B
M.Z.: 1B, 1C, 2C, 3B
L.L.: 1B, 1C, 2C, 3B
Disclosures
Ethical Compliance Statement
The institutional review boards of the participating centers reviewed and approved the protocol of this study (approval number Prog.1655CESC). All patients (or their guardians) were informed about the nature of the study and gave their written consent to participate (consent for research). Authorization has been obtained for disclosure (consent to disclose) of any recognizable persons in photographs. The study was registered at http://clinicaltrials.gov (NCT03573232). 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 Conflict of Interest
Financial support for the study was provided by the Brain Research Foundation Verona O.N.L.U.S. All authors report no disclosures and no conflict of interests.
Financial Disclosures for the previous 12 months
M.T. reports grants from University of Verona, grants from Verona Brain Research Foundation, grants from Cattolica Foundation, personal fees from UCB Pharma, grants and personal fees from Zambon, personal fees from Lundbeck, personal fees from Abbvie, and personal fees from Movement Disorders Society. M.G. reports no disclosures. R.C. has received speaker fees from AbbVie, General Electric, Zambon. M.C., E.A., and M.G.C. report no disclosures. L.B. has received speaker fees from GE Healthcare, received fundings from Mentis Cura AS, Oslo, Norway. M.O. has served on the scientific advisory boards of GlaxoSmithKline, Novartis, Lundbeck, Eisai, Valeant, Medtronic, and Newron; has received speaker honoraria from Zambon, the World Parkinson Congress, the Movement Disorder Society, and the Atypical Dementias congress; was an invited guest and lecturer for the Mental Disorders in Parkinson Disease Congress; serves on the editorial board of Medicine (Baltimore); has been employed as a speaker for Boehringer Ingelheim, GlaxoSmithKline, UCB, and Zambon; and has received research support from the Italian Ministry of Health and the Italian Ministry of Education. M.V., M.C., P.P., C.B., S.M., S.G., and N.S. report no disclosures. S.T. has received lecture honoraria from Abbvie and Pfizer, support for educational activities from FB Health and Pfizer, and travel grants from CSL Behring. L.V. has received lecture honoraria from Zambon, UCB and Chiesi. F.S. reports honoraria and consulting fees from UCB, Chiesi, Zambon, Britannia, Biogen, Boehringer Ingelheim, Lundbeck, Orion Novartis, Sunovion, Synagile, Teva, Newron, Merck Serono, and Pfizer. F.G.R. has received lecture honoraria from European Parkison Disease Association. C.A.A. has received travel grants from Zambon and Abbvie. M.Z. has received speaker's honoraria from Medtronic, Lundbeck, UCB Pharma, and AbbVie. L.L. has received honoraria for lecturing and travel grants from, UCB Pharma, AbbVie, DOC, Zambon and Bial. A.F. received honoraria for consultancies from Abbvie, Medtronic, Boston Scientific, Sunovion, Chiesi farmaceutici, UCB, and Ipsen; honoraria for participation in advisory boards from Abbvie, Boston Scientific, and Ipsen; research grants from University of Toronto, Weston Foundation, Abbvie, Medtronic, and Boston Scientific. C.G. received a grant from Verona Brain Research Foundation.
Supporting information
Figure S1. Patients with isolated and combined postural abnormalities (PA). Examples of isolated (A, B, C, D) and combined (E) PA in Parkinson's disease. A, upper CC 60°; B, lower CC 30°; C, PS 30°; D, AC 80°; E, upper CC 55° and PS 20°.
Table S1. Clinical features of Parkinson's disease patients with postural abnormalities.
Acknowledgments
We thank for their assistance with data collection Salvatore Bonvegna (University of Messina, Messina, Italy) and Roberta Telese (Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti‐Pescara, Chieti‐Pescara, Italy).
Relevant disclosures and conflicts of interest are listed at the end of this article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. Patients with isolated and combined postural abnormalities (PA). Examples of isolated (A, B, C, D) and combined (E) PA in Parkinson's disease. A, upper CC 60°; B, lower CC 30°; C, PS 30°; D, AC 80°; E, upper CC 55° and PS 20°.
Table S1. Clinical features of Parkinson's disease patients with postural abnormalities.