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Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China
Parkinsonism and Related Disorders xxx (2018) 1e7
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China Ruwei Ou, Hui Liu, Yanbing Hou, Wei Song, Bei Cao, Qianqian Wei, Xiaoqin Yuan, Yongping Chen, Bi Zhao, Huifang Shang* Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 June 2017 Received in revised form 21 March 2018 Accepted 25 March 2018
Background: Camptocormia is becoming increasingly recognized as a prominent phenomenon in Parkinson's disease (PD). Objective: This study aims to investigate the clinical predictors of future camptocormia in a cohort of PD patients. Methods: A total of 263 PD patients without camptocormia were prospectively monitored for approximately 3 years. The end-point was the occurrence of camptocormia. Results: Overall, camptocormia was observed in 23 patients (8.7%) during the study period. The following variables including the proportion of males; age; disease duration; total levodopa equivalent daily dosage; Unified PD Rating Scale (UPDRS) III score; Hoehn and Yahr stage; the percentages of festination, freezing of gait and falls; and the subscores (e.g., “problems having sex”) and frequencies (e.g., “forget to do things”) of the Non-Motor Symptoms Scale were significantly higher in patients with camptocormia compared to those variables in patients without camptocormia (P < 0.05). Patients with camptocormia showed lower “orientation” subscore of the Montreal Cognitive Assessment scale than patients without camptocormia (P < 0.05). The binary logistic regression model indicated that the presence of camptocormia was associated with male sex (OR ¼ 6.758, P ¼ 0.001), a higher UPDRS III score (OR ¼ 1.099, P ¼ 0.001), a higher sexual dysfunction score (OR ¼ 1.033, P ¼ 0.038) and a lower orientation score (OR ¼ 0.392, P ¼ 0.018). Conclusions: Camptocormia may emerge as PD progresses. Male patients and those with sexual dysfunction or disorientation are likely to present with camptocormia in the future. © 2018 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Camptocormia Male sex Sexual dysfunction Disorientation
1. Introduction Camptocormia is an abnormal severe forward flexion of the thoracolumbar spine and trunk that occurs while standing or walking and abates or disappears in a supine position [1]. It is becoming increasingly recognized as a prominent phenomenon in Parkinson's disease (PD) [2,3], which may produce many negative consequences such as self-embarrassment or postural instability and even falls [4]. A recent study has found that postural abnormalities in PD can increase the risk of deep venous thrombosis in the legs [5]. However, the pathogenesis of this disabling PD feature is not well understood and it may be because of dystonia rigidity [6]
* Corresponding author. Department of Neurology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China. E-mail address: [email protected] (H. Shang).
or extensor truncal myopathy [7]. To date, there is no established consensus for the treatment of camptocormia in PD, so early identification of patients who are at risk of developing camptocormia is becoming more important. Several studies have reported the clinical features of camptocormia in PD. Our previous cross-sectional study found that camptocormia is relatively uncommon (6.5%) in Chinese patients with PD [8]. Pooled evidence reveals that the prevalence of camptocormia in PD patients ranges from 3% to 17.7% [4]. It has been reported that camptocormia is related to the severity of PD [2,8,9]. Further studies found that camptocormia in PD is associated with some non-motor symptoms (NMS) such as constipation and urinary incontinence [9]. In our previous study which compared the severity and frequency of NMS between patients with and without camptocormia [10], we found that PD patients who manifested camptocormia presented with more frequent autonomic and
https://doi.org/10.1016/j.parkreldis.2018.03.020 1353-8020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
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R. Ou et al. / Parkinsonism and Related Disorders xxx (2018) 1e7
miscellaneous symptoms and suffered from more severe neuropsychiatric symptoms and sleep disorders. Although many studies on the clinical characteristics of camptocormia have been conducted on a cross-sectional level, studies on the longitudinal observation of camptocormia are absent. Having more information would help us to improve the preventive strategies for PD patients who are at risk of developing camptocormia. Thus, we performed the present prospective study to investigate the clinical predictors of future camptocormia from a large cohort of Chinese PD patients.
applied additional special scales to evaluate these NMS. Cognitive function was evaluated using the Frontal Assessment Battery (FAB) [16] and the Montreal Cognitive Assessment (MoCA) [17]. The severity of depression was assessed using the Hamilton Depression Rating Scale (HAMD; 24 items) [18], while the severity of anxiety was evaluated using the Hamilton Anxiety Rating Scale (HAMA) [19]. The presence of RBD was based on the Chinese version of the Rapid Eye Movement Sleep Behaviour Disorder Screening Questionnaire (RBDSQ) with cut off 5.
2. Patients and methods
2.3. Outcome definition
2.1. Subjects
The primary outcome was the occurrence of camptocormia, regardless of whether the patients were in the “ON” or “OFF” drug condition. During the one-year visit, only those who completed the face-to-face visit were assessed for camptocormia. At the final visit, the forward flexion angle of the thoracolumbar spine and trunk was measured for all participants to confirm camptocormia. If a PD patient with a minimum angle of 45 between a vertical plane and a line passing through the trochanter and the edge of the acromion obtained with a goniometer resulted in a marked flexion in the sagittal plane originating in the thoracolumbar spine that abates or disappears in the supine position [20], then he/she was identified as having camptocormia. Thus, we classified the patients into two groups (with and without camptocormia).
After obtaining an approval from the local Ethics Committee, a total of 292 patients with PD were recruited between June 2012 and December 2013 from the Department of Neurology, West China Hospital of Sichuan University. All participants came from the neurological in-patient ward or the outpatient clinic. All included patients met the United Kingdom PD Society Brain Bank Clinical Diagnostic Criteria for PD, and all of the patients signed written informed consents. At baseline, participants were excluded if they presented with significant camptocormia, myasthenia, primary dystonia, history of spinal/vertebral surgery, secondary parkinsonism, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), or if they declined to participate. The diagnoses of PSP and MSA were based on the published diagnostic criteria for PSP [11] and MSA [12], respectively. 2.2. Clinical assessment Since camptocormia is a rare phenomenon in PD, to obtain more positive outcomes, the planned final visit was set at 3 years (range 2.5e3.5 years; Fig. 1). In addition, we also performed a visit after one-year of enrolment (range 0.5e1.5 years). During the one-year time interval, either a face-to-face interview or a telephone call was conducted. Patients were allowed to adjust the treatment regimen according to their requirements. Patients who reported no or little response to levodopa or those reported the onset of atypical symptoms of Parkinsonism during the telephone call were asked to return to the hospital for re-examination. In total, 212 patients were evaluated by face-to-face visits after one-year of enrolment. At the final visit, all patients were asked to return to the hospital for a faceto-face interview. During the one-year and three-year follow-up visits, we reconfirmed the diagnosis of PD, recorded the treatment regimen and re-evaluated the motor severity. At baseline, we recorded the following demographic and clinical data: education level, sex, age, age of onset, disease duration, treatment regimen, levodopa equivalent daily dose (LEDD), freezing of gait, festination, falls, rapid eye movement sleep behaviour disorder (RBD) and motor complications. In addition, all of the recruited patients underwent a series of detailed clinical assessments. The Unified PD Rating Scale (UPDRS) part III score and the degree of Hoehn and Yahr (H&Y) stage, which were conducted when patients were in the “ON” medication state, were utilized to evaluate the motor disability [13,14]. The Non-Motor Symptoms Scale (NMSS) was used to evaluate the global severity and frequency of NMS [15]. The severity of each symptom was calculated by multiplying its frequency (1e4) by its severity (0e3) [15], while the frequency of each symptom was calculated from the percentage of patients who obtained scores 1 for each item and domain of the NMSS [15]. To further explore the severity of cognition, depression and anxiety symptoms on the development of camptocormia, we
2.4. Lost to follow-up During the one-year and three-year follow-up visits, assessments were not completed in 29 patients: 18 patients refused to return, 6 patients could not be contacted, 1 patient died, 3 patients were diagnosed with MSA, and 1 patient was diagnosed with PSP. Patients who were lost to follow-up showed similar age, sex distribution and disease duration compared to those who completed the last visit. The remaining 263 patients were included in the data analysis. 2.5. Statistical analyses All analyses were performed with the Statistical Package for the Social Sciences version 19.0 (SPSS, Inc., Chicago, IL, USA). All statistical tests were two-tailed and P-values < 0.05 were considered statistically significant. Categorical variables are presented as counts (percentages) and were analysed by Fisher's exact test or a Chi-square test. Ranked data (H&Y stage) are presented as the median values (quartile) and was analysed by a Mann-Whitney U test. Continuous data are presented as the mean ± standard deviation and were analysed by Student's T test or analyses of covariance (ANCOVAs) as appropriate. For the comparison of the MoCA subdomains, a P-value < 0.007 was set as statistically significant. Finally, a forward stepwise binary logistic regression model was conducted to explore the potential risk factors related to future camptocormia, with the following factors included as independent variables: sex; age; disease duration; total LEDD; UPDRS III score; freezing of gait; festination; the NMSS subscores, including domains of “perceptual problems/hallucinations”, “gastrointestinal”, “urinary”, and “sexual dysfunction”; and the MoCA subscores, including domains of “attention”, “memory”, and “orientation”. Presence or absence of camptocormia was set as the dependent variable. The independent variables were chosen according to the positive results from a comparison between patients with and without camptocormia or based on results that had been previously reported.
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
R. Ou et al. / Parkinsonism and Related Disorders xxx (2018) 1e7
Patients who were registered (n=574)
Patients included at baseline (n=292)
3
Excluded: -Incompleted data (n=53) -Refused to be followed up (n=176) -Presence of camptocormia (n=38) -Presence of primary dystonia (n=5) -Presence of myasthenia (n=4) -With history of spinal/vertebral surgery (n=6) Excluded: -Withdrew informed consent (n=9) -Loss to contact (n=2) -Diagnosed as MSA (n=2) -Diagnosed as PSP (n=1)
One year after enrollment (n=278)
Excluded: -Withdrew informed consent (n=9) -Loss to contact (n=4) -Diagnosed as MSA (n=1) -Died (n=1)
Three years after enrollment (n=263)
Presence of camptocormia (n=23)
Absence of camptocormia (n=240) Fig. 1. Flow Chart of follow-up for camptocormia.
3. Results Follow-up data were obtained at a mean of 2.9 ± 0.4 years from baseline. At the end of the study, 23 PD patients developed camptocormia (8.7%). Comparisons of baseline demographic and clinical features between PD patients with camptocormia and those without camptocormia are presented in Table 1. At baseline, patients with camptocormia showed a significantly higher proportion of male sex, older age, longer PD duration, higher total LEDD, higher UPDRS III score, greater H&Y stage, and higher percentages of freezing of gait, festination and falls, compared to those without camptocormia (P < 0.05). The HAMD and HAMA scores were not significantly different between the two groups. Comparisons of baseline cognitive assessment results between patients with camptocormia and those without camptocormia are presented in Table 2. At baseline, patients with camptocormia had a significantly lower score in the “orientation” subdomain of the MoCA than those without camptocormia (P < 0.05). The FAB total score and the MoCA total score, as well as the remaining subscores of MoCA, were not significantly different between the two groups. Comparisons of the baseline NMSS assessment between patients with and without camptocormia are presented in Table 3. At baseline, patients with camptocormia exhibited significantly higher subscores of “double vision”, “forget things or events”, “forget to do things”, “interest in sex” and “problems having sex”, as well as a higher frequency of “forget to do things” from the NMSS than those subscores of PD patients without camptocormia (P < 0.05). The NMSS total score and the scores of its remaining items were not different between the two groups. The potential predictors related to future camptocormia are
presented in Table 4. The binary logistic regression model indicated that male sex (OR ¼ 6.758, P ¼ 0.001), a higher UPDRS III score (OR ¼ 1.099, P ¼ 0.001), a higher sexual dysfunction score (OR ¼ 1.033, P ¼ 0.038) and a lower orientation score (OR ¼ 0.392, P ¼ 0.018) were associated with the presence of camptocormia. 4. Discussion To the best of our knowledge, this is the first prospective study to investigate the clinical predictors of camptocormia in a large cohort of PD patients. We found that male patients are more likely to develop camptocormia and that camptocormia develops with the progression of PD. We further found that patients with more severe NMS, especially sexual dysfunction and disorientation, are prone to develop future camptocormia. Despite the prior studies [2,9] which showed that sex distribution was not different between patients with and without camptocormia, the proportion of male patients with camptocormia in our study was significantly higher than the proportion of female patients with camptocormia. Interestingly, we further found that male sex is an independent risk factor for camptocormia from a multivariate logistic analysis, implying that the pathophysiological mechanisms of camptocormia are probably determined by biological sex differences. It has been reported that males are at higher risk for PD and present with a faster deterioration of motor and non-motor functions [21]. Current evidence indicates that sex influences the normal functioning of the nigrostriatal dopamine pathway [21]. Sex hormones, specifically oestrogens in females, seem to play a key role. By far, sex hormones are the most important factors for driving structural and functional sex differences in
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
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Table 1 Baseline demographic and clinical features of PD patients with and without camptocormia.
Number of patients Education level (years) Male Age (years) Age of onset (years) Disease duration (years) LEDD (mg/day) DLEDD Use of levodopa Use of dopaminergic agonist Use of amantadine Use of anticholinergic agents Use of entacapone Use of selegiline UPDRS III DUPDRS III H&Y stage Motor fluctuation Dyskinesia Freezing of gait Festination Falls RBD HAMD HAMA
Total
With camptocormia
Without camptocormia
Test
P-value
263 10.8 ± 4.1 148 (56.3%) 62.3 ± 11.8 55.7 ± 11.6 6.6 ± 3.9 261.1 ± 238.9 325.3 ± 280.3 161 (61.2%) 89 (33.8%) 55 (20.9%) 24 (9.1%) 9 (3.4%) 3 (1.1%) 26.8 ± 12.7 3.4 ± 3.2 2 (0) 40 (15.2%) 11 (4.2%) 54 (20.5%) 58 (22.1%) 27 (10.3%) 92 (35.0%) 12.1 ± 9.3 9.0 ± 7.1
23 (8.7%) 10.4 ± 4.1 19 (82.6%) 68.5 ± 8.3 58.4 ± 8.8 10.1 ± 5.2 390.2 ± 300.7 351.7 ± 391.1 16 (69.6%) 10 (43.5%) 6 (26.1%) 4 (17.4%) 2 (8.7%) 0 41.3 ± 11.7 4.4 ± 3.5 2 (1) 6 (26.1%) 0 9 (39.1%) 9 (39.1%) 6 (26.1%) 10 (43.5%) 15.4 ± 10.0 10.9 ± 7.7
240 (91.3%) 10.8 ± 4.1 129 (53.8%) 61.7 ± 11.9 55.4 ± 8.8 6.2 ± 3.5 248.7 ± 229.1 318.9 ± 272.7 145 (60.4%) 79 (32.9%) 49 (20.4%) 20 (8.3%) 7 (2.9%) 3 (1.3%) 25.4 ± 12.0 3.3 ± 3.1 2 (0) 34 (14.2%) 11 (4.6%) 45 (18.8%) 49 (20.4%0 21 (8.8%) 82 (34.2%) 11.7 ± 9.1 8.8 ± 7.0
1 2 1 1 1 1 1 2 2 2 2 2 2 3 3 4 2 2 2 2 2 2 1 1
0.884 0.008* 0.001* 0.248 0.002* 0.038* 0.235 0.390 0.306 0.591 0.144 0.181 1.000 <0.001* 0.059 <0.001* 0.128 0.606 0.030* 0.039* 0.021* 0.370 0.070 0.192
PD, Parkinson's disease; LEDD, levodopa equivalent daily doses; UPDRS, Unified PD Rating Scale; RBD, rapid eye movement sleep behavior disorder; FAB, frontal assessment battery; MoCA, Montreal Cognitive Assessment; HAMD, Hamilton Depression Rating Scale; HAMA, Hamilton Anxiety Rating Scale. DLEDD ¼ the final LEDD e the initial LEDD. DUPDRS ¼ (the final score e the initial score) * 365/(the last visit date e the initial visit date). Test 1: Student T test. Test 2: Chi-square test. Test 3: ANCOVA test with adjustment for sex, age and disease duration. Test 4: Wilcoxon rank sum test. *Significant difference.
Table 2 Baseline cognitive assessments of PD patients with and without camptocormia.
FAB MoCA Visuospatial/executive abilities Naming Attention Language Abstraction Memory Orientation
Total
With camptocormia
Without camptocormia
P-value
16.3 ± 2.1 24.8 ± 4.5 3.7 ± 1.4 2.6 ± 0.8 5.4 ± 0.9 2.0 ± 1.0 1.3 ± 0.8 3.4 ± 1.4 5.7 ± 0.7
15.9 ± 2.5 23.6 ± 6.1 3.6 ± 1.8 2.5 ± 1.0 5.3 ± 1.4 1.8 ± 1.1 1.4 ± 0.8 3.1 ± 1.6 5.4 ± 1.1
16.4 ± 2.0 24.9 ± 4.3 3.8 ± 1.3 2.6 ± 0.8 5.4 ± 0.9 2.0 ± 0.9 1.3 ± 0.8 3.4 ± 1.4 5.8 ± 0.7
0.143a 0.109a 0.526b 0.680b 0.415b 0.228b 0.559b 0.304b 0.005b*
PD, Parkinson's disease; FAB, frontal assessment battery; MoCA, Montreal Cognitive Assessment. a P-value was calculated from an ANCOVA test with adjustment for sex, age and disease duration. b P-value was calculated from a Student T test. *Significant difference.
the brain and are critical drivers of clinical differences between male and female PD patients. Compared to male patients, the development of symptomatic PD in female patients may be delayed by the presence of higher physiological striatal dopamine levels [22] which are possibly due to the activity of oestrogen, a kind of gonadal steroid hormone that can protect dopaminergic neurons, striatal neurotransmitter neurons and dopamine receptor density and sensitivity [23]. We infer that oestrogen may also play a protective role in the pathogenesis of camptocormia in female PD patients, which needs to be verified by further pathological studies. At baseline, the observation of more severe motor disabilities in our PD patients with camptocormia is consistent with our previous observational studies [8,10] and two non-Asian reports [2,9]. Further multifactorial analyses indicate that camptocormia emerged as the disease progresses, likely implying that the
pathophysiology of camptocormia is associated with a dopaminergic mechanism. The evidence that camptocormia symptoms could be reversed by levodopa and deep brain stimulation [4] support the involvement of a dopaminergic mechanism in the development of camptocormia. However, the lack of association between disease duration and the development of camptocormia in the current study indicates that camptocormia may well be an independent special symptom in PD that is only affected by the severity of PD but not duration of the disease. In terms of the pathogenesis of camptocormia, there is a viewpoint [6] that camptocormia is a type of axial dystonia and both camptocormia and parkinsonism might result from an additional nondopaminergic neuronal dysfunction in the basal ganglia. A [123I] b-CIT SPECT study on two PD patients [24] revealed reduced striatal dopamine transporter binding accompanied with PD and that a
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
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Table 3 Baseline global NMS assessments of PD patients with and without camptocormia. NMS severity
D1. Cardiovascular 1.Light-headedness/dizziness 2. Falls because of fainting D2. Sleep/Fatigue 3. Daytime sleepiness 4. Fatigue 5. Difficulty falling asleep 6. Restless legs D3. Mood/Apathy 7. Lost interest in surroundings 8. Lack of motivation 9. Feelings of nervousness 10. Feelings of sadness 11. Flat mood 12. Difficulty experiencing pleasure D4. Perceptual problems/Hallucinations 13. Hallucinations 14. Delusions 15. Double vision D5. Attention/memory 16. Concentration 17. Forget things or events 18. Forget to do things D6. Gastrointestinal 19. Dribbling saliva 20. Swallowing 21. Constipation D7. Urinary 22. Urgency 23. Frequency 24. Nocturia D8. Sexual dysfunction 25. Interest in sex 26. Problems having sex D9. Miscellaneous 27. Pain 28. Taste or smell 29. Weight change 30. Excessive sweating NMSS total
NMS frequency
With camptocormia
Without camptocormia
P-valuea
With camptocormia
Without camptocormia
P-valueb
1.0 ± 2.7 1.0 ± 2.6 0.0 ± 0.2 9.7 ± 7.8 2.6 ± 2.3 1.9 ± 2.9 3.5 ± 4.3 1.7 ± 3.0 8.9 ± 13.0 1.5 ± 2.3 1.6 ± 2.4 1.6 ± 2.9 1.6 ± 2.6 1.4 ± 2.4 1.2 ± 2.3 1.8 ± 6.9 0.6 ± 2.5 0.6 ± 2.5 0.7 ± 2.0 5.7 ± 6.1 1.0 ± 1.8 3.1 ± 3.1 1.7 ± 2.9 4.5 ± 5.5 0.9 ± 1.7 0.8 ± 1.6 2.8 ± 4.0 8.4 ± 8.8 1.6 ± 3.3 2.6 ± 3.8 4.2 ± 3.6 4.6 ± 8.2 2.3 ± 4.1 2.3 ± 4.2 4.4 ± 5.9 1.7 ± 2.6 1.3 ± 1.8 0.3 ± 0.9 1.5 ± 3.1 49.3 ± 38.5
0.9 ± 2.1 0.9 ± 1.9 0.0 ± 0.4 7.0 ± 7.4 1.5 ± 2.4 2.0 ± 2.9 2.4 ± 3.3 1.2 ± 2.6 8.4 ± 10.9 1.4 ± 2.2 1.4 ± 2.2 1.3 ± 2.4 2.2 ± 2.8 0.9 ± 2.0 1.3 ± 2.4 0.3 ± 1.8 0.1 ± 0.9 0.1 ± 0.9 0.1 ± 0.5 3.0 ± 3.7 0.6 ± 1.5 1.8 ± 2.3 0.6 ± 1.2 2.7 ± 4.3 0.5 ± 1.7 0.3 ± 1.0 1.9 ± 3.4 4.5 ± 7.2 1.1 ± 2.5 1.3 ± 2.7 2.2 ± 3.1 1.5 ± 2.8 0.8 ± 1.4 0.7 ± 1.4 3.8 ± 4.4 1.8 ± 3.2 1.3 ± 2.4 0.2 ± 0.9 1.1 ± 2.2 32.8 ± 30.4
0.395 0.322 0.737 0.109 0.182 0.732 0.100 0.415 0.761 0.825 0.547 0.442 0.636 0.401 0.784 0.022* 0.088 0.053 0.008* 0.003* 0.353 0.011* 0.001* 0.600 0.972 0.301 0.733 0.306 0.747 0.382 0.062 0.022* 0.028* 0.021* 0.714 0.855 0.381 0.643 0.925 0.360
7 (30.4%) 7 (30.4%) 1 (4.3%) 20 (87.0%) 16 (69.6%) 9 (39.1%) 14 (60.9%) 9 (39.1%) 15 (65.2%) 11 (47.8%) 10 (43.5%) 6 (26.1%) 10 (43.5%) 8 (34.8%) 8 (34.8%) 5 (21.7%) 2 (8.7%) 2 (8.7%) 4 (17.4%) 19 (82.6%) 6 (26.1%) 18 (78.3%) 13 (56.5%) 13 (56.5%) 6 (26.1%) 7 (30.4%) 10 (43.5%) 17 (73.9%) 6 (26.1%) 10 (43.5%) 15 (65.2%) 10 (43.5%) 10 (43.5%) 10 (43.5%) 14 (60.9%) 9 (39.1%) 10 (43.5%) 3 (13.0%) 6 (26.1%) 22 (95.7%)
66 (27.5%) 66 (27.5%) 4 (1.7%) 194 (80.8%) 111 (46.3%) 110 (45.8%) 129 (53.8%) 67 (27.9%) 160 (66.7%) 104 (43.3%) 94 (39.2%) 79 (32.9%) 129 (53.8%) 59 (24.6%) 82 (34.2%) 30 (12.5%) 10 (4.2%) 5 (2.1%) 21 (8.8%) 162 (67.5%) 60 (25.0%) 141 (58.8%) 69 (28.8%) 116 (48.3%) 39 (16.3%) 33 (13.8%) 87 (36.3%) 129 (53.8%) 56 (23.3%) 61 (25.4%) 109 (45.4%) 105 (43.8%) 99 (41.3%) 86 (35.8%) 160 (66.7%) 92 (38.3%) 78 (32.5%) 22 (9.2%) 65 (27.1%) 229 (95.4%)
0.764 0.764 0.370 0.586 0.033 0.537 0.513 0.257 0.888 0.678 0.686 0.503 0.346 0.284 0.953 0.206 0.283 0.117 0.251 0.135 0.909 0.068 0.006* 0.453 0.247 0.060 0.492 0.063 0.766 0.062 0.069 0.980 0.836 0.467 0.575 0.202 0.286 0.467 0.918 0.959
NMS, non-motor symptoms; PD, Parkinson's disease; NMSS, Non-Motor Symptoms Scale. a P-value was calculated from an ANCOVA test with adjustment for sex, age and disease duration. b P-value was calculated from a chi-square test. *Significant difference.
Table 4 Regression analyses of clinical variables associated with future camptocormia in PD. Independent significant covariates
OR (95%CI)
P-valuea
Male UPDRS III Sexual dysfunction in NMSS Orientation in MoCA
6.758 1.099 1.033 0.392
0.001 0.001 0.038 0.018
(1.852e24.665) (1.039e1.163) (1.011e1.025) (0.180e0.853)
PD, Parkinson's disease; UPDRS, Unified PD Rating Scale; NMSS, Non-Motor Symptom Scale; MoCA, Montreal Cognitive Assessment. a P-value was calculated from a binary regression analyses model, with sex, age, disease duration, total LEDD, UPDRS III score, freezing of gait, festination, NMSS subscore (including domains of Perceptual problems/Hallucinations, Gastrointestinal, Urinary, and Sexual dysfunction), and MoCA subscore (including domains of Attention, Memory, and Orientation) were included as independent variables, and presence/absence of camptocormia was set as dependent variable.
sensory trick can overcome camptocormia, which may suggest that camptocormia may well be a form of dystonia in PD. The lack of association between dopaminergic therapy and the development of camptocormia also suggests that the pathophysiology of camptocormia involves nondopaminergic mechanisms. In most cases, the camptocormia phenomenon is not levodopa
responsive [25] and occurs both in the “OFF” and “ON” medication states. However, a case report [26] showed that the symptoms of camptocormia in a PD patient were the result of using a dopaminergic agent, which may indicate that the pathogenesis of camptocormia between patients in “ON” and “OFF” medication states is potentially different to some extent. In the current study, we did not identify the risk factors in different subtypes of camptocormia (“ON” versus “OFF” mediation states); thus, a further layered study with a larger sample size may help to clarify the relationship between levodopa treatment and camptocormia. It is worth noting that patients with more severe sexual dysfunction tend to develop future camptocormia. High frequencies of autonomic symptoms such as constipation and urinary incontinence have been observed in Japanese PD patients with camptocormia [9]. Recovery of autonomic dysfunction in PD patients is often resistant to levodopa treatment and is known to be related to nondopaminergic systems [27]. This evidence also supports the role of nondopaminergic mechanisms in the pathogenesis of camptocormia. In a structural brain MRI study on camptocormia in patients with PD, the severity of camptocormia was negatively correlated with the normalized sagittal surface of the pons and the whole brain volume [28], implying that the pathological changes in
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
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patients with camptocormia may be more severe and may spread throughout the brain, particularly in the brainstem where many nuclei regulate autonomic functions. In addition, camptocormia in PD may also result from peripheral mechanisms. Increased creatine kinase levels, myopathic signs observed via electromyography, paraspinal myopathic changes revealed by muscle biopsy and slight fatty degeneration of the bilateral paravertebral musculature identified by MRI have been identified in PD patients with camptocormia [7,29,30], suggesting a myopathy-related aetiology of camptocormia. The multiple pathogenic mechanisms involved in the development of camptocormia indicate that the treatment of camptocormia in PD is very troublesome. However, our limitation was that we did not use electromyography to investigate the electrophysiological differences between our patients with and without camptocormia. Cognitive impairment in PD patients with camptocormia has been found in several previous studies [2,8]. However, all results from these studies were based on a global cognitive assessment scale such as the mini-mental state examination (MMSE). Although we did not find that the MoCA total score was different between patients with and without camptocormia, a lower score in “orientation”, an independent subdomain from the MoCA, was observed in our patients with camptocormia. We further found that these patients with orientation impairment tended to develop camptocormia. This phenomenon is difficult to clearly explain because no relevant imaging or pathological studies are available to clarify this issue. We suspect that disorientation and camptocormia may share the same pathophysiological pathway, which needs to be further identified. However, it is necessary to be aware that the test for the subdomain of “orientation” from the MoCA only refers to the ability of orientation to time and place, so this oversimplified scale is not a rigorous tool to test the orientation of overall cognition. Further comprehensive neuropsychological batteries on the cognition of orientation may help to clarify the relationship between camptocormia and the dysfunction in orientation in PD patients. The present study has several limitations. First, although the prevalence of camptocormia in PD is low, the less positive outcome of camptocormia in the current study may also be attributed to the relatively short follow-up period. Second, other potential factors that may affect the results still exist. Third, the unclear specific mechanisms in camptocormia make it difficult to explain our current results. Finally, we did not identify the risk factors of camptocormia in patients with different medication states (“OFF” or “ON”), so the role of levodopa therapy in the development of camptocormia cannot be definitely identified. 5. Conclusion In conclusion, our study indicates that camptocormia may emerge as PD progresses. Male patients and those with sexual dysfunction or disorientation are more prone to develop future camptocormia. Conflicts of interest The authors declare that they have no conflicts of interest. Acknowledgements The authors thank the patients and their families for their participation in the study. The present study was supported by the funding of the National Science Fund of China (Grant No. 81571247) and the National Key Research and Development Program of China (No. 2016YFC0901504).
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Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China Ruwei Ou, Hui Liu, Yanbing Hou, Wei Song, Bei Cao, Qianqian Wei, Xiaoqin Yuan, Yongping Chen, Bi Zhao, Huifang Shang* Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 June 2017 Received in revised form 21 March 2018 Accepted 25 March 2018
Background: Camptocormia is becoming increasingly recognized as a prominent phenomenon in Parkinson's disease (PD). Objective: This study aims to investigate the clinical predictors of future camptocormia in a cohort of PD patients. Methods: A total of 263 PD patients without camptocormia were prospectively monitored for approximately 3 years. The end-point was the occurrence of camptocormia. Results: Overall, camptocormia was observed in 23 patients (8.7%) during the study period. The following variables including the proportion of males; age; disease duration; total levodopa equivalent daily dosage; Unified PD Rating Scale (UPDRS) III score; Hoehn and Yahr stage; the percentages of festination, freezing of gait and falls; and the subscores (e.g., “problems having sex”) and frequencies (e.g., “forget to do things”) of the Non-Motor Symptoms Scale were significantly higher in patients with camptocormia compared to those variables in patients without camptocormia (P < 0.05). Patients with camptocormia showed lower “orientation” subscore of the Montreal Cognitive Assessment scale than patients without camptocormia (P < 0.05). The binary logistic regression model indicated that the presence of camptocormia was associated with male sex (OR ¼ 6.758, P ¼ 0.001), a higher UPDRS III score (OR ¼ 1.099, P ¼ 0.001), a higher sexual dysfunction score (OR ¼ 1.033, P ¼ 0.038) and a lower orientation score (OR ¼ 0.392, P ¼ 0.018). Conclusions: Camptocormia may emerge as PD progresses. Male patients and those with sexual dysfunction or disorientation are likely to present with camptocormia in the future. © 2018 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Camptocormia Male sex Sexual dysfunction Disorientation
1. Introduction Camptocormia is an abnormal severe forward flexion of the thoracolumbar spine and trunk that occurs while standing or walking and abates or disappears in a supine position [1]. It is becoming increasingly recognized as a prominent phenomenon in Parkinson's disease (PD) [2,3], which may produce many negative consequences such as self-embarrassment or postural instability and even falls [4]. A recent study has found that postural abnormalities in PD can increase the risk of deep venous thrombosis in the legs [5]. However, the pathogenesis of this disabling PD feature is not well understood and it may be because of dystonia rigidity [6]
* Corresponding author. Department of Neurology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China. E-mail address: [email protected] (H. Shang).
or extensor truncal myopathy [7]. To date, there is no established consensus for the treatment of camptocormia in PD, so early identification of patients who are at risk of developing camptocormia is becoming more important. Several studies have reported the clinical features of camptocormia in PD. Our previous cross-sectional study found that camptocormia is relatively uncommon (6.5%) in Chinese patients with PD [8]. Pooled evidence reveals that the prevalence of camptocormia in PD patients ranges from 3% to 17.7% [4]. It has been reported that camptocormia is related to the severity of PD [2,8,9]. Further studies found that camptocormia in PD is associated with some non-motor symptoms (NMS) such as constipation and urinary incontinence [9]. In our previous study which compared the severity and frequency of NMS between patients with and without camptocormia [10], we found that PD patients who manifested camptocormia presented with more frequent autonomic and
https://doi.org/10.1016/j.parkreldis.2018.03.020 1353-8020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
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miscellaneous symptoms and suffered from more severe neuropsychiatric symptoms and sleep disorders. Although many studies on the clinical characteristics of camptocormia have been conducted on a cross-sectional level, studies on the longitudinal observation of camptocormia are absent. Having more information would help us to improve the preventive strategies for PD patients who are at risk of developing camptocormia. Thus, we performed the present prospective study to investigate the clinical predictors of future camptocormia from a large cohort of Chinese PD patients.
applied additional special scales to evaluate these NMS. Cognitive function was evaluated using the Frontal Assessment Battery (FAB) [16] and the Montreal Cognitive Assessment (MoCA) [17]. The severity of depression was assessed using the Hamilton Depression Rating Scale (HAMD; 24 items) [18], while the severity of anxiety was evaluated using the Hamilton Anxiety Rating Scale (HAMA) [19]. The presence of RBD was based on the Chinese version of the Rapid Eye Movement Sleep Behaviour Disorder Screening Questionnaire (RBDSQ) with cut off 5.
2. Patients and methods
2.3. Outcome definition
2.1. Subjects
The primary outcome was the occurrence of camptocormia, regardless of whether the patients were in the “ON” or “OFF” drug condition. During the one-year visit, only those who completed the face-to-face visit were assessed for camptocormia. At the final visit, the forward flexion angle of the thoracolumbar spine and trunk was measured for all participants to confirm camptocormia. If a PD patient with a minimum angle of 45 between a vertical plane and a line passing through the trochanter and the edge of the acromion obtained with a goniometer resulted in a marked flexion in the sagittal plane originating in the thoracolumbar spine that abates or disappears in the supine position [20], then he/she was identified as having camptocormia. Thus, we classified the patients into two groups (with and without camptocormia).
After obtaining an approval from the local Ethics Committee, a total of 292 patients with PD were recruited between June 2012 and December 2013 from the Department of Neurology, West China Hospital of Sichuan University. All participants came from the neurological in-patient ward or the outpatient clinic. All included patients met the United Kingdom PD Society Brain Bank Clinical Diagnostic Criteria for PD, and all of the patients signed written informed consents. At baseline, participants were excluded if they presented with significant camptocormia, myasthenia, primary dystonia, history of spinal/vertebral surgery, secondary parkinsonism, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), or if they declined to participate. The diagnoses of PSP and MSA were based on the published diagnostic criteria for PSP [11] and MSA [12], respectively. 2.2. Clinical assessment Since camptocormia is a rare phenomenon in PD, to obtain more positive outcomes, the planned final visit was set at 3 years (range 2.5e3.5 years; Fig. 1). In addition, we also performed a visit after one-year of enrolment (range 0.5e1.5 years). During the one-year time interval, either a face-to-face interview or a telephone call was conducted. Patients were allowed to adjust the treatment regimen according to their requirements. Patients who reported no or little response to levodopa or those reported the onset of atypical symptoms of Parkinsonism during the telephone call were asked to return to the hospital for re-examination. In total, 212 patients were evaluated by face-to-face visits after one-year of enrolment. At the final visit, all patients were asked to return to the hospital for a faceto-face interview. During the one-year and three-year follow-up visits, we reconfirmed the diagnosis of PD, recorded the treatment regimen and re-evaluated the motor severity. At baseline, we recorded the following demographic and clinical data: education level, sex, age, age of onset, disease duration, treatment regimen, levodopa equivalent daily dose (LEDD), freezing of gait, festination, falls, rapid eye movement sleep behaviour disorder (RBD) and motor complications. In addition, all of the recruited patients underwent a series of detailed clinical assessments. The Unified PD Rating Scale (UPDRS) part III score and the degree of Hoehn and Yahr (H&Y) stage, which were conducted when patients were in the “ON” medication state, were utilized to evaluate the motor disability [13,14]. The Non-Motor Symptoms Scale (NMSS) was used to evaluate the global severity and frequency of NMS [15]. The severity of each symptom was calculated by multiplying its frequency (1e4) by its severity (0e3) [15], while the frequency of each symptom was calculated from the percentage of patients who obtained scores 1 for each item and domain of the NMSS [15]. To further explore the severity of cognition, depression and anxiety symptoms on the development of camptocormia, we
2.4. Lost to follow-up During the one-year and three-year follow-up visits, assessments were not completed in 29 patients: 18 patients refused to return, 6 patients could not be contacted, 1 patient died, 3 patients were diagnosed with MSA, and 1 patient was diagnosed with PSP. Patients who were lost to follow-up showed similar age, sex distribution and disease duration compared to those who completed the last visit. The remaining 263 patients were included in the data analysis. 2.5. Statistical analyses All analyses were performed with the Statistical Package for the Social Sciences version 19.0 (SPSS, Inc., Chicago, IL, USA). All statistical tests were two-tailed and P-values < 0.05 were considered statistically significant. Categorical variables are presented as counts (percentages) and were analysed by Fisher's exact test or a Chi-square test. Ranked data (H&Y stage) are presented as the median values (quartile) and was analysed by a Mann-Whitney U test. Continuous data are presented as the mean ± standard deviation and were analysed by Student's T test or analyses of covariance (ANCOVAs) as appropriate. For the comparison of the MoCA subdomains, a P-value < 0.007 was set as statistically significant. Finally, a forward stepwise binary logistic regression model was conducted to explore the potential risk factors related to future camptocormia, with the following factors included as independent variables: sex; age; disease duration; total LEDD; UPDRS III score; freezing of gait; festination; the NMSS subscores, including domains of “perceptual problems/hallucinations”, “gastrointestinal”, “urinary”, and “sexual dysfunction”; and the MoCA subscores, including domains of “attention”, “memory”, and “orientation”. Presence or absence of camptocormia was set as the dependent variable. The independent variables were chosen according to the positive results from a comparison between patients with and without camptocormia or based on results that had been previously reported.
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
R. Ou et al. / Parkinsonism and Related Disorders xxx (2018) 1e7
Patients who were registered (n=574)
Patients included at baseline (n=292)
3
Excluded: -Incompleted data (n=53) -Refused to be followed up (n=176) -Presence of camptocormia (n=38) -Presence of primary dystonia (n=5) -Presence of myasthenia (n=4) -With history of spinal/vertebral surgery (n=6) Excluded: -Withdrew informed consent (n=9) -Loss to contact (n=2) -Diagnosed as MSA (n=2) -Diagnosed as PSP (n=1)
One year after enrollment (n=278)
Excluded: -Withdrew informed consent (n=9) -Loss to contact (n=4) -Diagnosed as MSA (n=1) -Died (n=1)
Three years after enrollment (n=263)
Presence of camptocormia (n=23)
Absence of camptocormia (n=240) Fig. 1. Flow Chart of follow-up for camptocormia.
3. Results Follow-up data were obtained at a mean of 2.9 ± 0.4 years from baseline. At the end of the study, 23 PD patients developed camptocormia (8.7%). Comparisons of baseline demographic and clinical features between PD patients with camptocormia and those without camptocormia are presented in Table 1. At baseline, patients with camptocormia showed a significantly higher proportion of male sex, older age, longer PD duration, higher total LEDD, higher UPDRS III score, greater H&Y stage, and higher percentages of freezing of gait, festination and falls, compared to those without camptocormia (P < 0.05). The HAMD and HAMA scores were not significantly different between the two groups. Comparisons of baseline cognitive assessment results between patients with camptocormia and those without camptocormia are presented in Table 2. At baseline, patients with camptocormia had a significantly lower score in the “orientation” subdomain of the MoCA than those without camptocormia (P < 0.05). The FAB total score and the MoCA total score, as well as the remaining subscores of MoCA, were not significantly different between the two groups. Comparisons of the baseline NMSS assessment between patients with and without camptocormia are presented in Table 3. At baseline, patients with camptocormia exhibited significantly higher subscores of “double vision”, “forget things or events”, “forget to do things”, “interest in sex” and “problems having sex”, as well as a higher frequency of “forget to do things” from the NMSS than those subscores of PD patients without camptocormia (P < 0.05). The NMSS total score and the scores of its remaining items were not different between the two groups. The potential predictors related to future camptocormia are
presented in Table 4. The binary logistic regression model indicated that male sex (OR ¼ 6.758, P ¼ 0.001), a higher UPDRS III score (OR ¼ 1.099, P ¼ 0.001), a higher sexual dysfunction score (OR ¼ 1.033, P ¼ 0.038) and a lower orientation score (OR ¼ 0.392, P ¼ 0.018) were associated with the presence of camptocormia. 4. Discussion To the best of our knowledge, this is the first prospective study to investigate the clinical predictors of camptocormia in a large cohort of PD patients. We found that male patients are more likely to develop camptocormia and that camptocormia develops with the progression of PD. We further found that patients with more severe NMS, especially sexual dysfunction and disorientation, are prone to develop future camptocormia. Despite the prior studies [2,9] which showed that sex distribution was not different between patients with and without camptocormia, the proportion of male patients with camptocormia in our study was significantly higher than the proportion of female patients with camptocormia. Interestingly, we further found that male sex is an independent risk factor for camptocormia from a multivariate logistic analysis, implying that the pathophysiological mechanisms of camptocormia are probably determined by biological sex differences. It has been reported that males are at higher risk for PD and present with a faster deterioration of motor and non-motor functions [21]. Current evidence indicates that sex influences the normal functioning of the nigrostriatal dopamine pathway [21]. Sex hormones, specifically oestrogens in females, seem to play a key role. By far, sex hormones are the most important factors for driving structural and functional sex differences in
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
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Table 1 Baseline demographic and clinical features of PD patients with and without camptocormia.
Number of patients Education level (years) Male Age (years) Age of onset (years) Disease duration (years) LEDD (mg/day) DLEDD Use of levodopa Use of dopaminergic agonist Use of amantadine Use of anticholinergic agents Use of entacapone Use of selegiline UPDRS III DUPDRS III H&Y stage Motor fluctuation Dyskinesia Freezing of gait Festination Falls RBD HAMD HAMA
Total
With camptocormia
Without camptocormia
Test
P-value
263 10.8 ± 4.1 148 (56.3%) 62.3 ± 11.8 55.7 ± 11.6 6.6 ± 3.9 261.1 ± 238.9 325.3 ± 280.3 161 (61.2%) 89 (33.8%) 55 (20.9%) 24 (9.1%) 9 (3.4%) 3 (1.1%) 26.8 ± 12.7 3.4 ± 3.2 2 (0) 40 (15.2%) 11 (4.2%) 54 (20.5%) 58 (22.1%) 27 (10.3%) 92 (35.0%) 12.1 ± 9.3 9.0 ± 7.1
23 (8.7%) 10.4 ± 4.1 19 (82.6%) 68.5 ± 8.3 58.4 ± 8.8 10.1 ± 5.2 390.2 ± 300.7 351.7 ± 391.1 16 (69.6%) 10 (43.5%) 6 (26.1%) 4 (17.4%) 2 (8.7%) 0 41.3 ± 11.7 4.4 ± 3.5 2 (1) 6 (26.1%) 0 9 (39.1%) 9 (39.1%) 6 (26.1%) 10 (43.5%) 15.4 ± 10.0 10.9 ± 7.7
240 (91.3%) 10.8 ± 4.1 129 (53.8%) 61.7 ± 11.9 55.4 ± 8.8 6.2 ± 3.5 248.7 ± 229.1 318.9 ± 272.7 145 (60.4%) 79 (32.9%) 49 (20.4%) 20 (8.3%) 7 (2.9%) 3 (1.3%) 25.4 ± 12.0 3.3 ± 3.1 2 (0) 34 (14.2%) 11 (4.6%) 45 (18.8%) 49 (20.4%0 21 (8.8%) 82 (34.2%) 11.7 ± 9.1 8.8 ± 7.0
1 2 1 1 1 1 1 2 2 2 2 2 2 3 3 4 2 2 2 2 2 2 1 1
0.884 0.008* 0.001* 0.248 0.002* 0.038* 0.235 0.390 0.306 0.591 0.144 0.181 1.000 <0.001* 0.059 <0.001* 0.128 0.606 0.030* 0.039* 0.021* 0.370 0.070 0.192
PD, Parkinson's disease; LEDD, levodopa equivalent daily doses; UPDRS, Unified PD Rating Scale; RBD, rapid eye movement sleep behavior disorder; FAB, frontal assessment battery; MoCA, Montreal Cognitive Assessment; HAMD, Hamilton Depression Rating Scale; HAMA, Hamilton Anxiety Rating Scale. DLEDD ¼ the final LEDD e the initial LEDD. DUPDRS ¼ (the final score e the initial score) * 365/(the last visit date e the initial visit date). Test 1: Student T test. Test 2: Chi-square test. Test 3: ANCOVA test with adjustment for sex, age and disease duration. Test 4: Wilcoxon rank sum test. *Significant difference.
Table 2 Baseline cognitive assessments of PD patients with and without camptocormia.
FAB MoCA Visuospatial/executive abilities Naming Attention Language Abstraction Memory Orientation
Total
With camptocormia
Without camptocormia
P-value
16.3 ± 2.1 24.8 ± 4.5 3.7 ± 1.4 2.6 ± 0.8 5.4 ± 0.9 2.0 ± 1.0 1.3 ± 0.8 3.4 ± 1.4 5.7 ± 0.7
15.9 ± 2.5 23.6 ± 6.1 3.6 ± 1.8 2.5 ± 1.0 5.3 ± 1.4 1.8 ± 1.1 1.4 ± 0.8 3.1 ± 1.6 5.4 ± 1.1
16.4 ± 2.0 24.9 ± 4.3 3.8 ± 1.3 2.6 ± 0.8 5.4 ± 0.9 2.0 ± 0.9 1.3 ± 0.8 3.4 ± 1.4 5.8 ± 0.7
0.143a 0.109a 0.526b 0.680b 0.415b 0.228b 0.559b 0.304b 0.005b*
PD, Parkinson's disease; FAB, frontal assessment battery; MoCA, Montreal Cognitive Assessment. a P-value was calculated from an ANCOVA test with adjustment for sex, age and disease duration. b P-value was calculated from a Student T test. *Significant difference.
the brain and are critical drivers of clinical differences between male and female PD patients. Compared to male patients, the development of symptomatic PD in female patients may be delayed by the presence of higher physiological striatal dopamine levels [22] which are possibly due to the activity of oestrogen, a kind of gonadal steroid hormone that can protect dopaminergic neurons, striatal neurotransmitter neurons and dopamine receptor density and sensitivity [23]. We infer that oestrogen may also play a protective role in the pathogenesis of camptocormia in female PD patients, which needs to be verified by further pathological studies. At baseline, the observation of more severe motor disabilities in our PD patients with camptocormia is consistent with our previous observational studies [8,10] and two non-Asian reports [2,9]. Further multifactorial analyses indicate that camptocormia emerged as the disease progresses, likely implying that the
pathophysiology of camptocormia is associated with a dopaminergic mechanism. The evidence that camptocormia symptoms could be reversed by levodopa and deep brain stimulation [4] support the involvement of a dopaminergic mechanism in the development of camptocormia. However, the lack of association between disease duration and the development of camptocormia in the current study indicates that camptocormia may well be an independent special symptom in PD that is only affected by the severity of PD but not duration of the disease. In terms of the pathogenesis of camptocormia, there is a viewpoint [6] that camptocormia is a type of axial dystonia and both camptocormia and parkinsonism might result from an additional nondopaminergic neuronal dysfunction in the basal ganglia. A [123I] b-CIT SPECT study on two PD patients [24] revealed reduced striatal dopamine transporter binding accompanied with PD and that a
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
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Table 3 Baseline global NMS assessments of PD patients with and without camptocormia. NMS severity
D1. Cardiovascular 1.Light-headedness/dizziness 2. Falls because of fainting D2. Sleep/Fatigue 3. Daytime sleepiness 4. Fatigue 5. Difficulty falling asleep 6. Restless legs D3. Mood/Apathy 7. Lost interest in surroundings 8. Lack of motivation 9. Feelings of nervousness 10. Feelings of sadness 11. Flat mood 12. Difficulty experiencing pleasure D4. Perceptual problems/Hallucinations 13. Hallucinations 14. Delusions 15. Double vision D5. Attention/memory 16. Concentration 17. Forget things or events 18. Forget to do things D6. Gastrointestinal 19. Dribbling saliva 20. Swallowing 21. Constipation D7. Urinary 22. Urgency 23. Frequency 24. Nocturia D8. Sexual dysfunction 25. Interest in sex 26. Problems having sex D9. Miscellaneous 27. Pain 28. Taste or smell 29. Weight change 30. Excessive sweating NMSS total
NMS frequency
With camptocormia
Without camptocormia
P-valuea
With camptocormia
Without camptocormia
P-valueb
1.0 ± 2.7 1.0 ± 2.6 0.0 ± 0.2 9.7 ± 7.8 2.6 ± 2.3 1.9 ± 2.9 3.5 ± 4.3 1.7 ± 3.0 8.9 ± 13.0 1.5 ± 2.3 1.6 ± 2.4 1.6 ± 2.9 1.6 ± 2.6 1.4 ± 2.4 1.2 ± 2.3 1.8 ± 6.9 0.6 ± 2.5 0.6 ± 2.5 0.7 ± 2.0 5.7 ± 6.1 1.0 ± 1.8 3.1 ± 3.1 1.7 ± 2.9 4.5 ± 5.5 0.9 ± 1.7 0.8 ± 1.6 2.8 ± 4.0 8.4 ± 8.8 1.6 ± 3.3 2.6 ± 3.8 4.2 ± 3.6 4.6 ± 8.2 2.3 ± 4.1 2.3 ± 4.2 4.4 ± 5.9 1.7 ± 2.6 1.3 ± 1.8 0.3 ± 0.9 1.5 ± 3.1 49.3 ± 38.5
0.9 ± 2.1 0.9 ± 1.9 0.0 ± 0.4 7.0 ± 7.4 1.5 ± 2.4 2.0 ± 2.9 2.4 ± 3.3 1.2 ± 2.6 8.4 ± 10.9 1.4 ± 2.2 1.4 ± 2.2 1.3 ± 2.4 2.2 ± 2.8 0.9 ± 2.0 1.3 ± 2.4 0.3 ± 1.8 0.1 ± 0.9 0.1 ± 0.9 0.1 ± 0.5 3.0 ± 3.7 0.6 ± 1.5 1.8 ± 2.3 0.6 ± 1.2 2.7 ± 4.3 0.5 ± 1.7 0.3 ± 1.0 1.9 ± 3.4 4.5 ± 7.2 1.1 ± 2.5 1.3 ± 2.7 2.2 ± 3.1 1.5 ± 2.8 0.8 ± 1.4 0.7 ± 1.4 3.8 ± 4.4 1.8 ± 3.2 1.3 ± 2.4 0.2 ± 0.9 1.1 ± 2.2 32.8 ± 30.4
0.395 0.322 0.737 0.109 0.182 0.732 0.100 0.415 0.761 0.825 0.547 0.442 0.636 0.401 0.784 0.022* 0.088 0.053 0.008* 0.003* 0.353 0.011* 0.001* 0.600 0.972 0.301 0.733 0.306 0.747 0.382 0.062 0.022* 0.028* 0.021* 0.714 0.855 0.381 0.643 0.925 0.360
7 (30.4%) 7 (30.4%) 1 (4.3%) 20 (87.0%) 16 (69.6%) 9 (39.1%) 14 (60.9%) 9 (39.1%) 15 (65.2%) 11 (47.8%) 10 (43.5%) 6 (26.1%) 10 (43.5%) 8 (34.8%) 8 (34.8%) 5 (21.7%) 2 (8.7%) 2 (8.7%) 4 (17.4%) 19 (82.6%) 6 (26.1%) 18 (78.3%) 13 (56.5%) 13 (56.5%) 6 (26.1%) 7 (30.4%) 10 (43.5%) 17 (73.9%) 6 (26.1%) 10 (43.5%) 15 (65.2%) 10 (43.5%) 10 (43.5%) 10 (43.5%) 14 (60.9%) 9 (39.1%) 10 (43.5%) 3 (13.0%) 6 (26.1%) 22 (95.7%)
66 (27.5%) 66 (27.5%) 4 (1.7%) 194 (80.8%) 111 (46.3%) 110 (45.8%) 129 (53.8%) 67 (27.9%) 160 (66.7%) 104 (43.3%) 94 (39.2%) 79 (32.9%) 129 (53.8%) 59 (24.6%) 82 (34.2%) 30 (12.5%) 10 (4.2%) 5 (2.1%) 21 (8.8%) 162 (67.5%) 60 (25.0%) 141 (58.8%) 69 (28.8%) 116 (48.3%) 39 (16.3%) 33 (13.8%) 87 (36.3%) 129 (53.8%) 56 (23.3%) 61 (25.4%) 109 (45.4%) 105 (43.8%) 99 (41.3%) 86 (35.8%) 160 (66.7%) 92 (38.3%) 78 (32.5%) 22 (9.2%) 65 (27.1%) 229 (95.4%)
0.764 0.764 0.370 0.586 0.033 0.537 0.513 0.257 0.888 0.678 0.686 0.503 0.346 0.284 0.953 0.206 0.283 0.117 0.251 0.135 0.909 0.068 0.006* 0.453 0.247 0.060 0.492 0.063 0.766 0.062 0.069 0.980 0.836 0.467 0.575 0.202 0.286 0.467 0.918 0.959
NMS, non-motor symptoms; PD, Parkinson's disease; NMSS, Non-Motor Symptoms Scale. a P-value was calculated from an ANCOVA test with adjustment for sex, age and disease duration. b P-value was calculated from a chi-square test. *Significant difference.
Table 4 Regression analyses of clinical variables associated with future camptocormia in PD. Independent significant covariates
OR (95%CI)
P-valuea
Male UPDRS III Sexual dysfunction in NMSS Orientation in MoCA
6.758 1.099 1.033 0.392
0.001 0.001 0.038 0.018
(1.852e24.665) (1.039e1.163) (1.011e1.025) (0.180e0.853)
PD, Parkinson's disease; UPDRS, Unified PD Rating Scale; NMSS, Non-Motor Symptom Scale; MoCA, Montreal Cognitive Assessment. a P-value was calculated from a binary regression analyses model, with sex, age, disease duration, total LEDD, UPDRS III score, freezing of gait, festination, NMSS subscore (including domains of Perceptual problems/Hallucinations, Gastrointestinal, Urinary, and Sexual dysfunction), and MoCA subscore (including domains of Attention, Memory, and Orientation) were included as independent variables, and presence/absence of camptocormia was set as dependent variable.
sensory trick can overcome camptocormia, which may suggest that camptocormia may well be a form of dystonia in PD. The lack of association between dopaminergic therapy and the development of camptocormia also suggests that the pathophysiology of camptocormia involves nondopaminergic mechanisms. In most cases, the camptocormia phenomenon is not levodopa
responsive [25] and occurs both in the “OFF” and “ON” medication states. However, a case report [26] showed that the symptoms of camptocormia in a PD patient were the result of using a dopaminergic agent, which may indicate that the pathogenesis of camptocormia between patients in “ON” and “OFF” medication states is potentially different to some extent. In the current study, we did not identify the risk factors in different subtypes of camptocormia (“ON” versus “OFF” mediation states); thus, a further layered study with a larger sample size may help to clarify the relationship between levodopa treatment and camptocormia. It is worth noting that patients with more severe sexual dysfunction tend to develop future camptocormia. High frequencies of autonomic symptoms such as constipation and urinary incontinence have been observed in Japanese PD patients with camptocormia [9]. Recovery of autonomic dysfunction in PD patients is often resistant to levodopa treatment and is known to be related to nondopaminergic systems [27]. This evidence also supports the role of nondopaminergic mechanisms in the pathogenesis of camptocormia. In a structural brain MRI study on camptocormia in patients with PD, the severity of camptocormia was negatively correlated with the normalized sagittal surface of the pons and the whole brain volume [28], implying that the pathological changes in
Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020
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R. Ou et al. / Parkinsonism and Related Disorders xxx (2018) 1e7
patients with camptocormia may be more severe and may spread throughout the brain, particularly in the brainstem where many nuclei regulate autonomic functions. In addition, camptocormia in PD may also result from peripheral mechanisms. Increased creatine kinase levels, myopathic signs observed via electromyography, paraspinal myopathic changes revealed by muscle biopsy and slight fatty degeneration of the bilateral paravertebral musculature identified by MRI have been identified in PD patients with camptocormia [7,29,30], suggesting a myopathy-related aetiology of camptocormia. The multiple pathogenic mechanisms involved in the development of camptocormia indicate that the treatment of camptocormia in PD is very troublesome. However, our limitation was that we did not use electromyography to investigate the electrophysiological differences between our patients with and without camptocormia. Cognitive impairment in PD patients with camptocormia has been found in several previous studies [2,8]. However, all results from these studies were based on a global cognitive assessment scale such as the mini-mental state examination (MMSE). Although we did not find that the MoCA total score was different between patients with and without camptocormia, a lower score in “orientation”, an independent subdomain from the MoCA, was observed in our patients with camptocormia. We further found that these patients with orientation impairment tended to develop camptocormia. This phenomenon is difficult to clearly explain because no relevant imaging or pathological studies are available to clarify this issue. We suspect that disorientation and camptocormia may share the same pathophysiological pathway, which needs to be further identified. However, it is necessary to be aware that the test for the subdomain of “orientation” from the MoCA only refers to the ability of orientation to time and place, so this oversimplified scale is not a rigorous tool to test the orientation of overall cognition. Further comprehensive neuropsychological batteries on the cognition of orientation may help to clarify the relationship between camptocormia and the dysfunction in orientation in PD patients. The present study has several limitations. First, although the prevalence of camptocormia in PD is low, the less positive outcome of camptocormia in the current study may also be attributed to the relatively short follow-up period. Second, other potential factors that may affect the results still exist. Third, the unclear specific mechanisms in camptocormia make it difficult to explain our current results. Finally, we did not identify the risk factors of camptocormia in patients with different medication states (“OFF” or “ON”), so the role of levodopa therapy in the development of camptocormia cannot be definitely identified. 5. Conclusion In conclusion, our study indicates that camptocormia may emerge as PD progresses. Male patients and those with sexual dysfunction or disorientation are more prone to develop future camptocormia. Conflicts of interest The authors declare that they have no conflicts of interest. Acknowledgements The authors thank the patients and their families for their participation in the study. The present study was supported by the funding of the National Science Fund of China (Grant No. 81571247) and the National Key Research and Development Program of China (No. 2016YFC0901504).
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Please cite this article in press as: R. Ou, et al., Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China, Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.03.020