J Neural Transm DOI 10.1007/s00702-014-1198-y
NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - ORIGINAL ARTICLE
Nocturnal manifestations of atypical and vascular parkinsonism: How do they differ from Parkinson’s disease? Roongroj Bhidayasiri • Onanong Jitkritsadakul • Sitthi Petchrutchatachart • Lalita Kaewwilai • Pattamon Panyakaew • Nonglak Boonrod • Carlo Colosimo
Received: 1 February 2014 / Accepted: 12 March 2014 Ó Springer-Verlag Wien 2014
Abstract While nocturnal disturbances of Parkinson’s disease (PD) are increasingly recognized as being part of a continuum that includes daytime manifestations, there is still little analysis in the medical literature that assesses these complex phenomena in patients with atypical (AP) and vascular parkinsonisms (VP). The objective of our study was to determine the prevalence of these disturbances in patients with AP and VP and to determine the range of nighttime symptoms that occur compared with those in patients with PD. This comparison was done using a semi-structured interview and self-rated questionnaires in 63 AP and VP patients (PSP 24, MSA 24, CBD 5, and VP 10), and 208 PD patients. 61 AP and VP patients (96.8 %) and 201 PD patients (96.6 %) reported at least one nocturnal symptom with a score of less than 6 on the Modified Parkinson’s Disease Sleep Scale (MPDSS). Nocturnal akinesia, as measured on the Nocturnal Akinesia, Dystonia, and Cramp Score, was found to be significantly greater in patients with PSP (p = 0.006), MSA (p = 0.002), and CBD (p = 0.012) than PD patients, but not VP patients
R. Bhidayasiri (&) O. Jitkritsadakul S. Petchrutchatachart L. Kaewwilai P. Panyakaew N. Boonrod Chulalongkorn Center of Excellence on Parkinson’s Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University Hospital and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, 1873 Rama 4 Road, Bangkok 10330, Thailand e-mail: [email protected] R. Bhidayasiri Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles 90095, USA C. Colosimo Dipartimento di Scienze Neurologische, Sapienza Universita di Roma, 00185 Rome, Italy
(p = 0.428). Like those with PD, patients with AP and VP identified the problem of getting up at night to urinate (MPDSS item 8) as being the most frequent and troublesome nocturnal symptom. MSA and PSP patients reported more frequent (p = 0.001) and troublesome (p \ 0.001) urinary incontinence (MPDSS item 9) than PD patients and MSA patients had more severe problems with unexpectedly falling asleep during the day (MPDSS item 15) than PD patients (p = 0.003). In summary, our study determined that nocturnal manifestations are commonly experienced by patients with AP and VP and highlighted specific nocturnal symptoms, which are more prevalent and troublesome in certain AP syndromes. The concept of 24-h control of symptoms should not be limited to only PD and we recommend that all who are involved in the care of AP and VP patients should realize that many nocturnal symptoms are experienced by these patients and a multidisciplinary approach should be utilized to address these problems. Keywords Atypical parkinsonism Vascular parkinsonism Modified Parkinson’s Disease Sleep Scale Nocturnal Akinesia Dystonia and Cramp Score Urinary incontinence Nocturnal akinesia Nonmotor symptom
Introduction Nocturnal disturbances in Parkinson’s disease (PD) are increasingly recognized as being part of a continuum that includes daytime manifestations, but there is still little evidence in the medical literature to determine if these complex phenomena occur in patients with atypical (AP) and vascular parkinsonisms (VP) (Lees et al. 1988; Bhidayasiri and Truong 2012; Chaudhuri 2002; Grandas and Iranzo 2004). Based on our knowledge of the pathology of
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the anatomical substrates in AP and VP, which are more extensive outside the basal ganglia than in PD, we might expect that patients with AP and VP would experience the whole range of nocturnal disturbances, including motor symptoms, sleep disorders, autonomic dysfunctions, and neuropsychiatric manifestations at a similar, or even greater, frequency than in PD (Mackenzie 2005). This hypothesis is supported by the recent PRIAMO study which evaluated the presence of nonmotor symptoms in patients with different forms of parkinsonism and found that approximately 70.7–76.7 % of AP patients (except corticobasal degeneration, CBD) experienced similar or even greater sleep disturbances than PD patients (65 %) (Colosimo et al. 2010). In comparison to 58 % of PD patients, 90 % of patients with multiple system atrophy (MSA) reported urinary symptoms, which included nocturia, frequency, and urgency. Atypical is characterized by rapidly evolving parkinsonisms that usually have a poor or transient response to dopaminergic therapy and are often associated with one or more atypical features (Litvan 2005; Wenning et al. 2011). The common forms are MSA, CBD, and progressive supranuclear palsy (PSP). Within the context of parkinsonism, the term ‘‘atypical’’ defines the presence of the physical signs that usually become prominent in the later course of the disease and leave parkinsonism in the background (Litvan 2005). These clinical features may contribute to a whole range of nocturnal symptoms. Severe axial rigidity in PSP, for example, can lead to immobility in bed and difficulty with transfers (De Bruin et al. 1996). VP is a heterogeneous clinical entity with a broad clinical spectrum and variable natural history (Glass et al. 2012). There are no studies to date that systemically evaluate and describe the range of nocturnal disturbances in patients with AP and VP. Therefore, the aim of our study was to determine the prevalence, a range of nighttime symptoms that may occur in patients with AP and VP, to evaluate them, and compare them to those experienced by patients with PD. Appreciating the extent of nocturnal problems in patients with AP and VP has significant clinical implications in addition to being of research interest. Some of the nocturnal symptoms in AP, such as nocturnal stridor in MSA, can be potentially life-threatening, requiring prompt recognition and management (Silber and Levine 2000). Proper management of some of these conditions may prevent severe or even fatal complications such as severe supine hypertension at night in MSA patients, which may lead to intracerebral hemorrhage (Asahina et al. 2005). Importantly, physicians’ awareness of the nighttime problems in these patients is likely to result in the improvement of both patients’ and caregivers’ quality of life (QOL) and the reduction of caregivers’ burden. However, there are no
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studies that specifically evaluate the prevalence of nocturnal problems in patients with AP and VP.
Patients and methods Study design This is a cross-sectional study with a single point-in-time assessment. The objective was to assess the prevalence and manifestations of nocturnal problems of AP and VP patients and to compare the findings with those with PD. The study was approved by the local ethical committee and participants gave written informed consent. The study was conducted by the Chulalongkorn Center of Excellence on Parkinson’s Disease & Related Disorders which is the main tertiary referral center for patients with parkinsonism in Thailand with experiences in clinical studies at both national and international levels (Bhidayasiri et al. 2011). Subjects Patients with AP, VP and PD of all ages and in all stages of the disease were enrolled sequentially at the center. The center adopted the standard diagnostic criteria for the diagnosis of PD (Gibb and Lees 1988), MSA (Gilman et al. 2008), PSP (Litvan et al. 1996), CBD (Riley and Lang 2000), and VP (Zijlmans et al. 2004). Patients with MSA were divided into two groups based on the standard criteria [MSA-Parkinsonism (MSA-P) and MSA-Cerebellar (MSA-C)] (Gilman et al. 2008). The following exclusion criteria were applied: significant cognitive or other impairment that would interfere with the interview; severe and uncontrolled psychiatric comorbidity; enrollment in another study; severe medical conditions deemed by the investigator to impede full participation in the study; and participation in any other study during the previous 30 days. Methods Patients completed a brief questionnaire on demographic characteristics, including date of birth, sex, marital status, employment, education, date of the diagnosis, antiparkinsonian medications, and levodopa equivalent dose (LED) used at the time of the study. Sleep and nocturnal disabilities were assessed using a modified version of the original 15-item Parkinson’s Disease Sleep Scale (MPDSS). Four additional items were included to represent rapid eye movement (REM) behavioral disorder (RBD, item 16 and 17), sudden onset of sleep (item 18), and snoring (item 19) (Chaudhuri et al. 2002; Tanasanvimon et al. 2007). This modified version has been validated and
Nocturnal manifestations of atypical and vascular parkinsonism
tested in Thai PD patients and demonstrated good reliability (Cronbach’s alpha = 0.842) (Tanasanvimon et al. 2007). MPDSS items (assessed by visual analog scales: 0–10) were grouped together into three domains, including disturbed sleep (items 1, 2, 3, 8, 9, 14, 15, 16, 17, 18), motor symptoms at night (items 4, 5, 6, 12, 13), and PD symptoms (items 7, 10, 11, 19) to explore aspects of nocturnal disturbance of specific interest (Trenkwalder et al. 2011). A lower score indicates more severe symptoms. Individual scores below 6 were considered abnormal (Chaudhuri and Martinez-Martin 2004). The NADCS evaluates the severity of akinesia, dystonia, and cramps at night by an ordinal severity scale (0 = normal, 4 = maximal severity, with possible values of 0.5, 1.5, 2.5, and 3.5) (Stocchi et al. 1998). Overall disease severity was graded according to the modified Hoehn and Yahr (HY) (Hoehn and Yahr 1967) and Clinical Global Impression (CGI) scales (Guy 1976). Cognitive function was assessed by the Mini-Mental State Examination-Thai version (TMSE) (Train the Brain Forum Committee 1993). Additional evaluations included the Nonmotor Symptoms Questionnaire (NMSQuest) for nonmotor symptoms (Chaudhuri et al. 2006), and the shortform Parkinson’s Disease Questionnaire (PDQ-8) for quality of life (Jenkinson et al. 2012). For PDQ-8, the summary index is obtained by summing the 8 items and standardizing on a scale of 0–100 (Jenkinson et al. 2012). All scales used in the study are available and validated in Thai. Apart from HY, CGI, and MMSE scales, patients (with the aid of caregivers where necessary) completed the questionnaires while waiting to be seen by the study nurses or physicians. Average time taken to complete the questionnaires was 30 min. The interview was conducted in Thai. Statistical analysis Anonymized data, conforming with data protection legislation in Thailand, were transferred to the Chulalongkorn Center of Excellence on Parkinson’s Disease and Related Disorders for detailed statistical analysis. Baseline characteristics of both AP and PD patients were summarized using either means and standard deviations or frequencies and percentages as appropriate. One-way ANOVA was used for the analysis of group effects. The significance threshold was set to 0.05 with the Least Squares Method in case of multiple comparisons. For categorical data, we used Chi-square test to analyze the differences between the groups. Associations were explored by means of the Spearman rank correlation coefficient. A p value of less than 0.05 was considered to be statistically significant. Statistical analyses were performed using SPSS version 17.0 software (SPSS Inc., Chicago, IL, USA).
Results 208 PD patients (mean age 62.8 ± 10 years), 24 MSA patients (mean age 62.0 ± 6.7 years), 24 PSP patients (mean age 70.4 ± 7.2 years), 5 CBD patients (mean age 65.8 ± 3.4 years), and 10 VP patients (mean age 76.4 ± 6.7 years) were enrolled in the study. Demographics and clinical characteristics are summarized in Table 1. Patients with MSA were divided into two groups: the MSA-P group (16 patients, mean age 63.1 ± 5.6 years) made up 66.7 % of the MSA patients and the MSA-C group (8 patients, mean age 60.0 ± 8.5 years) made up the remaining 33.3 %. The prevalence was higher in men but not statistically significant in all disorders except for MSA, which was predominately female. There were significant differences between groups on age (p \ 0.001) and the age of onset (p \ 0.001) with relatively older age and older age at onset in patients with PSP and VP. Patients with MSA and VP received significantly lower LED than other groups (p \ 0.001). In addition, the differences were also significant in AP patients who had lower TMSE score (p \ 0.001), higher HY stages (p \ 0.001), and higher PDQ-8 SI score (p \ 0.001) than PD patients. Out of 63 AP and VP patients, 61 patients (96.8 %) reported at least one MPDSS item with a score of less than 6. The mean total MPDSS scores for all AP and VP patients were 141.9 (SD 27.5; range 54–183). In PD patients, 201 out of 208 patients (96.6 %) had nocturnal symptoms with a mean total MPDSS score of 138.1 (SD 4.3; range 23–177). While no differences were observed on the total MPDSS scores between PD patients and AP & VP patients groups (p = 0.28), patients with AP and VP had significantly higher total NADCS scores than PD patients (3.6 ± 3.0 vs. 2.5 ± 2.5, p = 0.003). When compared with PD and each individual disorder, no significant differences were noted on the total MPDSS (p = 0.796), and the total NADCS scores (p = 0.055), but significant difference was found in the nocturnal akinesia subscore (p \ 0.001) (Table 2). Significant differences on the nocturnal akinesia subscore were also identified between PD and PSP (p = 0.006), PD and MSA (p = 0.002), PD and CBD (p = 0.012), but not between PD and VP (p = 0.428). No differences on the total MPDSS (p = 0.35) and NADCS (p = 0.22) scores were observed between patients with MSA-P and MSA-C. Similar to PD, patients with AP and VP identified the problem of getting up at night to urinate (MPDSS item 8) as being the most frequent and troublesome nocturnal symptom (PD 56 %, 4.4 ± 3.9; PSP 70.8 %, 2.4 ± 3.8; MSA 75 %, 3.0 ± 4.3; CBD 60 %, 4.6 ± 4.6; VP 80 %, 2.4 ± 3.1). When comparing individual disorders, we observed the significant differences on MPDSS item 1 (the overall quality of the night’s sleep, p = 0.04), item 9
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R. Bhidayasiri et al. Table 1 Comparison of patient groups on demographic data Parameters
PD (N = 208)
PSP (N = 24)
MSA (N = 24)
CBD (N = 5)
Vascular parkinsonism (N = 10)
p value
Male gender
116 (55.8)
15 (62.5)
9 (37.5)
3 (60)
7 (70)
Age (year)
62.8 ± 10.0
70.4 ± 7.2
62.0 ± 6.7
65.8 ± 3.4
76.4 ± 6.7
\0.001d,*
Age of onset (year)
55.4 ± 10.7
64.5 ± 8.6
57.4 ± 5.9
61 ± 3.8
67.8 ± 10.0
\0.001d,*
Disease duration (year)
7.4 ± 5.6
5.7 ± 6.3
4.7 ± 3.3
4.8 ± 2.3
8.6 ± 8.9
0.109d
Marital status: married
176 (84.6)
17 (70.8)
18 (75)
3 (60)
7 (70)
0.191u
Comorbid
88 (42.3)
14 (58.3)
5 (20.8)
3 (60)
6 (60)
0.063u
LED TMSE score
788.5 ± 473 27.3 ± 2.8
956.7 ± 673.8 20.9 ± 10.1
390.5 ± 319 20.9 ± 11.4
1,092.5 ± 577.5 13.6 ± 13.7
427.2 ± 343.7 20.3 ± 10.8
\0.001d,* \0.001d,*
Hoehn and Yahr staging
2.2 ± 0.8
3.4 ± 0.8
3.6 ± 1.1
3.8 ± 1.7
3.3 ± 1.0
\0.001d,*
PDQ-8-SI score
6.2 ± 5.3
11.6 ± 8.5
10.7 ± 7.5
12.8 ± 10.4
11.7 ± 11.1
\0.001d,*
0.340u
PDQ8-SI Parkinson’s disease questionnaire * Statistically significant (p \ 0.05),
u
Chi-square test,
d
One-way ANOVA
Table 2 Comparison of patient groups on nocturnal parameter scores Parameters
PD (N = 208)
PSP (N = 24)
MSA (N = 24)
CBD (N = 5)
Vascular parkinsonism (N = 10)
p value
Total MPDSS score
138.1 ± 24.3
139.5 ± 21.5
142.2 ± 27.4
145.6 ± 44.2
145.4 ± 34.7
0.796d
Disturbed sleep domain Motor sleep domain
67.9 ± 13.3 39.6 ± 8.7
67.5 ± 12.3 40.8 ± 9.5
68.8 ± 14.7 41.4 ± 10.1
73.6 ± 21.5 42.2 ± 13.8
70.5 ± 18.1 43.1 ± 11.9
0.863d 0.624d
PD sleep domain
30.6 ± 8.2
31.1 ± 4.7
31.9 ± 6.7
29.8 ± 9.9
33.9 ± 7.1
0.924d
MPDSS # 1 (overall quality of night’s sleep)
6.8 ± 1.4
6.9 ± 2.9
7.7 ± 1.8
8.0 ± 2.1
7.4 ± 1.9
0.042d,*
MPDSS # 9 (urinary incontinence)
7.7 ± 3.1
4.3 ± 4.1
4.3 ± 4.2
5.0 ± 5.0
6.6 ± 3.8
\0.001d,*
MPDSS # 15 (unexpectedly fallen asleep during the day)
8.5 ± 2.9
7.2 ± 3.7
6.4 ± 4.1
7.0 ± 2.9
8.6 ± 2.8
0.015d,*
Nocturnal akinesia score
1.1 ± 1.2
1.9 ± 1.5
2.0 ± 1.4
2.6 ± 1.9
1.4 ± 1.3
\0.001d,*
Nocturnal dystonia score
0.6 ± 0.9
0.6 ± 1.2
0.9 ± 1.3
1.9 ± 1.4
0.9 ± 1.2
0.055d
Nocturnal cramp score
0.8 ± 1.0
1.0 ± 1.3
0.7 ± 1.0
0±0
1.1 ± 0.8
0.275d
Total NADCS score
2.5 ± 2.5
3.5 ± 3.4
3.5 ± 3.1
4.4 ± 3.3
3.5 ± 2.2
0.055d
10.5 ± 5.5
10.7 ± 4.3
11.0 ± 5.2
7.6 ± 4.7
8.9 ± 6.3
0.637d
Total NMS score
MPDSS modified Parkinson’s disease sleep scale, NADCS nocturnal akinesia dystonia cramp score, PDQ8-S Parkinson’s disease questionnaire, NMS nonmotor symptoms questionnaire * Statistically significant (p \ 0.05),
d
One-way ANOVA
(incontinence of urine because of ‘‘off’’ symptoms, p \ 0.001), and 15 (unexpectedly falling asleep during the day, p = 0.01). PD patients reported significantly more troublesome problems with sleep quality (MPDSS item 1) than MSA patients (p = 0.008), while MSA and PSP patients reported more frequent (p = 0.001) and troublesome (p \ 0.001) urinary incontinence (MPDSS item 9) than PD patients (Fig. 1). Moreover, MSA patients had more severe problems with unexpectedly falling asleep during the day (MPDSS item 15) than PD patients (p = 0.003) (Fig. 1). Concerning the prevalence of NMS in the different diagnostic groups, PSP patients reported more NMS in several domains than PD patients, including
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dribbling of saliva (NMS item 1, p = 0.02), difficulty swallowing (NMS item 3, p \ 0.001), bowel incontinence (NMS item 6, p \ 0.001), a sense of urgency to urinate (NMS item 8, p = 0.002), falling asleep (NMS item 21, p \ 0.001), and swelling of legs (NMS item 27, p = 0.003), but had less frequent experience with a diminished interest in sex (NMS item 18, p = 0.01), and believing things are happening to you that other people say are not true than PD patients (NMS item 30, p = 0.002). MSA patients had a significantly higher level of NMS complaints (item 1, 3, 6, 8, and 21) than PD patients, while all 5 CBD patients reported the problem of sexual dysfunction and unpleasant sensations in the legs at night, and
Nocturnal manifestations of atypical and vascular parkinsonism
Fig. 1 The bar graph demonstrating the percentage of patients with nocturnal symptoms and individual scores as determined by the Modified Parkinson’s Disease Sleep Scale (MPDSS)
a feeling that he/she needs to move. Table 3 summarizes the frequency of NMS domains in the different forms of AP and VP with the statistical analysis comparing them with PD. The correlation coefficients between the MPDSS and patient demographics, HY stage, CGI, PDQ-8 SI, NMS and NADCS scores are shown in Table 4. In PD patients, there were significant moderate correlations between MPDSS score and PDQ-8 SI, NMS scores, total NADCS and nocturnal akinesia subscores. Significant strong correlations between NMS scores and the total MPDSS were also observed in patients with MSA, CBD, and VP, but not with PSP. Nocturnal akinesia was strongly and significantly associated with the total MPDSS score in CBD patients.
Discussion Similar to PD, we found that, like PD, nocturnal disability as determined by MPDSS is very common among AP and VP patients, affecting 96.8 % of our study population. Within the context of NADCS, which evaluates the presence of nocturnal akinesia, dystonia, and cramps, AP and VP patients were found to have higher scores than PD patients reflecting worsening nighttime motor symptoms. In particular, the aspect of akinesia seems to be primarily
affected in PSP, MSA, and CBD, but not VP patients compared to PD. The main reason may be due to significantly higher HY stages among AP patients (AP 3.4–3.8 ± 0.8–1.7 vs. PD 2.2 ± 0.8), which indicate more severe disease and the involvement of axial structures. Anatomically, early and severe degeneration of descending projections from pedunculopontine nucleus to reticulospinal neurons of the medial pontine and medullary reticular formation may partly explain a predominant akinetic-rigid syndrome with rapid involvement of axial structures in AP (Benarroch 2013). While clinical evidence of nocturnal akinesia is limited in APs, immobility in bed and difficulty with transfers were shown in one clinical study to be more frequent in PSP patients than normal controls (De Bruin et al. 1996). As determined by MPDSS, several nocturnal symptoms were found to be significantly more prevalent and troublesome in AP than in PD patients. In particular, urinary incontinence due to ‘‘off’’ symptoms was significantly more frequent and troublesome in both MSA and PSP patients than in PD patients (Fig. 1). The symptom of urinary incontinence is considered as a feature of autonomic failure in the consensus statement on the diagnosis of MSA and was identified in 73 % of MSA (our study 58.3 %) and 35 % of PSP patients (our study 58.3 %) in two large European cohort studies (in contrast to 5 % of
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R. Bhidayasiri et al. Table 3 Comparison between atypical parkinsonian and PD patients on frequent NMS Symptoms Parameters
PD N (%)
PSP N (%)
MSA p value
N (%)
CBD p value
N (%)
Vascular parkinsonism p value
N (%)
p value
NMS item 1: dribbling of saliva
72 (34.6)
14 (58.3)
0.023*
14 (58.3)
0.023*
1 (20)
0.496
8 (80)
0.004*
NMS item 3: difficulty swallowing
80 (38.5)
20 (83.3) \0.001*
17 (70.8)
0.002*
3 (60)
0.329
3 (30)
0.590
NMS item 6: bowel incontinence NMS item 8: urgency to pass urine
19 (9.1) 96 (46.2)
8 (33.3) \0.001* 19 (79.2) 0.002*
9 (37.5) \0.001* 17 (70.8) 0.022*
2 (40) 1 (20)
0.022* 0.246
1 (10) 5 (50)
0.926 0.812
NMS item 18: less or more interested in sex
90 (43.3)
0.185
5 (100)
0.053
1 (10)
0.037*
NMS item 21: falling
50 (24)
15 (62.5) \0.001*
12 (50)
0.007*
1 (20)
0.834
2 (20)
0.770
NMS item 26: unpleasant sensations in your legs at night or while resting
98 (47.1)
10 (41.7)
0.612
6 (25)
0.039*
5 (100)
0.037*
2 (20)
0.093
NMS item 27: swelling of your legs
46 (22.1)
12 (50)
0.003*
8 (33.3)
0.218
3 (60)
0.047*
4 (40)
0.189
NMS item 30: believing things are happening to you that other people say are not true
32 (15.4)
1 (4.2)
1 (4.2)
0.136
1 (20)
0.778
10 (100)
0.179
4 (16.7)
0.012*
0.002*
7 (29.2)
All frequency comparisons were done with Chi-square test NMS nonmotor symptoms * Statistically significant (p \ 0.05), values in parenthesis are shown as percentage
PD patients) (Gilman et al. 2008; Wenning et al. 2013; Donker Kaat et al. 2007) While this feature seems to be more common in MSA and PSP, its utility as a discriminatory feature from PD is still unclear (Reimann et al. 2010). Although not more frequent, our MSA patients suffered from more severe sudden onset of sleep during the day than PD patients; the findings consistent with the SLEEMSA study, a large multicenter study of excessive daytime sleepiness (EDS) in Europe (Moreno-Lopez et al. 2011). In that study, in contrast to PD, EDS in MSA seems to be unrelated to the amount of dopaminergic treatment. Our study also evaluated the presence of NMS in AP and VP patients, compared with PD patients. While the total NMS scores did not show any differences between individual disorders, the differences were observed between specific NMS and AP in comparison to PD. Despite limited evidence in the medical literature, two recent studies suggested that AP patients do suffer from various NMS in which some domains may be more frequent and severe than PD patients (Colosimo et al. 2010; Lee et al. 2013). Although not possible for direct comparison since our study utilized different scales to measure NMS, the results of our study share some similarities with the recent PRIAMO study that PSP and MSA patients significantly experienced more gastrointestinal and urinary urgency than PD patients (Colosimo et al. 2010). In contrast, PD patients significantly reported more sexual problems than PSP and VP patients. If we explore only the nocturnal domain of NMSQuest (items 23, 24, 25, 26), no differences were noted between different forms of parkinsonism (including PD) except for CBD in which all five patients reported the symptoms of unpleasant sensations in
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the legs at night associated with a feeling that he/she needs to move. Although suggestive, this symptom alone is not diagnostic of restless legs syndrome (RLS) (Allen et al. 2003). Even though the small number of CBD patients may limit full statistical interpretation, one polysomnographic study reported that 4 out of 5 CBD patients displayed PLM and/or RLS (Roche et al. 2007). This finding merits further investigation. The occurrence of NMS correlates with the presence of nocturnal symptoms in PD and MSA patients. The correlation in CBD patients should be interpreted with caution due to a small number of subjects. Based on these findings, our study supports the presence of NMS in patients with AP and VP and certain NMS may be more prevalent in some forms of parkinsonism but the validity of these NMS in differentiating parkinsonian symptoms is not yet determined. There are some limitations in our study. First and foremost is the small numbers of CBD and VP patients which may limit adequate statistical comparison between these patients and a large number of PD patients. However, we employed stringent diagnostic criteria of individual forms of parkinsonism to ensure that we have recruited patients with a correct diagnosis. For example, we emphasized the relationship between the onset of parkinsonism and radiological evidence of cerebrovascular diseases for the diagnosis of VP (Zijlmans et al. 2004). Although atypical presentations of AP and different manifestations of VP are increasingly recognized, such cases are excluded from our study as these presentations may not fulfill the standard diagnostic criteria. Second, the scales that we employed in this study have not been formally validated in AP and VP. Therefore, the interpretation of
Nocturnal manifestations of atypical and vascular parkinsonism Table 4 Correlation between patient/disease characteristics and the total MPDSS scores on different patients groups Parameters
Total MPDSS score PD
PSP
MSA
CBD
Vascular parkinsonism
Age
-0.084
-0.189
0.140
0.462
-0.143
Disease duration
-0.249*
-0.035
0.112
-0.564
-0.391
LED
-0.298*
-0.241
-0.261
-0.200
-0.131
TMSE Hoehn and Yahr staging
0.187*
0.117
0.115
-0.266*
-0.115
-0.315
0.975*
-0.277
-0.894*
-0.688*
CGI
-0.286*
-0.104
-0.263
-0.866
-0.121
Total PDQ-8 SI Total NMS scores
-0.518* -0.546*
-0.038 -0.261
-0.413 -0.712*
-0.800 -0.900*
-0.618 -0.707*
Nocturnal akinesia
-0.359*
0.128
-0.339
-0.894*
-0.458
Nocturnal dystonia
-0.110
-0.055
-0.201
-0.821
-0.447
Nocturnal cramp
-0.164*
-0.163
-0.502
na
-0.098
Total NADCS
-0.351*
0.084
-0.451
-0.821
-0.508
All correlations were done by Spearman’s correlation MPDSS modified Parkinson’s disease sleep score, NADCS nocturnal akinesia dystonia cramps score, LED levodopa equivalent dose, TMSE Mini-mental status examination-Thai version, CGI clinical global impression, PDQ-8 S Parkinson’s disease questionnaire Short-form summary index, PDQ8-SI Parkinson’s disease questionnaire, NMS nonmotor symptoms questionnaire, na not analyzed * Statistically significant (p \ 0.05)
these scales in other forms of parkinsonism outside PD should be reviewed with caution. Since there are no existing validated scales to determine nocturnal disabilities in AP and VP patients and our aim is to compare these findings with PD patients, we have utilized different scales (both MPDSS and NADCS) to capture various nocturnal manifestations in different forms of parkinsonism. Finally, some nighttime symptoms may occur as a result of coexisting medical conditions in the elderly. For example, urinary incontinence may be partially attributable to benign prostatic hyperplasia. Daily management of AP and VP is challenging. Both patients and caregivers often are faced with diverse symptomatology in which many of them are found to be nonlevodopa responsive. Moreover, a significant proportion is devoted to nighttime problems as our study has highlighted a number of nocturnal issues that these patients frequently encounter. First of all, patients with AP and VP encounter the problems of nocturnal disturbances as frequently as or even more than patients with PD. Second, patients with PSP, MSA, and CBD suffer from more nocturnal akinesia than PD patients. PSP and MSA patients reported more problems with urinary incontinence in both frequency and severity than PD patients, while MSA patients were found to have more severe sudden onset of sleep than PD patients. Strong and significant correlations were also found between the NMS scores and the total MPDSS in both PD and MSA patients. Although our study has identified specific nocturnal symptoms in AP patients, the presence of these symptoms does not help in differentiating parkinsonian
syndromes. Longitudinal studies involving large patient samples are needed to identify the important nocturnal issues in these patients, which will further lead to therapeutic trials. Based on the results of our study, we propose that the concept of 24-h control of symptoms should not be limited to only PD and all parties who are involved in the care of AP and VP patients should be aware of a myriad nocturnal symptomatology in these patients and a multidisciplinary approach should be utilized to address these problems. Moreover, caregivers should not be neglected and support should be provided to them since they are most likely the only persons who are faced with the problems of the patients at night. Acknowledgments The study was supported by the Rachadaphiseksomphot Endowment Fund of the ‘‘Strengthen CU’s Researcher’s Project’’ and research unit (RU) Grant number GRU 56-012-30-002 of Chulalongkorn Center of Excellence on Parkinson’s Disease and Related Disorders, Chulalongkorn University, Bangkok, Thailand. We would like to thank Ratanaruedee Devahastin, Onnalin Jandaew, and Kamolwan Boonpeng for their assistance in patient recruitment and data assortment.
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NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - ORIGINAL ARTICLE
Nocturnal manifestations of atypical and vascular parkinsonism: How do they differ from Parkinson’s disease? Roongroj Bhidayasiri • Onanong Jitkritsadakul • Sitthi Petchrutchatachart • Lalita Kaewwilai • Pattamon Panyakaew • Nonglak Boonrod • Carlo Colosimo
Received: 1 February 2014 / Accepted: 12 March 2014 Ó Springer-Verlag Wien 2014
Abstract While nocturnal disturbances of Parkinson’s disease (PD) are increasingly recognized as being part of a continuum that includes daytime manifestations, there is still little analysis in the medical literature that assesses these complex phenomena in patients with atypical (AP) and vascular parkinsonisms (VP). The objective of our study was to determine the prevalence of these disturbances in patients with AP and VP and to determine the range of nighttime symptoms that occur compared with those in patients with PD. This comparison was done using a semi-structured interview and self-rated questionnaires in 63 AP and VP patients (PSP 24, MSA 24, CBD 5, and VP 10), and 208 PD patients. 61 AP and VP patients (96.8 %) and 201 PD patients (96.6 %) reported at least one nocturnal symptom with a score of less than 6 on the Modified Parkinson’s Disease Sleep Scale (MPDSS). Nocturnal akinesia, as measured on the Nocturnal Akinesia, Dystonia, and Cramp Score, was found to be significantly greater in patients with PSP (p = 0.006), MSA (p = 0.002), and CBD (p = 0.012) than PD patients, but not VP patients
R. Bhidayasiri (&) O. Jitkritsadakul S. Petchrutchatachart L. Kaewwilai P. Panyakaew N. Boonrod Chulalongkorn Center of Excellence on Parkinson’s Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University Hospital and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, 1873 Rama 4 Road, Bangkok 10330, Thailand e-mail: [email protected] R. Bhidayasiri Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles 90095, USA C. Colosimo Dipartimento di Scienze Neurologische, Sapienza Universita di Roma, 00185 Rome, Italy
(p = 0.428). Like those with PD, patients with AP and VP identified the problem of getting up at night to urinate (MPDSS item 8) as being the most frequent and troublesome nocturnal symptom. MSA and PSP patients reported more frequent (p = 0.001) and troublesome (p \ 0.001) urinary incontinence (MPDSS item 9) than PD patients and MSA patients had more severe problems with unexpectedly falling asleep during the day (MPDSS item 15) than PD patients (p = 0.003). In summary, our study determined that nocturnal manifestations are commonly experienced by patients with AP and VP and highlighted specific nocturnal symptoms, which are more prevalent and troublesome in certain AP syndromes. The concept of 24-h control of symptoms should not be limited to only PD and we recommend that all who are involved in the care of AP and VP patients should realize that many nocturnal symptoms are experienced by these patients and a multidisciplinary approach should be utilized to address these problems. Keywords Atypical parkinsonism Vascular parkinsonism Modified Parkinson’s Disease Sleep Scale Nocturnal Akinesia Dystonia and Cramp Score Urinary incontinence Nocturnal akinesia Nonmotor symptom
Introduction Nocturnal disturbances in Parkinson’s disease (PD) are increasingly recognized as being part of a continuum that includes daytime manifestations, but there is still little evidence in the medical literature to determine if these complex phenomena occur in patients with atypical (AP) and vascular parkinsonisms (VP) (Lees et al. 1988; Bhidayasiri and Truong 2012; Chaudhuri 2002; Grandas and Iranzo 2004). Based on our knowledge of the pathology of
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the anatomical substrates in AP and VP, which are more extensive outside the basal ganglia than in PD, we might expect that patients with AP and VP would experience the whole range of nocturnal disturbances, including motor symptoms, sleep disorders, autonomic dysfunctions, and neuropsychiatric manifestations at a similar, or even greater, frequency than in PD (Mackenzie 2005). This hypothesis is supported by the recent PRIAMO study which evaluated the presence of nonmotor symptoms in patients with different forms of parkinsonism and found that approximately 70.7–76.7 % of AP patients (except corticobasal degeneration, CBD) experienced similar or even greater sleep disturbances than PD patients (65 %) (Colosimo et al. 2010). In comparison to 58 % of PD patients, 90 % of patients with multiple system atrophy (MSA) reported urinary symptoms, which included nocturia, frequency, and urgency. Atypical is characterized by rapidly evolving parkinsonisms that usually have a poor or transient response to dopaminergic therapy and are often associated with one or more atypical features (Litvan 2005; Wenning et al. 2011). The common forms are MSA, CBD, and progressive supranuclear palsy (PSP). Within the context of parkinsonism, the term ‘‘atypical’’ defines the presence of the physical signs that usually become prominent in the later course of the disease and leave parkinsonism in the background (Litvan 2005). These clinical features may contribute to a whole range of nocturnal symptoms. Severe axial rigidity in PSP, for example, can lead to immobility in bed and difficulty with transfers (De Bruin et al. 1996). VP is a heterogeneous clinical entity with a broad clinical spectrum and variable natural history (Glass et al. 2012). There are no studies to date that systemically evaluate and describe the range of nocturnal disturbances in patients with AP and VP. Therefore, the aim of our study was to determine the prevalence, a range of nighttime symptoms that may occur in patients with AP and VP, to evaluate them, and compare them to those experienced by patients with PD. Appreciating the extent of nocturnal problems in patients with AP and VP has significant clinical implications in addition to being of research interest. Some of the nocturnal symptoms in AP, such as nocturnal stridor in MSA, can be potentially life-threatening, requiring prompt recognition and management (Silber and Levine 2000). Proper management of some of these conditions may prevent severe or even fatal complications such as severe supine hypertension at night in MSA patients, which may lead to intracerebral hemorrhage (Asahina et al. 2005). Importantly, physicians’ awareness of the nighttime problems in these patients is likely to result in the improvement of both patients’ and caregivers’ quality of life (QOL) and the reduction of caregivers’ burden. However, there are no
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studies that specifically evaluate the prevalence of nocturnal problems in patients with AP and VP.
Patients and methods Study design This is a cross-sectional study with a single point-in-time assessment. The objective was to assess the prevalence and manifestations of nocturnal problems of AP and VP patients and to compare the findings with those with PD. The study was approved by the local ethical committee and participants gave written informed consent. The study was conducted by the Chulalongkorn Center of Excellence on Parkinson’s Disease & Related Disorders which is the main tertiary referral center for patients with parkinsonism in Thailand with experiences in clinical studies at both national and international levels (Bhidayasiri et al. 2011). Subjects Patients with AP, VP and PD of all ages and in all stages of the disease were enrolled sequentially at the center. The center adopted the standard diagnostic criteria for the diagnosis of PD (Gibb and Lees 1988), MSA (Gilman et al. 2008), PSP (Litvan et al. 1996), CBD (Riley and Lang 2000), and VP (Zijlmans et al. 2004). Patients with MSA were divided into two groups based on the standard criteria [MSA-Parkinsonism (MSA-P) and MSA-Cerebellar (MSA-C)] (Gilman et al. 2008). The following exclusion criteria were applied: significant cognitive or other impairment that would interfere with the interview; severe and uncontrolled psychiatric comorbidity; enrollment in another study; severe medical conditions deemed by the investigator to impede full participation in the study; and participation in any other study during the previous 30 days. Methods Patients completed a brief questionnaire on demographic characteristics, including date of birth, sex, marital status, employment, education, date of the diagnosis, antiparkinsonian medications, and levodopa equivalent dose (LED) used at the time of the study. Sleep and nocturnal disabilities were assessed using a modified version of the original 15-item Parkinson’s Disease Sleep Scale (MPDSS). Four additional items were included to represent rapid eye movement (REM) behavioral disorder (RBD, item 16 and 17), sudden onset of sleep (item 18), and snoring (item 19) (Chaudhuri et al. 2002; Tanasanvimon et al. 2007). This modified version has been validated and
Nocturnal manifestations of atypical and vascular parkinsonism
tested in Thai PD patients and demonstrated good reliability (Cronbach’s alpha = 0.842) (Tanasanvimon et al. 2007). MPDSS items (assessed by visual analog scales: 0–10) were grouped together into three domains, including disturbed sleep (items 1, 2, 3, 8, 9, 14, 15, 16, 17, 18), motor symptoms at night (items 4, 5, 6, 12, 13), and PD symptoms (items 7, 10, 11, 19) to explore aspects of nocturnal disturbance of specific interest (Trenkwalder et al. 2011). A lower score indicates more severe symptoms. Individual scores below 6 were considered abnormal (Chaudhuri and Martinez-Martin 2004). The NADCS evaluates the severity of akinesia, dystonia, and cramps at night by an ordinal severity scale (0 = normal, 4 = maximal severity, with possible values of 0.5, 1.5, 2.5, and 3.5) (Stocchi et al. 1998). Overall disease severity was graded according to the modified Hoehn and Yahr (HY) (Hoehn and Yahr 1967) and Clinical Global Impression (CGI) scales (Guy 1976). Cognitive function was assessed by the Mini-Mental State Examination-Thai version (TMSE) (Train the Brain Forum Committee 1993). Additional evaluations included the Nonmotor Symptoms Questionnaire (NMSQuest) for nonmotor symptoms (Chaudhuri et al. 2006), and the shortform Parkinson’s Disease Questionnaire (PDQ-8) for quality of life (Jenkinson et al. 2012). For PDQ-8, the summary index is obtained by summing the 8 items and standardizing on a scale of 0–100 (Jenkinson et al. 2012). All scales used in the study are available and validated in Thai. Apart from HY, CGI, and MMSE scales, patients (with the aid of caregivers where necessary) completed the questionnaires while waiting to be seen by the study nurses or physicians. Average time taken to complete the questionnaires was 30 min. The interview was conducted in Thai. Statistical analysis Anonymized data, conforming with data protection legislation in Thailand, were transferred to the Chulalongkorn Center of Excellence on Parkinson’s Disease and Related Disorders for detailed statistical analysis. Baseline characteristics of both AP and PD patients were summarized using either means and standard deviations or frequencies and percentages as appropriate. One-way ANOVA was used for the analysis of group effects. The significance threshold was set to 0.05 with the Least Squares Method in case of multiple comparisons. For categorical data, we used Chi-square test to analyze the differences between the groups. Associations were explored by means of the Spearman rank correlation coefficient. A p value of less than 0.05 was considered to be statistically significant. Statistical analyses were performed using SPSS version 17.0 software (SPSS Inc., Chicago, IL, USA).
Results 208 PD patients (mean age 62.8 ± 10 years), 24 MSA patients (mean age 62.0 ± 6.7 years), 24 PSP patients (mean age 70.4 ± 7.2 years), 5 CBD patients (mean age 65.8 ± 3.4 years), and 10 VP patients (mean age 76.4 ± 6.7 years) were enrolled in the study. Demographics and clinical characteristics are summarized in Table 1. Patients with MSA were divided into two groups: the MSA-P group (16 patients, mean age 63.1 ± 5.6 years) made up 66.7 % of the MSA patients and the MSA-C group (8 patients, mean age 60.0 ± 8.5 years) made up the remaining 33.3 %. The prevalence was higher in men but not statistically significant in all disorders except for MSA, which was predominately female. There were significant differences between groups on age (p \ 0.001) and the age of onset (p \ 0.001) with relatively older age and older age at onset in patients with PSP and VP. Patients with MSA and VP received significantly lower LED than other groups (p \ 0.001). In addition, the differences were also significant in AP patients who had lower TMSE score (p \ 0.001), higher HY stages (p \ 0.001), and higher PDQ-8 SI score (p \ 0.001) than PD patients. Out of 63 AP and VP patients, 61 patients (96.8 %) reported at least one MPDSS item with a score of less than 6. The mean total MPDSS scores for all AP and VP patients were 141.9 (SD 27.5; range 54–183). In PD patients, 201 out of 208 patients (96.6 %) had nocturnal symptoms with a mean total MPDSS score of 138.1 (SD 4.3; range 23–177). While no differences were observed on the total MPDSS scores between PD patients and AP & VP patients groups (p = 0.28), patients with AP and VP had significantly higher total NADCS scores than PD patients (3.6 ± 3.0 vs. 2.5 ± 2.5, p = 0.003). When compared with PD and each individual disorder, no significant differences were noted on the total MPDSS (p = 0.796), and the total NADCS scores (p = 0.055), but significant difference was found in the nocturnal akinesia subscore (p \ 0.001) (Table 2). Significant differences on the nocturnal akinesia subscore were also identified between PD and PSP (p = 0.006), PD and MSA (p = 0.002), PD and CBD (p = 0.012), but not between PD and VP (p = 0.428). No differences on the total MPDSS (p = 0.35) and NADCS (p = 0.22) scores were observed between patients with MSA-P and MSA-C. Similar to PD, patients with AP and VP identified the problem of getting up at night to urinate (MPDSS item 8) as being the most frequent and troublesome nocturnal symptom (PD 56 %, 4.4 ± 3.9; PSP 70.8 %, 2.4 ± 3.8; MSA 75 %, 3.0 ± 4.3; CBD 60 %, 4.6 ± 4.6; VP 80 %, 2.4 ± 3.1). When comparing individual disorders, we observed the significant differences on MPDSS item 1 (the overall quality of the night’s sleep, p = 0.04), item 9
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R. Bhidayasiri et al. Table 1 Comparison of patient groups on demographic data Parameters
PD (N = 208)
PSP (N = 24)
MSA (N = 24)
CBD (N = 5)
Vascular parkinsonism (N = 10)
p value
Male gender
116 (55.8)
15 (62.5)
9 (37.5)
3 (60)
7 (70)
Age (year)
62.8 ± 10.0
70.4 ± 7.2
62.0 ± 6.7
65.8 ± 3.4
76.4 ± 6.7
\0.001d,*
Age of onset (year)
55.4 ± 10.7
64.5 ± 8.6
57.4 ± 5.9
61 ± 3.8
67.8 ± 10.0
\0.001d,*
Disease duration (year)
7.4 ± 5.6
5.7 ± 6.3
4.7 ± 3.3
4.8 ± 2.3
8.6 ± 8.9
0.109d
Marital status: married
176 (84.6)
17 (70.8)
18 (75)
3 (60)
7 (70)
0.191u
Comorbid
88 (42.3)
14 (58.3)
5 (20.8)
3 (60)
6 (60)
0.063u
LED TMSE score
788.5 ± 473 27.3 ± 2.8
956.7 ± 673.8 20.9 ± 10.1
390.5 ± 319 20.9 ± 11.4
1,092.5 ± 577.5 13.6 ± 13.7
427.2 ± 343.7 20.3 ± 10.8
\0.001d,* \0.001d,*
Hoehn and Yahr staging
2.2 ± 0.8
3.4 ± 0.8
3.6 ± 1.1
3.8 ± 1.7
3.3 ± 1.0
\0.001d,*
PDQ-8-SI score
6.2 ± 5.3
11.6 ± 8.5
10.7 ± 7.5
12.8 ± 10.4
11.7 ± 11.1
\0.001d,*
0.340u
PDQ8-SI Parkinson’s disease questionnaire * Statistically significant (p \ 0.05),
u
Chi-square test,
d
One-way ANOVA
Table 2 Comparison of patient groups on nocturnal parameter scores Parameters
PD (N = 208)
PSP (N = 24)
MSA (N = 24)
CBD (N = 5)
Vascular parkinsonism (N = 10)
p value
Total MPDSS score
138.1 ± 24.3
139.5 ± 21.5
142.2 ± 27.4
145.6 ± 44.2
145.4 ± 34.7
0.796d
Disturbed sleep domain Motor sleep domain
67.9 ± 13.3 39.6 ± 8.7
67.5 ± 12.3 40.8 ± 9.5
68.8 ± 14.7 41.4 ± 10.1
73.6 ± 21.5 42.2 ± 13.8
70.5 ± 18.1 43.1 ± 11.9
0.863d 0.624d
PD sleep domain
30.6 ± 8.2
31.1 ± 4.7
31.9 ± 6.7
29.8 ± 9.9
33.9 ± 7.1
0.924d
MPDSS # 1 (overall quality of night’s sleep)
6.8 ± 1.4
6.9 ± 2.9
7.7 ± 1.8
8.0 ± 2.1
7.4 ± 1.9
0.042d,*
MPDSS # 9 (urinary incontinence)
7.7 ± 3.1
4.3 ± 4.1
4.3 ± 4.2
5.0 ± 5.0
6.6 ± 3.8
\0.001d,*
MPDSS # 15 (unexpectedly fallen asleep during the day)
8.5 ± 2.9
7.2 ± 3.7
6.4 ± 4.1
7.0 ± 2.9
8.6 ± 2.8
0.015d,*
Nocturnal akinesia score
1.1 ± 1.2
1.9 ± 1.5
2.0 ± 1.4
2.6 ± 1.9
1.4 ± 1.3
\0.001d,*
Nocturnal dystonia score
0.6 ± 0.9
0.6 ± 1.2
0.9 ± 1.3
1.9 ± 1.4
0.9 ± 1.2
0.055d
Nocturnal cramp score
0.8 ± 1.0
1.0 ± 1.3
0.7 ± 1.0
0±0
1.1 ± 0.8
0.275d
Total NADCS score
2.5 ± 2.5
3.5 ± 3.4
3.5 ± 3.1
4.4 ± 3.3
3.5 ± 2.2
0.055d
10.5 ± 5.5
10.7 ± 4.3
11.0 ± 5.2
7.6 ± 4.7
8.9 ± 6.3
0.637d
Total NMS score
MPDSS modified Parkinson’s disease sleep scale, NADCS nocturnal akinesia dystonia cramp score, PDQ8-S Parkinson’s disease questionnaire, NMS nonmotor symptoms questionnaire * Statistically significant (p \ 0.05),
d
One-way ANOVA
(incontinence of urine because of ‘‘off’’ symptoms, p \ 0.001), and 15 (unexpectedly falling asleep during the day, p = 0.01). PD patients reported significantly more troublesome problems with sleep quality (MPDSS item 1) than MSA patients (p = 0.008), while MSA and PSP patients reported more frequent (p = 0.001) and troublesome (p \ 0.001) urinary incontinence (MPDSS item 9) than PD patients (Fig. 1). Moreover, MSA patients had more severe problems with unexpectedly falling asleep during the day (MPDSS item 15) than PD patients (p = 0.003) (Fig. 1). Concerning the prevalence of NMS in the different diagnostic groups, PSP patients reported more NMS in several domains than PD patients, including
123
dribbling of saliva (NMS item 1, p = 0.02), difficulty swallowing (NMS item 3, p \ 0.001), bowel incontinence (NMS item 6, p \ 0.001), a sense of urgency to urinate (NMS item 8, p = 0.002), falling asleep (NMS item 21, p \ 0.001), and swelling of legs (NMS item 27, p = 0.003), but had less frequent experience with a diminished interest in sex (NMS item 18, p = 0.01), and believing things are happening to you that other people say are not true than PD patients (NMS item 30, p = 0.002). MSA patients had a significantly higher level of NMS complaints (item 1, 3, 6, 8, and 21) than PD patients, while all 5 CBD patients reported the problem of sexual dysfunction and unpleasant sensations in the legs at night, and
Nocturnal manifestations of atypical and vascular parkinsonism
Fig. 1 The bar graph demonstrating the percentage of patients with nocturnal symptoms and individual scores as determined by the Modified Parkinson’s Disease Sleep Scale (MPDSS)
a feeling that he/she needs to move. Table 3 summarizes the frequency of NMS domains in the different forms of AP and VP with the statistical analysis comparing them with PD. The correlation coefficients between the MPDSS and patient demographics, HY stage, CGI, PDQ-8 SI, NMS and NADCS scores are shown in Table 4. In PD patients, there were significant moderate correlations between MPDSS score and PDQ-8 SI, NMS scores, total NADCS and nocturnal akinesia subscores. Significant strong correlations between NMS scores and the total MPDSS were also observed in patients with MSA, CBD, and VP, but not with PSP. Nocturnal akinesia was strongly and significantly associated with the total MPDSS score in CBD patients.
Discussion Similar to PD, we found that, like PD, nocturnal disability as determined by MPDSS is very common among AP and VP patients, affecting 96.8 % of our study population. Within the context of NADCS, which evaluates the presence of nocturnal akinesia, dystonia, and cramps, AP and VP patients were found to have higher scores than PD patients reflecting worsening nighttime motor symptoms. In particular, the aspect of akinesia seems to be primarily
affected in PSP, MSA, and CBD, but not VP patients compared to PD. The main reason may be due to significantly higher HY stages among AP patients (AP 3.4–3.8 ± 0.8–1.7 vs. PD 2.2 ± 0.8), which indicate more severe disease and the involvement of axial structures. Anatomically, early and severe degeneration of descending projections from pedunculopontine nucleus to reticulospinal neurons of the medial pontine and medullary reticular formation may partly explain a predominant akinetic-rigid syndrome with rapid involvement of axial structures in AP (Benarroch 2013). While clinical evidence of nocturnal akinesia is limited in APs, immobility in bed and difficulty with transfers were shown in one clinical study to be more frequent in PSP patients than normal controls (De Bruin et al. 1996). As determined by MPDSS, several nocturnal symptoms were found to be significantly more prevalent and troublesome in AP than in PD patients. In particular, urinary incontinence due to ‘‘off’’ symptoms was significantly more frequent and troublesome in both MSA and PSP patients than in PD patients (Fig. 1). The symptom of urinary incontinence is considered as a feature of autonomic failure in the consensus statement on the diagnosis of MSA and was identified in 73 % of MSA (our study 58.3 %) and 35 % of PSP patients (our study 58.3 %) in two large European cohort studies (in contrast to 5 % of
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R. Bhidayasiri et al. Table 3 Comparison between atypical parkinsonian and PD patients on frequent NMS Symptoms Parameters
PD N (%)
PSP N (%)
MSA p value
N (%)
CBD p value
N (%)
Vascular parkinsonism p value
N (%)
p value
NMS item 1: dribbling of saliva
72 (34.6)
14 (58.3)
0.023*
14 (58.3)
0.023*
1 (20)
0.496
8 (80)
0.004*
NMS item 3: difficulty swallowing
80 (38.5)
20 (83.3) \0.001*
17 (70.8)
0.002*
3 (60)
0.329
3 (30)
0.590
NMS item 6: bowel incontinence NMS item 8: urgency to pass urine
19 (9.1) 96 (46.2)
8 (33.3) \0.001* 19 (79.2) 0.002*
9 (37.5) \0.001* 17 (70.8) 0.022*
2 (40) 1 (20)
0.022* 0.246
1 (10) 5 (50)
0.926 0.812
NMS item 18: less or more interested in sex
90 (43.3)
0.185
5 (100)
0.053
1 (10)
0.037*
NMS item 21: falling
50 (24)
15 (62.5) \0.001*
12 (50)
0.007*
1 (20)
0.834
2 (20)
0.770
NMS item 26: unpleasant sensations in your legs at night or while resting
98 (47.1)
10 (41.7)
0.612
6 (25)
0.039*
5 (100)
0.037*
2 (20)
0.093
NMS item 27: swelling of your legs
46 (22.1)
12 (50)
0.003*
8 (33.3)
0.218
3 (60)
0.047*
4 (40)
0.189
NMS item 30: believing things are happening to you that other people say are not true
32 (15.4)
1 (4.2)
1 (4.2)
0.136
1 (20)
0.778
10 (100)
0.179
4 (16.7)
0.012*
0.002*
7 (29.2)
All frequency comparisons were done with Chi-square test NMS nonmotor symptoms * Statistically significant (p \ 0.05), values in parenthesis are shown as percentage
PD patients) (Gilman et al. 2008; Wenning et al. 2013; Donker Kaat et al. 2007) While this feature seems to be more common in MSA and PSP, its utility as a discriminatory feature from PD is still unclear (Reimann et al. 2010). Although not more frequent, our MSA patients suffered from more severe sudden onset of sleep during the day than PD patients; the findings consistent with the SLEEMSA study, a large multicenter study of excessive daytime sleepiness (EDS) in Europe (Moreno-Lopez et al. 2011). In that study, in contrast to PD, EDS in MSA seems to be unrelated to the amount of dopaminergic treatment. Our study also evaluated the presence of NMS in AP and VP patients, compared with PD patients. While the total NMS scores did not show any differences between individual disorders, the differences were observed between specific NMS and AP in comparison to PD. Despite limited evidence in the medical literature, two recent studies suggested that AP patients do suffer from various NMS in which some domains may be more frequent and severe than PD patients (Colosimo et al. 2010; Lee et al. 2013). Although not possible for direct comparison since our study utilized different scales to measure NMS, the results of our study share some similarities with the recent PRIAMO study that PSP and MSA patients significantly experienced more gastrointestinal and urinary urgency than PD patients (Colosimo et al. 2010). In contrast, PD patients significantly reported more sexual problems than PSP and VP patients. If we explore only the nocturnal domain of NMSQuest (items 23, 24, 25, 26), no differences were noted between different forms of parkinsonism (including PD) except for CBD in which all five patients reported the symptoms of unpleasant sensations in
123
the legs at night associated with a feeling that he/she needs to move. Although suggestive, this symptom alone is not diagnostic of restless legs syndrome (RLS) (Allen et al. 2003). Even though the small number of CBD patients may limit full statistical interpretation, one polysomnographic study reported that 4 out of 5 CBD patients displayed PLM and/or RLS (Roche et al. 2007). This finding merits further investigation. The occurrence of NMS correlates with the presence of nocturnal symptoms in PD and MSA patients. The correlation in CBD patients should be interpreted with caution due to a small number of subjects. Based on these findings, our study supports the presence of NMS in patients with AP and VP and certain NMS may be more prevalent in some forms of parkinsonism but the validity of these NMS in differentiating parkinsonian symptoms is not yet determined. There are some limitations in our study. First and foremost is the small numbers of CBD and VP patients which may limit adequate statistical comparison between these patients and a large number of PD patients. However, we employed stringent diagnostic criteria of individual forms of parkinsonism to ensure that we have recruited patients with a correct diagnosis. For example, we emphasized the relationship between the onset of parkinsonism and radiological evidence of cerebrovascular diseases for the diagnosis of VP (Zijlmans et al. 2004). Although atypical presentations of AP and different manifestations of VP are increasingly recognized, such cases are excluded from our study as these presentations may not fulfill the standard diagnostic criteria. Second, the scales that we employed in this study have not been formally validated in AP and VP. Therefore, the interpretation of
Nocturnal manifestations of atypical and vascular parkinsonism Table 4 Correlation between patient/disease characteristics and the total MPDSS scores on different patients groups Parameters
Total MPDSS score PD
PSP
MSA
CBD
Vascular parkinsonism
Age
-0.084
-0.189
0.140
0.462
-0.143
Disease duration
-0.249*
-0.035
0.112
-0.564
-0.391
LED
-0.298*
-0.241
-0.261
-0.200
-0.131
TMSE Hoehn and Yahr staging
0.187*
0.117
0.115
-0.266*
-0.115
-0.315
0.975*
-0.277
-0.894*
-0.688*
CGI
-0.286*
-0.104
-0.263
-0.866
-0.121
Total PDQ-8 SI Total NMS scores
-0.518* -0.546*
-0.038 -0.261
-0.413 -0.712*
-0.800 -0.900*
-0.618 -0.707*
Nocturnal akinesia
-0.359*
0.128
-0.339
-0.894*
-0.458
Nocturnal dystonia
-0.110
-0.055
-0.201
-0.821
-0.447
Nocturnal cramp
-0.164*
-0.163
-0.502
na
-0.098
Total NADCS
-0.351*
0.084
-0.451
-0.821
-0.508
All correlations were done by Spearman’s correlation MPDSS modified Parkinson’s disease sleep score, NADCS nocturnal akinesia dystonia cramps score, LED levodopa equivalent dose, TMSE Mini-mental status examination-Thai version, CGI clinical global impression, PDQ-8 S Parkinson’s disease questionnaire Short-form summary index, PDQ8-SI Parkinson’s disease questionnaire, NMS nonmotor symptoms questionnaire, na not analyzed * Statistically significant (p \ 0.05)
these scales in other forms of parkinsonism outside PD should be reviewed with caution. Since there are no existing validated scales to determine nocturnal disabilities in AP and VP patients and our aim is to compare these findings with PD patients, we have utilized different scales (both MPDSS and NADCS) to capture various nocturnal manifestations in different forms of parkinsonism. Finally, some nighttime symptoms may occur as a result of coexisting medical conditions in the elderly. For example, urinary incontinence may be partially attributable to benign prostatic hyperplasia. Daily management of AP and VP is challenging. Both patients and caregivers often are faced with diverse symptomatology in which many of them are found to be nonlevodopa responsive. Moreover, a significant proportion is devoted to nighttime problems as our study has highlighted a number of nocturnal issues that these patients frequently encounter. First of all, patients with AP and VP encounter the problems of nocturnal disturbances as frequently as or even more than patients with PD. Second, patients with PSP, MSA, and CBD suffer from more nocturnal akinesia than PD patients. PSP and MSA patients reported more problems with urinary incontinence in both frequency and severity than PD patients, while MSA patients were found to have more severe sudden onset of sleep than PD patients. Strong and significant correlations were also found between the NMS scores and the total MPDSS in both PD and MSA patients. Although our study has identified specific nocturnal symptoms in AP patients, the presence of these symptoms does not help in differentiating parkinsonian
syndromes. Longitudinal studies involving large patient samples are needed to identify the important nocturnal issues in these patients, which will further lead to therapeutic trials. Based on the results of our study, we propose that the concept of 24-h control of symptoms should not be limited to only PD and all parties who are involved in the care of AP and VP patients should be aware of a myriad nocturnal symptomatology in these patients and a multidisciplinary approach should be utilized to address these problems. Moreover, caregivers should not be neglected and support should be provided to them since they are most likely the only persons who are faced with the problems of the patients at night. Acknowledgments The study was supported by the Rachadaphiseksomphot Endowment Fund of the ‘‘Strengthen CU’s Researcher’s Project’’ and research unit (RU) Grant number GRU 56-012-30-002 of Chulalongkorn Center of Excellence on Parkinson’s Disease and Related Disorders, Chulalongkorn University, Bangkok, Thailand. We would like to thank Ratanaruedee Devahastin, Onnalin Jandaew, and Kamolwan Boonpeng for their assistance in patient recruitment and data assortment.
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