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Clinical REM sleep behavior disorder and motor subtypes in Parkinson’s disease: A questionnaire-based study
Clinical Neurology and Neurosurgery 119 (2014) 54–58
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Clinical REM sleep behavior disorder and motor subtypes in Parkinson’s disease: A questionnaire-based study Dursun Aygun a,∗ , Yakup Turkel a , Musa Kazım Onar a , Tevfik Sunter b a b
Ondokuz Mayis University, Medical School, Department of Nurology, Samsun, Turkey Ondokuz Mayis University, Medical School, Department of Public Health, Samsun, Turkey
a r t i c l e
i n f o
Article history: Received 14 March 2012 Received in revised form 14 June 2013 Accepted 11 January 2014 Available online 24 January 2014 Keywords: Parkinson’s disease Clinical rapid eye movement sleep behavioral disorder Tremor dominant Parkinson’s disease Non-tremor dominant Parkinson’s disease Subtypes of Parkinson’s disease
a b s t r a c t Objectives: Studies documenting the association between rapid eye movement sleep behavior disorder (RBD) and motor subtypes in Parkinson’s disease (PD) are rare. Our hypothesis is that RBD may be more severe in non-tremor dominant (NTD) patients with RBD than those tremor dominant (TD) with RBD. In this study, we investigated the association between motor subtypes and clinical RBD in PD. Patients and methods: We evaluated 104 consecutive patients older than 18 years presenting with PD to the Neurology Clinic of the University Hospital for one year in this study. The clinical diagnosis of RBD was based on the minimal diagnostic criteria of International Classification of Sleep Disorders, revised. The Stavanger Sleepiness Questionnaire was used to rate the severity of clinical RBD. The patients were divided into two subgroups as TD and NTD. The patient and control groups were compared with each other for severity and frequency of clinical RBD, and the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn–Yahr stage scores. The correlation between severity of clinical RBD and clinical severity of PD was analyzed in the patient groups. Results: Of the patients, 45.2% (n = 47) had the NTD subtype of PD and 54.8% (n = 57) had the TD subtype of PD. There was no significant difference among the groups in terms of frequency and severity of clinical RBD. For the NTD patients, there was a weak positive correlation between severity of clinical RBD and clinical severity of PD. However, there was no correlation in the TD subgroup. Conclusion: In our study, frequency of clinical RBD was unrelated to motor subtypes of PD. However, in the present study, we found a weak correlation between clinical severity (UPDRS and the Hoehn–Yahr) of PD and severity of clinical RBD in the NTD subtype but not in the TD subtype. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Today, it is generally agreed that there are different subtypes of Parkinson’s disease (PD), such as a tremor dominant (TD) and a non-tremor dominant (NTD) [1–6]. Even, it has been reported that there is degeneration in A8 neurons of the midbrain in TD patients but not in NTD patients [7]. It has been well documented that PD patients with NTD subtype have a worse prognosis for motor and non motor functions [2–4]. Previous studies have demonstrated that PD patients with TD have a lower number of non-motor symptoms [8–10]. Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by the presence of abnormal movements of the body and limbs, for example, kicking and hitting,
∗ Corresponding author at: Ondokuz Mayis University, Medical School, Department of Neurology, Samsun 55139, Turkey. Tel.: +90 0362 3121919/3243; fax: +90 0362 457 60 41. E-mail address: [email protected] (D. Aygun). 0303-8467/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2014.01.011
and vocalizations, such as talking, shouting, crying, and laughing associated with dream mentation at REM sleep without muscle atonia [7,11,12]. It has been reported that RBD is seen in up to two-thirds of patients with PD [6]. There are contrasting evidences that PD patients with RBD are different from those without RBD in term of association with cognitive impairment or dementia. Emre et al. [13] have reported that RBD is a risk factor for development of PD dementia. Contrary to this study, a recent study [14] reported that there was no difference between PD patients with and without RBD in regards to development of dementia and other clinical features of disease. On the other hand, studies documenting features of RBD in TD and NTD subtypes of PD are uncommon [5,12,15]. Kumru et al. [5] investigated the frequency of RBD and pre-motor onset of RBD in subtypes of PD. A new study of 36 patients found that the frequency of RBD was lower in the TD group than in the NTD group (14% versus 53%) [16]. Thus, the relationship between RBD and other clinical features in PD is inconsistent across studies and has remained controversial. In the literature, we could not find any studies comparing the motor subtypes of PD for clinical
D. Aygun et al. / Clinical Neurology and Neurosurgery 119 (2014) 54–58
severity of RBD. Our hypothesis is that RBD may be more severe in NTD patients with RBD than those TD with RBD. In our study, we investigated not only the frequency and occurrence time of RBD but also the severity of RBD in each motor subtype. 2. Material and methods
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Table 1 The modified Stavanger Sleepiness Questionnaire [9]. Score
Features of REM sleep behaviors
0 1
Physical and verbal behaviors are not present during sleep Mild physical restlessness and/or vocalizations, for example, talking, crying, or laughing, while sleep Moderate physical and verbal restlessness, for example, shouting, during sleep, tend to awake partner Severe physical, for example, hitting, may injure partner or him/herself, and verbal restlessness while asleep
2
This prospective questionnaire-based study was approved by the Local Ethics Committee of our University. We evaluated 104 consecutive patients (68 men, 36 women) older than 18 years presenting with PD to the Neurology Clinic of the University Hospital for one year in this study. A written informed consent was obtained from all subjects. Diagnosis of PD was based on the United Kingdom Brain Bank’s criteria as bradykinesia in association with rest tremor, rigidity, or postural instability [17]. PD patients have been assessed by a neurologist (DA) experienced in the movement disorders. From each patient, a detailed history for the motor and non-motor symptoms including RBD of PD was obtained and their clinical condition was rated on the UPDRS and HY scores assessed in the ‘ON’ state. Inclusion criteria were: (1) clinical diagnosis of idiopathic Parkinson’s disease; and (2) age older than 18 years. Exclusion criteria were as follows: (1) single patients; (2) patients without a 24 h caregiver; (3) patients without a good history (e.g. a good partner’s report or sleep diary information) of motor behaviors and vocalizations during REM sleep; and (4) patients whose motor subtype of PD could not be determined due to insufficient history of onset motor symptoms. The study excluded 16 out of the 120 consecutive patients attended our clinic during one-year period because they met the exclusion criteria. The control group (n = 30) was composed of patients with non-degenerative neurological disease including peripheral neuropathies (n = 2) and headache (n = 3), and health workers employed at the University Hospital. The control group was similar in age and gender distribution to the patient groups.
All data of PD patients and controls were recorded in a computer program. Statistical analysis was performed by Y.B. The results were analyzed using the computer software (SPSS version 15.0). A p < 0.05 was considered statistically significant in all tests. Because the data was not normally distributed, the statistical analysis was performed using non-parametric tests to compare variables of groups. For the severity and frequency of clinical RBD, gender, and the age at when the questionnaire was applied, the groups (TD and NTD) were compared with each other and with the control group using Mann–Whitney and Chi-Square tests. For occurrence time of clinical RBD throughout the disease course, stage (HY) score, duration of PD, and UPDRS score, the subtypes (TD and NTD) were compared with each other using Mann–Whitney test. Spearman’s rho correlation test was used to analyze the relationship between the severity of clinical RBD and the duration of PD, UPDRS score, and stage score in each the motor subtype.
2.1. Definitions of Parkinson’s disease subtypes [4]
3. Results
In our study, Parkinson’s disease subtypes include tremor dominant and non-tremor dominant. For tremor dominant subtype, tremors are seen at the disease onset as the sole initial symptom or there is a prominent dominance of tremors over other motor symptoms (i.e., rigidity, bradykinesia, and postural instability) at presentation. For the non-tremor dominant subtype, predominantly other motor symptoms with no or only mild tremor are seen at the disease onset or there is a prominent dominance of other motor symptoms over tremors at presentation.
3
with the patients and their caregivers, bed partners, and families. The control group also completed the questionnaire. In this questionnaire, the severity of motor or vocal activity during sleep was scored from 0 to 3 (Table 1). 2.3. Statistical analysis
The mean age of enrolment was 66.5 ± 10 years in the patients and was 66.5 ± 8.1 years in the controls (17 men, 13 women) (p > 0.05; Fig. 1). Of the PD patients, 57.6% (n = 60) met the ICSDR minimal clinical diagnostic criteria for RBD. Of the patients, 45.2% (n = 47) had NTD subtype and 54.8% (n = 57) had TD subtype. The mean age was 66.7 ± 10 years for the TD patients (36 men, 21 women) and 65.8 ± 11 years for the NTD patients (32 men, 15 women) (p > 0.05; Fig. 1). There was no significant difference
90,00
All of the following clinical signs associated with RBD were interrogated in history: talking, crying out, swearing, laughing, shouting, awaking partner, physical restlessness, punching, kicking, hitting, and falling out of bed while asleep. In this study, the diagnosis of clinical RBD based on the minimal diagnostic criteria of International Classification of Sleep Disorders, revised (ICSD-R) included limb or body movements associated with dream mentation and at least one of the following: harmful or potentially harmful sleep behaviors; dreams that appear to be acted out; or sleep behaviors that disrupt sleep continuity [6,18,19]. The Stavanger Sleepiness Questionnaire (SSQ) used in several previous studies was adapted to the present study and used to rate the severity of clinical RBD [19–21]. Focusing on the clinical features of RBD, this questionnaire was performed during face-to-face interviews
80,00
Age (Year)
2.2. The clinical diagnosis of RBD
70,00 60,00 50,00 40,00 TD
NTD
Control
Tremor Fig. 1. The age distribution in the PD subtypes and control group.
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6
TD NTD - - - - - - -
Score of RBD
5 4 3 2 1
Stage 0 0
1
2
3
4
5
6
Fig. 2. Correlation between the severity of RBD and Hoehn–Yahr stage in the PD subtypes. p = 0.044 (r: 0.298), the NTD subtype versus the TD subtype. TD: tremor dominant; NTD: non-tremor dominant; RBD: rapid eye movement (REM) sleep behavioral disorder.
between the control group and the motor subtypes of PD in terms of gender and mean age (p > 0.05). Disease duration did not differ between the subtype. The median UPDRS scores (motor/total) were 19 (14.0–33.5)/35 (25.5–52.5) in the TD subtype and 22 (15.75–31.0)/37 (24.75–49.5) in the NTD subtype (p > 0.05). While a stage score of ≤2 was seen more in the TD patients than in those with NTD, stages of >2 were seen more in the NTD patients. However, difference between the subtypes not statistically significant. Of patients in the NTD group, 31.9% (n = 15) had a clinical RBD severity score of 3, versus 19.3% (n = 11) in the TD group (p > 0.05). The frequency of clinical RBD was 54.3% (n = 31) in the TD patients and 61.8% (n = 29) in the NTD patients (p > 0.05). The patient groups had a significantly high severity and frequency of clinical RBD when compared with the control group. Of the 30 control subjects, only 5 had a clinical RBD severity score of 1, whereas in the remaining 25 control subjects, score was 0. For the NTD patients, there was a weak positive correlation between the severity of RBD and the clinical severity of PD (UPDRS III, UPDRS total, and HY stage) (p = 0.043, r: 0.300; p = 0.026, r: 0.328; and p = 0.044, r: 0.298, respectively; Fig. 2). For the TD patients, however, there was no correlation between the clinical severity of disease and the severity of clinical RBD (p > 0.05). Clinical RBD was preceded the onset of motor symptoms of PD in the 20 patients (12 TD patients vs. 8 NTD patients, 38.7% vs. 27.5%, respectively; p > 0.05).
4. Discussion The major finding of this study is the presence of a weak correlation between clinical severity (UPDRS and the Hoehn–Yahr) of PD and severity of clinical RBD in the NTD subtype but not in the TD subtype. Although, in our study, the SSQ score was higher in the NTD subtype than the TD subtype, the difference between the subtypes was not significant. In addition, a score of 3 was more common in the NTD patients than in the TD group (52% versus 31%). However, this difference between the subtypes was not significant. Similarly, although the difference between the subtypes was not statistically significant, UPDRS scores (motor/total) were higher in the NTD patients with RBD than the TD patients with RBD (23.5/40.0 vs. 19.5/36.5). These results may indicate that RBD is more associated with non-tremor motor signs than with tremor. Lee et al. [6] found that the presence of RBD was inversely correlated with UPDRS tremor scores. Thus, these results support that the PPN have a role in both REM sleep and kinesis [3,15]. In our study, the other important results, discussed below are: (1) that the frequency of clinical RBD is similar for both motor subtypes and (2) that the presence of clinical RBD in the premotor period may not be useful for estimating the PD subtypes to develop
In this study, two motor subtypes of PD have been defined according to prominent motor symptoms at the onset of disease or predominant motor findings on the basis of UPDRS III at presentation [4]. Van Rooden et al. [22] have reviewed that subtypes of PD generally were classified according to predominant clinical features (tremor, bradykinesia/rigidity, postural instability, and cognitive impairment), age-at-onset, and rate of progression. In a study using the cluster analysis, the clusters have been described on the basis of the differences in means of the variables (including UPDRS motor items) [23]. For example authors have used a mean score of UPDRS items 16, 20, and 21 for TD subgroup. Although, we did not state it in the method section, TD patients had a higher score on the UPDRS tremor items than non tremor motor items. Kumru et al. [5] have been reported that tremor-predominant subtype was considered for patients with tremor severity of 3 and 4 according to the UPDRS part III. Previous studies found that TD patients had fewer non-motor symptoms and exhibited a slower progression than those with NTD [8–10]. Emre et al. [13] reported that both RBD and NTD PD were associated with an increased risk of PD dementia. On the other hand, it has been suggested that the presence of cognitive dysfunction in PD patients is a predictor factor for RBD [6,24]. Thus, NTD PD patients with RBD have more nonmotor symptoms and accordingly, a more widespread involvement of the CNS. In PD, anatomical and psychopathological relationships between the CNS regions associated with motor signs and the CNS regions involved in RBD may be important. It is well known that the dopamine-containing regions of the brain are the peri- and retrorubral field (A8), substantia nigra (A9), and ventral tegmental area (A10). It has been reported that A9-DA neurons have high levels of neuromelanin (NM) with high iron content and appear to be selectively targeted for vulnerability to oxidative stress; however, A10 and A8-DA neurons have low levels of NM and are less vulnerable to oxidative damage [25]. Shamoto-Nagai et al. [26], suggested that NM induces oxidative stress in mitochondria through release of iron. It has been reported that patients with TD PD have considerably more cell loss in the A8, whereas patients with NTD PD have a more severe damage of the A9 according to data of postmortem studies [27]. These data show that PD tremor may result from loss of dopaminergic neurons in the A8. In a recent review, authors have proposed that PD tremor involves both the basal ganglia and the cerebello-thalamo-cortical circuit [27]. A specific mitochondrial complex I defect, described in the substantia nigra of patients with PD similar to the destruction effect via the inhibition of complex I in the A9 in animal models of MPTP [28]. Therefore these data show that NTD subtype is associated with greater mitochondrial disfunction and oxidative stress than TD subtype. Coenzyme Q10 (CoQ10) accepts electrons from complexes I and II, and is a cofactor for complex III in mitochondrial oxidative phosphorylation as well as a potent antioxidant in mitochondria and lipid membranes [29]. Moreover it has been reported that CoQ10 is able to attenuate degeneration of dopaminergic neurons through free radical scavenging and the specific regulation of the mitochondrial permeability transition pore [28]. It has been reported that omega3 (-3) polyunsaturated fatty acids are an important component of cell membranes in the brain and modulate membrane order, gene transcription, cell signaling, and caspase activation [30]. The results of a preclinical study suggest that high -3 consumption exerts an antioxidant action against MPTP-induced toxicity on the DAergic system [30]. Therefore, CoQ10 and omega-3 deficiency may play a role in the pathogenesis of NTD subtype more than TD subtype. In previous studies, the frequency of RBD has varied from 15 to 72 [6,12,24,31]. This wide range may have resulted from the diagnostic criteria for RBD and the methods used in these studies. Gjerstad et al. [19] demonstrated that the features of RBD changed with time, after an 8-year follow-up of PD patients with RBD applied the SSQ. In our study, 57.6% of the patients had RBD. This data is
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consistent with results of previous studies. In the literature, there are studies reporting the features of RBD in motor subtypes of PD [5,6,16]. In Kumru et al.’s study [5], NTD subtype was 83% of all PD patients, in contrast to other most studies in the literature. This group was 45% of the PD patients in our study. The studies regarding the increased frequency of RBD in cases with NTDPD are uncommon [5,16]. Postuma et al. [16] found that the frequency of RBD was lower in TD patients compared with those with NTD subtype (14% versus 53%). Although, in the present study, the frequency of RBD was higher in the NTD group than the TD group, the difference was not significant (61.8% versus 54.3%). These different results may be due to differences in methods of data collection. However, our results support the data of the literature. The relation to parkinsonian degeneration in the brainstem nuclei regulating REM sleep of RBD is well known [11,15]. It has been believed that the pathophysiology of RBD involves the nucleus reticularis magnocellularis and peri-locus coeruleus in the pons and the pedunculopontine nucleus (PPN) in the meso-pontin area [1,7,15,32]. On the other hand, it is also thought to be related to akinesia of the PPN [3,6]. This relationship also may explain why RBD is more common among NTD patients. It has been reported that RBD often seems in the premotor period of PD [7,11,12]. Some studies have reported that RBD may appear years before motor symptoms in PD [19,33]. A study reported that in 60% of subjects with idiopathic RBD, PD developed during a 7-year period [34]. The Braak staging theory suggests that neuronal degeneration begins in the medulla and progresses upwards (e.g., to the neocortex) in PD [35]. According to this theory, RBD corresponds to the second-stage of Braak, which is the premotor period of PD [24,35]. In 33.3% of our patients, RBD started during the premotor period of PD. This result is consistent with the literature [6]. Another study reported that while RBD followed motor symptoms in TD patients, it developed during the premotor period in NTD patients (20.4%) [5]. Contrary to previous studies we found that the premotor onset of clinical RBD was more common in the TD patients than the NTD patients (38.7% versus 27.5%) [5]. However, this difference between the subtypes was not statistically significant. This may be associated with differences in study methodologies. However, our results may also indicate that the presence of clinical RBD in the premotor period may not be useful for estimating the PD subtypes to develop. The most important limitation of this study was the use of the ICSD-R minimal diagnosis criteria without polysomnography to diagnose RBD. The new diagnostic criteria of RBD according to the ICSD 2005 have required a polysomnographical documentation of normal skeletal muscle atonia loss in REM sleep [1,16]. However, many recent studies of PD have used the ICSD-R minimal diagnostic criteria; do not require a polysomnographic examination for clinical diagnosis of RBD, as in the present study [6,12,15,19]. Because of the most important aim of this study is to assessment the clinical severity of RBD in PD subtypes, we have used the ICSD-R minimal diagnosis criteria. Stiasny-Kolster et al. [36], developed a 10-item patient self-rating questionnaire (maximum total score 13 points) according to clinical features of RBD in the ICSD 2005. They excluded patients without a clinical history of RBD, who have only PSG findings of RBD. They recommended using the RBD screening questionnaire (RBDSQ) for the recruitment of RBD patients in research studies. Another limitation of our study was the relatively small numbers of patients with RBD. In our study, the frequency of clinical RBD was unrelated to motor subtypes of PD. However, in the present study, we found a weak correlation between clinical severity (UPDRS and the Hoehn–Yahr) of PD and severity of clinical RBD in the NTD subtype but not in the TD subtype. Also the onset of clinical RBD during the premotor period was not different between motor subtypes of PD.
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Clinical REM sleep behavior disorder and motor subtypes in Parkinson’s disease: A questionnaire-based study Dursun Aygun a,∗ , Yakup Turkel a , Musa Kazım Onar a , Tevfik Sunter b a b
Ondokuz Mayis University, Medical School, Department of Nurology, Samsun, Turkey Ondokuz Mayis University, Medical School, Department of Public Health, Samsun, Turkey
a r t i c l e
i n f o
Article history: Received 14 March 2012 Received in revised form 14 June 2013 Accepted 11 January 2014 Available online 24 January 2014 Keywords: Parkinson’s disease Clinical rapid eye movement sleep behavioral disorder Tremor dominant Parkinson’s disease Non-tremor dominant Parkinson’s disease Subtypes of Parkinson’s disease
a b s t r a c t Objectives: Studies documenting the association between rapid eye movement sleep behavior disorder (RBD) and motor subtypes in Parkinson’s disease (PD) are rare. Our hypothesis is that RBD may be more severe in non-tremor dominant (NTD) patients with RBD than those tremor dominant (TD) with RBD. In this study, we investigated the association between motor subtypes and clinical RBD in PD. Patients and methods: We evaluated 104 consecutive patients older than 18 years presenting with PD to the Neurology Clinic of the University Hospital for one year in this study. The clinical diagnosis of RBD was based on the minimal diagnostic criteria of International Classification of Sleep Disorders, revised. The Stavanger Sleepiness Questionnaire was used to rate the severity of clinical RBD. The patients were divided into two subgroups as TD and NTD. The patient and control groups were compared with each other for severity and frequency of clinical RBD, and the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn–Yahr stage scores. The correlation between severity of clinical RBD and clinical severity of PD was analyzed in the patient groups. Results: Of the patients, 45.2% (n = 47) had the NTD subtype of PD and 54.8% (n = 57) had the TD subtype of PD. There was no significant difference among the groups in terms of frequency and severity of clinical RBD. For the NTD patients, there was a weak positive correlation between severity of clinical RBD and clinical severity of PD. However, there was no correlation in the TD subgroup. Conclusion: In our study, frequency of clinical RBD was unrelated to motor subtypes of PD. However, in the present study, we found a weak correlation between clinical severity (UPDRS and the Hoehn–Yahr) of PD and severity of clinical RBD in the NTD subtype but not in the TD subtype. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Today, it is generally agreed that there are different subtypes of Parkinson’s disease (PD), such as a tremor dominant (TD) and a non-tremor dominant (NTD) [1–6]. Even, it has been reported that there is degeneration in A8 neurons of the midbrain in TD patients but not in NTD patients [7]. It has been well documented that PD patients with NTD subtype have a worse prognosis for motor and non motor functions [2–4]. Previous studies have demonstrated that PD patients with TD have a lower number of non-motor symptoms [8–10]. Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by the presence of abnormal movements of the body and limbs, for example, kicking and hitting,
∗ Corresponding author at: Ondokuz Mayis University, Medical School, Department of Neurology, Samsun 55139, Turkey. Tel.: +90 0362 3121919/3243; fax: +90 0362 457 60 41. E-mail address: [email protected] (D. Aygun). 0303-8467/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2014.01.011
and vocalizations, such as talking, shouting, crying, and laughing associated with dream mentation at REM sleep without muscle atonia [7,11,12]. It has been reported that RBD is seen in up to two-thirds of patients with PD [6]. There are contrasting evidences that PD patients with RBD are different from those without RBD in term of association with cognitive impairment or dementia. Emre et al. [13] have reported that RBD is a risk factor for development of PD dementia. Contrary to this study, a recent study [14] reported that there was no difference between PD patients with and without RBD in regards to development of dementia and other clinical features of disease. On the other hand, studies documenting features of RBD in TD and NTD subtypes of PD are uncommon [5,12,15]. Kumru et al. [5] investigated the frequency of RBD and pre-motor onset of RBD in subtypes of PD. A new study of 36 patients found that the frequency of RBD was lower in the TD group than in the NTD group (14% versus 53%) [16]. Thus, the relationship between RBD and other clinical features in PD is inconsistent across studies and has remained controversial. In the literature, we could not find any studies comparing the motor subtypes of PD for clinical
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severity of RBD. Our hypothesis is that RBD may be more severe in NTD patients with RBD than those TD with RBD. In our study, we investigated not only the frequency and occurrence time of RBD but also the severity of RBD in each motor subtype. 2. Material and methods
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Table 1 The modified Stavanger Sleepiness Questionnaire [9]. Score
Features of REM sleep behaviors
0 1
Physical and verbal behaviors are not present during sleep Mild physical restlessness and/or vocalizations, for example, talking, crying, or laughing, while sleep Moderate physical and verbal restlessness, for example, shouting, during sleep, tend to awake partner Severe physical, for example, hitting, may injure partner or him/herself, and verbal restlessness while asleep
2
This prospective questionnaire-based study was approved by the Local Ethics Committee of our University. We evaluated 104 consecutive patients (68 men, 36 women) older than 18 years presenting with PD to the Neurology Clinic of the University Hospital for one year in this study. A written informed consent was obtained from all subjects. Diagnosis of PD was based on the United Kingdom Brain Bank’s criteria as bradykinesia in association with rest tremor, rigidity, or postural instability [17]. PD patients have been assessed by a neurologist (DA) experienced in the movement disorders. From each patient, a detailed history for the motor and non-motor symptoms including RBD of PD was obtained and their clinical condition was rated on the UPDRS and HY scores assessed in the ‘ON’ state. Inclusion criteria were: (1) clinical diagnosis of idiopathic Parkinson’s disease; and (2) age older than 18 years. Exclusion criteria were as follows: (1) single patients; (2) patients without a 24 h caregiver; (3) patients without a good history (e.g. a good partner’s report or sleep diary information) of motor behaviors and vocalizations during REM sleep; and (4) patients whose motor subtype of PD could not be determined due to insufficient history of onset motor symptoms. The study excluded 16 out of the 120 consecutive patients attended our clinic during one-year period because they met the exclusion criteria. The control group (n = 30) was composed of patients with non-degenerative neurological disease including peripheral neuropathies (n = 2) and headache (n = 3), and health workers employed at the University Hospital. The control group was similar in age and gender distribution to the patient groups.
All data of PD patients and controls were recorded in a computer program. Statistical analysis was performed by Y.B. The results were analyzed using the computer software (SPSS version 15.0). A p < 0.05 was considered statistically significant in all tests. Because the data was not normally distributed, the statistical analysis was performed using non-parametric tests to compare variables of groups. For the severity and frequency of clinical RBD, gender, and the age at when the questionnaire was applied, the groups (TD and NTD) were compared with each other and with the control group using Mann–Whitney and Chi-Square tests. For occurrence time of clinical RBD throughout the disease course, stage (HY) score, duration of PD, and UPDRS score, the subtypes (TD and NTD) were compared with each other using Mann–Whitney test. Spearman’s rho correlation test was used to analyze the relationship between the severity of clinical RBD and the duration of PD, UPDRS score, and stage score in each the motor subtype.
2.1. Definitions of Parkinson’s disease subtypes [4]
3. Results
In our study, Parkinson’s disease subtypes include tremor dominant and non-tremor dominant. For tremor dominant subtype, tremors are seen at the disease onset as the sole initial symptom or there is a prominent dominance of tremors over other motor symptoms (i.e., rigidity, bradykinesia, and postural instability) at presentation. For the non-tremor dominant subtype, predominantly other motor symptoms with no or only mild tremor are seen at the disease onset or there is a prominent dominance of other motor symptoms over tremors at presentation.
3
with the patients and their caregivers, bed partners, and families. The control group also completed the questionnaire. In this questionnaire, the severity of motor or vocal activity during sleep was scored from 0 to 3 (Table 1). 2.3. Statistical analysis
The mean age of enrolment was 66.5 ± 10 years in the patients and was 66.5 ± 8.1 years in the controls (17 men, 13 women) (p > 0.05; Fig. 1). Of the PD patients, 57.6% (n = 60) met the ICSDR minimal clinical diagnostic criteria for RBD. Of the patients, 45.2% (n = 47) had NTD subtype and 54.8% (n = 57) had TD subtype. The mean age was 66.7 ± 10 years for the TD patients (36 men, 21 women) and 65.8 ± 11 years for the NTD patients (32 men, 15 women) (p > 0.05; Fig. 1). There was no significant difference
90,00
All of the following clinical signs associated with RBD were interrogated in history: talking, crying out, swearing, laughing, shouting, awaking partner, physical restlessness, punching, kicking, hitting, and falling out of bed while asleep. In this study, the diagnosis of clinical RBD based on the minimal diagnostic criteria of International Classification of Sleep Disorders, revised (ICSD-R) included limb or body movements associated with dream mentation and at least one of the following: harmful or potentially harmful sleep behaviors; dreams that appear to be acted out; or sleep behaviors that disrupt sleep continuity [6,18,19]. The Stavanger Sleepiness Questionnaire (SSQ) used in several previous studies was adapted to the present study and used to rate the severity of clinical RBD [19–21]. Focusing on the clinical features of RBD, this questionnaire was performed during face-to-face interviews
80,00
Age (Year)
2.2. The clinical diagnosis of RBD
70,00 60,00 50,00 40,00 TD
NTD
Control
Tremor Fig. 1. The age distribution in the PD subtypes and control group.
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6
TD NTD - - - - - - -
Score of RBD
5 4 3 2 1
Stage 0 0
1
2
3
4
5
6
Fig. 2. Correlation between the severity of RBD and Hoehn–Yahr stage in the PD subtypes. p = 0.044 (r: 0.298), the NTD subtype versus the TD subtype. TD: tremor dominant; NTD: non-tremor dominant; RBD: rapid eye movement (REM) sleep behavioral disorder.
between the control group and the motor subtypes of PD in terms of gender and mean age (p > 0.05). Disease duration did not differ between the subtype. The median UPDRS scores (motor/total) were 19 (14.0–33.5)/35 (25.5–52.5) in the TD subtype and 22 (15.75–31.0)/37 (24.75–49.5) in the NTD subtype (p > 0.05). While a stage score of ≤2 was seen more in the TD patients than in those with NTD, stages of >2 were seen more in the NTD patients. However, difference between the subtypes not statistically significant. Of patients in the NTD group, 31.9% (n = 15) had a clinical RBD severity score of 3, versus 19.3% (n = 11) in the TD group (p > 0.05). The frequency of clinical RBD was 54.3% (n = 31) in the TD patients and 61.8% (n = 29) in the NTD patients (p > 0.05). The patient groups had a significantly high severity and frequency of clinical RBD when compared with the control group. Of the 30 control subjects, only 5 had a clinical RBD severity score of 1, whereas in the remaining 25 control subjects, score was 0. For the NTD patients, there was a weak positive correlation between the severity of RBD and the clinical severity of PD (UPDRS III, UPDRS total, and HY stage) (p = 0.043, r: 0.300; p = 0.026, r: 0.328; and p = 0.044, r: 0.298, respectively; Fig. 2). For the TD patients, however, there was no correlation between the clinical severity of disease and the severity of clinical RBD (p > 0.05). Clinical RBD was preceded the onset of motor symptoms of PD in the 20 patients (12 TD patients vs. 8 NTD patients, 38.7% vs. 27.5%, respectively; p > 0.05).
4. Discussion The major finding of this study is the presence of a weak correlation between clinical severity (UPDRS and the Hoehn–Yahr) of PD and severity of clinical RBD in the NTD subtype but not in the TD subtype. Although, in our study, the SSQ score was higher in the NTD subtype than the TD subtype, the difference between the subtypes was not significant. In addition, a score of 3 was more common in the NTD patients than in the TD group (52% versus 31%). However, this difference between the subtypes was not significant. Similarly, although the difference between the subtypes was not statistically significant, UPDRS scores (motor/total) were higher in the NTD patients with RBD than the TD patients with RBD (23.5/40.0 vs. 19.5/36.5). These results may indicate that RBD is more associated with non-tremor motor signs than with tremor. Lee et al. [6] found that the presence of RBD was inversely correlated with UPDRS tremor scores. Thus, these results support that the PPN have a role in both REM sleep and kinesis [3,15]. In our study, the other important results, discussed below are: (1) that the frequency of clinical RBD is similar for both motor subtypes and (2) that the presence of clinical RBD in the premotor period may not be useful for estimating the PD subtypes to develop
In this study, two motor subtypes of PD have been defined according to prominent motor symptoms at the onset of disease or predominant motor findings on the basis of UPDRS III at presentation [4]. Van Rooden et al. [22] have reviewed that subtypes of PD generally were classified according to predominant clinical features (tremor, bradykinesia/rigidity, postural instability, and cognitive impairment), age-at-onset, and rate of progression. In a study using the cluster analysis, the clusters have been described on the basis of the differences in means of the variables (including UPDRS motor items) [23]. For example authors have used a mean score of UPDRS items 16, 20, and 21 for TD subgroup. Although, we did not state it in the method section, TD patients had a higher score on the UPDRS tremor items than non tremor motor items. Kumru et al. [5] have been reported that tremor-predominant subtype was considered for patients with tremor severity of 3 and 4 according to the UPDRS part III. Previous studies found that TD patients had fewer non-motor symptoms and exhibited a slower progression than those with NTD [8–10]. Emre et al. [13] reported that both RBD and NTD PD were associated with an increased risk of PD dementia. On the other hand, it has been suggested that the presence of cognitive dysfunction in PD patients is a predictor factor for RBD [6,24]. Thus, NTD PD patients with RBD have more nonmotor symptoms and accordingly, a more widespread involvement of the CNS. In PD, anatomical and psychopathological relationships between the CNS regions associated with motor signs and the CNS regions involved in RBD may be important. It is well known that the dopamine-containing regions of the brain are the peri- and retrorubral field (A8), substantia nigra (A9), and ventral tegmental area (A10). It has been reported that A9-DA neurons have high levels of neuromelanin (NM) with high iron content and appear to be selectively targeted for vulnerability to oxidative stress; however, A10 and A8-DA neurons have low levels of NM and are less vulnerable to oxidative damage [25]. Shamoto-Nagai et al. [26], suggested that NM induces oxidative stress in mitochondria through release of iron. It has been reported that patients with TD PD have considerably more cell loss in the A8, whereas patients with NTD PD have a more severe damage of the A9 according to data of postmortem studies [27]. These data show that PD tremor may result from loss of dopaminergic neurons in the A8. In a recent review, authors have proposed that PD tremor involves both the basal ganglia and the cerebello-thalamo-cortical circuit [27]. A specific mitochondrial complex I defect, described in the substantia nigra of patients with PD similar to the destruction effect via the inhibition of complex I in the A9 in animal models of MPTP [28]. Therefore these data show that NTD subtype is associated with greater mitochondrial disfunction and oxidative stress than TD subtype. Coenzyme Q10 (CoQ10) accepts electrons from complexes I and II, and is a cofactor for complex III in mitochondrial oxidative phosphorylation as well as a potent antioxidant in mitochondria and lipid membranes [29]. Moreover it has been reported that CoQ10 is able to attenuate degeneration of dopaminergic neurons through free radical scavenging and the specific regulation of the mitochondrial permeability transition pore [28]. It has been reported that omega3 (-3) polyunsaturated fatty acids are an important component of cell membranes in the brain and modulate membrane order, gene transcription, cell signaling, and caspase activation [30]. The results of a preclinical study suggest that high -3 consumption exerts an antioxidant action against MPTP-induced toxicity on the DAergic system [30]. Therefore, CoQ10 and omega-3 deficiency may play a role in the pathogenesis of NTD subtype more than TD subtype. In previous studies, the frequency of RBD has varied from 15 to 72 [6,12,24,31]. This wide range may have resulted from the diagnostic criteria for RBD and the methods used in these studies. Gjerstad et al. [19] demonstrated that the features of RBD changed with time, after an 8-year follow-up of PD patients with RBD applied the SSQ. In our study, 57.6% of the patients had RBD. This data is
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consistent with results of previous studies. In the literature, there are studies reporting the features of RBD in motor subtypes of PD [5,6,16]. In Kumru et al.’s study [5], NTD subtype was 83% of all PD patients, in contrast to other most studies in the literature. This group was 45% of the PD patients in our study. The studies regarding the increased frequency of RBD in cases with NTDPD are uncommon [5,16]. Postuma et al. [16] found that the frequency of RBD was lower in TD patients compared with those with NTD subtype (14% versus 53%). Although, in the present study, the frequency of RBD was higher in the NTD group than the TD group, the difference was not significant (61.8% versus 54.3%). These different results may be due to differences in methods of data collection. However, our results support the data of the literature. The relation to parkinsonian degeneration in the brainstem nuclei regulating REM sleep of RBD is well known [11,15]. It has been believed that the pathophysiology of RBD involves the nucleus reticularis magnocellularis and peri-locus coeruleus in the pons and the pedunculopontine nucleus (PPN) in the meso-pontin area [1,7,15,32]. On the other hand, it is also thought to be related to akinesia of the PPN [3,6]. This relationship also may explain why RBD is more common among NTD patients. It has been reported that RBD often seems in the premotor period of PD [7,11,12]. Some studies have reported that RBD may appear years before motor symptoms in PD [19,33]. A study reported that in 60% of subjects with idiopathic RBD, PD developed during a 7-year period [34]. The Braak staging theory suggests that neuronal degeneration begins in the medulla and progresses upwards (e.g., to the neocortex) in PD [35]. According to this theory, RBD corresponds to the second-stage of Braak, which is the premotor period of PD [24,35]. In 33.3% of our patients, RBD started during the premotor period of PD. This result is consistent with the literature [6]. Another study reported that while RBD followed motor symptoms in TD patients, it developed during the premotor period in NTD patients (20.4%) [5]. Contrary to previous studies we found that the premotor onset of clinical RBD was more common in the TD patients than the NTD patients (38.7% versus 27.5%) [5]. However, this difference between the subtypes was not statistically significant. This may be associated with differences in study methodologies. However, our results may also indicate that the presence of clinical RBD in the premotor period may not be useful for estimating the PD subtypes to develop. The most important limitation of this study was the use of the ICSD-R minimal diagnosis criteria without polysomnography to diagnose RBD. The new diagnostic criteria of RBD according to the ICSD 2005 have required a polysomnographical documentation of normal skeletal muscle atonia loss in REM sleep [1,16]. However, many recent studies of PD have used the ICSD-R minimal diagnostic criteria; do not require a polysomnographic examination for clinical diagnosis of RBD, as in the present study [6,12,15,19]. Because of the most important aim of this study is to assessment the clinical severity of RBD in PD subtypes, we have used the ICSD-R minimal diagnosis criteria. Stiasny-Kolster et al. [36], developed a 10-item patient self-rating questionnaire (maximum total score 13 points) according to clinical features of RBD in the ICSD 2005. They excluded patients without a clinical history of RBD, who have only PSG findings of RBD. They recommended using the RBD screening questionnaire (RBDSQ) for the recruitment of RBD patients in research studies. Another limitation of our study was the relatively small numbers of patients with RBD. In our study, the frequency of clinical RBD was unrelated to motor subtypes of PD. However, in the present study, we found a weak correlation between clinical severity (UPDRS and the Hoehn–Yahr) of PD and severity of clinical RBD in the NTD subtype but not in the TD subtype. Also the onset of clinical RBD during the premotor period was not different between motor subtypes of PD.
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