Probable rapid eye movement sleep behavior disorder, nocturnal disturbances and quality of life in patients with Parkinson's disease: a case-controlled study using the rapid eye movement sleep behavior disorder screening questionnaire.

BACKGROUND: Increasing evidence provides a clear association between rapid eye movement sleep behavior disorders (RBD) and Parkinson's disease (PD), but the clinical features that determine the co-morbidity of RBD and PD are not yet fully understood. METHODS: We evaluated the characteristics of nocturnal disturbances and other motor and non-motor features related to RBD in patients with PD and the impact of RBD on their quality of life. Probable RBD (pRBD) was evaluated using the Japanese version of the RBD screening questionnaire (RBDSQ-J). RESULTS: A significantly higher frequency of pRBD was observed in PD patients than in the controls (RBDSQ-J ≥ 5 or ≥ 6: 29.0% vs. 8.6%; 17.2% vs. 2.2%, respectively). After excluding restless legs syndrome and snorers in the PD patients, the pRBD group (RBDSQ-J≥5) showed higher scores compared with the non-pRBD group on the Parkinson's disease sleep scale-2 (PDSS-2) total and three-domain scores. Early morning dystonia was more frequent in the pRBD group. The Parkinson's Disease Questionnaire (PDQ-39) domain scores for cognition and emotional well-being were higher in the patients with pRBD than in the patients without pRBD. There were no differences between these two groups with respect to the clinical subtype, disease severity or motor function. When using a cut-off of RBDSQ-J = 6, a similar trend was observed for the PDSS-2 and PDQ-39 scores. Patients with PD and pRBD had frequent sleep onset insomnia, distressing dreams and hallucinations. The stepwise linear regression analysis showed that the PDSS-2 domain "motor symptoms at night", particularly the PDSS sub-item 6 "distressing dreams", was the only predictor of RBDSQ-J in PD. CONCLUSION: Our results indicate a significant impact of RBD co-morbidity on night-time disturbances and quality of life in PD, particularly on cognition and emotional well-being. RBDSQ may be a useful tool for not only screening RBD in PD patients but also predicting diffuse and complex clinical PD phenotypes associated with RBD, cognitive impairment and hallucinations.

Odor identification test as an indicator of idiopathic REM sleep behavior disorder.

Reduction of olfactory function in idiopathic rapid-eye-movement (REM) sleep behavior disorder (iRBD) is of the same magnitude as that found in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We assessed olfactory function using the Odor Stick Identification Test for Japanese (OSIT-J) in 48 Japanese patients with iRBD, 21 with PD, and 34 with obstructive sleep apnea syndrome (OSAS). Possible score of the OSIT-J ranges from 0 to 12. OSIT-J scores were 4.9 +/- 2.8 in patients with iRBD, 4.8 +/- 2.8 in patients with PD, and 9.9 +/- 1.4 in OSAS patients. An OSIT-J score of 8.5 was associated with a sensitivity of 88.2 and 85.3%, respectively, and specificity of 83.3 and 85.7%, respectively, in differentiating iRBD or PD patients from OSAS patients. Odor identification is impaired in Japanese patients with iRBD and PD. The results suggest that OSIT-J, which is a short and simple nonlexical olfactory identification test, can be useful as a clinical indicator for iRBD with Lewy body formation and is appropriate in the Japanese elderly population.

123I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder.

OBJECTIVE: RBD is considered to be a manifestation of an evolving synucleinopathy, such as Parkinson disease (PD), dementia of Lewy bodies (DLB), and multiple system atrophy (MSA). We tested whether the degree of accumulation of cardiac 123I-MIBG scintigraphy can distinguish the clinical syndromes associated with Lewy body-related disease from the syndrome of PSP (a tauopathy) and MSA. DESIGN: Cross-sectional. SETTING: University-based sleep disorders laboratory. PATIENTS: Subjects comprised 95 patients (31, idiopathic RBD; 26, PD; 10, MSA; 6, DLB; 13, progressive supranuclear palsy [PSP]) and 9 control subjects. INTERVENTION: To compare tracer uptake of cardiac 123I-MIBG between idiopathic RBD, PD, MSA, DLB, and PSP and control subjects. MEASUREMENTS AND RESULTS: Cardiac 123I-MIBG accumulation was evaluated by the heart/mediastinum (H/M) ratio. Mean value of the H/M ratio (early, delayed) was significantly reduced in patients with idiopathic RBD compared to MSA patients, PSP patients, control subjects (P < 0.001 in each group) and PD patients in early images (P < 0.05). There was a correlation between the H/M ratio and disease duration in the idiopathic RBD group. ROC analysis revealed that an H/M cut-off value of 1.9 was useful for differentiating RBD from MSA and PSP as well as distinguishing control subjects from those with RBD in both early and delayed images. CONCLUSION: Cardiac 123I-MIBG findings are similar among idiopathic RBD and the syndromes of PD and DLB, but differ from those of PSP and MSA.

[Orbital apex syndrome due to relapse during steroid tapering in a patient with MPO-ANCA-positive IgG4-related hypertrophic pachymeningitis].

A 75-year-old man developed hearing loss and hoarseness; 5 months later, he suffered from headache and loss of appetite. A blood test showed an inflammatory reaction, a high level of serum IgG4 (254.0 mg/dl), and positive reaction for MPO-ANCA. Gadolinium enhanced T1 weighted head magnetic resonance imaging (MRI) revealed dural thickening with marked enhancement. Infiltration of lymphocytes and anti-IgG4-positive plasma cells were detected in the dura mater by meningeal biopsy; thus, he was diagnosed with MPO-ANCA-positive IgG4-related hypertrophic pachymeningitis. His clinical manifestations, and serologic and MRI findings improved with steroid treatment; however, they recurred during steroid tapering and he presented with right orbital apex syndrome. We then added an immunosuppressive drug to his regimen. It was difficult to reduce the symptoms of this case, with oral steroid monotherapy, and its combination with an immunosuppressive drug was necessary.

Snoring is associated with an impaired motor function, disease severity and the quality of life but not with excessive daytime sleepiness in patients with Parkinson's disease.

OBJECTIVE: There are conflicting results regarding the frequency and clinical significance of sleep related breathing disorders in patients with Parkinson's disease (PD). The aim of this study was to investigate the relationship between snoring and its clinical correlates in patients with PD. METHODS: A total of 93 PD patients and 93 controls were analyzed from a previously conducted cross-sectional study. Snoring was defined as a snoring frequency of ≥ 2 days/week (a score of 2 or higher on the PD Sleep Scale-2 subitem 15). Excessive daytime sleepiness (EDS) was defined as an Epworth Sleepiness Scale score of ≥ 10. RESULTS: Snoring was more prevalent in the patients with PD than in the controls (14.0% vs. 1.1%). The PD patients who snored exhibited greater disease severity, worse scores on the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) and the Parkinson fatigue scale and more impaired scores in several domains of the Parkinson's Disease Questionnaire, including the domains of mobility, activities of daily living, emotional well-being, communication and bodily discomfort, when compared to those who did not snore. No between-group differences were found in EDS. A higher proportion of the UPDRS motor scores for bradykinesia was seen in the PD patients who snored compared to that observed in the PD patients who did not snore. CONCLUSION: We found that snoring was more frequent in PD patients than in controls. Furthermore, snoring in PD patients was associated with disease severity, an impaired motor function and a decreased quality of life, although it was not associated with EDS.

Impaired decision-making in idiopathic REM sleep behavior disorder.

BACKGROUND: Patients with REM sleep behavior disorder (RBD) frequently develop Parkinson's disease (PD), which can impair decision-making ability. This study was undertaken to investigate decision-making ability and its relation to olfactory function in patients with idiopathic RBD. METHODS: This study used the Iowa Gambling Task (IGT) and the Sniffin' Stick Test for examination of 38 patients with idiopathic RBD (iRBD) and 34 age-matched healthy control subjects (HC). Associations between these test results and other clinical RBD variables were also assessed. RESULTS: Total IGT score and Sniffin' Stick Test scores were significantly lower in the iRBD group than in the HC group. The iRBD group IGT scores in the first, third, and final blocks were significantly lower than those of the HC group. In the iRBD group, no association was found between the total IGT score and the Sniffin' Stick Test score or any clinical RBD variable. CONCLUSIONS: Impaired decision-making associated with iRBD can herald PD. However, decision-making disability is thought to appear irrespective of olfactory dysfunction and progression of RBD pathology.

[Sleep disturbances in patients with Parkinson disease].

Sleep disturbances are among the most common disabling nonmotor symptoms of Parkinson disease (PD). Recently, awareness of sleep disorders related to PD has increased, reflecting their significant negative impact on the quality of life of the patient. However, sleep disturbances are still often under-recognized. In PD, multiple factors are associated with sleep disturbances; impaired arousal systems and sleep structure as disease-related changes, nocturnal motor symptoms, hallucinations and psychosis, pain, nocturia, depressive symptoms and dopaminergic medication can all cause insomnia. Further, these factors can coexist and influence each other during the course of the disease. In addition, sleep-related breathing disorder, restless legs syndrome (RLS) and rapid eye movement sleep behavior disorder (RBD) can also lead to impaired sleep. Some idiopathic RBD patients have been associated with a risk for developing neurodegenerative diseases, including PD. Therefore, early diagnosis of RBD may have significant clinical implications for neuroprotective strategies. Several studies have revealed an increased incidence of RLS in PD patients compared to the general population. The favorable responses to dopaminergic medications in treating both RLS and PD suggest shared pathophysiologies between the two diseases; however, neuroimaging studies of dopaminergic systems remain inconclusive. In this review, we discuss the current understanding of sleep disturbances in PD and the existing treatments.

Preclinical substantia nigra dysfunction in rapid eye movement sleep behaviour disorder.

OBJECTIVES: Transcranial sonography (TCS) has been shown to reveal hyperechogenicity of the substantia nigra (SN) in people with Parkinson's disease and in approximately 10% of healthy subjects. It is hypothesized that SN hyperechogenicity in healthy subjects and patients with idiopathic rapid eye movement (REM) sleep behaviour disorder (iRBD) patients is a marker of vulnerability for Parkinson's disease. METHODS: TCS and positron emission tomography (PET) with 6-[(18)F] fluoro-meta-tyrosine (FMT), which can assess the level of the presynaptic dopaminergic nerve, were performed in 19 male patients with iRBD, mean age 66.4 (standard deviation [SD] 4.9) years, to assess nigrostriatal function. RESULTS: Nine patients had pathological SN hyperechogenicity (mean age 66.8 [SD 3.9] years; 0.31 [SD 0.12] cm(2)) and 10 patients did not have SN hyperechogenicity (mean age 66.0 [SD 5.8] years; 0.11 [SD 0.06] cm(2)). FMT uptake at the putamen and caudate was significantly lower in iRBD patients with pathological SN hyperechogenicity compared with those without SN hyperechogenicity. However, no correlation was found between SN echogenicity and FMT uptake. This is in conflict with previous findings which showed that subjects with hyperechogenicity had lower FMT uptake in the striatum. CONCLUSION: Pathological hyperechogenic alterations in the SN in patients with iRBD may suggest the existence of preclinical SN dysfunction as determined by FMT-PET.

Nocturnal disturbances and restlessness in Parkinson's disease: using the Japanese version of the Parkinson's disease sleep scale-2.

OBJECTIVE: The aim of this study was to assess the validity and the reliability of the Japanese version of the Parkinson's disease sleep scale (PDSS)-2 and to use this scale to identify nocturnal symptoms and their impact on patient's quality of life. METHODS: A cross-sectional, case-controlled study was conducted consisting of 93 patients with Parkinson's disease (PD) and 93 age- and gender-matched control subjects. The Japanese version of the PDSS-2 was used for the evaluation of nocturnal disturbances. The patient's quality of life was evaluated with the Parkinson's Disease Quality of Life questionnaire (PDQ-39) and their depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II), respectively. In addition, the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and Parkinson Fatigue Scale (PFS) were administered. RESULTS: As assessed using the PDSS-2, PD patients had significantly impaired scores compared with control subjects (15.0±9.7 vs. 9.1±6.6, p<0.001). The ESS, BDI-II and PFS scores were significantly impaired in PD patients compared with controls. A satisfactory internal consistency and test-retest reliability score were obtained for the PDSS-2 total score (Cronbach's alpha=0.86). The PDSS-2 was correlated with the PSQI, ESS, BDI-II, PFS, PDQ-39 summary index, all of the PDQ-39 domains and Unified Parkinson's Disease Rating Scale part III. The frequency of restless legs syndrome (RLS) was not significantly different between PD patients and controls (5.5% vs. 2.2%), but nocturnal restlessness was significantly more frequent in PD patients than controls. Stepwise linear regression analyses revealed the PDQ-39 summary index and the PSQI global score as significant predictors for the PDSS-2 total score. CONCLUSIONS: Our study confirmed the usefulness of the Japanese version of the PDSS-2 that enables the comprehensive assessment of nocturnal disturbances in PD. The association between RLS and nocturnal restlessness in PD requires further study.

Idiopathic REM Sleep Behavior Disorder: Implications for the Pathogenesis of Lewy Body Diseases.

Objectives. Both results of the odor identification and cardiac (123)I-metaiodobenzylguanidine accumulation have been investigated for their potential to enhance the detection of pathogenesis resembling that of Lewy body-related α-synucleinopathies in patients clinically diagnosed as having idiopathic REM sleep behavior disorder. Methods. We performed both the Odor Stick Identification Test for Japanese and (123)I-metaiodobenzylguanidine scintigraphy in 30 patients with idiopathic REM sleep behavior disorder, 38 patients with Parkinson's disease, and 20 control subjects. Results. In idiopathic REM sleep behavior disorder, reduced odor identification score and an early or delayed heart to mediastinum ratio on (123)I-metaiodobenzylguanidine were almost as severe as in Parkinson's disease patients. Delayed cardiac (123)I-metaiodobenzylguanidine uptake was even more severe in the idiopathic REM sleep behavior disorder group than in the Parkinson's disease group. Conclusions. Reduced cardiac (123)I-metaiodobenzylguanidine uptake, which is independent of parkinsonism, may be more closely associated with idiopathic REM sleep behavior disorder than olfactory impairment.

Sleep disturbances associated with Parkinson's disease.

Sleep disturbances are common problems affecting the quality life of Parkinson's disease (PD) patients and are often underestimated. The causes of sleep disturbances are multifactorial and include nocturnal motor disturbances, nocturia, depressive symptoms, and medication use. Comorbidity of PD with sleep apnea syndrome, restless legs syndrome, rapid eye movement sleep behavior disorder, or circadian cycle disruption also results in impaired sleep. In addition, the involvement of serotoninergic, noradrenergic, and cholinergic neurons in the brainstem as a disease-related change contributes to impaired sleep structures. Excessive daytime sleepiness is not only secondary to nocturnal disturbances or dopaminergic medication but may also be due to independent mechanisms related to impairments in ascending arousal system and the orexin system. Notably, several recent lines of evidence suggest a strong link between rapid eye movement sleep behavior disorder and the risk of neurodegenerative diseases such as PD. In the present paper, we review the current literature concerning sleep disorders in PD.

Relevance of substantia nigra hyperechogenicity and reduced odor identification in idiopathic REM sleep behavior disorder.

BACKGROUND: Substantia nigra (SN) hyperechogenicity determined by transcranial sonography (TCS) and olfactory dysfunction are common findings in Parkinson disease (PD), which may reveal a prodromal synucleinopathy in idiopathic REM sleep behavior disorder (iRBD). METHODS: TCS and the Odor Stick Identification Test for Japanese (OSIT-J) were performed in 34 consecutive patients with iRBD (67.9+/-6.1years), 17 consecutive patients with PD (66.4+/-6.7years), and 21 control group subjects (64.4+/-5.8years). RESULTS: There was a significantly increased area of echogenicity in the SN in the iRBD group (0.20+/-0.13cm2) and PD group (0.22+/-0.11cm2) compared with the control group (0.06+/-0.06cm(2)). We found pathological SN hyperechogenicity (0.20cm2) in 41.2% of the iRBD group, 52.6% of the PD group, and 9.5% of the control group. Further, there were abnormal findings of both pathological SN hyperechogenicity (0.20cm2) and functional anosmia or hyposmia in 4 (11.8%) or 9 (26.5%) of the iRBD group subjects, respectively, and 7 (57.9%) or 2 (11.8%) of the PD group subjects, respectively. CONCLUSION: Pathological SN hyperechogenic abnormality and functional anosmia in iRBD may be a disease state in the transition to a neurodegenerative disease.

Olfactory dysfunction in idiopathic REM sleep behavior disorder.

BACKGROUND: Olfactory dysfunction is frequently observed in patients with idiopathic REM sleep behavior disorder (iRBD) such as Parkinson's disease or dementia with Lewy bodies. METHODS: Olfactory function tests using Sniffin' Sticks and Odor Stick Identification Test for Japanese (OSIT-J) were performed in 73 consecutive middle-aged (range, 50-69 years) patients with iRBD, 33 consecutive older-aged (71-82 years) patients with iRBD, and 28 control subjects (55-70 years). RESULTS: Odor identification was more frequently impaired than odor threshold or discrimination among the iRBD group and allowed better discrimination between the middle-aged iRBD group and age-adjusted control subjects. The area under the curve for threshold, discrimination, identification, TDI score and OSIT-J score determined from receiver operating characteristic curves were 0.831 (0.753-0.909), 0.761 (0.666-0.855), 0.938 (0.894-0.982), 0.939 (0.897-0.981), and 0.965 (0.931-0.999), respectively. Discrimination and identification scores were significantly lower in the older-aged iRBD group than in the middle-aged iRBD group. A significant correlation was observed between the identification score on Sniffin' Sticks and OSIT-J score (r=0.5910, P<0.0001, n=106, Spearman's rank). CONCLUSION: Anosmia/hyposmia may be a feature of iRBD. Olfactory dysfunction in iRBD is a consistent, widespread central nervous abnormality of different olfactory modalities with different cognitive complexity.

[Paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome associated with anti P/Q-type voltage-gated calcium channel antibody in a patient with primary double lung cancer].

We report the case of a 50-year-old man with paraneoplastic cerebellar degeneration (PCD) and Lambert-Eaton myasthenic syndrome (LEMS) associated with primary double lung cancer. He developed acute progressive double vision, slurred speech, and gait disturbance. Neurological examination revealed diplopia, mild ptosis, bilateral horizontal gaze-evoked nystagmus, and cerebellar limb and truncal ataxia. The diffusion image of brain magnetic resonance imaging (MRI) revealed no abnormal findings in the cerebellum. On the basis of the diagnosis of acute cerebelitis, he was given methylprednisolone pulse therapy followed by oral prednisolone, which gradually improved his neurological signs and symptoms. The analysis of the possible etiology suggested that the PCD was induced by lung cancer, which led to ataxia. A chest computed tomography scan revealed mass lesions of irregular shape and unclear margins in the upper lobe of the right lung and a small nodule tumor in the upper lobe of the left lung. We performed transbronchial needle aspiration and detected the bronchioloalveolar carcinoma of the right lung. An electromyogram showed waxing phenomenon in the ulnar nerve at high-frequency (50Hz) stimulation. The serum levels of anti-P/Q-type voltage-gated calcium channel (VGCC) antibody were elavated in the patient. These findings confirmed that the pathogenesis of the condition of this patient to be associated with LEMS. His cerebellar symptoms were considered to be caused by the PCD, and the diplopia, ptosis, and hyporeflexia were attributed to LEMS. We performed upper left lobectomy with mediastinal lymphnode dissection via video-assisted thoracoscopic surgery. A histological study detected small cell carcinoma. A diagnosis of double primary lung cancer was made. Physicians need to be aware that patients may develop PCD and LEMS associated with anti-VGCC antibody caused by small cell lung cancer, and a mass survey should be conducted and careful examinations performed.

[Pathophysiology of restless legs syndrome].

Restless legs syndrome (RLS) is a sensorimotor disorder that is frequently associated with periodic leg movements (PLMS). RLS is generally considered to be a central nervous system (CNS)-related disorder although no specific lesion has been found to be associated with the syndrome. Reduced intracortical inhibition has been demonstrated in RLS by transcranial magnetic stimulation. Some MRI studies have revealed the presence of morphologic changes in the somatosensory cortex, motor cortex and thalamic gray matter. The results of SPECT and PET studies showed that the limbic and opioid systems also play important roles in the pathophysiology of RLS. A functional MRI study revealed abnormal bilateral cerebellar and thalamic activation during the manifestation of sensory symptoms, with additional red nucleus and reticular formation activity during PLMS. PLMS is likely to occur in patients with spinal cord lesions, and some patients with sensory polyneuropathy may exhibit RLS symptoms. RLS symptoms seem to depend on abnormal spinal sensorimotor integration at the spinal cord level and abnormal central somatosensory processing. PLMS appears to depend on increased excitability of the spinal cord and a decreased supraspinal inhibitory mechanism from the All diencephalic dopaminergic system. RLS symptoms respond very dramatically to dopaminergic therapy. The results of analysis by PET and SPECT studies of striatal D2 receptor binding in humans are inconclusive. However, studies in animal models suggest that the participation of the All dopaminergic system and the D3 receptor in RLS symptoms. The symptoms of RLS are aggravated in those with iron deficiency, and iron treatment ameliorates the symptoms in some patients. Neuroimaging studies, analysis of the cerebrospinal fluid, and studies on postmortem tissue and use of animal models have indicated that low brain iron concentrations and dysfunction of iron metabolism and intracellular iron may play key roles in the pathogenesis of RLS. The "iron-dopamine model" explains that iron deficiency in the brain causes an abnormality in the dopaminergic system leading to manifestation of RLS. Genetic factors are also important in the development of RLS. A positive family history for RLS has been reported by 40% to 60% of RLS patients. Five loci (RLS 1: 12q, RLS 2: 14q, RLS 3: 9p, RLS 4: 2q, RLS 5: 20p) have been described. Genome-wide association studies have identified variants within the intronic or intergenetic regions of MEIS1 (2p), LBXCOR1/MAP2K5 (15q), BTBD9 (6p), neuronal nitric oxide synthase (NOS1) (12q) and protein tyrosine phosphatase receptor type delta (9p) genes. In conclusion, disturbances in the central dopaminergic system, disturbances in iron metabolism, and genetics seem to be the primary factors in the pathophysiology of RLS.

The REM sleep behavior disorder screening questionnaire: validation study of a Japanese version.

BACKGROUND: REM sleep behavior disorder (RBD) is a parasomnia characterized by intermittent loss of normal skeletal muscle atonia during REM sleep and elaborate motor activity associated with dream mentation. Idiopathic RBD (iRBD) has a known association with neurodegenerative diseases such as synucleinopathies. Recently, a specific screening scale for assessment of REM sleep behavior disorder (RBDSQ) was validated. Detection of RBD using a Japanese version of the RBDSQ would be useful in the stepwise diagnostic process. We investigated the validity and reliability of a Japanese version of this instrument, the RBDSQ-J. METHODS: Subjects were 52 patients with iRBD diagnosed according to criteria in the International Classification of sleep disorders, second edition, 55 obstructive sleep apnea syndrome (OSAS) patients who responded well to CPAP therapy after a diagnosis of RBD was ruled out by history and polysomnography (PSG) and 65 healthy subjects. RESULTS: An RBDSQ-J score cut-off of 5.0 was considered useful for differentiating the iRBD group from the healthy subjects or the OSAS group. Cronbach's alpha for the entire RBDSQ-J was 0.866. CONCLUSION: The RBDSQ-J had high sensitivity, specificity, and reliability and would be applicable as a screening method for iRBD in the elderly Japanese population.