Nonmotor and Dopamine Transporter Change in REM Sleep Behavior Disorder by Olfactory Impairment.

OBJECTIVE: It is unclear whether the decline in dopamine transporters (DAT) differs among idiopathic rapid eye movement sleep behavior disorder (iRBD) patients with different levels of olfactory impairment. This study aimed to characterize DAT changes in relation to nonmotor features in iRBD patients by olfactory loss. METHODS: This prospective cohort study consisted of three age-matched groups: 30 polysomnography-confirmed iRBD patients, 30 drug-naïve Parkinson's disease patients, and 19 healthy controls without olfactory impairment. The iRBD group was divided into two groups based on olfactory testing results. Participants were evaluated for reported prodromal markers and then underwent 18F-FP-CIT positron emission tomography and 3T MRI. Tracer uptakes were analyzed in the caudate, anterior and posterior putamen, substantia nigra, and raphe nuclei. RESULTS: Olfactory impairment was defined in 38.5% of iRBD patients. Mild parkinsonian signs and cognitive functions were not different between the two iRBD subgroups; however, additional prodromal features, constipation, and urinary and sexual dysfunctions were found in iRBD patients with olfactory impairment but not in those without. Tracer uptake showed significant group differences in all brain regions, except the raphe nuclei. The iRBD patients with olfactory impairment had uptake reductions in the anterior and posterior putamen, caudate, and substantia nigra (p < 0.016 in all, adjusted for age), which ranged from 0.6 to 0.8 of age-normative values. In contrast, those without olfactory impairment had insignificant changes in all regions ranging above 0.8. CONCLUSION: There was a clear distinction in DAT loss and nonmotor profiles by olfactory status in iRBD.

A 7-year observation of the effect of subthalamic deep brain stimulation on impulse control disorder in patients with Parkinson's disease.

INTRODUCTION: Previous studies have reported improvement of impulse control disorders (ICDs) after subthalamic nucleus (STN) deep brain stimulation (DBS) as well as some de novo ICDs. However, it is not clear how STN DBS changes ICDs in the long-term. METHODS MATERIALS: Eighty-nine patients with Parkinson's disease (PD) who had received a bilateral STN DBS from 2005 to 2009 and were included in our previous study were followed for 7 years with the modified Minnesota Impulsive Disorders Interview (mMIDI). Their mMIDI scores, medication, and frontal function tests measured preoperatively and at 1 and 7 years postoperatively were compared. RESULTS: A total of 61 patients were analyzed after excluding 10 and 18 patients due to death and lost to follow-up, respectively. The numbers of the patients with an ICD at each point were 8, 10, and 7, respectively. All preoperative ICDs disappeared after DBS. De novo ICDs within 1 year after DBS disappeared except for 1 patient. Six of the seven patients, who reported ICDs 7 years after the DBS developed that ICD between 1 and 7 years. Their total levodopa equivalent daily dose (LEDD) and dopamine agonist dose were not higher compared to the other 54 patients without ICDs. There was no correlation with the frontal lobe dysfunction and the electrode position in the subthalamus. CONCLUSION: STN DBS improves baseline ICDs and results in the development of "transient" de novo ICDs in the short-term. In addition, there is a unique group of the patients who develop ICDs a long time after DBS.

Amantadine and the Risk of Dyskinesia in Patients with Early Parkinson's Disease: An Open-Label, Pragmatic Trial.

OBJECTIVE: We examined whether amantadine can prevent the development of dyskinesia. METHODS: Patients with drug-naïve Parkinson's disease (PD), younger than 70 years of age and in the early stage of PD (Hoehn and Yahr scale < 3), were recruited from April 2011 to December 2014. The exclusion criteria included the previous use of antiparkinsonian medication, the presence of dyskinesia, significant psychological disorders, and previous history of a hypersensitivity reaction. Patients were consecutively assigned to one of 3 treatment groups in an open label fashion: Group A-1, amantadine first and then levodopa when needed; Group A-2, amantadine first, dopamine agonist when needed, and then levodopa; and Group B, dopamine agonist first and then levodopa when needed. The primary endpoint was the development of dyskinesia, which was analyzed by the Kaplan-Meier survival rate. RESULTS: A total of 80 patients were enrolled: Group A-1 (n = 27), Group A-2 (n = 27), and Group B (n = 26). Twenty-four patients were excluded from the analysis due to the following: withdrawal of amantadine or dopamine agonist (n = 9), alternative diagnosis (n = 2), withdrawal of consent (n = 1), and breach in the protocol (n = 12). After exclusion, 5 of the 56 (8.93%) patients developed dyskinesia. Patients in Group A-1 and A-2 tended to develop dyskinesia less often than those in Group B (cumulative survival rates of 0.933, 0.929, and 0.700 for A-1, A-2, and B, respectively; p = 0.453). CONCLUSION: Amantadine as an initial treatment may decrease the incidence of dyskinesia in patients with drug-naïve PD.

Emergence of non-motor fluctuations with reference to motor fluctuations in Parkinson's disease.

INTRODUCTION: Non-motor fluctuations (NMF) and motor fluctuations (MF) are frequent in patients with Parkinson's disease (PD) with long-term medical treatment. We aimed to examine the timing of the emergence of NMF with reference to MF in a prospective cohort of patients with PD without symptom fluctuations. METHODS: A total of 334 patients with PD who had neither MF nor NMF were recruited. The exclusion criteria included a Mini-Mental State Examination score of less than 26 points at baseline and an alternative diagnosis or significant comorbidity during follow-up. The "SNUH-Fluctuation Questionnaire" consisting of 29 items (9 on MF and 20 on NMF) was administered on a semi-annually basis for 3 years. RESULTS: Three hundred seven out of 334 patients were analyzed for symptom fluctuations with the Kaplan-Meier survival analysis. MF were observed in more patients and developed earlier than NMF (cumulative survival of 0.572 for MF and 0.619 for NMF at 36 months of follow-up). In 212 patients who finished the follow-up for 36 months, MF and NMF developed simultaneously in 58 (27.4%), MF developed first in 45 (21.2%), and NMF developed first in only 3 (1.4%). The remaining 106 patients (50.0%) did not develop either MF or NMF. CONCLUSION: NMF developed simultaneously with or later than MF. From these data, we hypothesize that NMF develop in the disease state where the pathology in the brain has been severe enough to develop MF. Hence, pharmacologic management should consider targeting both dopaminergic and non-dopaminergic systems to treat NMF.

Validation of Freezing-of-Gait Monitoring Using Smartphone.

BACKGROUND: Freezing of gait (FOG) is a commonly observed motor symptom for patients with Parkinson's disease (PD). The symptoms of FOG include reduced step lengths or motor blocks, even with an evident intention of walking. FOG should be monitored carefully because it not only lowers the patient's quality of life, but also significantly increases the risk of injury. INTRODUCTION: In previous studies, patients had to wear several sensors on the body and another computing device was needed to run the FOG detection algorithm. Moreover, the features used in the algorithm were based on low-level and hand-crafted features. In this study, we propose a FOG detection system based on a smartphone, which can be placed in the patient's daily wear, with a novel convolutional neural network (CNN). METHODS: The walking data of 32 PD patients were collected from the accelerometer and gyroscope embedded in the smartphone, located in the trouser pocket. The motion signals measured by the sensors were converted into the frequency domain and stacked into a 2D image for the CNN input. A specialized CNN model for FOG detection was determined through a validation process. RESULTS: We compared our performances with the results acquired by the previously reported settings. The proposed architecture discriminated the freezing events from the normal activities with an average sensitivity of 93.8% and a specificity of 90.1%. CONCLUSIONS: Using our methodology, the precise and continuous monitoring of freezing events with unconstrained sensing can assist patients in managing their chronic disease in daily life effectively.

REM sleep behavior disorder portends poor prognosis in Parkinson's disease: A systematic review.

REM sleep behavior disorder (RBD) is a parasomnia wherein a loss of REM sleep atonia manifests as dream-enactment, often violent. Aside from its significance as a predictor of PD, RBD in PD may imply more than merely screaming at night and experiencing sleep fragmentation. To probe its significance as a prognostic factor in PD, we performed a systematic literature review. Analysis of prospective studies reveals baseline RBD confers a higher risk of developing dementia and hallucinations. In cross-sectional studies, RBD is associated with the non-tremor predominant motor phenotype and autonomic dysfunction. Clinical, imaging, and autopsy studies support the presence of dense and diffuse pathology extending beyond the brainstem in PD with RBD. As RBD in PD is associated with a greater disease burden and an increased risk of mortality, we propose the RBD subtype in PD to highlight that RBD may mark a distinct subtype with relatively poor prognosis.

Depression may negatively affect the change in freezing of gait following subthalamic nucleus stimulation in Parkinson's disease.

OBJECTIVE: To assess the influence of preoperative depression on the change in freezing of gait (FOG) following subthalamic nucleus stimulation (STN-DBS) in patients with Parkinson's disease (PD). METHODS: One hundred and twelve PD patients were included who received bilateral STN-DBS. Of these, 33 had no preoperative depression (PD-ND) and the other 79 had preoperative depression (PD-D). Each PD-ND patient was matched with one PD-D patient by the propensity score for which sex, age at PD onset, disease duration, UPDRS-III score during off-medication state, levodopa-equivalent daily dose, and mini mental state examination were the independent variables. We compared both a FOG-questionnaire (FOG-Q) and the axial score from UPDRS-III between the two groups over 12-month follow-up. RESULTS: During the off-medication state, FOG-Q at 12-month was decreased with STN-DBS in both PD-ND (-52.9%, p < 0.001) and PD-D (-24.2%, p < 0.001) with a significant difference in the change of FOG in favor of PD-ND (p = 0.001). Similarly, there was an improvement in the axial score for both PD-ND (-66.1%, p < 0.001) and PD-D (-45.3%, p < 0.001) at 12-month with a significant difference between the groups. (p = 0.005). During the on-medication state, both the FOG-Q and axial score at 12-month were not improved with STN-DBS in the PD-ND and PD-D with no difference between the groups. CONCLUSIONS: Our findings suggest that preoperative depression negatively affects the outcome of FOG following STN-DBS in the off-medication state but not in the on-medication state.

Psychiatric symptoms in myoclonus-dystonia syndrome are just concomitant features regardless of the SGCE gene mutation.

INTRODUCTION: Among myoclonus-dystonia syndrome (MD) patients, psychiatric disorders including depression, anxiety, alcohol dependence, obsessive-compulsive disorder (OCD) and panic disorder have been frequently reported to be related with the epsilon-sarcoglycan gene (SGCE) mutation. However, the rate of psychiatric disorders has not been compared between MD patients with the SGCE mutation (SGCE (+)) and without the SGCE mutation (SGCE (-)). We analyzed the psychiatric data in both SGCE (+) and SGCE (-) MD patients to determine the association of the SGCE mutation with psychiatric disorders in MD. METHODS: Twenty-six MD patients who fulfilled the Grunewald's criteria and underwent a SGCE gene study were enrolled. Patients were divided into two groups according to their SGCE status (SGCE (+) and SGCE (-) group). They were systematically assessed using a standardized protocol including motor severity scales and psychiatric questionnaires for depression, anxiety, alcohol dependence, OCD and panic disorder. RESULTS: Fifteen SGCE (+) and eleven SGCE (-) patients were enrolled. Mean age at onset, disease duration, family history, alcohol responsiveness and motor severity were not different between the SGCE (+) and SGCE (-) group. Although more than half (53.8%) of all the MD patients had psychiatric symptoms, there were no significant differences between the SGCE (+) and SGCE (-) group in terms of their psychiatric questionnaire scores and rate of psychiatric disorders. CONCLUSIONS: Psychiatric features are not likely to be related with the SGCE mutation itself but just bespeak disability in clinical MD syndrome regardless of the SGCE mutation.

Correlation of electrode position and clinical outcomes in globus pallidus stimulation for dystonia.

BACKGROUND: The correlation between the electrode location and the clinical outcome for internal globus pallidus (GPi) deep brain stimulation (DBS) has not been fully elucidated. OBJECTIVE: The aim of this study was to determine the discrepancies between the theoretical target planned by magnetic resonance imaging (MRI) and the actual electrode location in postoperative MRI, as well as to find the correlation between the final electrode locations and the clinical outcome after GPi DBS. METHODS: Thirty-six patients who underwent GPi DBS for dystonia were included in this retrospective study. The X coordinate was defined as the lateral distance from the midline, the Y coordinate as the anterior distance from the midcommissural point, and the Z coordinate as the inferior distance from the intercommissural line. RESULTS: All coordinates showed a significant difference between theoretical and actual values for all electrode locations (p < 0.05). In particular, greater differences were exhibited for Y than for the X and Z coordinates. There was no significant difference in the accuracy of the localization of the left-side versus the right-side electrode for any coordinates. The patients whose electrodes were located within or near the posteroventral GPi showed better clinical outcomes. CONCLUSIONS: The actual electrode location was slightly more posterior to the theoretically planned target. Electrodes concentrated near the posteroventral GPi tended to yield favorable outcomes.

Pregnancy and Delivery in a Generalized Dystonia Patient Treated with Internal Globus Pallidal Deep Brain Stimulation: a Case Report.

Internal globus pallidus (GPi) deep brain stimulation (DBS) has been widely accepted as an effective treatment modality of medically refractory dystonia. However, there have been few studies regarding the safety issue of pregnancy and childbirth related with DBS. This report describes a female patient who was pregnant and delivered a baby after GPi DBS surgery. A 33-year-old female patient with acquired generalized dystonia underwent bilateral GPi DBS implantation. She obtained considerable improvement in both movement and disability after DBS implantation. Four years later, she was pregnant and the obstetricians consulted us about the safety of the delivery. At 38-weeks into pregnancy, a scheduled caesarian section was carried out under general anesthesia. After induction using thiopental and succinylcholine, intubation was done quickly, followed by DBS turn off. For hemostasis, only bipolar electrocautery was used. Before awakening from the anesthesia, DBS was turned on as the same parameters previously adjusted. After delivery, she could feed her baby by herself, because the dystonia of left upper extremity and hand was improved. Until now, she has been showing continual improvement and being good at housework, carrying for children, with no trouble in daily life. This observation indicates that the patients who underwent DBS could safely be pregnant and deliver a baby.

Combined focal myoclonus and dystonia secondary to a cerebellar hemorrhage: a case report.

BACKGROUND: Myoclonus is a clinical sign characterized by sudden, brief jerky, shock-like involuntary movements of a muscle or group of muscles. Dystonia is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Cases of myoclonus or dystonia secondary to a structural lesion in the cerebellum have been reported. However, there has never been a reported case of combined myoclonus and dystonia secondary to a cerebellar lesion. CASE PRESENTATION: Herein, we report a 22-year-old female patient with sudden-onset myoclonic jerks, dystonic posture and mild ataxia in the right upper extremity. At age 19, she experienced sudden headache with vomiting. The neurological examination showed ataxia, myoclonus and dystonia in the right upper extremity. Brain images demonstrated a hemorrhage in the right cerebellar hemisphere secondary to a cavernous malformation. After resection of the hemorrhagic mass, headache with vomiting disappeared and ataxia improved, but myoclonus and dystonia persisted. CONCLUSIONS: It is the first report of combined focal myoclonus and dystonia secondary to a cerebellar lesion.

Survival of Korean Huntington's Disease Patients.

OBJECTIVE: The survival of Huntington's disease (HD) patients is reported to be 15-20 years. However, most studies on the survival of HD have been conducted in patients without genetic confirmation with the possible inclusion of non-HD patients, and all studies have been conducted in Western countries. The survival of patients with HD in East Asia, where its prevalence is 10-50-fold lower compared with Western populations, has not yet been reported. METHODS: Forty-seven genetically confirmed Korean HD patients from independent families were included in this retrospective medical record review study. RESULTS: The mean age at onset among the 47 patients was 46.1 ± 14.0 years. At the time of data collection, 25 patients had died, and these patients had a mean age at death of 57.8 ± 13.7 years. The Kaplan-Meier estimate of the median survival from onset in the 47 patients was 14.5 years (95% confidence interval: 12.3-16.6). None of the following factors were associated with the survival time in the univariate Cox regression analysis: gender, age at onset, normal CAG repeat size, mutant CAG repeat size, and the absence or presence of non-motor symptoms at onset. CONCLUSION: This is the first Asian study on survival in HD patients. Survival in Korean HD patients may be shorter than that reported for Western populations, or at least is in the lower range of expected survival. A larger longitudinal observation study is needed to confirm the results found in this study.

Predictors of the placebo response in clinical trials on Parkinson's disease: A meta-analysis.

INTRODUCTION: Previous studies have assessed the placebo response in clinical trials on PD using the individual data of participants from the placebo-assigned group. The aim of this study was to examine the group predictors of the placebo response in randomized placebo-controlled trials on PD using a meta-analysis with meta-regression models. METHODS: The placebo response was defined as the mean change in the UPDRS part III score from baseline to the primary efficacy end point in the placebo group. The impacts of the predictors were assessed with meta-regression analyses, and significant predictors were used in a multivariable analysis. Subgroup analyses were conducted in studies that enrolled PD patients with or without motor fluctuations. RESULTS: Forty-eight studies (consisting of 5618 participants on placebo) were included. Motor fluctuation and baseline UPDRS part III score were significant predictors in the univariable analyses. The high baseline UPDRS part III score (ß = -0.21, 95% CI -0.34, -0.08; p = 0.005) significantly increased the magnitude of the positive placebo response in the multivariable analysis. In the subgroup analyses, the positive placebo response was significant only in studies that enrolled patients with motor fluctuations; high baseline UPDRS part III score and low baseline daily levodopa dose increased the positive placebo response independently in the subgroup with motor fluctuations. CONCLUSION: Researchers should consider the positive placebo response when they design clinical trials in advanced PD patients with motor fluctuations and severe motor symptoms. Baseline daily levodopa dose may be the independent predictor in studies that enrolled fluctuating patients.

Long-Term Clinical Outcome of Internal Globus Pallidus Deep Brain Stimulation for Dystonia.

BACKGROUND: GPi (Internal globus pallidus) DBS (deep brain stimulation) is recognized as a safe, reliable, reversible and adjustable treatment in patients with medically refractory dystonia. OBJECTIVES: This report describes the long-term clinical outcome of 36 patients implanted with GPi DBS at the Neurosurgery Department of Seoul National University Hospital. METHODS: Nine patients with a known genetic cause, 12 patients with acquired dystonia, and 15 patients with isolated dystonia without a known genetic cause were included. When categorized by phenomenology, 29 patients had generalized, 5 patients had segmental, and 2 patients had multifocal dystonia. Patients were assessed preoperatively and at defined follow-up examinations postoperatively, using the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) for movement and functional disability assessment. The mean follow-up duration was 47 months (range, 12-84). RESULTS: The mean movement scores significantly decreased from 44.88 points preoperatively to 26.45 points at 60-month follow up (N = 19, P = 0.006). The mean disability score was also decreased over time, from 11.54 points preoperatively to 8.26 points at 60-month follow up, despite no statistical significance (N = 19, P = 0.073). When analyzed the movement and disability improvement rates at 12-month follow up point, no significant difference was noted according to etiology, disease duration, age at surgery, age of onset, and phenomenology. However, the patients with DYT-1 dystonia and isolated dystonia without a known genetic cause showed marked improvement. CONCLUSIONS: GPi DBS is a safe and efficient therapeutic method for treatment of dystonia patients to improve both movement and disability. However, this study has some limitations caused by the retrospective design with small sample size in a single-center.

Leukocyte glucocerebrosidase and ß-hexosaminidase activity in sporadic and genetic Parkinson disease.

BACKGROUND: Recent reports have shown that the activities of lysosomal enzymes are altered in the CNS of sporadic PD (sPD) without GBA mutations. We hypothesized that the activities of lysosomal enzymes are altered in peripheral blood leukocytes (PBLs) of patients with sPD and other genetic parkinsonism. METHODS: Glucocerebrosidase and ß-hexosaminidase activities in PBLs were measured in 36 patients with sPD, 5 PD patients with PARK2 mutations, 10 patients with spinocerebellar ataxia (SCA) 17 with parkinsonism, and 20 healthy controls. RESULTS: The glucocerebrosidase and ß-hexosaminidase activities were not different in patients with sPD, PD with PARK2 mutations, and SCA17 with parkinsonism from those of the controls. In the patients with sPD, the activity of GCase was positively correlated with disease duration. CONCLUSION: The glucocerebrosidase and ß-hexosaminidase activities in PBLs cannot be used as a biomarker in sPD and other genetic parkinsonism.

Unconstrained detection of freezing of Gait in Parkinson's disease patients using smartphone.

Freezing of gait (FOG) is a common motor impairment to suffer an inability to walk, experienced by Parkinson's disease (PD) patients. FOG interferes with daily activities and increases fall risk, which can cause severe health problems. We propose a novel smartphone-based system to detect FOG symptoms in an unconstrained way. The feasibility of single device to sense gait characteristic was tested on the various body positions such as ankle, trouser pocket, waist and chest pocket. Using measured data from accelerometer and gyroscope in the smartphone, machine learning algorithm was applied to classify freezing episodes from normal walking. The performance of AdaBoost.M1 classifier showed the best sensitivity of 86% at the waist, 84% and 81% in the trouser pocket and at the ankle respectively, which is comparable to the results of previous studies.

Preliminary analysis of Huntington's Disease in South Korea.

BACKGROUND: There have been epidemiological studies of Huntington's disease (HD) in various populations and nations. Only a few studies describing clinical characteristics have been reported in Asia. OBJECTIVE: To conduct preliminary analyses of demographic, clinical and genetic characteristics of HD in South Korea. METHODS: From 1994 to 2011, thirty six subjects were diagnosed as HD in Seoul National University Hospital. Demographic, clinical and genetic data were carefully analyzed in all subjects. RESULTS: Mean age of onset was 46.5 ± 12.7 years and mean expanded CAG repeat size was 45.4 ± 4.7. Twenty-eight subjects (80%) had a family history of HD. Chorea was the most frequent symptom at first visit (89%). Proportion of cognitive decline (36%) and psychiatric symptom (28%) at first visit were lower than proportion of previous reports. A negative correlation (Pearson correlation coefficient -0.757, p = 0.001) was found between expanded CAG repeat size and age of onset. Seven subjects without family history of HD had higher mean age of onset (54.0 ± 8.1) and smaller expanded CAG repeat size (42.4 ± 2.7). Cognitive problems at first visit of subjects without family history were more prominent than those with family history (86% vs. 25%). CONCLUSIONS: This study is the first demographic, clinical and genetic analyses in South Korea. These results will be helpful to stimulate more large-scale research in South Korea and other Asian nations.

Ischemic stroke during sleep: its association with worse early functional outcome.

BACKGROUND AND PURPOSE: Approximately one fourth of stroke occur during sleep. Despite the clinical and radiological similarities between wake-up stroke (WUS) and non-WUS, the functional outcomes of WUS are largely unknown. METHODS: This retrospective analysis reviewed 2289 consecutive patients with acute ischemic stroke who were admitted between November 2002 and December 2009. We used 3 end-point analytic techniques to evaluate the association between WUS and functional outcomes: dichotomized analysis for "functional dependency" (a discharge modified Rankin Scale [mRS] score ≥2 regardless of initial stroke severity), severity-adjusted responder analysis for "unfavorable outcome" (a discharge mRS ≥1 for an admission National Institutes of Health Stroke Scale score 0 to 7; mRS ≥2 for National Institutes of Health Stroke Scale 8 to 14; or mRS ≥3 for National Institutes of Health Stroke Scale ≥15), and shift analysis for changes in overall distributions of discharge mRS scores. RESULTS: The initial National Institutes of Health Stroke Scale score of patients with WUS was significantly higher than that of their non-WUS counterparts (median [interquartile range]; 4 [2 to 7] versus 3 [1 to 6]; P<0.01). The dichotomized analysis strategy failed to detect a significant association between WUS and functional dependency at discharge (adjusted OR, 0.99; 95% CI, 0.76 to 1.28). However, the responder analysis showed that patients with WUS were more likely to have "unfavorable outcomes" (adjusted OR, 1.33; 95% CI, 1.02 to 1.72), and the shift analysis also detected significant effect of WUS on the mRS score distributions toward increased dependency (adjusted OR, 1.22; 95% CI, 1.01 to 1.48). CONCLUSIONS: From our study, we documented that WUS was associated with worse short-term outcomes after ischemic stroke. Careful selection of appropriate analytic techniques may help to detect modest associations in observational studies.