Basic clinical features do not predict dopamine transporter binding in idiopathic REM behavior disorder.

REM sleep behavior disorder (RBD) is strongly associated with development of Parkinson's Disease and other α-synuclein-related disorders. Dopamine transporter (DAT) binding deficit predicts conversion to α-synuclein-related disorders in individuals with RBD. In turn, identifying which individuals with RBD have the highest likelihood of having abnormal DAT binding would be useful. The objective of this analysis was to examine if there are basic clinical predictors of DAT deficit in RBD. Participants referred for inclusion in the RBD cohort of the Parkinson Progression Markers Initiative were included. Assessments at the screening visit including DAT SPECT imaging, physical examination, cognitive function screen, and questionnaire-based non-motor assessment. The group with DAT binding deficit (n = 49) was compared to those without (n = 26). There were no significant differences in demographic or clinical features between the two groups. When recruiting RBD cohorts enriched for high risk of neurodegenerative disorders, our data support the need for objective biomarker assessments.

Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder.

INTRODUCTION: Cognitive decline is common in Parkinson's disease (PD), and identifying patients at highest risk for it is essential. We aimed to examine the effect of possible REM sleep behavior disorder (pRBD) on rate of cognitive decline in early PD, for both global cognition and in specific cognitive domains. METHODS: Parkinson's Progression Markers Initiative (PPMI) is a multi-site, international study of PD patients untreated at enrollment. pRBD was assessed with the REM sleep behavior disorder questionnaire (RBDSQ). Global cognition was assessed at baseline and annually using the Montreal Cognitive Assessment (MoCA) and a cognitive battery. Linear mixed effects models were used to examine the relationship between pRBD (RBDSQ≥6) and rate of change in cognitive variables. Age, sex, years of education, and baseline motor and cognitive scores were included as covariates. RESULTS: The baseline sample consisted of 423 individuals with PD, mean age 61.7 years and 65.5% male. Data was available on 389, 366, and 196 participants at 1-year, 2-year, and 3-year follow-up respectively. Possible RBD occurred in 108 (25.5%) at baseline. In multivariate analyses, baseline RBD was associated with greater annual rate of decline in MoCA score (ß = -0.34, 95%CI -0.54, -0.13, p < 0.001), Symbol Digit Modalities Test (ß = -0.69, 95%CI -1.3, -0.09, p = 0.024), and Hopkins Verbal Learning Test-Revised, delayed free recall (ß = -0.21, 95%CI -0.41, -0.013, p = 0.037). CONCLUSIONS: Possible RBD is common in early PD and predicts future cognitive decline, particularly in attention and memory domains.

Back to the basics: regular exercise matters in parkinson's disease: results from the National Parkinson Foundation QII registry study.

BACKGROUND: There is a substantial interest in the impact of exercise on reduction of disability and rate of progression of Parkinson's disease (PD). OBJECTIVE: The primary aim was to describe exercise habits of PD patients and factors associated with greater levels of exercise. The secondary aim was to explore whether regular exercise is associated with a slower decline of function, disease-related quality of life, and caregiver burden. METHODS: The National Parkinson's Foundation (NPF) QII Registry data was used to analyze variables that correlate with levels of exercise in PD patients across disease severity. Subjects were categorized into three groups: non-exercisers (0 min/week), low exercisers (1-150 min/week), and regular exercisers (>150 min/week). Health related outcomes, disease metrics, and demographic factors associated with exercise were examined using bivariate analyses. Multiple regression models controlled for disease duration, severity, and cognitive function. An exploratory analysis was completed on the association of baseline level of exercise with health outcomes at one year follow up. RESULTS: 4866 subjects were included in the baseline analysis and 2252 subjects who had second visits were included in the longitudinal data. Regular exercisers at baseline were associated with better QOL, mobility, and physical function, less progression of disease, less caregiver burden and less cognitive decline one year later, after controlling for demographic and disease severity variables. CONCLUSIONS: This study provides important preliminary evidence of the beneficial effects of regular exercise in a large PD cohort. Longitudinal studies will be essential to confirm findings.

Mobility, mood and site of care impact health related quality of life in Parkinson's disease.

OBJECTIVE: Examine the correlates of Health Related Quality of Life (HRQL) in a large cohort of Parkinson's disease (PD) patients from National Parkinson Foundation (NPF) Centers of Excellence (COEs). BACKGROUND: Improving outcomes for PD will depend upon uncovering disease features impacting HRQL to identify targets for intervention and variables for risk-adjustment models. Differences in HRQL outcomes between COEs could uncover modifiable aspects of care delivery. METHODS: This cross-sectional study examined the relative contribution of demographic, social, clinical and treatment features potentially related to HRQL, as measured by the PDQ-39, in 4601 consecutive subjects from 18 COEs. Stepwise linear regression was utilized to identify correlates of HRQL. RESULTS: The variability in the PDQ-39 summary index score correlated with H&Y stage (R(2) = 22%), Timed up and Go (TUG) (17%), disease duration (11%), comorbidities (8%), cognitive status (8%), antidepressant use (6%) and center at which a patient received care (5%). Stepwise regression reordered the importance of the variables, with the H&Y first and TUG and the center becoming equal and the second most important variables determining the PDQ-39 total score. All independent variables together accounted for 44% of the variability in HRQL. CONCLUSIONS: We confirmed many but not all HRQL associations found in smaller studies. A novel observation was that the site of care was an important contributor to HRQL, suggesting that comparison of outcomes and processes among centers may identify best practices.

Caregiver strain in Parkinson's disease: national Parkinson Foundation Quality Initiative study.

BACKGROUND: National Parkinson Foundation Quality Improvement Initiatives (NPF-QII) is the first large scale data-driven initiative in Parkinson's disease (PD) aimed at identifying variables predicting best care models and outcomes. OBJECTIVE: To determine what measures of PD disability, demographics, and patient quality of life are associated with caregiver strain among caregivers of patients with PD. METHODS: All PD patients at 18 participating sites are eligible for enrollment into the NPF-QII registry. Dataset includes multidimensional measures of disease severity, health care utilization, PD quality of life questionnaire-39 (PDQ-39) and multidimensional caregiver strain inventory (MCSI). A univariate as well as an adjusted analysis was performed to examine the relationship between caregiver strain and variables of PD disability. RESULTS: The single best factor associated with high caregiver strain was the PDQ-39 total score (c-statistic of continuous variable = 0.792, p < 0.001) followed by the PDQ-mobility subscore (c = 0.776, p < 0.001). PDQ-39 ≥ 47 was the optimal cut off associated with a high caregiver strain with a sensitivity = 83% and specificity = 64%. A multiple logistic regression model with stepwise selection showed that in addition to PDQ-39 ≥ 47 (OR and 95% confidence interval = 5.1 (3.2, 8.2), the following subject characteristics were associated with high caregiver strain: (model p < 0.001, c = 0.838): Hoehn and Yahr stage >3 (2.0 (1.3, 3.1)), presence of concomitant medications such as antidepressants (2.1 (1.5, 3.1)) and antipsychotics (2.5 (1.5, 4.2)), social worker visits (1.6 (1.2, 2.1)), male gender (2.3 (1.5, 3.5)), and decreased verbal fluency (0.95 (0.92, 0.98)). CONCLUSIONS: There is a high prevalence of caregiver strain in PD. PDQ-39 total score has the strongest association with high levels of caregiver strain. These results could guide clinicians in the assessment of caregivers at risk.

Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology.

OBJECTIVE: To address the need for brief, reliable, valid, and standardized quality of life (QOL) assessment applicable across neurologic conditions. METHODS: Drawing from larger calibrated item banks, we developed short measures (8-9 items each) of 13 different QOL domains across physical, mental, and social health and evaluated their validity and reliability. Three samples were utilized during short form development: general population (Internet-based, n = 2,113); clinical panel (Internet-based, n = 553); and clinical outpatient (clinic-based, n = 581). All short forms are expressed as T scores with a mean of 50 and SD of 10. RESULTS: Internal consistency (Cronbach α) of the 13 short forms ranged from 0.85 to 0.97. Correlations between short form and full-length item bank scores ranged from 0.88 to 0.99 (0.82-0.96 after removing common items from banks). Online respondents were asked whether they had any of 19 different chronic health conditions, and whether or not those reported conditions interfered with ability to function normally. All short forms, across physical, mental, and social health, were able to separate people who reported no health condition from those who reported 1-2 or 3 or more. In addition, scores on all 13 domains were worse for people who acknowledged being limited by the health conditions they reported, compared to those who reported conditions but were not limited by them. CONCLUSION: These 13 brief measures of self-reported QOL are reliable and show preliminary evidence of concurrent validity inasmuch as they differentiate people based upon number of reported health conditions and whether those reported conditions impede normal function.

Clinical vignettes in Parkinson's disease: a collection of unusual medication-induced hallucinations, delusions, and compulsive behaviours.

Hallucinations, delusions, and compulsive behaviors are frequent iatrogenic complications of the treatment of motor dysfunction in Parkinson's disease (PD). Although these have been studied, and the phenomenology described, there are few detailed descriptions of the various psychiatric problems our treated PD patients live with that allow physicians who do not have a great deal of experience with PD patients to appreciate the extent of their altered lives. This report is a compilation of vignettes describing these behavioral problems that the treating neurologist or psychiatrist attributed to the medications used for treating PD.

Capecitabine-induced multifocal leukoencephalopathy: a report of five cases.

Capecitabine is used to treat advanced breast and gastrointestinal malignancies. A single case of encephalopathy and three cases of peripheral neuropathy are the only neurotoxicities reported. The authors report five additional cases of capecitabine-induced multifocal leukoencephalopathy.

Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study.

OBJECTIVE: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD). METHODS: This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog). RESULTS: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale.There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant. CONCLUSIONS: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.

Other Parkinson syndromes.

The etiology of parkinsonism is varied. Symptomatic parkinsonism is seen in the setting of genetic disorders, infectious processes, structural lesions, and as a result of concomitant medications. A thorough history and good examination will differentiate PD from the diverse group of conditions that can mimic it.

Revision of deep brain stimulator for tremor. Technical note.

The treatment of essential tremor with thalamic deep brain stimulation (DBS) is considered to be more effective and to cause less morbidity than treatment with thalamotomy. Nonetheless, implantation of an indwelling electrode, connectors, and a generator is associated with specific types of morbidity. The authors describe three patients who required revision of their DBS systems due to lead breakage. The connector between the DBS electrode and the extension wire, which connects to the subclavicular pulse generator, was originally placed subcutaneously in the cervical region to decrease the risk of erosion through the scalp and to improve cosmesis. Three patients presented with fractured DBS electrodes that were located in the cervical region near the connector, necessitating reoperation with stereotactic retargeting and placement of a new intracranial electrode. At reoperation, the connectors were placed subgaleally over the parietal region. Management of these cases has led to modifications in the operative procedure designed to improve the durability of DBS systems. The authors recommend that surgeons avoid placing the connection between the DBS electrode and the extension wire in the cervical region because patient movement can cause microfractures in the electrode. Such microfractures require intracranial revision, which may be associated with a higher risk of morbidity than the initial operation. The authors also recommend considering prophylactic relocation of the connectors from the cervical area to the subgaleal parietal region to decrease the risk of future DBS electrode fracture, which would necessitate a more lengthy procedure to revise the intracranial electrode.

Efficacy of unilateral deep brain stimulation of the thalamic ventralis intermedius nucleus in a patient with bipolar disorder associated with Klinefelter syndrome and essential tremor. Case report.

Deep brain stimulation (DBS) of the ventralis intermedius nucleus (Vim) is a safe and effective treatment for essential tremor. Bipolar disorder and essential tremor had each been reported to occur in association with Klinefelter syndrome but the three diseases have been reported to occur together in only one patient. The genetic basis and natural history of these disorders are not completely understood and may be related rather than coincidental. The authors report on a 23-year-old man with Klinefelter syndrome (47,XXY) and bipolar disorder who was treated successfully with unilateral DBS of the thalamic Vim for essential tremor.

Long-term deep brain stimulation in a patient with essential tremor: clinical response and postmortem correlation with stimulator termination sites in ventral thalamus. Case report.

Essential tremor can be suppressed with chronic, bilateral deep brain stimulation (DBS) of the ventralis intermedius nucleus (Vim), the cerebellar receiving area of the motor thalamus. The goal in this study was to correlate the location of the electrodes with the clinical efficacy of DBS in a patient with essential tremor. The authors report on a woman with essential tremor in whom chronic bilateral DBS directed to the ventral thalamus produced adequate tremor suppression until her death from unrelated causes 16 months after placement of the electrodes. Neuropathological postmortem studies of the brain in this patient demonstrated that both stimulators terminated in the Vim region of the thalamus, and that chronic DBS elicited minor reactive changes confined to the immediate vicinity of the electrode tracks. Although the authors could not identify neuropathological abnormalities specific to essential tremor, they believe that suppression of essential tremor by chronic DBS correlates with bilateral termination of the stimulators in the Vim region of the thalamus.

Does levodopa accelerate Parkinson's disease?

Therapeutic options for the treatment of Parkinson's disease (PD) have expanded tremendously over the last 5 years, although levodopa remains the gold standard of therapy. A major therapeutic controversy has been the question of levodopa's potential to cause toxic effects on nigrostriatal cells, thus potentiating the progression of the disease. The answer to that question will guide physicians in the timing of levodopa initiation and its dosage. The issue of levodopa toxicity was initially raised because of its potential to cause long term adverse effects (dyskinesias and motor fluctuations), which are not observed in untreated patients. Levodopa-induced toxicity can be related to its potential to produce free radicals, which are known to be toxic to cells, in the process of its conversion to dopamine. In vitro data reveals some evidence of the toxic effect of levodopa although recent studies suggest that levodopa toxicity is dependent on its concentration and can be ameliorated in the presence of glial cells. In vivo data from healthy animals and humans does not convincingly demonstrate levodopa toxicity. There is no evidence of levodopa-induced neurotoxicity in patients with PD. Despite the absence of toxic effect in patients with PD, levodopa can cause long term complications like motor fluctuations and dyskinesias and should be used judiciously in the minimal clinically effective dose. In this article we review evidence for and against levodopa neurotoxicity and the implications of the 'levo-dopa controversy' on clinical practice.

Clinical manifestations of Parkinson's disease.

Although the clinical manifestations of PD remain similar to those described by Parkinson in the nineteenth century, knowledge of associated findings has increased dramatically. The ability to characterize the myriad of findings associated with PD enables clinicians to care better for patients with PD. Knowledge of the associated symptoms as well as the cardinal manifestations allows clinicians to target treatment to specific symptoms and thereby improve the quality of life of those affected with PD.

Targeting for thalamic deep brain stimulator implantation without computer guidance: assessment of targeting accuracy.

The authors assess the accuracy of targeting nucleus ventralis intermedius (Vim) with fast spin echo inversion recovery (FSE/IR) magnetic resonance imaging (MRI) in 18 successful deep brain stimulator (DBS) implants for medically refractory tremor. FSE/IR-MRI-derived coordinates are compared to the final coordinates employed for DBS lead placement, selected with intraoperative neurophysiology. The authors conclude that FSE/IR MRI is sufficiently reliable to serve as the sole means of anatomically targeting Vim for DBS lead placement. An independent computer workstation is not required for accurate targeting; however, intraoperative neurophysiology remains essential.