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IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

Background: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13–40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit “confined stimulation.” We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone. Methods: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa-Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation. Results: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8). Conclusions: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone.

BACKGROUND Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients. OBJECTIVE To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline. METHODS The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually. RESULTS 1616 participants comprised the analytic sample. Mean observation was 4.1 (SD = 1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was - 0.0064 (SE = 0.002, p = 0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (p

BACKGROUND Sarcoidosis is a presumptive autoimmune disorder characterized by the presence of noncaseating granulomas and is usually treated successfully with immunosuppression. METHODS AND RESULTS Here, we describe the case of a 63-year-old male renal transplant recipient with a remote history of pulmonary sarcoidosis on chronic immunosuppression who developed recurrent aseptic meningitis and underwent brain biopsy revealing a diagnosis of neurosarcoidosis. CONCLUSIONS This case highlights the possibility of recurrence of sarcoidosis in the setting of maintenance immunosuppression, the need for heightened awareness of alternative sites of recurrence of autoimmune disease, and future studies to determine the underlying mechanism of recurrence in organ transplant recipients.

Summary Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov , number NCT01280123 . Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. Funding National Institute of Neurological Disorders and Stroke.

Abnormal movements are a common reason for hospital neurology consultation. Tremor and myoclonus are the most common abnormal movements seen in the inpatient setting. Medications and metabolic disturbances are the most common identified etiologies. Equally important, drug withdrawal can result in abnormal movements.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of neuronal dopamine production in the brain. Oral therapies primarily augment the dopaminergic pathway. As the disease progresses, more continuous delivery of therapy is commonly needed. Deep brain stimulation (DBS) has become an effective therapy option for several different neurologic and psychiatric conditions, including PD. It currently has US Food and Drug Administration approval for PD and essential tremor, as well as a humanitarian device exception for dystonia and obsessive-compulsive disorder. For PD treatment, it is currently approved specifically for those patients suffering from complications of pharmacotherapy, including motor fluctuations or dyskinesias, and a disease process of at least 4 years of duration. Studies have demonstrated superiority of DBS and medical management compared to medical management alone in selected PD patients. Optimal patient selection criteria, choice of target, and programming methods for PD and the other indications for DBS are important topics that continue to be explored and remain works in progress. In addition, new hardware options, such as different types of leads, and different software options have recently become available, increasing the potential for greater efficacy and/or reduced side effects. This review gives an overview of therapeutic management in PD, specifically highlighting DBS and some of the recent changes with surgical therapy.

Postoperative programming in deep brain stimulation (DBS) therapy for movement disorders can be challenging and time consuming. Providing the neurologist with tools to visualize the electrode location relative to the patient's anatomy along with models of tissue activation and statistical data can therefore be very helpful. In this study, we evaluate the consistency between neurologists in interpreting and using such information provided by our DBS programming assistance software.Five neurologists experienced in DBS programming were each given a dataset of 29 leads implanted in 17 patients. For each patient, probabilistic maps of stimulation response, anatomical images, models of tissue activation volumes, and electrode positions were presented inside a software framework called CRAnialVault Explorer (CRAVE) developed in house. Consistency between neurologists in optimal contact selection using the software was measured.With only the efficacy map, the average consistency among the five neurologists with respect to the mode and mean of their selections was 97% and 95%, respectively, while these numbers were 93% and 89%, respectively, when both efficacy and an adverse effect map were used simultaneously. Fleiss' kappa statistic also showed very strong agreement among the neurologists (0.87 when using one map and 0.72 when using two maps).Our five neurologists demonstrated high consistency in interpreting information provided by the CRAVE interactive visualization software for DBS postoperative programming assistance. Three of our five neurologists had no prior experience with the software, which suggests that the software has a short learning curve and contact selection is not dependent on familiarity with the program tools.

Background Recognizing the factors associated with falling in Parkinson's disease (PD) would improve identification of at-risk individuals. Objective To examine frequency of falling and baseline characteristics associated with falling in PD using the National Institute of Neurological Disorders and Stroke (NINDS) Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1) dataset. Methods The LS-1 database included 1741 early treated PD subjects (median 4 year follow-up). Baseline characteristics were tested for a univariate association with post-baseline falling during the trial. Significant variables were included in a multivariable logistic regression model. A separate analysis using a negative binomial model investigated baseline factors on fall rate. Results 728 subjects (42%) fell during the trial, including at baseline. A baseline history of falls was the factor most associated with post-baseline falling. Men had lower odds of post-baseline falling compared to women, but for men, the probability of a post-baseline fall increased with age such that after age 70, men and women had similar odds of falling. Other baseline factors associated with a post-baseline fall and increased fall rate included the Unified PD Rating Scale (UPDRS) Activities of Daily Living (ADL) score, total functional capacity (TFC), baseline ambulatory capacity score and dopamine agonist monotherapy. Conclusion Falls are common in early treated PD. The biggest risk factor for falls in PD remains a history of falling. Measures of functional ability (UPDRS ADL, TFC) and ambulatory capacity are novel clinical risk factors needing further study. A significant age by sex interaction may help to explain why age has been an inconsistent risk factor for falls in PD.

Background The effects of dopaminergic therapy in parkinson's disease (PD) can vary depending on the class of medication selected. Objective The aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD. Methods A non-parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life. Results The outcomes measured at the beginning of the study showed lower disease burden for participants on initial DA monotherapy compared to those taking combined LD and DA therapy after controlling for age, education, taking cog-meds and amantadine. Conclusion This observation suggests that clinicians treating early PD patients favor combined LD and DA therapy in patients with more disabling features over DA monotherapy. As such, studies of PD progression in treated PD patients may be affected by the class of symptomatic dopaminergic therapy.

Dyskinesia is a common side effect of prolonged dopaminergic therapy in Parkinson's disease patients. Assessing the severity of dyskinesia could help develop better pharmacological and surgical interventions. We have developed a semi-automatic video-based objective dyskinesia quantifying measure called the severity score (SVS) that was evaluated on 35 patient videos. We present a study to evaluate the utility of our severity score and compare its performance to clinical ratings of neurologists. In addition to the Unified Dyskinesia Rating Scale (UDysRS) score for each video, four neurologists provided three sets of time lapsed ratings and rankings of the 35 videos using a specifically developed protocol. The statistical analysis of our data using Kendall's tau-b and intra-class correlations shows that (a) ranking patient videos based on severity is suitable for studying the utility of the SVS, and (b) SVS exhibits moderate utility to quantify dyskinesia severity when compared to manual assessment of dyskinesia by neurologists using the UDysRS. These results support the effective use of SVS as an objective measure to quantify dyskinesia and the rationale for a ranking system that complements traditional rating scales.

Previous reports have suggested that essential tremor (ET) represents a risk factor for the development of Parkinson's disease (PD). Patients with long-standing ET who develop PD tend to have a tremor-dominant subtype. To further clarify this association, we examined patients from kindreds with autosomal dominant ET who had signs of isolated PD but did not meet criteria for overlapping ET. We identified 22 patients with PD meeting these diagnostic criteria, and 90% (20 of 22) had tremor-predominant subtype of PD. Unilateral rest tremor was the presenting symptom in 15 of 22 patients, bradykinesia or rigidity in 5 of 22, and gait problems in 2 of 22. Postural tremor was relatively mild, and the severity of kinetic tremor tightly correlated with rest tremor (r = 0.83, P < 0.001). Tremor-dominant subtype of PD in patients with a positive family history of ET suggests that these patients have inherited a genetic susceptibility factor for tremor, which affects the motor phenotype of PD.

The presence of bilateral arm tremor is a key diagnostic feature of essential tremor (ET). We analyzed the presence of unilateral arm tremor in familial ET cohort of 133 autosomal dominant ET kindreds with 412 affected individuals. Inclusion criteria in patients with unilateral arm postural and/or kinetic tremor required the duration of tremor for at least 5 years, without hypokinetic-rigid syndrome, dystonic posturing, or history of sudden onset of tremor. Only subjects with at least one living first degree relative who met diagnostic criteria for definite ET were included. Eighteen subjects met the inclusion criteria and five had postural tremor only, while the majority (13/18) had a combination of postural and kinetic tremor. Our data shows that unilateral tremor associated with ET is relatively rare and can be identified in 4.4% patients in a cohort of familial ET.

Progranulin gene (PGRN) mutations cause frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Patients usually present with a frontotemporal dementia syndrome and have prominent atrophy and neuronal loss in frontal and temporal cortices and the striatum, with neuronal intranuclear and cytoplasmic inclusions. Clinical, neuropathological, and genetic studies are reported on an individual with PGRN mutation and her family members. We describe a patient with a PGRN c.26C>A mutation who presented with progressive stuttering dysarthria, oculomotor abnormalities, choreic buccolingual movements, and mild parkinsonism. Two other family members were affected, one with a behavioral variant frontotemporal dementia syndrome, the other with a diagnosis of probable Alzheimer's disease. At autopsy there was no neuronal loss in the cortex or medial temporal lobe structures, but there was striatal gliosis. Immunohistochemistry for ubiquitin and TDP-43 revealed neuronal cytoplasmic and intranuclear inclusions as well as neurites. This study further expands the clinical and pathological spectrum of PGRN mutations, and suggests the diagnosis could be missed in some individuals with atypical presentations. (C) 2008 Movement Disorder Society.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Parkinson's disease is the second most common neurodegenerative disorder. Despite fairly typical clinical and pathologic features, the etiology remains unknown. Many cellular mechanisms such as oxidative stress, mitochondrial dysfunction, lysosomal dysfunction, neuroinflammatory changes, and the formation of pathologic inclusions have been proposed as potential causes. Potential links between environmental and genetic changes appear to predispose individuals to develop Parkinson's disease. Considering these observations, albeit with different levels of evidence, it is becoming more probable that Parkinson's disease is a heterogeneous disorder or a syndrome that arises from the contribution of many different factors.

Dopaminergic agents remain the principal treatments for patients with Parkinson disease (PD). In many patients, however, a combination of relatively resistant motor symptoms, motor complications such as dyskinesias, or nonmotor symptoms such as dysautonomia may lead to substantial disability in spite of dopaminergic therapy. This chapter will review both dopaminergic and nondopaminergic therapies for motor and nonmotor symptoms in PD.Although the basic principles of pharmacotherapy for the motor symptoms of PD have largely remained unchanged over the past decade, several new therapies have become available to refine treatment. In addition, there has been an increasing interest in agents targeting nonmotor symptoms, such as dementia and sleepiness. As patients with PD live longer and acquire additional comorbidities, addressing these nonmotor symptoms has become increasingly important. In this chapter, the major antiparkinsonian dopaminergic compounds will be reviewed, followed by a patient-focused guide to implementation of these treatments as part of an overall management plan.

Publisher Summary Parkinson's disease (PD) is a neurodegenerative movement disorder defined by its motor features that asymmetric resting tremor, rigidity, bradykinesia, and postural instability. Autonomic symptoms may be present to varying degrees in patients with PD, but very severe dysautonomia in patients with mild motor findings suggests a diagnosis of multiple system atrophy (MSA). There are several differing criteria in use to diagnose PD and parkinsonian syndromes. Histopathology of postmortem tissue is typically required for definitive diagnosis. Commonly, separating PD from parkinsonian syndromes rests largely upon the response of the physical examination to dopamine replacement therapy (DRT). Nonpharmacologic interventions such as compression stockings may be helpful for many patients. In some cases, prophylactic treatments with oral water or midodrine, an alpha1-adrenergic receptor agonist, may also be necessary. Additional drug-induced autonomic effects can also negatively impact PD therapy. Type B monoamine oxidase (MAO-B) inhibitors, used to prolong the duration of action of dopamine, may cause severe hypertension.

Previous reports have suggested that essential tremor (ET) represents a risk factor for the development of Parkinson's disease (PD). Patients with long-standing ET who develop PD tend to have a tremor-dominant subtype. To further clarify this association, we examined patients from kindreds with autosomal dominant ET who had signs of isolated PD but did not meet criteria for overlapping ET. We identified 22 patients with PD meeting these diagnostic criteria, and 90% (20 of 22) had tremor-predominant subtype of PD. Unilateral rest tremor was the presenting symptom in 15 of 22 patients, bradykinesia or rigidity in 5 of 22, and gait problems in 2 of 22. Postural tremor was relatively mild, and the severity of kinetic tremor tightly correlated with rest tremor (r = 0.83, P0.001). Tremor-dominant subtype of PD in patients with a positive family history of ET suggests that these patients have inherited a genetic susceptibility factor for tremor, which affects the motor phenotype of PD.

The presence of bilateral arm tremor is a key diagnostic feature of essential tremor (ET). We analyzed the presence of unilateral arm tremor in familial ET cohort of 133 autosomal dominant ET kindreds with 412 affected individuals. Inclusion criteria in patients with unilateral arm postural and/or kinetic tremor required the duration of tremor for at least 5 years, without hypokinetic-rigid syndrome, dystonic posturing, or history of sudden onset of tremor. Only subjects with at least one living first degree relative who met diagnostic criteria for definite ET were included. Eighteen subjects met the inclusion criteria and five had postural tremor only, while the majority (13/18) had a combination of postural and kinetic tremor. Our data shows that unilateral tremor associated with ET is relatively rare and can be identified in 4.4% patients in a cohort of familial ET.

Analyze the distribution of polymorphism in the dopamine receptor D3 (DRD3) gene, which was previously reported as a susceptibility risk for essential tremor (ET), in a large cohort of ET.The role of 312GA DRD3 polymorphism was analyzed using linkage analysis, association study and transmission disequilibrium test in a group of 433 ET patients, and two unrelated control groups with 121 and 151 individuals.Allelic frequencies of glycine and serine forms of the DRD3 gene did not differ between patients and both control groups, and were in Hardy-Weinberg equilibrium. Linkage analysis identified obligatory recombinants in every large pedigree, even in those with relatively high frequency of glycine allele, thus excluding the linkage to this locus. Both alleles were transmitted with an equal likelihood to affected offspring. We also failed to replicate the relationship between glycine homozygosity and an earlier age of onset or more severe tremor course.Our comprehensive genetic analysis in a large ET cohort strongly argues against the role of the DRD3 gene in ET pathogenesis.

This study reports a retrospective analysis of 16 patients to determine changes in medication costs associated with deep brain stimulation of the bilateral subthalamic nucleus (DBS B-STN). Antiparkinsonian medication (APMED) costs were evaluated pre- and post-operatively at 1 and 2 years, based on prescribed dosages. After treatment with DBS, patients experienced a 32% reduction in APMED costs after 1 year and a 39% reduction after 2 years. Hypothetical projections of total potential savings are presented, accounting for increasingly complex medication regimens and medication cost inflation. DBS patients may experience a significant long-term reduction in the cost of their pharmacologic treatment.

This placebo-controlled crossover trial investigate the safety and efficacy of onabotulinumtoxinA (BOTOX, Allergan, Inc.) for the treatment of cervical myofascial pain syndrome (CMPS). A group of subjects with Cervical Dystonia (CD) served as additional controls. A change in diary pain score from baseline to week 3 in placebo vs. onabotulinumtoxinA was the primary outcome measure. Both CMPS and CD subjects showed a trend towards significant pain relief from onabotulinumtoxinA. This suggests that the study was underpowered and that a larger sample size would be necessary in future trials of onabotulinumtoxinA for CMPS.

Background There is an ongoing debate whether essential tremor (ET) represents a monosymptomatic disorder or other neurologic symptoms are compatible with the diagnosis of ET. Many patients with clinically definite ET develop dystonia. It remains unknown whether tremor associated with dystonia represent a subtype of ET. We hypothesized that ET with dystonia represents a distinct subtype of ET. Methods We studied patients diagnosed with familial ET and dystonia. We included only those patients whose first-degree relatives met diagnostic criteria for ET or dystonia with tremor. This cohort was ascertained for the presence of focal, segmental, multifocal, hemidystonia or generalized dystonia, and ET. Results We included 463 patients from 97 kindreds with autosomal dominant mode of inheritance (AD), defined by the vertical transmission of the disease. ET was the predominant phenotype in every ascertained family and each was phenotypically classified as AD ET. "Pure" ET was present in 365 individuals. Focal or segmental dystonia was present in 98 of the 463 patients; 87 of the 98 patients had ET associated with dystonia, one had dystonic tremor and ten had isolated dystonia. The age of onset and tremor severity did not differ between patients with "pure" ET and ET associated with dystonia. We did not observe a random distribution of dystonia in AD ET pedigrees and all patients with dystonia associated with ET were clustered in 28% of all included pedigrees (27/97, p < 0.001). Conclusions Our results suggest that familial ET associated with dystonia may represent a distinct subtype of ET.