The beneficial effects of amantadine on motor response complications are maintained for at least 1 year after treatment initiation.

These findings suggest that amantadine given as adjuvant to levodopa can markedly improve motor response complications and support the view that hyperfunction of NMDA receptors contributes to the pathogenesis of levodopa-associated motor complications.

17beta-estradiol appears to display a slight prodopaminergic (or antiparkinsonian) effect without consistently altering dyskinesias. Standard postmenopausal replacement therapy with transdermal 17beta-estradiol is likely to be well tolerated by many female parkinsonian patients.

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 (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.INTERVENTIONS Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. MAIN OUTCOMES AND MEASURESThe primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. RESULTSBased on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine 11.1 [95% CI,] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, −0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).CONCLUSIONS AND RELEVANCE Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.

A positive family history is present in many patients with essential tremor (ET), but twin studies and segregation analysis have suggested that ET is not entirely a genetic disorder. Two genetic loci have been identified in autosomal dominant (AD) ET and polymorphisms in the DRD3 and HS1-BP3 genes have been proposed as the possible susceptibility factors for ET. There is also evidence for further genetic heterogeneity. We evaluated 4 unrelated large kindreds with ET with an apparent AD mode of transmission. Each kindred spanned at least 3 generations and contained at least 13 living affected subjects who met criteria for definitive ET. None of the pedigrees had evidence for inheritance of ET from both parents. Known genetic ET loci were excluded in these families. We detected a preferential transmission of ET in every kindred and the proportion of affected offspring varied from 75% to 90% (P < 0.05) in the generations with complete ascertainment. Our data indicate that non-Mendelian preferential transmission of an affected allele is a feature in many ET kindreds with multiple affected members and an apparent AD mode of inheritance. ET may have a complex etiology. Additional genetic models need to be considered, including an interaction of susceptibility genes and environmental risk factors.

Background/Aims: Deep brain stimulation (DBS) of the nucleus ventralis intermedius (VIM) provides a safe and effective therapy for medically refractory essential tremor (ET). However, as many as 9% of VIM DBS patients deteriorate after several years of good tremor control. For these patients, the high voltage needed to adequately control tremor also generates circumferential current spread causing intolerable adverse effects. Methods: We report 3 ET patients where adding a second parallel thalamic lead anterior-medially to the original and connecting the 2 adjacent leads to a dual-channel pulse generator (Medtronic Synergy, model No. 7427) successfully recaptured tremor control with fewer adverse effects. Results: This approach allowed us to direct the stimulation field away from nearby structures responsible for the adverse effects. Such confined stimulation can be achieved by connecting 2 adjacent DBS leads to a common voltage source, providing current flow between leads. Conclusion: This dual lead stimulation method can be used as a reversible rescue therapy in ET patients who require unacceptably high intensity stimulation.

BackgroundThere 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.MethodsWe 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.ResultsWe 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).ConclusionsOur results suggest that familial ET associated with dystonia may represent a distinct subtype of ET.

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.