Non-motor Outcomes Research Articles

Nonmotor outcomes in Parkinson’s disease: is deep brain stimulation better than dopamine replacement therapy?

Nonmotor symptoms are an integral part of Parkinson's disease and cause significant morbidity. Pharmacological therapy helps alleviate the disease but produces nonmotor manifestations. While deep brain stimulation (DBS) has emerged as the treatment of choice for motor dysfunction, the effect on nonmotor symptoms is not well known. Compared with pharmacological therapy, bilateral subthalamic nucleus (STN)-DBS or globus pallidum interna (GPi)-DBS has significant beneficial effects on pain, sleep, gastrointestinal and urological symptoms. STN-DBS is associated with a mild worsening in verbal fluency while GPi-DBS has no effect on cognition. STN-DBS may improve cardiovascular autonomic disturbances by reducing the dose of dopaminergic drugs. Because the motor effects of STN-DBS and GPi-DBS appear to be similar, nonmotor symptoms may determine the target choice in surgery of future patients.

A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes

The ADAGIO study investigated whether rasagiline has disease-modifying effects in Parkinson's disease. Rasagiline 1 mg per day, but not 2 mg per day, was shown to be efficacious in the primary analysis. Here, we report additional secondary and post-hoc analyses of the ADAGIO study. ADAGIO was a placebo-controlled, double-blind, multicentre, delayed-start study, in which 1176 patients with untreated early Parkinson's disease were randomly assigned to receive rasagiline 1 mg or 2 mg per day for 72 weeks (early-start groups) or placebo for 36 weeks followed by rasagiline 1 mg or 2 mg per day for 36 weeks (delayed-start groups). We assessed the need for additional antiparkinsonian therapy and changes in non-motor experiences of daily living and fatigue scales (prespecified outcomes) and changes in unified Parkinson's disease rating scale (UPDRS) scores and subscores in placebo and active groups (post-hoc outcomes). The ADAGIO study is registered with ClinicalTrials.gov, number NCT00256204. The need for additional antiparkinsonian therapy was reduced with rasagiline 1 mg (25 of 288 [9%] patients) and 2 mg (26 of 293 [9%]) versus placebo (108 of 593 [18%]; odds ratio for 1 mg rasagiline vs placebo 0·41, 95% CI 0·25-0·65, p=0·0002; 2 mg rasagiline vs placebo 0·41, 0·26-0·64, p=0·0001). At week 36, both doses significantly improved UPDRS motor subscores compared with placebo (1 mg rasagiline mean difference -1·88 [SE 0·35]; 2 mg rasagiline -2·18 [0·35]; both p<0·0001) and activities of daily living subscores (ADL; 1 mg rasagiline -0·86 [0·18]; 2 mg rasagiline -0·88 [0·18]; both p<0·0001), and 1 mg rasagiline significantly improved UPDRS mentation subscore (-0·22 [0·08]; p=0·004). At week 72, the only significant difference between early-start and delayed-start groups was for ADL subscore with the 1 mg dose (-0·62 [0·29]; p=0·035). When assessed for the effect on non-motor symptoms at week 36, both doses showed benefits on the Parkinson fatigue scale versus placebo (1 mg rasagiline mean difference -0·14 [SE 0·05], p=0·0032; 2 mg rasagiline -0·19 [0·05], p<0·0001), and the 1 mg dose showed benefits on the scale for non-motor experiences of daily living compared with placebo (mean difference -0·33 [0·17]; p=0·049). The rate of progression of total UPDRS score for patients in the placebo group was 4·3 points [SE 0·3] over 36 weeks, with extrapolation to about 6 units per year. In the placebo group, patients with the lowest quartile of baseline UPDRS scores (≤14; n=160) progressed more slowly than did those with highest scores (>25·5; n=145; mean difference -3·46 [SE 0·77]; p<0·0001). These findings show that rasagiline delayed the need for symptomatic antiparkinsonian drugs and emphasise the contribution of the UPDRS ADL in the response of the rasagiline 1 mg per day early-start versus delayed-start group. The rate of UPDRS deterioration was less than was anticipated from previous studies and correlated with baseline severity. Understanding of the pattern of UPDRS deterioration is essential to assess disease modification. Teva Pharmaceutical Industries and H Lundbeck A/S.

Predicting Outcomes in Parkinson's Disease: Comparison of Simple Motor Performance Measures and the Unified Parkinson's Disease Rating Scale-III

The Unified Parkinson's Disease Rating Scale (UPDRS) part III is the principal motor assessment method for Parkinson's disease (PD), but has recognized limitations including subjectivity and insensitivity. Easy to administer, objective, quantitative tests that are good indicators of PD progression could offer advantages in both clinical and research settings. We administered four simple, motor performance measures--functional reach, timed hall walk, a timed block sort task, and timed dotting--as well as the UPDRS to 609 PD patients of a single neurologist. The unadjusted Spearman correlations of these performance measures with the UPDRS motor score (UPDRS III) ranged from 0.29 to 0.49. Moreover, these measures generally had high reliability on repeated testing. We defined specific outcomes in PD--overall disability, gait instability and falls, as well as non-motor outcomes of depression, dementia, and psychosis, and assessed the ability of the measures to predict these outcomes over the entire follow-up of the cohort (average: 2.4 years) and over the first year of follow-up. The associations between the measures and the outcomes were generally stronger and more precise for the performance measures than for the UPDRS III. A summary score of the performance measures was a particularly good predictor of the outcomes. These motor performance measures could provide a rapid, simple means of assessing PD progression that could benefit both clinical and research endeavors.

La ceguera en la obra de Jorge Luis Borges: Siete noches: La ceguera

The comprehensive evaluation of nonmotor symptoms (NMS) in Parkinson's disease (PD) starts with the awareness of physicians, patients, and caregivers on their nature, clinical presentation, and effect on patient's daily activities and quality of life. This awareness can be better achieved if the symptoms can be visualized, measured, and monitored. As NMS are largely subjective in nature, a majority of them cannot be visualized (unlike tremor, which is easily seen), making their identification and quantification difficult. While symptoms are nonmotor, it does not mean that they are not measurable, as many NMS are integral to motor symptoms of Parkinson's, yet often neglected. In this review, we attempt to provide the most up-to-date and comprehensive literature review on the objective measurement and monitoring of NMS in PD. The aim is to make it clinically relevant by approaching NMS by domains as identified in the NMS Questionnaire. A section on the assessment of nonmotor fluctuations is also included, providing prospects for future objective monitoring. With the advances of technology, it is likely that many NMS will have objective outcomes, thus making these symptoms easily measurable and hopefully lead to future clinical trials that incorporate nonmotor outcomes. Nevertheless, it still requires a physician's judgment to determine which method, scales, objective measures, or monitoring devices or a combination of these is most appropriate to the individual patient in order to answer a particular clinical question.

Presumed perinatal ischemic stroke: Vascular classification predicts outcomes

Perinatal stroke commonly causes childhood neurological morbidity. Presumed perinatal ischemic stroke (PPIS) defines children presenting outside a normal perinatal period with chronic, focal infarction on neuroimaging. Infarcts are assumed to represent arterial strokes, but recent evidence suggests the periventricular venous infarction (PVI) of infants born preterm may also occur in utero and present as PPIS. Using the largest published cohort, we aimed to define arterial and PVI PPIS syndromes and their outcomes. A PPIS consecutive cohort was identified (SickKids Children's Stroke Program, 1992-2006). Systematic neuroradiological scoring executed by blinded investigators included previously defined arterial stroke syndromes. PVI criteria included unilateral injury with at least four of the following conditions: (1) focal periventricular encephalomalacia, (2) internal capsule T2 prolongation, (3) cortical and (4) relative basal ganglia sparing, and (5) remote hemorrhage. Arterial and PVI classifications were validated and correlated with neurological outcomes (Pediatric Stroke Outcome Measure). In 59 PPISs (64% male), 94% of lesions fell within potential middle cerebral artery territories. Although arterial proximal M1 infarction was most common (n = 19; 35%), venous PVI was second (n = 12; 22%) and accounted for 75% of subcortical injuries. Motor outcomes (mean follow-up, 5.3 years) were predicted by basal ganglia involvement including leg hemiparesis, spasticity, and need for assistive devices (p < 0.01). Nonmotor outcomes were associated with cortical involvement, including cognitive/behavioral outcomes, visual deficits, and epilepsy (p < 0.01). Classification interrater reliability was excellent (correlation coefficients > 0.975). Recognizable PPIS patterns predict long-term morbidity and may guide surveillance, therapy, and counseling. PVI is an underrecognized cause of PPIS and congenital hemiplegia.

Deep brain stimulation in Parkinson disease: a metaanalysis of patient outcomes

Deep brain stimulation (DBS) to treat advanced Parkinson disease (PD) has been focused on one of two anatomical targets: the subthalamic nucleus (STN) and the globus pallidus internus (GPI). Authors of more than 65 articles have reported on bilateral DBS outcomes. With one exception, these studies involved pre- and postintervention comparisons of a single target. Despite the paucity of data directly comparing STN and GPI DBS, many clinicians already consider the STN to be the preferred target site. In this study the authors conducted a metaanalysis of the existing literature on patient outcomes following DBS of the STN and the GPI. This metaanalysis includes 31 STN and 14 GPI studies. Motor function improved significantly following stimulation (54% in patients whose STN was targeted and 40% in those whose GPI was stimulated), with effect sizes (ESs) of 2.59 and 2.04, respectively. After controlling for participant and study characteristics, patients who had undergone either STN or GPI DBS experienced comparable improved motor function following surgery (p = 0.094). The performance of activities of daily living improved significantly in patients with either target (40%). Medication requirements were significantly reduced following stimulation of the STN (ES = 1.51) but did not change when the GPI was stimulated (ES = -0.02). In this analysis the authors highlight the need for uniform, detailed reporting of comprehensive motor and nonmotor DBS outcomes at multiple time points and for a randomized trial of bilateral STN and GPI DBS.