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To assess the prevalence of gastrointestinal symptoms (GIS) in Parkinson’s disease (PD) compared to control subjects and their timing of appearance in relationship to the onset of motor symptoms. There is a rostrocaudal gradient of alpha-synuclein (α-SYN) neuropathology in the enteric nervous system at early stages of PD with higher burden in the upper than the lower gut. However, only constipation has been recognized as a premotor gastrointestinal manifestation of PD. 129 PD patients and 120 controls underwent a structured questionnaire to assess the presence of GIS and, in PD patients, the time of their appearance respect to the onset of motor manifestations. GIS significantly more prevalent in PD patients were dry mouth, drooling, dysphagia, constipation and defecatory dysfunction. Constipation and defecatory dysfunction preceded motor manifestations. Whereas gastroparesis symptoms preceded motor manifestations, their prevalence was not significantly different from controls. Despite evidence of a higher α-SYN burden in the upper gut, only constipation and defecatory dysfunction were prominent premotor GIS of PD.

Preladenant is an adenosine 2A (A 2A) receptor antagonist. In animal models of Parkinson's disease, preladenant monotherapy improves motor function without causing dyskinesia and, as an adjunct to levodopa, it improves motor function without worsening dyskinesia. We aimed to assess the efficacy and safety of preladenant in patients with Parkinson's disease and motor fluctuations who were receiving levodopa and other antiparkinsonian drugs. In this phase 2, dose-finding trial, patients with Parkinson's disease who were receiving levodopa were enrolled and treated at 44 sites in 15 countries between December, 2006, and November, 2008. Assignment to treatment was done centrally with an interactive voice response system, according to a block randomisation schedule that was computer generated by the sponsor. Patients were assigned to receive 1, 2, 5, or 10 mg oral preladenant twice daily, or matching placebo for 12 weeks. Patients, study staff, investigators, and all sponsor personnel were masked to treatment assignment. The primary outcome was change in mean daily off time from baseline to week 12, as assessed by home diaries. Efficacy analysis included all patients who received at least one dose of study drug and had data for assessments after baseline. This trial is registered with ClinicalTrials.gov, number NCT00406029. 253 patients were randomised to receive preladenant (1 mg [n=49], 2 mg [n=49], 5 mg [n=49], 10 mg [n=57]) or placebo (n=49), of whom 234 on preladenant (1 mg [n=47], 2 mg [n=48], 5 mg [n=45], 10 mg [n=49]) and placebo (n=45) were eligible for the efficacy analysis. Mean daily off time from baseline to week 12 was reduced versus placebo in patients on 5 mg preladenant (difference −1·0 h, 95% CI −2·1 to 0·0; p=0·0486) and 10 mg preladenant (−1·2 h, −2·2 to −0·2; p=0·019). Changes in mean daily off time versus placebo were not significant for 1 mg preladenant (0·2 h, −0·9 to 1·2; p=0·753) or 2 mg preladenant (−0·7 h, −1·7 to 0·3; p=0·162). The most common adverse events in the combined preladenant group versus placebo were worsening of Parkinson's disease (22 [11%] vs 4 [9%]), somnolence (20 [10%] vs 3 [6%]), dyskinesia (18 [9%] vs 6 [13%]), nausea (17 [9%] vs 5 [11%]), constipation (15 [8%] vs 1 [2%]), and insomnia (15 [8%] vs 4 [9%]). 5 and 10 mg preladenant twice daily might be clinically useful to reduce off time in patients with Parkinson's disease and motor fluctuations. Schering-Plough, a subsidiary of Merck.

Spasticity is a symptom occurring in many neurological conditions including stroke, multiple sclerosis, hypoxic brain damage, traumatic brain injury, tumours and heredodegenerative diseases. It affects large numbers of patients and may cause major disability. So far, spasticity has merely been described as part of the upper motor neurone syndrome or defined in a narrowed neurophysiological sense. This consensus organised by IAB—Interdisciplinary Working Group Movement Disorders wants to provide a brief and practical new definition of spasticity—for the first time—based on its various forms of muscle hyperactivity as described in the current movement disorders terminology. We propose the following new definition system: Spasticity describes involuntary muscle hyperactivity in the presence of central paresis. The involuntary muscle hyperactivity can consist of various forms of muscle hyperactivity: spasticity sensu strictu describes involuntary muscle hyperactivity triggered by rapid passive joint movements, rigidity involuntary muscle hyperactivity triggered by slow passive joint movements, dystonia spontaneous involuntary muscle hyperactivity and spasms complex involuntary movements usually triggered by sensory or acoustic stimuli. Spasticity can be described by a documentation system grouped along clinical picture (axis 1), aetiology (axis 2), localisation (axis 3) and additional central nervous system deficits (axis 4). Our new definition allows distinction of spasticity components accessible to BT therapy and those inaccessible. The documentation sheet presented provides essential information for planning of BT therapy.

Objectives. To determine the prevalence of weight loss (WL) in PD patients, its relationship to the severity of motor manifestations and appetite changes. Methods. 144 PD patients and 120 controls were evaluated in a single session. All subjects were asked about changes in body weight and appetite. PD patients were examined with the UPDRS-III and the Hoehn and Yahr (HY) scales. Subscores of tremor, bradykinesia /rigidity, and non-dopaminergic symptoms (NDS) were analyzed individually. Multivariable logistic regression analysis was used to determine an association between WL and PD motor manifestations. Results. 48.6 % of PD patients presented WL compared to 20.8 % of controls (p < 0.001). Weight losers were significantly older and had longer disease duration, higher scores in HY stages, UPDRS-III, and NDS-subscore. Multivariable logistic regression analysis demonstrated that WL was associated with NDS-subscore (p= 0.002; OR: 1.33) and older age (p= 0.037; OR: 1.05). Appetite in PD cases losing weight was unchanged (35.7 %), decreased (31.4 %), or even increased (32.9). Conclusions. Our results showed that WL occurs in almost half of PD patients and it is largely the consequence of disease progression rather than involuntary movements or a decrease in food intake.

Impulsive–compulsive behaviors (ICB) are over‐represented in Parkinson's disease (PD) patients. Neurons in the ventral subthalamic nucleus (STN) might play a predominant role in the modulation of impulsivity. We characterized the firing regularity of 742 subthalamic neurons from 24 PD patients (12 ICB+ and 12 ICB‐) in an OFF medication state. We computed the firing regularity in the dorsal and ventral STN regions, and we compared their performance in discriminating ICB patients. Regularity of ventral neurons in ICB+ patients is higher and supports a significant discrimination between the two cohorts. These results substantiate a ventral location of neurons involved in impulsivity.

Botulinum toxin (BT) therapy is an established treatment of spasticity due to stroke. For multiple sclerosis (MS) spasticity this is not the case. IAB-Interdisciplinary Working Group for Movement Disorders formed a task force to explore the use of BT therapy for treatment of MS spasticity. A formalised PubMed literature search produced 55 publications (3 randomised controlled trials, 3 interventional studies, 11 observational studies, 2 case studies, 35 reviews, 1 guideline) all unanimously favouring the use of BT therapy for MS spasticity. There is no reason to believe that BT should be less effective and safe in MS spasticity than it is in stroke spasticity. Recommendations include an update of the current prevalence of MS spasticity and its clinical features according to classifications used in movement disorders. Immunological data on MS patients already treated should be analysed with respect to frequencies of MS relapses and BT antibody formation. Registration authorities should expand registration of BT therapy for spasticity regardless of its aetiology. MS specialists should consider BT therapy for symptomatic treatment of spasticity.

To describe the results and long-term follow-up after functional surgery of the internal segment of the globus pallidus (GPi) in 10 patients with primary generalized dystonia. Nine of the 10 patients were positive for the DYT1 gene mutation. Bilateral deep brain stimulation (DBS) of the GPi was performed in three cases, bilateral pallidotomy in two, and combined surgery (unilateral GPi lesion with contralateral stimulation) in the remaining five. All patients were evaluated with the Burke–Fahn–Marsden dystonia scale (BFMDS) before, immediately after surgery, at 3 weeks, 3 and 6 months and then yearly. Follow up time ranged from 15 to 105 months (mean: 66.1 months) with six patients having more than 6 years follow up. All patients improved after surgery. All patients with unilateral or bilateral DBS experienced an immediate improvement before starting stimulation. The magnitude of this initial micro lesion effect did not predict the magnitude of the long-term benefit of DBS. The mean decrease in the in the BFMDS was 34%, 55%, and 65% in the movement scale; and 32%, 48%, and 49% in the disability scale for patients with bilateral pallidal DBS, combined unilateral DBS and contralateral pallidotomy, and bilateral pallidotomy, respectively. Worsening of dystonia after a plateau of sustained benefit was observed in three patients. Two patients required multiple pallidal surgeries. Adverse events included: permanent anarthria (1), misplacement of the electrode requiring further surgery (2), scalp infection (1), and hardware related problems (3). This long-term follow up study confirms the beneficial effect of pallidal DBS or pallidotomy in primary generalized dystonia. In addition, our results extent previous observations by showing that, in these patients, (1) the microlesion effect of DBS is not predictive of long-term benefit; (2) combined DBS with contralateral pallidotomy appears to be more effective than bilateral pallidal DBS; and (3) dystonia can reappear after an initial good response during long term follow up.

Mutations in Leucine Repeat Rich Kinase 2 (LRRK2) , primarily located in codons G2019 and R1441, represent the most common genetic cause of Parkinson’s disease in European-derived populations. However, little is known about the frequency of these mutations in Latin American populations. In addition, a prior study suggested that a LRRK2 polymorphism (p.Q1111H) specific to Latino and Amerindian populations might be a risk factor for Parkinson’s disease, but this finding requires replication. We screened 1734 Parkinson’s disease patients and 1097 controls enrolled in the Latin American Research Consortium on the Genetics of Parkinson’s disease (LARGE-PD), which includes sites in Argentina, Brazil, Colombia, Ecuador, Peru, and Uruguay. Genotypes were determined by TaqMan assay (p.G2019S and p.Q1111H) or by sequencing of exon 31 (p.R1441C/G/H/S). Admixture proportion was determined using a panel of 29 ancestry informative markers. We identified a total of 29 Parkinson’s disease patients (1.7%) who carried p.G2019S and the frequency ranged from 0.2% in Peru to 4.2% in Uruguay. Only two Parkinson’s disease patients carried p.R1441G and one patient carried p.R1441C. There was no significant difference in the frequency of p.Q1111H in patients (3.8%) compared to controls (3.1%; OR 1.02, p  = 0.873). The frequency of LRRK2 -p.G2019S varied greatly between different Latin American countries and was directly correlated with the amount of European ancestry observed. p.R1441G is rare in Latin America despite the large genetic contribution made by settlers from Spain, where the mutation is relatively common. Genetic risk: Uncovering ethnic-specific mutations A new study reveals the frequency of Leucine-Rich Repeat Kinase 2 ( LRRK2 ) mutations associated with Parkinson’s disease (PD) in Latin Americans. Ignacio F. Mata at the University of Washington and the VA Puget Sound Health Care System, Seattle, USA, and colleagues from six South American countries have screened the largest cohort of Latino PD patients ever assembled (1739) and 1104 healthy controls for LRRK2 mutations that are known to cause PD in European-derived populations. They found that the p.G2019S missense mutation was the most common, although its frequency varied greatly between countries and was directly correlated with European ancestry. In contrast, the p.R1441G mutation which is common in Spain is rare in Latin America. Further analyses of this cohort will help to further characterize the genetic profile of PD patients in Latin America and contribute to the development of personalized medicines.