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Botulinum toxin (BoNT) has become a therapeutic agent for a large variety of medical conditions. It is a symptomatic treatment and in most cases requires repeat injections at regular intervals. The first session is crucial in establishing rapport between the physician and the patient to ensure a continuity of treatment on a long term basis. Since the clinical practice varies widely across different therapeutic indications and in different clinical settings around the world, a general set of strategic approach is difficult to be formulated. This article will focus on the important issues when starting BoNT treatment in patients with cervical dystonia (CD).

Methods We used a population-based sample of 403 Parkinson's disease cases and 405 controls to examine risks by occupation. Results were compared to a previous clinic-based analysis. Results With censoring of jobs held within 10 years of diagnosis, the following had significantly or strongly increased risks: social science, law and library jobs (OR = 1.8); farming and horticulture jobs (OR = 2.0); gas station jobs (OR = 2.6); and welders (OR = 3.0). The following had significantly decreased risks: management and administration jobs (OR = 0.70); and other health care jobs (OR = 0.44). Conclusions These results were consistent with other findings for social science and farming occupations. Risks for teaching, medicine and health occupations were not elevated, unlike our previous clinic-based study. This underscores the value of population-based over clinic-based samples. Occupational studies may be particularly susceptible to referral bias because social networks may spread preferentially via jobs. Am. J. Ind. Med. 57:163–171, 2014. © 2013 Wiley Periodicals, Inc.

Background Head injury is a hypothesised risk factor for Parkinson9s disease, but there is a knowledge gap concerning the potential effect of injury circumstances (eg, work-related injuries) on risk. The objective of this study is to address this gap while addressing issues of recall bias and potential for reverse causation by prediagnosis symptoms. Methods We conducted a population based case-control study of Parkinson9s disease in British Columbia, Canada (403 cases, 405 controls). Interviews queried injury history; whether injuries occurred at work, in a motor vehicle accident or during sports. Participants were also asked to report their suspicions about the causes of Parkinson9s disease to provide an indicator of potential recall bias. Associations were estimated with logistic regression, adjusted for age, sex and smoking history. Results Associations were strongest for injuries involving concussion (OR: 2.08, 95% CI 1.30 to 3.33) and unconsciousness (OR: 2.64, 95% CI 1.39 to 5.03). Effects remained for injuries that occurred long before diagnosis and after adjustment for suspicion of head injury as a cause of Parkinson9s disease. Injuries that occurred at work were consistently associated with stronger ORs, although small numbers meant that estimates were not statistically significant. Conclusions This study adds to the body of literature suggesting a link between head injury and Parkinson9s disease and indicates further scrutiny of workplace incurred head injuries is warranted.

Circulating endothlein (ET) levels are elevated in heart failure and positively correlated with severity of heart failure. Recent studies demonstrated arginine vasopressin (AVP) V 2 mRNA expression was upregulated in the inner medullary collecting duct (IMCD) of cardiomyopathic hamsters (CM). The goal of the present studies was to determine if ET-1 is involved in upregulating the expression of AVP V 2 mRNA in the IMCD of CM by using a mixed ETA/ETB receptor antagonist bosentan. Our results showed plasma ET-1 levels increased in CM hamsters and related with the severity of heart failure. The competitive reverse-transcriptase polymerase chain reaction (RT-PCR) method was used to quantify the expression of AVP V 2 and aquaporin 2 (AQP2) mRNA in the IMCD. AVP V 2 mRNA expression was elevated in placebo-treated CM hamsters and decreased significantly with 14 days of bosentan treatment. Similar results were seen with AQP2 mRNA. The effect of bosentan in normalizing the expression of AVP V 2 and AQP2 mRNA in the IMCD of CM was confirmed by in situ hybridization studies. Bosentan treatments reduced the intensitites of the signals in the IMCD of CM hamsters to that seen in normal hamsters. This study demonstrated that AVP V 2 and AQP2 mRNA are upregulated in CM hamsters and these upregulations are attenuated by bosentan treatment, suggesting that ET-1 plays a role in upregulating the expression of AVP V 2 mRNA in CM hamsters.

Object. Aquaporin-4 (AQP4) plays a significant role in the regulation of brain water homeostasis. In this study the authors investigated the regulation of AQP4 following a focal cortical contusion injury in rats. Methods. Thirty-three adult male Wistar rats received a focal cortical contusion of the parietal cortex. An additional nine rats underwent a craniectomy, but no trauma was inflicted (sham injury). Animals were killed 1, 4, and 24 hours later. The rat brains were examined for water content by comparing the wet and dry weights of each hemisphere. Aquaporin-4 messenger (m)RNA was measured by reverse transcription—polymerase chain reaction. A ratio of AQP4 mRNA expression in the lesioned hemisphere compared with that in the contralateral control hemisphere was calculated for each animal at the injury site (parietal cortex) and at sites adjacent to (occipital cortex) and distant from the injury (frontal pole cortex). Brain edema was significantly increased at the injury site. The expression of AQP4 mRNA was significantly increased at the injury site, significantly decreased adjacent to the injury site, and not significantly different at a site distant from the injury. The magnitude of AQP4 mRNA upregulation at the injured parietal cortex correlated with the degree of downregulation in the adjacent occipital cortex. Conclusions. Data from this study demonstrate that an upregulation of AQP4 occurs at the site of traumatic brain injury and that a downregulation of this molecule occurs adjacent to the site of injury. Understanding the physiology of AQP4 and its regulation following brain injury may allow for the development of novel treatments for cerebral edema that accompanies head injury.

Le tremblement de la tete dans la dystonie cerviale. Objectif: Comparer les caracteristiques cliniques, l'histoire naturelle et la reponse therapeutique de patients dystoniques avec tremblement de la tete (TT+) et sans tremblement de la tete (TT-). Methodes: Il s'agit d'une etude prospective, effectuee sur une periode de 9 mois de 114 patients consecutifs presentant une dystonie cervicale (DC) evalues au moyen d'un questionnaire detaille. L'analyse statistique a ete faite au moyen du test du X carre et du test de t. Resultats: Soixante-dix-huit patients (68.4%) avaient un tremblement de la tete et chez 27 d'entre eux (34.6%) ce tremblement etait un des premiers symptomes. L'âge de debut des symptomes etait le meme dans le groupe TT+ et TT-; cependant, il y avait plus de femmes dans le premier groupe que dans le second (66.7% contre 41.7%; p=0.01). Les patients du groupe TT+ avaient plus frequemment une histoire familiale positive de tremblement de type essentiel de la tete/des mains (21.8% contre 5.5%; p

Background: An apparent excess of teachers and healthcare workers among the Parkinson’s disease patients of a large tertiary care movement disorders clinic suggested the hypothesis that high exposure to viral (or other) respiratory infections in these occupations might be a risk factor for Parkinson’s disease. Methods: A case-control study of the association between occupation and Parkinson’s disease was conducted. Cases (414) were all Parkinson’s disease patients seen at the University of British Columbia Hospital Movement Disorders Clinic between 1986 and 1993, residing in Greater Vancouver, and under 65 in 1991. Controls (6,659) were randomly selected from the 1991 Canadian Census. Findings: Parkinson’s disease was associated with teaching (OR 2.50, 95% CI 1.67–3.74) and occupation in healthcare services (OR 2.07, 95% CI 1.34–3.20), but there were several other substantial associations, both positive and negative. Interpretation: While referral bias cannot be ruled out, the authors find the consistency of the overall pattern of associations with the respiratory infection hypothesis striking.

Mechanical stress producing head injury is associated with Parkinson's disease, suggesting that relations with other physical hazards such as whole-body vibration (WBV) should be tested. In this study, the authors evaluated the relation between occupational exposure to WBV and Parkinson's disease. A population-based case-control study with 403 cases and 405 controls was conducted in British Columbia, Canada, between 2001 and 2008. From detailed occupational histories and published measurements, metrics of occupational WBV exposure were constructed and tested for associations with Parkinson's disease using logistic regression and adjusting for age and sex first, and then also for smoking and history of head injury. While ever being occupationally exposed to WBV was inversely associated with Parkinson's disease (odds ratio = 0.67, 95% confidence interval: 0.48, 0.94), higher intensities had consistently elevated odds ratios, with a statistically significant effect being noted for intermediate intensities when exposures were restricted to the 10 years or more prior to diagnosis. Possible mechanisms of an inverse relation between low levels of WBV exposure and Parkinson's disease could include direct protective effects or correlation with other protective effects such as exercise. Higher intensities of WBV could result in micro-injury, leading to vascular or inflammatory pathology in susceptible neurons. Language: en

The ultimate causes of idiopathic Parkinson's disease (PD) are not fully known, but environmental and occupational causes are suspected. Postencephalitic parkinsonism has been linked to influenza, and other viral infections have also been suspected to relate to PD. We estimated the relationship between PD and both infections and possible vectors of infection (i.e., animal and human) in a population-based, case-control study in British Columbia, Canada. We recruited 403 cases detected by their use of antiparkinsonian medications and 405 controls from the registrants of the provincial universal health insurance plan. Severe influenza was associated with PD (odds ratio [OR]: 2.01; 95% confidence interval [CI]: 1.16-3.48), although this effect was attenuated when reports were restricted to those occurring 10 or more years before diagnosis. Childhood illnesses were inversely associated with PD, particularly red measles (OR: 0.65; 95% CI: 0.48-0.90). Several animal exposures were associated with PD, with statistically significant effects for cats (OR: 2.06; 95% CI: 1.09-3.92) and cattle (OR: 2.23; 95% CI: 1.22-4.09). Influenza infection may be associated with PD. The inverse relationships with childhood infections may suggest an increased risk with subclinical or asymptomatic childhood infections. Occupational exposure to animals may increase risk through transmission of infections or may indicate exposure to another agent of interest (e.g., bacterial endotoxin).

We studied the effect of botulinum-A toxin on spasticity of the leg adductors in 9 patients who were either chair-bound or bed-bound with chronic stable multiple sclerosis. We injected botulinum toxin (400 mouse units) or placebo into the adductor muscles in a randomized, crossover, double-blind design. Two physicians, who were unaware of the treatment order, used an objective rating scale and independently assessed the patients; interobserver correlation was excellent (r = 0.93-0.81). We found that botulinum toxin produced a significant reduction in spasticity (p = 0.009) and a significant improvement in the ease of nursing care (p = 0.009). There were no adverse effects during this short-term trial. This is the first demonstration of the beneficial effect of botulinum toxin on focal spastic muscle contractions.

A 25-year-old man developed classical hydrophobic rabies 3 months after being bitten on the face. We present his involuntary movements on videotape and discuss the clinical and epidemiological features of rabies. Though rabies is seen in tropical countries commonly and in North America occasionally, recording of the clinical features is rare.

Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) is an effective treatment for generalized dystonia. Its role in the management of other types of dystonia is uncertain. Therefore we performed a prospective, single-blind, multicentre study assessing the efficacy and safety of bilateral GPi-DBS in 10 patients with severe, chronic, medication-resistant cervical dystonia. Two blinded neurologists assessed patients before surgery and at 6 and 12 months post-operatively using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). The primary outcome measure was the severity subscore (range 0-30, higher scores indicating greater impairment). Secondary outcomes included disability (0 to 30), pain (0 to 40) subscores and total scores of the TWSTRS, Short Form-36 and Beck depression inventory. Swallowing and neuropsychological assessment were also performed at baseline and 12 months. One-way repeated measures analysis of variance was used to analyse the data. The TWSTRS severity score improved from a mean (SD) of 14.7 (4.2) before surgery to 8.4 (4.4) at 12 months post-operatively (P = 0.003). The disability and pain scores improved from 14.9 (3.8) and 26.6 (3.6) before surgery, to 5.4 (7.0) and 9.2 (13.1) at 12 months, respectively (both P < 0.001). General health and physical functioning as well as depression scores improved significantly. Complications were mild and reversible in four patients. Some changes in neuropsychological tests were observed, although these did not impact daily life or employment. Our results support the efficacy and safety of GPi-DBS for the treatment of patients with severe and prolonged cervical dystonia who have failed medical management.

Background The spatial and temporal pattern of excessive disease occurrence, termed clustering , may provide clues about the underlying etiology. Objective To report the occurrence of 3 clusters of Parkinson disease (PD) in Canada. Design and Patients We determined the population groups containing the clusters, geographical limits, and duration of exposure to the specific environments. We tested whether there was an excessive presence of Parkinson disease by calculating the probability of the observed cases occurring under the null hypothesis that the disease developed independently and at random in cluster subjects. Results of genetic testing for mutations in the α-synuclein, parkin, tau genes, and spinocerebellar ataxia genes ( SCA2 and SCA3 ) were negative. Results The probabilities of random occurrence ( P values) in the 3 clusters were P = 7.9 × 10 −7 for cluster 1, P = 2.6 × 10 −7 for cluster 2, and P = 1.5 × 10 −7 for cluster 3. Conclusions Our findings indicate an important role for environmental causation in Parkinson disease. A possible role exists for environmental factors such as viral infection and toxins in the light of current evidence.

The etiology of Parkinson's disease (PD) remains obscure. Current research suggests that a variety of occupational and environmental risk factors may be linked to PD. This paper provides an overview of major occupational and environmental factors that have been associated with the development of PD and tries to assess current thinking about these factors and their possible mechanisms of operation. While clear links to rural living, dietary factors, exposure to metals, head injury, and exposure to infectious diseases during childhood have not been established, there is general agreement that smoking and exposure to pesticides affect the probability of developing PD.

N-0923 is a non-ergot, dopaminergic D2 agonist designed to be transdermally available. It has anti-parkinsonian effects when infused intravenously. An adhesive matrix patch was developed to deliver N-0923 transdermally (N-0923 TDS). In this phase II trial, we evaluated the effectiveness of various doses of N-0923 TDS at replacing levodopa. Eighty-five Parkinson's disease (PD) patients were randomized to placebo or one of four doses of N-0923 TDS for 21 days. Change in daily levodopa dose was the primary efficacy measure. Significantly greater reductions in levodopa dose were achieved as compared to placebo for the two highest doses of N-0923 TDS. Patients treated with 33.5 mg and 67 mg N-0923 TDS decreased levodopa use by 26% and 28%, vs. 7% for placebo. N-0923 TDS was safe and well tolerated. © 2001 Movement Disorder Society.

New methods of drug delivery and slowing down the progression of Parkinson’s disease (PD) are the major goals of research. More steady drug levels in the blood are possible by means of controlled-release preparations of levodopa and long-acting dopamine agonists, as well as transcutaneous duodenal tubes and pumps for controlled subcutaneous infusion. Patches containing dopamine agonists absorbed through the skin may be developed. The role of D1 agonists as compared with D2 agonists remains to be elucidated. Agonists on autoreceptors of dopaminergic neurons may potentially reduce excessive stimulation of the intact neurons and this may slow down the rate of neuronal death in PD. Monoamine oxidase-B inhibitors may have a potentially protective action on neurons. Investigations are being carried out to evaluate this claim. Catechol-o-methyl-transferase inhibitors may be helpful in theory. There is also recent interest in inhibitors of excitatory amino acids, which may contribute to neuronal loss in PD.

Object. The goal of this study was to determine whether unilateral pallidotomy reduces parkinsonian pain.Methods. Twenty-one patients suffering from Parkinson's disease (PD) were followed prospectively for 1 year after they had undergone a unilateral pallidotomy to assess the procedure's effect on pain related to PD. Pain unrelated to PD was not studied. Patients scored the level of their PD pain on an ordinal scale (0–10 points) preoperatively and 6 weeks and 1 year postoperatively. The results were analyzed using Wilcoxon's paired-ranks test (with Bonferroni correction) and showed a significant reduction in overall pain scores at 6 weeks (p < 0.001) and 1 year (p = 0.001) following pallidotomy. Various types of PD pain are described and their possible pathophysiological mechanisms are presented.Conclusions. Unilateral pallidotomy significantly reduces pain attributable to Parkinson's disease.

Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of idiopathic parkinsonism (IP). We investigated the effects of lamotrigine (LTG), a glutamate-release inhibitor, in the symptomatic treatment of IP in two double-blind, placebo-controlled studies. Single doses of L-dopa/carbidopa (equal to 50% of the usual morning dose) were administered together with either LTG (100, 200, or 400 mg) or two random placebo doses in 14 patients with IP. The patients were assessed using the Modified Columbia Rating Scale (MCRS) and the Purdue Pegboard Test (PPBT) at multiple intervals over 8 hours. There were no significant differences between the placebo doses and the three doses of LTG on the MCRS and PPBT scores. In a 3-month study, 12 patients took LTG titrated up to 400 mg or placebo with their antiparkinsonian medication for 3 months and were then crossed over. Nine of 12 patients did not complete the study because of dyskinesia (n = 2), hallucinations (n = 3), and deterioration of parkinsonian symptoms (n = 4) on LTG. There was no significant difference between placebo and LTG on the MCRS and PPBT in the three patients who completed the study. The results failed to demonstrate any symptomatically beneficial effects of LTG in IP.

Botulinum toxin is a presynaptic neuromuscular blocking agent that, when injected intramuscularly in minute quantities, can produce selective muscle weakness. This property is employed therapeutically to provide symptomatic relief in conditions related to excessive muscle activities in strabismus, blepharospasm, hemifacial spasm, cervical dystonia, spasmodic dysphonia (adductor type), and jaw closing dystonia. It is investigational for a long list of medical conditions. It is a marketed drug in a number of countries in the world, but its use has only been approved by different regulatory agencies for use in a limited number of conditions. The long-term effects, appropriate dose for children, and in pregnancy, and maximum dose without causing toxicity remain unclear.

The authors evaluated intraparotid injections of botulinum toxin A in reducing salivary secretions and drooling in nine patients with PD. There was a marked objective reduction in secretion, and two thirds of the patients had subjective improvement in drooling. No side effects were observed. The authors conclude that botulinum toxin A promises to be a simple and effective treatment for the common problem of drooling saliva in chronic neurologic disease.

We treated 20 patients with writer's cramp in a double-blind, placebo-controlled study. Each patient received two treatments in tandem, one with botulinum-A toxin (BTX-A) injections and another with normal saline, separated by 3 months. Treatment order was randomized and unknown to the patient and physician. Patients were assessed before each treatment and 2 and 6 weeks after each treatment by objective measurements of pen control. Twelve patients had improvement in pen control after treatment with BTX-A, but only four had significant improvement in writing. BTX-A injections are effective in relieving symptoms in selected cases of writer's cramp, particularly in those with significant wrist-joint deviation.

We studied 6 parkinsonian patients 6 weeks after unilateral adrenal-to-caudate implants. We withheld medications the night before each of 2 study days and gave the patients a single test dose of either a combination of levodopa and carbidopa, or levodopa alone in double-blind random order. We administered the modified Columbia scale, objective measurements of rigidity and movement velocity, and the pegboard test at regular intervals after the single test dose. The results revealed that the improvements in performance recorded by the Columbia scale and the pegboard test were significantly less on the side contralateral to the operation when patients received carbidopa, whereas there was no significant difference in performance between the 2 observations on the ipsilateral side. Carbidopa apparently crossed the disrupted blood-brain barrier and lowered the efficacy of levodopa.

Dystonic torticollis has been treated with local injections of botulinum toxin in a single blind study of 12 patients. A significant decrease of abnormal movements was recorded, and pain improved. Further studies are desirable to define the optimum dosage and site for injections, and the long term effects of repeated injections.

We randomly placed 10 parkinsonian patients on high- and low-protein diets that tasted and looked alike, each for 1 week. All patients were taking L-dopa and carbidopa with or without other antiparkinson medications; medications remained unchanged. A "blind" physician recorded the modified Columbia scores, objective measurements of rigidity, movement velocity, and pegboard tests three times a day for 5 days during each week. The patients recorded fluctuations hour to hour. We measured serial blood L-dopa levels on day 4 of each week. Performance was significantly better while the patients were on low-protein diets. These results did not correlate with blood L-dopa levels, which had higher peaks in three patients while they were on high-protein diets despite inferior performance and increased number of "off" hours. Thus, high dietary protein probably affects the efficacy of L-dopa at a central level.

We carried out a double-blind rising dose study of a D-1 dopamine agonist, CY 208-243, in 6 parkinsonian patients. Deficits monitored by Columbia scores were significantly improved at single doses ranging from 5 to 40 mg, though efficacy was low. Used alone, CY 208-243 was not a satisfactory therapeutic agent, and toxicity data precluded further increases in dosage.