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Surgical intervention for advanced Parkinson's disease is an option if medical therapy fails to control symptoms adequately. We aimed to assess whether surgery and best medical therapy improved self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. The PD SURG trial is an ongoing randomised, open-label trial. At 13 neurosurgical centres in the UK, between November, 2000, and December, 2006, patients with Parkinson's disease that was not adequately controlled by medical therapy were randomly assigned by use of a computerised minimisation procedure to immediate surgery (lesioning or deep brain stimulation at the discretion of the local clinician) and best medical therapy or to best medical therapy alone. Patients were analysed in the treatment group to which they were randomised, irrespective of whether they received their allocated treatment. The primary endpoint was patient self-reported quality of life on the 39-item Parkinson's disease questionnaire (PDQ-39). Changes between baseline and 1 year were compared by use of t tests. This trial is registered with Current Controlled Trials, number ISRCTN34111222. 366 patients were randomly assigned to receive immediate surgery and best medical therapy (183) or best medical therapy alone (183). All patients who had surgery had deep brain stimulation. At 1 year, the mean improvement in PDQ-39 summary index score compared with baseline was 5·0 points in the surgery group and 0·3 points in the medical therapy group (difference −4·7, 95% CI −7·6 to −1·8; p=0·001); the difference in mean change in PDQ-39 score in the mobility domain between the surgery group and the best medical therapy group was −8·9 (95% CI −13·8 to −4·0; p=0·0004), in the activities of daily living domain was −12·4 (−17·3 to −7·5; p<0·0001), and in the bodily discomfort domain was −7·5 (−12·6 to −2·4; p=0·004). Differences between groups in all other domains of the PDQ-39 were not significant. 36 (19%) patients had serious surgery-related adverse events; there were no suicides but there was one procedure-related death. 20 patients in the surgery group and 13 in the best medical therapy group had serious adverse events related to Parkinson's disease and drug treatment. At 1 year, surgery and best medical therapy improved patient self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. These differences are clinically meaningful, but surgery is not without risk and targeting of patients most likely to benefit might be warranted. UK Medical Research Council, Parkinson's UK, and UK Department of Health.

Tardive dyskinesia (TD) is a heterogeneous, hyperkinetic movement disorder induced by dopamine-receptor blocking agents that presents a unique challenge in the treatment of psychosis. Although acceptance of TD as a serious consequence of antipsychotic treatment was resisted initially, subsequent research by many investigators in psychopharmacology contributed to a rich store of knowledge on many aspects of the disorder. While basic neuroscience investigations continue to deepen our understanding of underlying motor circuitry, past trials of potential treatments of TD focusing on a range of theoretical targets were often inconclusive. Development of newer antipsychotics promised to reduce the risk of TD compared to older drugs, but their improved tolerability unexpectedly enabled an expanding market that paradoxically both increased the absolute number of patients at risk and diminished attention to TD which was relegated to legacy status. Fortunately, development and approval of novel vesicular monoamine transporter inhibitors offered evidence-based symptomatic treatment of TD for the first time and rekindled interest in the disorder. Despite recent progress, many questions remain for future research including the mechanisms underlying TD, genetic predisposition, phenomenological diversity, whether new cases are reversible, how to implement best practices to prevent and treat TD, and whether the development of novel antipsychotics free of the risk of TD is attainable. We owe our patients the aspirational goal of striving for zero prevalence of persistent symptoms of TD in anyone treated for psychosis.

Background Paroxysmal dyskinesias (PDs) are a group of central nervous system diseases characterized by episodes of abnormal involuntary hyperkinetic movement without altered consciousness that increasingly have been recognized in dogs. Objectives To present the phenotypical characterization, treatment, and outcome of a PD observed in Maltese dogs. Animals Client‐owned Maltese dogs (n = 19) with presumed diagnosis of PD. Methods Data were collected retrospectively from medical records (2014‐2019), and supporting information was added prospectively by using a questionnaire directed to the owners of the affected dogs. Results The episodes were characterized mainly by sudden dystonia of ≥1 limbs and generalized body tremors with preserved consciousness. The mean age of clinical onset was 5.4 years. Episode frequency varied widely both among and within individuals. Median episode duration was 4.5 minutes. Most episodes were stress‐ or exercise‐induced. Acetazolamide was administered to 6 dogs, and 4 dogs experienced a decrease in episode frequency. In 7 dogs that received a gluten‐free diet, 6 dogs became episode‐free. In 4 dogs, the episodes stopped spontaneously and in 2 dogs no medication or specific diet was given and the episodes continued at the same frequency. Conclusions and Clinical Importance Given the breed predisposition and regional distribution of the disease, additional research should focus on elucidating the underlying genetic cause doing so might advance both our understanding of the pathophysiology and treatment of this disease, not only in dogs, but also in humans. Regardless of the treatment protocol selected, prognosis appears fair to good.

The mechanism of tardive dyskinesia (TD) is complex and not well understood. Dopamine-receptor blockade in the nigrostriatal pathway may lead to a hyperdopaminergic state that can interfere with mechanisms of movement control, leading to TD. Medications for the treatment of movement disorders, including TD, typically require fine-tuning of doses to optimize control of abnormal movements; however, doses are often not titrated sufficiently. The vesicular monoamine transporter 2 inhibitor deutetrabenazine is an FDA-approved treatment for TD in adults. This post hoc analysis examined dosing patterns in patients with TD according to baseline Abnormal Involuntary Movement Scale (AIMS) item 8 score, a clinician-rated global judgment of the overall severity of abnormal movements. Patients who completed the pivotal 12-week studies, ARM-TD and AIM-TD, were eligible to enroll in the 3-year, open-label extension study. Deutetrabenazine was initiated at 12 mg/day and titrated in a response-driven manner on a weekly basis in intervals of 6 mg/day for 6 weeks, up to a maximum dose of 48 mg/day, based on dyskinesia control and tolerability. Further dose adjustments during the long-term maintenance period were permitted on a weekly basis. Subgroups were defined by AIMS item 8 scores of either 0/1/2 or 3/4 at baseline. Total daily dose categories and treatment exposure over time were evaluated in each subgroup. A total of 336 patients were included in the analysis (baseline AIMS item 8 scores 0/1/2, n = 117; scores 3/4, n = 219). At week 15, the proportions of patients by deutetrabenazine total daily dose (mg) for scores 0/1/2 and 3/4, respectively, were: <24, 10% and 3%; ≥24 to ≤36, 41% and 48%; >36 to ≤48, 49% and 49%. At week 54, proportions by total daily dose (mg) for scores 0/1/2 and 3/4, respectively, were: <24, 11% and 4%; ≥24 to ≤36, 42% and 41%; >36 to ≤48, 46% and 55%; >48, 1% and 0. Similar patterns were observed at weeks 106 and 145 across total daily dose categories. For scores 0/1/2, mean ± SE total daily dose (mg) at weeks 15, 54, 106, and 145, respectively, was 36.9 ± 1.04 (n = 108), 37.1 ± 1.22 (n = 90), 37.7 ± 1.32 (n = 76), and 37.9 ± 1.44 (n = 64). For scores 3/4, mean ± SE total daily dose (mg) at weeks 15, 54, 106, and 145, respectively, was 39.2 ± 0.65 (n = 186), 39.8 ± 0.75 (n = 150), 40.3 ± 0.88 (n = 112), and 40.5 ± 0.99 (n = 97). Dosing decisions in the treatment of TD are individualized, as treatment response is likely driven by complex factors. Findings from this analysis suggest that in order to achieve adequate control of TD symptoms, patients benefit from response-driven titration of deutetrabenazine to doses >24 mg/day, regardless of the baseline severity of abnormal movements assessed by AIMS item 8. These results highlight the importance of patient-driven titration of deutetrabenazine until adequate movement control is achieved, while maintaining safety/tolerability in the treatment of TD. Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.

Dyskinesias encompass a variety of different hyperkinetic phenomenologies, particularly chorea, dystonia, stereotypies, and akathisia. The main types of drug-induced dyskinesias include levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease and tardive syndrome (TS), typically present in patients with psychiatric or gastrointenstinal disorders treated with dopamine receptor blocking drugs, also referred to as neuroleptics. Besides preventive measures (i.e., avoiding the use of the offending drugs), general treatment strategies include slow taper of the offending agent and use of dopamine-depleting agents like tetrabenazine. Botulinum toxin may be helpful for wearing off focal dystonia and some forms of tardive dystonia. Deep brain stimulation is usually reserved for patients with disabling motor fluctuations, LID, and for severe TS that cannot be managed medically.

Cerebral palsy is the most frequent cause of severe physical disability in childhood. Dyskinetic cerebral palsy (DCP) is the second most common type of cerebral palsy after spastic forms. DCP is typically caused by non-progressive lesions to the basal ganglia or thalamus, or both, and is characterised by abnormal postures or movements associated with impaired tone regulation or movement coordination. In DCP, two major movement disorders, dystonia and choreoathetosis, are present together most of the time. Dystonia is often more pronounced and severe than choreoathetosis, with a major effect on daily activity, quality of life, and societal participation. The pathophysiology of both movement disorders is largely unknown. Some emerging hypotheses are an imbalance between indirect and direct basal ganglia pathways, disturbed sensory processing, and impaired plasticity in the basal ganglia. Rehabilitation strategies are typically multidisciplinary. Use of oral drugs to provide symptomatic relief of the movement disorders is limited by adverse effects and the scarcity of evidence that the drugs are effective. Neuromodulation interventions, such as intrathecal baclofen and deep brain stimulation, are promising options.

The scapula serves many roles in order for proper shoulder function to occur. These roles include providing synchronous scapular rotation during humeral motion, serving as a stable base for rotator cuff activation and functioning as a link in the kinetic chain. Each role is vital to proper arm function and can only occur when the anatomy around the shoulder is uncompromised. The presence of bony and soft tissue injury as well as muscle weakness and inflexibility can alter the roles of the scapula and alter scapular resting position and/or dynamic motion. This altered scapular position/movement has been termed ‘scapular dyskinesis’. Although it occurs in a large number of shoulder injuries, it appears that scapular dyskinesis is a non-specific response to a painful condition in the shoulder rather than a specific response to certain glenohumeral pathology. The presence or absence of scapular dyskinesis needs to be determined during the clinical examination. An examination consisting of visual inspection of the scapular position at rest and during dynamic humeral movements, along with the performance of objective posture measurements and scapular corrective maneuvers, will help the clinician ascertain the extent to which the scapula is involved in the shoulder injury. Treatment of scapular dyskinesis should begin with optimised anatomy and then progress to the restoration of dynamic scapular stability by strengthening of the scapular stabilisers utilising kinetic chain-based rehabilitation protocols.

In this randomized trial comparing neurostimulation of the subthalamic nucleus with medical management alone in 156 patients with severe Parkinson's disease, neurostimulation improved the quality of life and motor symptoms. Severe adverse events included a fatal intracerebral hemorrhage resulting from surgical placement of the neurostimulator. In patients with severe Parkinson's disease, neurostimulation improved the quality of life and motor symptoms. Severe adverse events included a fatal intracerebral hemorrhage resulting from surgical placement of the neurostimulator. Parkinson's disease is one of the most disabling chronic neurologic diseases and leads to a significant loss of quality of life. 1 , 2 Several drugs are available that can effectively treat the symptoms of the disease, but long-term medical management is often complicated by the appearance of levodopa-induced motor complications, leading to rapid changes between periods of severe akinesia and periods of mobility that may be accompanied by troublesome hyperkinesias. 3 Dopamine agonists, amantadine, catechol O -methyltransferase (COMT) inhibitors, 3 and other drugs can effectively improve mobility and reduce dyskinesias initially but typically fail after several years. 4 The administration of high-frequency continuous electrical . . .

Deep brain stimulation (DBS) is an established procedure for the symptomatic treatment of Parkinson's disease. Several deep brain nuclei have been stimulated, producing a wide range of effects on the motor and non-motor symptoms of Parkinson's disease. Long-term, high-quality evidence is available for stimulation of the subthalamic nucleus and globus pallidus internus, both of which uniformly improve motor features, and for stimulation of the thalamic ventralis intermedius, which improves tremor. Short-term data are available for stimulation of other deep brain targets, such as the pedunculopontine nucleus and the centremedian/parafascicular thalamic complex. Some non-motor symptoms improve after DBS, partly because of motor benefit or reduction of drug treatment, and partly as a direct effect of stimulation. More evidence on the effects of DBS on non-motor symptoms is needed and specifically designed studies are warranted.

The exact cause of Parkinson disease is unknown, but it is assumed to be the result of a combination of environmental influences superimposed on genetic predisposition or susceptibility (Table 2).14-16 There is increasing evidence that the genetic and environmental insults leading to [Jankovic J. Parkinson] disease commonly lead to abnormal forms of a normal protein, α-synuclein, which seems to contribute to cell death.16,23 The onset of Parkinson disease can be categorized as juvenile (age < 21 yr), early onset (21-50 yr) and late onset (generally > 60 yr).24,25 The juvenile form is rare, is often familial (in as many as 50% of cases), is most frequently associated with a parkin gene mutation and has an atypical presentation.25,26 Of patients with Parkinson disease, 10%-16% have an affected first- or second-degree relative; first-degree relatives may have double the risk of Parkinson disease compared with the general population.26-29 In early- and late-onset Parkinson disease, the frequency of a positive family history is not statistically different.24 In advanced Parkinson disease, the efficacy of levodopa can decline and fluctuate throughout the day switching between \"on\" and \"off' medication periods.92 The motor and nonmotor fluctuations mirror those seen in levodopa plasma concentrations resulting from levodopa's short half-life.93 Providing continuous dopaminergic stimulation is the goal of treating fluctuations in patients with advanced Parkinson disease.94-96 We now have surgical options, including deep brain stimulation and levodopacarbidopa intestinal gel, to provide treatment to such patients. Currently, deep brain stimulation has the highest level of evidence with the largest number of randomized controlled trials.97 Emerging therapies currently being studied in Parkinson disease are listed in Appendix 7, available at www.cmaj.ca/lookup/suppl/doi :10.1503/cmaj.151179/-/DC1. The response to deep brain stimulation is equal to the best response on levodopa, but more effective than medical therapy in improving \"on\" time without troublesome dyskinesias.101,102 Deep brain stimulation typically improves levodoparesponsive symptoms (e.g., tremor, bradykinesia, rigidity) and on-off fluctuations and dyskinesias, whereas impairments in gait, balance and speech are less likely to improve. Patients should be considered for deep brain stimulation only if adequate trials of multiple medications for Parkinson disease (e.g., levodopa-carbidopa, dopamine agonists, monoamine oxidase B inhibitors and amantadine) have been unsuccessful.100 Although duration of efficacy is not clearly established, patients who undergo deep brain stimulation may have sustained benefit for at least 10 years.100 A recent study suggests that deep brain stimulation for Parkinson disease may be offered earlier for patients (mean age 52 yr, disease duration 7.5 yr) just beginning to have motor fluctuations.103 Thalamic deep brain stimulation may be considered as an option in patients who predominantly have disabling tremor where subthalamic nucleus stimulation cannot be performed.57