P. David Charles

Efficacy and safety of botulinum type A toxin (Dysport) in cervical dystonia: Results of the first US randomized, double-blind, placebo-controlled study

Botulinum toxin type A (Dysport) has been shown in European studies to be a safe and effective treatment for cervical dystonia. This multicenter, double‐blind, randomized, controlled trial assessed the safety and efficacy of Dysport in cervical dystonia patients in the United States. Eighty patients were randomly assigned to receive one treatment with Dysport (500 units) or placebo. Participants were followed up for 4 to 20 weeks, until they needed further treatment. They were assessed at baseline and weeks 2, 4, 8, 12, 16, and 20 after treatment. Dysport was significantly more efficacious than placebo at weeks 4, 8, and 12 as assessed by the Toronto Western Spasmodic Torticollis Rating Scale (10‐point vs. 3.8‐point reduction in total score, respectively, at week 4; P ≤ 0.013). Of participants in the Dysport group, 38% showed positive treatment response, compared to 16% in the placebo group (95% confidence interval, 0.02–0.41). The median duration of response to Dysport was 18.5 weeks. Side effects were generally similar in the two treatment groups; only blurred vision and weakness occurred significantly more often with Dysport. No participants in the Dysport group converted from negative to positive antibodies after treatment. These results confirm previous reports that Dysport (500 units) is safe, effective, and well‐tolerated in patients with cervical dystonia.

Deep brain stimulation in early stage Parkinson's disease: operative experience from a prospective randomised clinical trial

Background Recent evidence suggests that deep brain stimulation of the subthalamic nucleus (STN-DBS) may have a disease modifying effect in early Parkinsons disease (PD). A randomised, prospective study is underway to determine whether STN-DBS in early PD is safe and tolerable. Objectives/methods 15 of 30 early PD patients were randomised to receive STN-DBS implants in an institutional review board approved protocol. Operative technique, location of DBS leads and perioperative adverse events are reported. Active contact used for stimulation in these patients was compared with 47 advanced PD patients undergoing an identical procedure by the same surgeon. Results 14 of the 15 patients did not sustain any long term (>3 months) complications from the surgery. One subject suffered a stroke resulting in mild cognitive changes and slight right arm and face weakness. The average optimal contact used in symptomatic treatment of early PD patients was: anterior −1.1±1.7 mm, lateral 10.7±1.7 mm and superior −3.3±2.5 mm (anterior and posterior commissure coordinates). This location is statistically no different (0.77 mm, p>0.05) than the optimal contact used in the treatment of 47 advanced PD patients. Conclusions The perioperative adverse events in this trial of subjects with early stage PD are comparable with those reported for STN-DBS in advanced PD. The active contact position used in early PD is not significantly different from that used in late stage disease. This is the first report of the operative experience from a randomised, surgical versus best medical therapy trial for the early treatment of PD.

Is deep brain stimulation neuroprotective if applied early in the course of PD

This Viewpoint contributes to the topical debate on the therapeutic benefits of deep brain stimulation in Parkinsons disease (PD). The authors argue that there is more to this treatment approach than just providing symptomatic benefits, and suggest that it may actually become the first therapy proven to slow the progression of PD.

Subthalamic Nucleus Neuronal Firing Rate Increases with Parkinson’s Disease Progression

Parkinsons disease is a neurodegenerative disorder characterized by progressive loss of dopaminergic cells in the central nervous system, in particular the substantia nigra, resulting in an unrelenting loss of motor and nonmotor function. Animal models of Parkinsons disease reveal hyperactive neurons in the subthalamic nucleus that have increased firing rates and bursting activity compared with controls. Although subthalamic nucleus activity has been characterized in patients with advanced‐stage Parkinsons disease, it has not been described in patients with early‐stage Parkinsons disease. Here we present the results of subthalamic nucleus neuronal recordings from patients with early‐stage Parkinsons disease (Hoehn and Yahr stage II) enrolled in an ongoing clinical trial compared with recordings from age‐ and sex‐matched patients with advanced Parkinsons disease. Subthalamic nucleus neurons had a significantly lower firing rate in early versus advanced Parkinsons disease (28.7 vs 36.3 Hz; P < .01). The overall activity of the subthalamic nucleus was also significantly lower in early versus late Parkinsons disease, as measured by background neuronal noise (12.4 vs 14.0 mV; P < .05). No significant difference was identified between groups in the bursting or variability of neuronal firing in the subthalamic nucleus, as measured by a burst index or the interspike interval coefficient of variability. The results suggest that neuronal firing in the subthalamic nucleus increases with Parkinsons disease progression.

Surgical targets for dystonic tremor: Considerations between the globus pallidus and ventral intermediate thalamic nucleus

Dystonic tremor (DT) is characterized by coexisting tremor and abnormal dystonic posturing in the same segment. DT is often medically refractory and DBS is an important therapeutic option. However, the optimal surgical target for DT remains uncertain with Vim, GPi and zona incerta previously reported as effective. We retrospectively reviewed the outcome data from all patients with DT involving at least one upper extremity who underwent DBS at Vanderbilt University from July 2006 to July 2010. We evaluated the improvement of tremor and dystonia after their response to DBS was judged to be maximal. Ten patients met the inclusion criteria. Vim was targeted in four patients and three had unilateral procedure and one bilateral Vim DBS. GPi was targeted in four patients with bilateral DBS procedure in every patient from this subgroup. A combined bilateral GPi and unilateral Vim DBS was performed in two patients. The best results for tremor control were observed in patients with Vim DBS but they had persisting mild dystonia. Patients with GPi DBS had average DT improvement by approximately 50% but their dystonia symptoms were markedly improved. We propose that the patients with DT with a mild dystonia should be considered for Vim DBS procedure and the coexistence of severe DT and dystonia may be successfully controlled by combined GPi and Vim DBS surgeries.

Sneddon and antiphospholipid antibody syndromes causing bilateral thalamic infarction.

A child suffered bilateral thalamic infarction secondary to Sneddon and antiphospholipid antibody syndromes. Her initial findings of hypersomnolence, mood disturbance, and amnesia are characteristic of bilateral thalamic infarction. Clinical and laboratory evaluation confirmed the diagnosis of both Sneddon and antiphospholipid antibody syndromes as the cause of her unusual stroke. The treatment of this patient, based on experience with adult patients, was long-term, high-intensity warfarin anticoagulation.

FUS in familial essential tremor – The search for common causes is still on

The genetic etiology of essential tremor remains unknown despite the significant proportion of familial cases. The search for monogenic causes has repeatedly failed until recent identification of three disease-causing mutations in FUS (fused in sarcoma), a gene previously linked to a rare forms of familial amyotrophic lateral sclerosis with frontotemporal dementia. The genetic epidemiology of FUS in ET is unknown. Herein, we screened 104 patients from 52 pedigrees for mutations in the coding sequence of FUS. Two of the most genetically distant affected individuals from each pedigree were selected for Sanger sequencing to potentially increase the success of genetic analysis. We did not identify a single pathogenic mutation. Our data suggest that FUS mutations are a rare cause of familial ET.

Pharmacological treatment of disabling tremor

Tremor is often a disabling primary condition or secondary to another disorder. No universally effective pharmacological agent exists for the treatment of essential tremor, and patients differ greatly in their response to therapies, thus requiring individualised regimens. Deep brain stimulation is the best option for patients with disabling, drug-resistant essential tremor. Resting tremor in Parkinson’s disease is usually not the primary disabling feature, and in most cases, levodopa/carbidopa is satisfactory for many years. Young Parkinson’s patients with dominant, disabling tremor benefit from anticholinergics in addition to dopaminergic therapies. However, older Parkinson’s patients with more disabling tremor may suffer from dose-dependent side effects, and deep brain stimulation should be considered. This article outlines the available pharmacological agents and treatment considerations for various disabling tremors, including essential tremor and Parkinson’s disease.

Spasticity treatment facilitates direct care delivery for adults with profound intellectual disability

Many adults with intellectual disabilities (ID) have spasticity, where increased muscle tone impairs activities of daily living (ADL) self‐performance and care delivery. There are few reports of spasticity treatment for people with ID, and none of functionally meaningful outcomes. Our objective is to determine the effect of comprehensive spasticity management on ADL self‐performance and care delivery. Baseline evaluation included repeated modified Ashworth and range of motion assessments, and timed and videotaped care task observations. Spasticity treatment was initiated immediately thereafter. Follow‐up evaluation was conducted after spasticity management was optimized, one year after initiation. All individuals with spasticity at a single developmental center for whom treatment goals could be identified were included. Treatment was recommended by a neurologist from any accepted treatment for spasticity except oral medications, including botulinum neurotoxin A, intrathecal baclofen and orthopedic procedures. The main outcome measure is comparison of ease of videotaped care delivery, rated by direct caregivers blinded to participant treatment status. Spasticity treatment resulted in significant improvement across all outcome measures. Range of motion improved by 9° (P = 0.005) and MAS by 0.4 (P = 0.022). Participants took 14% percent less time to complete tasks post‐treatment (P = 0.01). Thirteen caregivers completed evaluations of 35 video pairs with an intra‐class correlation of 0.9. After treatment, undergarment change (P = 0.031) and shirt change (P = 0.017) were rated easier, and all goals (P = 0.0006). Transfers trended toward improvement (P = 0.053). This study shows comprehensive spasticity management provides meaningful improvement in ADL care for patients with ID, which may improve quality of life and reduce caregiver burden.

Positive family history of essential tremor influences the motor phenotype of Parkinson's disease.

Previous reports have suggested that essential tremor (ET) represents a risk factor for the development of Parkinsons disease (PD). Patients with long‐standing ET who develop PD tend to have a tremor‐dominant subtype. To further clarify this association, we examined patients from kindreds with autosomal dominant ET who had signs of isolated PD but did not meet criteria for overlapping ET. We identified 22 patients with PD meeting these diagnostic criteria, and 90% (20 of 22) had tremor‐predominant subtype of PD. Unilateral rest tremor was the presenting symptom in 15 of 22 patients, bradykinesia or rigidity in 5 of 22, and gait problems in 2 of 22. Postural tremor was relatively mild, and the severity of kinetic tremor tightly correlated with rest tremor (r = 0.83, P < 0.001). Tremor‐dominant subtype of PD in patients with a positive family history of ET suggests that these patients have inherited a genetic susceptibility factor for tremor, which affects the motor phenotype of PD.