Fenna T. Phibbs

Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease.

BACKGROUND Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinsons disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. METHODS Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50-75, on medication ≥6 months but ≤4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n = 15) or DBS + ODT (n = 15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. RESULTS As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. Medication requirements in the DBS + ODT group were lower at all time points with a maximal difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS + ODT group suffered serious adverse events; remaining adverse events were mild or transient. CONCLUSIONS This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD.

Deep brain stimulation in early Parkinson's disease: Enrollment experience from a pilot trial

BACKGROUND Deep brain stimulation (DBS) of the subthalamic nucleus is an accepted therapy for advanced Parkinsons disease (PD). In animal models, pharmacologic ablation and stimulation of the subthalamic nucleus have resulted in clinical improvement and, in some cases, improved survival of dopaminergic neurons. DBS has not been studied in the early stages of PD, but early application should be explored to evaluate safety, efficacy, and the potential to alter disease progression. METHODS We are conducting a prospective, randomized, single-blind clinical trial of optimal drug therapy (ODT) compared to medication plus DBS (ODT + DBS) in subjects with Hoehn & Yahr Stage II idiopathic PD who are without motor fluctuations or dementia. We report here subject screening, enrollment, baseline characteristics, and adverse events. RESULTS 30 subjects (average age 60 ± 6.9 years, average duration of medicine 2.1 ± 1.3 years, average UPDRS-III scores 14.9 on medication and 27.0 off medication) are enrolled in the ongoing study. Twelve of 15 subjects randomized to DBS experienced perioperative adverse events, the majority of which were related to the procedure or device and resolved without sequelae. Frequently reported adverse events included wound healing problems, headache, edema, and confusion. CONCLUSION This report demonstrates that subjects with early stage PD can be successfully recruited, consented and retained in a long-term clinical trial of DBS. Our ongoing pilot investigation will provide important preliminary safety and tolerability data concerning the application of DBS in early stage PD.

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.

Reappraisal of the role of the DRD3 gene in essential tremor

OBJECTIVES Analyze the distribution of polymorphism in the dopamine receptor D3 (DRD3) gene, which was previously reported as a susceptibility risk for essential tremor (ET), in a large cohort of ET. METHODS The role of 312G>A DRD3 polymorphism was analyzed using linkage analysis, association study and transmission disequilibrium test in a group of 433 ET patients, and two unrelated control groups with 121 and 151 individuals. RESULTS Allelic frequencies of glycine and serine forms of the DRD3 gene did not differ between patients and both control groups, and were in Hardy-Weinberg equilibrium. Linkage analysis identified obligatory recombinants in every large pedigree, even in those with relatively high frequency of glycine allele, thus excluding the linkage to this locus. Both alleles were transmitted with an equal likelihood to affected offspring. We also failed to replicate the relationship between glycine homozygosity and an earlier age of onset or more severe tremor course. CONCLUSIONS Our comprehensive genetic analysis in a large ET cohort strongly argues against the role of the DRD3 gene in ET pathogenesis.

Prevalence of unilateral tremor in autosomal dominant essential tremor

The presence of bilateral arm tremor is a key diagnostic feature of essential tremor (ET). We analyzed the presence of unilateral arm tremor in familial ET cohort of 133 autosomal dominant ET kindreds with 412 affected individuals. Inclusion criteria in patients with unilateral arm postural and/or kinetic tremor required the duration of tremor for at least 5 years, without hypokinetic‐rigid syndrome, dystonic posturing, or history of sudden onset of tremor. Only subjects with at least one living first degree relative who met diagnostic criteria for definite ET were included. Eighteen subjects met the inclusion criteria and five had postural tremor only, while the majority (13/18) had a combination of postural and kinetic tremor. Our data shows that unilateral tremor associated with ET is relatively rare and can be identified in 4.4% patients in a cohort of familial ET.

Treating post-traumatic tremor with deep brain stimulation: Report of five cases

BACKGROUND Post-traumatic tremor is one of the most common movement disorders resulting from severe head trauma. However, literature regarding successful deep brain stimulation (DBS) treatment is scarce, resulting in ambiguity regarding the optimal lead location. Most cases support the ventral intermediate nucleus, but there is evidence to defend DBS of the zona incerta, ventral oralis anterior/posterior, and/or a combination of these targets. We report five patients with disabling post-traumatic tremor treated with DBS of the ventral intermediate nucleus and of the globus pallidus internus. METHODS Patients were referred to the Vanderbilt Movement Disorders Division, and surgical intervention was determined by a DBS Multidisciplinary Committee. Standard DBS procedure was followed. RESULTS Patients 1-4 sustained severe diffuse axonal injuries. Patients 1-3 underwent unilateral ventral intermediate nucleus DBS for contralateral tremor, while Patient 4 underwent bilateral ventral intermediate nucleus DBS. Patients 1-3 experienced good tremor reduction, while Patient 4 experienced moderate tremor reduction with some dystonic posturing of the hands. Patient 5 had dystonic posturing of the right upper extremity with tremor of the left upper extremity. He was treated with bilateral DBS of the globus pallidus internus and showed good tremor reduction at follow-up. CONCLUSION Unilateral or bilateral DBS of the ventral intermediate nucleus and bilateral DBS of the globus pallidus internus may be effective and safe treatment modalities for intractable post-traumatic tremor. Further studies are needed to clarify the optimal target for surgical treatment of post-traumatic tremor.

The Factors Involved in Deep Brain Stimulation Infection: A Large Case Series

Background: Deep brain stimulation (DBS) is a proven treatment for various movement disorders resistant to medical management. Complications such as postsurgical infection can negate benefits and increase patient morbidity. We sought to better define risk factors for infection. Methods: We performed a review of DBS cases at our institution from January 1996 to June 2011. Information on multiple metrics including surgical complications, procedural complications and infection were entered into a secure online database. Results: A total of 447 patients received DBS surgery. Twenty-six (5.82%) developed infection sometime after DBS surgery with 9 (2.01%) developing infection within 30 days after the final staged surgery. Operating surgeon (p = 0.012), scalp erosion (p = 0.0001), surgical incision opening time (0.0001) and number of individuals in the operating room (0.0027) were significant in the cumulative infection group. Conclusion: The 30-day infection rate was comparably low to other published studies. Several factors were noted to be significant in the cumulative infection group, but none in the 30-day infection group. Further understanding of infection risk factors is important to optimize patient selection and standardize infection-preventative techniques.

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.

60-Hz frequency effect on gait in Parkinson's disease with subthalamic nucleus deep brain stimulation.

Gait dysfunction is common in advancing Parkinsons disease and has a disappointing response to dopamine replacement and subthalamic nucleus deep brain stimulation programming parameters. Low‐frequency stimulation, less than 130 Hz in combination with increased voltage, has been shown to decrease freezing episodes and number of steps with little impact on overall performance measured by the Unified Parkinsons Disease Rating Scale. This was in the setting of delivering the same total energy, which required both a change in voltage and frequency. We wanted to determine if the benefit came from low frequency alone.

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.