Role of Directional Configuration in Deep Brain Stimulation for Essential Tremor: A Single Center Experience.

Background: Traditionally, the standard of care for medication refractory essential tremor has been to utilize omnidirectional deep brain stimulation of the ventral intermediate nucleus. The advent of directional stimulation allows for spatial restriction of the stimulation on selected targets without involving the neighboring structures, thereby limiting off-target side effects and improving clinical utility. Methods: We performed a retrospective review of patients between February 2017 and September 2019 who had received ventral intermediate nucleus deep brain stimulation that allowed for directional programming (specifically Abbott/St. Jude). Initial and final major programming sessions post-operatively (approximately 30- and 90-days post-surgery) were examined to determine frequency and reason for use of directional programming. Results: A total of 33 total patients were identified. A little over half were males (58%, N = 19), with an average age of 68 years old (SD 9.3) at the time of surgery, and a disease duration of almost 30 years (27.2, SD 19) with a wide range from 2-62 years. After initial programming, over 50% (17 of 33) of patients were using directional configurations. This increased to 85% (28 of 33) at the 90-day programming. Reasons for conversion to directional configuration included avoidance of side effects (specifically, muscle contractions (9/33), paresthesia (5/33), dysarthria (1/33) and gait ataxia (1/33)) or improved tremor control (12/33). Discussion: Our single-center experience suggests that in the large majority of cases, directional leads were utilized and offered advantages in tremor control or side effect avoidance.

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3.

INTRODUCTION: Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients. METHODS: We analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay. RESULTS: PolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset. CONCLUSION: As clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.

Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.