Directed stimulation of the dentato-rubro-thalamic tract for deep brain stimulation in essential tremor: a blinded clinical trial.

OBJECTIVE: Observational studies utilising diffusion tractography have suggested a common mechanism for tremor alleviation in deep brain stimulation for essential tremor: the decussating portion of the dentato-rubro-thalamic tract. We hypothesised that directional stimulation of the dentato-rubro-thalamic tract would result in greater tremor improvement compared to sham programming, as well as comparable improvement as more tedious standard-of-care programming. METHODS: A prospective, blinded crossover trial was performed to assess the feasibility, safety and outcomes of programming based solely on dentato-rubro-thalamic tract anatomy. Using magnetic resonance imaging diffusion-tractography, the dentato-rubro-thalamic tract was identified and a connectivity-based treatment setting was derived by modelling a volume of tissue activated using directional current steering oriented towards the dentato-rubro-thalamic tract centre. A sham setting was created at approximately 180° opposite the connectivity-based treatment. Standard-of-care programming at 3 months was compared to connectivity-based treatment and sham settings that were blinded to the programmer. The primary outcome measure was percentage improvement in the Fahn-Tolosa-Marín tremor rating score compared to the preoperative baseline. RESULTS: Among the six patients, tremor rating scores differed significantly among the three experimental conditions (P=0.030). The mean tremor rating score improvement was greater with the connectivity-based treatment settings (64.6% ± 14.3%) than with sham (44.8% ± 18.6%; P=0.031) and standard-of-care programming (50.7% ± 19.2%; P=0.062). The distance between the centre of the dentato-rubro-thalamic tract and the volume of tissue activated inversely correlated with the percentage improvement in the tremor rating score (R2=0.24; P=0.04). No significant adverse events were encountered. CONCLUSIONS: Using a blinded, crossover trial design, we have shown the technical feasibility, safety and potential efficacy of connectivity-based stimulation settings in deep brain stimulation for treatment of essential tremor.

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.

Physiology-Based Treatment of Myoclonus.

Myoclonus can cause significant disability for patients. Myoclonus has a strikingly diverse array of underlying etiologies, clinical presentations, and pathophysiological mechanisms. Treatment of myoclonus is vital to improving the quality of life of patients with these disorders. The optimal treatment strategy for myoclonus is best determined based upon careful evaluation and consideration of the underlying etiology and neurophysiological classification. Electrophysiological testing including EEG (electroencephalogram) and EMG (electromyogram) data is helpful in determining the neurophysiological classification of myoclonus. The neurophysiological subtypes of myoclonus include cortical, cortical-subcortical, subcortical-nonsegmental, segmental, and peripheral. Levetiracetam, valproic acid, and clonazepam are often used to treat cortical myoclonus. In cortical-subcortical myoclonus, treatment of myoclonic seizures is prioritized, valproic acid being the mainstay of therapy. Subcortical-nonsegmental myoclonus may be treated with clonazepam, though numerous agents have been used depending on the etiology. Segmental and peripheral myoclonus are often resistant to treatment, but anticonvulsants and botulinum toxin injections may be of utility depending upon the case. Pharmacological treatments are often hampered by scarce evidence-based knowledge, adverse effects, and variable efficacy of medications.

Botulinum toxin for cervical dystonia: addressing treatment failure and improving outcomes.

INTRODUCTION: Cervical dystonia is a form of focal dystonia characterised by tilting and turning of the head and neck. This can cause significant disability in affected patients. Botulinum toxin injections are the mainstay of therapy. However, approximately 30% of patients discontinue treatment. CLINICAL REFLECTIONS: Tyslerowicz et al. have provided a comprehensive review of the factors contributing to treatment failure. Such factors include appropriate identification of dystonia patterns, accurate injection of muscles, and addressing non-motor features of cervical dystonia. CLINICAL IMPLICATIONS: A systematic approach is needed to identify and address the potentially modifiable factors that contribute to treatment failure.