Joseph Candelario

Bilateral globus pallidus stimulation for severe Tourette's syndrome: a double-blind, randomised crossover trial

BACKGROUND Deep brain stimulation (DBS) has been proposed as a treatment option for severe Tourettes syndrome on the basis of findings from open-label series and small double-blind trials. We aimed to further assess the safety and efficacy of bilateral globus pallidus internus (GPi) DBS in patients with severe Tourettes syndrome. METHODS In a randomised, double-blind, crossover trial, we recruited eligible patients (severe medically refractory Tourettes syndrome, age ≥20 years) from two clinics for tertiary movement disorders in the UK. Enrolled patients received surgery for GPi DBS and then were randomly assigned in a 1:1 ratio (computer-generated pairwise randomisation according to order of enrolment) to receive either stimulation on-first or stimulation off-first for 3 months, followed by a switch to the opposite condition for a further 3 month period. Patients and rating clinicians were masked to treatment allocation; an unmasked clinician was responsible for programming the stimulation. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) total score between the two blinded conditions, assessed with repeated measures ANOVA, in all patients who completed assessments during both blinded periods. After the end of the blinded crossover phase, all patients were offered continued DBS and continued to have open-label stimulation adjustments and objective assessments of tic severity until database lock 1 month after the final patients final trial-related visit. This trial is registered with ClinicalTrials.gov, number NCT01647269. FINDINGS Between Nov 5, 2009, and Oct 16, 2013, we enrolled 15 patients (11 men, four women; mean age 34·7 years [SD 10·0]). 14 patients were randomly assigned and 13 completed assessments in both blinded periods (seven in the on-first group, six in the off-first group). Mean YGTSS total score in these 13 patients was 87·9 (SD 9·2) at baseline, 80·7 (SD 12·0) for the off-stimulation period, and 68·3 (SD 18·6) for the on-stimulation period. Pairwise comparisons in YGTSS total scores after Bonferroni correction were significantly lower at the end of the on-stimulation period compared with the off-stimulation period, with a mean improvement of 12·4 points (95% CI 0·1-24·7, p=0·048), equivalent to a difference of 15·3% (95% CI 5·3-25·3). All 15 patients received stimulation in the open-label phase. Overall, three serious adverse events occurred (two infections in DBS hardware at 2 and 7 weeks postoperatively, and one episode of deep-brain-stimulation-induced hypomania during the blinded on-stimulation period); all three resolved with treatment. INTERPRETATION GPi stimulation led to a significant improvement in tic severity, with an overall acceptable safety profile. Future research should concentrate on identifying the most effective target for DBS to control both tics and associated comorbidities, and further clarify factors that predict individual patient response. FUNDING UK National Health Service.

Long-term outcome of subthalamic nucleus deep brain stimulation for Parkinson's disease using an MRI-guided and MRI-verified approach

Background Subthalamic nucleus (STN) deep brain stimulation (DBS) represents a well-established treatment for patients with advanced Parkinsons disease (PD) insufficiently controlled with medical therapies. This study presents the long-term outcomes of patients with PD treated with STN-DBS using an MRI-guided/MRI-verified approach without microelectrode recording. Methods A cohort of 41 patients who underwent STN-DBS were followed for a minimum period of 5 years, with a subgroup of 12 patients being followed for 8–11 years. Motor status was evaluated using part III of the Unified Parkinsons Disease Rating Scale (UPDRS-III), in on- and off-medication/on-stimulation conditions. Preoperative and postoperative assessments further included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), neuropsychological and speech assessments, as well as evaluation of quality of life. Active contacts localisation was calculated and compared with clinical outcomes. Results STN-DBS significantly improved the off-medication UPDRS-III scores, compared with baseline. However, UPDRS scores increased over time after DBS. Dyskinesias, motor fluctuations and demands in dopaminergic medication remained significantly reduced in the long term. Conversely, UPDRS-III on-medication scores deteriorated at 5 and 8 years, mostly driven by axial and bradykinesia subscores. Quality of life, as well as depression and anxiety scores, did not significantly change at long-term follow-up compared with baseline. In our series, severe cognitive decline was observed in 17.1% and 16.7% of the patients at 5 and 8 years respectively. Conclusions Our data confirm that STN-DBS, using an MRI-guided/MRI-verified technique, remains an effective treatment for motor ‘off’ symptoms of PD in the long term with low morbidity.

Predictive factors of speech intelligibility following subthalamic nucleus stimulation in consecutive patients with Parkinson's disease

Speech changes after bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) can be variable, with the majority of patients experiencing speech deterioration over time. The aim of this study was to describe the perceptual characteristics of speech following chronic STN‐DBS and to analyze clinical and surgical factors that could predict speech change. Fifty‐four consecutive patients (34 men; mean age ± standard deviation (SD), 58.8 ± 6.3 years; mean ± SD disease duration, 12.5 ± 4.7 years; mean ± SD levodopa equivalent, 1556 ± 671 mg/day; mean ± SD Unified Parkinsons Disease Rating Scale motor part (UPDRS‐III) off‐medication score, 48.1 ± 17.9 [range, 20‐89]; and mean ± SD UPDRS‐III on‐medication score, 12.4 ± 7.8 [range, 2‐31]) participated in this study. They were assessed before and at 1 year after surgery using the Assessment of Intelligibility for the Dysarthric Speech, the perceptual scale from Darley et al., and the UPDRS‐III. Speech intelligibility deteriorated on average by 14.4% (P = 0.0006) after 1 year of STN‐DBS when off‐medication and by 12.3% (P = 0.001) when on‐medication. The effect on speech was not linked to age at surgery, unlike the effect on motor outcome. The most significant predictive factors for deterioration of speech intelligibility when patients were off‐medication/on‐stimulation were lower preoperative speech intelligibility on‐medication, longer disease duration, and medially placed left hemisphere active electrode contact. Speech change after STN‐DBS is variable and multifactorial. Consistent preoperative speech evaluation would help inform patients about the possible effects of surgery. Appropriate consideration of speech deficits might assist surgical targeting, particularly of the left electrode.

Genotype and phenotype in Parkinson's disease: lessons in heterogeneity from deep brain stimulation.

Variation in the genetic risk(s) of developing Parkinsons disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l‐dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype‐phenotype relationships.

Treatment of dysarthria following subthalamic nucleus deep brain stimulation for Parkinson's disease

Deep brain stimulation of the subthalamic nucleus (STN‐DBS) is an established treatment for patients with Parkinsons disease (PD). Speech impairment is a frequent side effect of the surgery. This study examined the efficacy of an intensive speech treatment, the Lee Silverman Voice Treatment (LSVT) on dysarthria after STN‐DBS.

Pyramidal tract activation due to subthalamic deep brain stimulation in Parkinson's disease

Background: Subthalamic deep brain stimulation (STN‐DBS) is an effective treatment for Parkinsons disease (PD), but can have side effects caused by stimulus spread to structures outside the target volume such as the pyramidal tract.

Bilateral Deep Brain Stimulation of the Globus Pallidus Pars Interna in a Patient with Variant Ataxia-Telangiectasia

Globus Pallidus Pars Interna in a Patient with Variant Ataxia-Telangiectasia Dejan Georgiev, MD, PhD, Dwij Mehta, MD, Andr e Zacharia, MD, Ruben Saman Vinke, MD, Catherine Milabo, Joseph Candelario, Elina Tripoliti, PhD, Jonathan A. Hyam, FHEA, DPhil, FRCS, Ludvic Zrinzo, MD, MSc, FRCSEd, PhD, Marwan Hariz, MD, PhD, Se an O’Riordan, MD, FRCPI, Thomas Foltynie, BSc, MBBS, MRCP, PhD, Patricia Limousin, MD, PhD*