Graham A. Glass

Subthalamic nucleus deep brain stimulation in primary cervical dystonia

Objectives: The globus pallidus internus (GPi) has been the primary target for deep brain stimulation (DBS) to treat severe medication-refractory dystonia. Some patients with primary cervical or segmental dystonia develop subtle bradykinesia occurring in previously nondystonic body regions during GPi DBS. Subthalamic nucleus (STN) DBS may provide an alternative target choice for treating dystonia, but has only been described in a few short reports, without blinded rating scales, statistical analysis, or detailed neuropsychological studies. Methods: In this prospective pilot study, we analyzed the effect of bilateral STN DBS on safety, efficacy, quality of life, and neuropsychological functioning in 9 patients with medically refractory primary cervical dystonia. Severity of dystonia was scored by a blinded rater (unaware of the patients preoperative or postoperative status) using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) preoperatively and 3, 6, and 12 months postsurgery. Lead location, medications, and adverse events were also measured. Results: STN DBS was well-tolerated with no serious adverse effects. The TWSTRS total score improved (p < 0.001) from a mean (±SEM) of 53.1 (±2.57), to 19.6 (±5.48) at 12 months. Quality of life measures were also improved. STN DBS induced no consistent neuropsychological deficits. Several patients reported depression in the study and 3 had marked weight gain. No patients developed bradykinetic side effects from stimulation, but all patients developed transient dyskinetic movements during stimulation. Conclusions: This prospective study showed that bilateral STN DBS resulted in improvement in dystonia and suggests that STN DBS may be an alternative to GPi DBS for treating primary cervical dystonia. Classification of evidence: This study provides Class III evidence that bilateral subthalamic nucleus deep brain stimulation results in significant improvement in cervical dystonia without bradykinetic side effects.

Regional alterations of brain microstructure in Parkinson's disease using diffusion tensor imaging

This study tested the hypothesis that diffusion tensor imaging can detect alteration in microscopic integrity of white matter and basal ganglia regions known to be involved in Parkinsons disease (PD) pathology. It was also hypothesized that there is an association between diffusion abnormality and PD severity and subtype. Diffusion tensor imaging at 4 Tesla was obtained in 12 PD and 20 control subjects, and measures of fractional anisotropy and mean diffusivity were evaluated using both region‐of‐interest and voxel‐based methods. Movement deficits and subtypes in PD subjects were assessed using the Motor Subscale (Part III) of the Unified Parkinsons Disease Rating Scale. Reduced fractional anisotropy (P < .05, corrected) was found in PD subjects in regions related to the precentral gyrus, substantia nigra, putamen, posterior striatum, frontal lobe, and the supplementary motor areas. Reduced fractional anisotropy in the substantia nigra correlated (P < .05, corrected) with the increased rating scale motor scores. Significant spatial correlations between fractional anisotropy alterations in the putamen and other PD‐affected regions were also found in the context of PD subtypes index analysis. Our data suggest that microstructural alterations detected with diffusion tensor might serve as a potential biomarker for PD.

Physiological identification of the human pedunculopontine nucleus

Background: The pedunculopontine nucleus (PPN) is a brainstem structure with widespread connections to the basal ganglia. Despite the recent introduction of PPN deep brain stimulation (DBS) for the treatment of gait disorders, little is known about its physiology in humans. Methods: Single unit discharge characteristics of neurons in the PPN region were analysed in four patients and PPN local field potentials (LFP) in one patient, recorded during the course of DBS implantation. Two patients had Parkinson disease, and two had non-sinemet responsive parkinsonism. Cell locations were plotted in the coordinate system of a human brainstem atlas. Results: Fifty-six units in the PPN region were studied, of which 32 mapped to within PPN boundaries. The mean (SD) discharge rate of neurons in the PPN was 23.2 (15.6) Hz. Spontaneous neuronal firing rate and burst discharge rate were significantly different between neurons in the region dorsal to PPN and those in the PPN. Responses to passive movement of contralateral and ipsilateral limbs were found. Theta and beta band oscillations were present in the PPN LFP. Conclusion: PPN discharge characteristics may prove useful in the electrophysiological identification of PPN during DBS implantation surgery.

Pedunculopontine nucleus deep brain stimulation in a patient with primary progressive freezing gait disorder

Background: Pedunculopontine nucleus (PPN) deep brain stimulation (DBS) has recently been suggested for treatment of medication-unresponsive gait and axial symptoms in Parkinson’s disease. Patients with the rare primary progressive freezing gait disorder (PPFG) have similar disabling symptoms and few therapeutic options. We report here on our experience with PPN DBS in treating a 76-year-old man with medication-refractory PPFG. Methods: The patient was treated with staged PPN DBS and underwent careful pre- and postoperative clinical evaluations up to 12 months after surgery. Results: PPN DBS resulted in only mild improvement in symptoms after 12 months of stimulation. Conclusion: In this single case of a patient with PPFG, PPN DBS served only a limited role in treating his symptoms and adds to the very limited published literature describing patients treated with DBS at this brain target.

Age of Parkinson's disease onset as a predictor for the development of dyskinesia

The risk of developing levodopa‐associated dyskinesia is known to vary inversely with the age of Parkinsons disease onset. This study quantifies dyskinesia risks for different Parkinsons onset ages in a patient population treated at the Parkinsons Disease Research, Education, and Clinical Center at the San Francisco Veterans Affairs Medical Center. Medical records were reviewed to determine age of Parkinsons onset, medication history, and dyskinesia onset. Dyskinesia risks were determined by using Kaplan‐Meier analysis. Cox proportional hazard models were used to compare age groups and to perform multivariate modeling. This study included 109 patients with Parkinsons, 105 of whom had onset of symptoms after 1989. At 5 years of levodopa treatment, the dyskinesia risk for patients with onset age 40–49 was 70%, decreasing to 42% for onset ages 50–59, 33% for onset ages 60–69, and 24% for onset ages 70–79. Pairwise comparisons between the 40–49 age group and the other age groups were statistically significant in time‐to‐event models. After 5 years of levodopa treatment, dyskinesia risks became uniformly high regardless of age of onset. These results suggest it is appropriate to use different baseline dyskinesia risks in clinical decision‐making for patients on the basis of their ages of onset. However, the most significant difference occurs between ages 40–49 and ages 50–79, and if more than 5 years of levodopa therapy are anticipated, dyskinesia risk may have less utility when deciding upon Parkinsons therapy. Drug studies for Parkinsons disease should also take age of Parkinsons onset into account when analyzing dyskinesia outcomes.

Fluoroscopic, EMG-guided injection of botulinum toxin into the longus colli for the treatment of anterocollis

BACKGROUND Anterocollis is a form of cervical dystonia characterized by forward neck flexion. While botulinum toxin is the treatment of choice for cervical dystonia, patients with anterocollis, who receive injections into the sternocleidomastoid and anterior scalene muscles, represent a disproportionate number of treatment failures. Deep cervical muscles such as the longus colli likely play an important role in neck flexion but are not routinely injected. OBJECTIVE To describe a technique for longus colli injection in cases of anterocollis and to report the clinical outcomes of 10 such injections of botulinum toxin. METHODS Three patients were referred for evaluation and treatment of anterocollis. All had previous treatment failures with sternocleidomastoid/anterior scalene injections or no activity noted on needle EMG investigation of these muscles. All patients received injections of botulinum toxin into the longus colli under fluoroscopic and EMG guidance. RESULTS All patients experienced symptomatic improvement (eight of 10 injections). Two patients reported mild dysphagia without serious complications after dose increases in botulinum toxin. CONCLUSIONS Incomplete muscle selection may be one cause of treatment failures in anterocollis. Deep cervical flexors such as the longus colli represent an under-recognized potential target for symptomatic treatment of anterocollis.

Bilateral Ventral Intermediate Nucleus Thalamic Deep Brain Stimulation in Orthostatic Tremor

Background: Orthostatic tremor (OT) is characterized by high-frequency leg tremor when standing still, resulting in a sense of imbalance, with limited treatment options. Ventral intermediate (Vim) nucleus thalamic deep brain stimulation (DBS) has been reported as beneficial in a few cases. Objective: To report clinical outcomes, lead locations, and stimulation parameters in 2 patients with severe medication-refractory OT treated with Vim DBS. Methods: The patients underwent surface electromyography (EMG) to confirm the OT diagnosis. Outcomes were measured as change in tolerated standing time at the last follow-up. Lead locations were quantified using postoperative MRI. Results: Vim DBS was well tolerated and resulted in improvement in standing time (patient 1: 50 s at baseline to 15 min 16 months after surgery; patient 2: 34 s at baseline to 4.2 min 7 months after surgery). Postoperative surface EMG for patient 1 demonstrated a delayed onset of tremor, lower-amplitude tremor, and periods of quiescence, but an unchanged tremor frequency. Conclusion: These cases provide further support for Vim DBS to improve standing time in severe medication-refractory OT. The location of the effective thalamic target for OT does not differ from the effective target for essential tremor.

Multichannel Electromyographic Mapping to Optimize OnabotulinumtoxinA Efficacy in Cervical Dystonia.

Background Cervical dystonia (CD) is characterized by sustained, involuntary contraction of head and neck muscles. Botulinum toxin injections are established as safe and effective, but unfortunately 15–25% of patients fail to respond. The aim of this study was to examine whether multichannel electromyogaphic mapping improved outcomes in a cohort of antibody-negative onabotulinumtoxinA non-responders by more precisely identifying which muscles were involved in the dystonia. Methods Patients with cervical dystonia who had “failed chemodenervation therapy” administered by an outside provider were enrolled in a single-blind, randomized, crossover design study. Patients received either a multichannel electromyographic mapping study prior to the first botulinum toxin injection, which was followed by use of only a single-lead injection 16 weeks later (injected by an alternate and blinded movement disorders specialist) or vice versa. The primary outcome measure was change in total Toronto Western Spasmodic Torticollis Rating Scale score 4 weeks after each injection compared with each pre-injection baseline score. Results Nine subjects completed this study. Mean percentage improvement in Total Toronto Western Spasmodic Torticollis Rating Scale was 23.5% using multichannel electromyography compared with 9% using the single-channel technique (p = 0.11). Discussion This pilot study suggests that multichannel electromyographic mapping may result in improved efficacy in the treatment of antibody-negative onabotulinumtoxinA refractory CD.

Dissociated gray matter atrophy and hypoperfusion in Alzheimer's disease and Parkinson's disease

et al). MRI scans at 3 year follow-up were compared between groups. The CC was semi-automatically outlined on MRI images and quantified at baseline and follow-up. ARWMCs were visually scored using Fazekas scale (mild, moderate, severe) at baseline. Total CC area at follow-up was entered into ANCOVA analysis to test for differences between groups (AD, SD, non-demented). Subregional differences were analysed using repeatedmeasures ANCOVA, and significant results were further examined using univariate analysis. Results: Groups differed with regards to age, ARWMC-load and gender. Therefore the variables were entered into the ANCOVA analysis as covariates. AD, SD and non-demented elderly subjects did not differ in total CC area. AD and SD patients had smaller CC1 and CC5 compared to non-demented elderly subjects at 3 year follow-up, but did not differ in other CC subregions. No difference in subregional areas between the 2 patient groups. Conclusions: The presented results indicate that anterior and posterior CC atrophy is associated with dementia. No specific atrophy pattern was identified in dementia subtypes, although this may have been due to the relatively small number of subjects who developed dementia.