Long-Term Outcomes of Bilateral Pallidal Deep Brain Stimulation for X-Linked Dystonia and Parkinsonism.

BACKGROUND: X-linked dystonia parkinsonism (XDP) causes adult-onset progressive dystonia and parkinsonism, which may not respond to pharmacotherapy. OBJECTIVE: Previous case reports have reported beneficial effects from bilateral pallidal (GPi) deep brain stimulation (DBS). Here, we report the long-term clinical outcomes of 3 patients treated at our center. METHODS: All patients presented with medication refractory dystonia and parkinsonism. They were followed prospectively. Clinical evaluations included the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS). Adverse events were recorded. RESULTS: The average length of follow-up was 45.7 months. No serious adverse events occurred. All patients experienced an immediate and sustained improvement in dystonia. Mean percentage improvement in motor subscores of BFMDRS was 63.5% at the last follow-up visit. Parkinsonism was less responsive to neuromodulation, with a mean improvement in UPDRS-III of 39.5%. Standard pallidal stimulation parameters were used. Freezing of gait developed after DBS therapy in 2 patients, stimulation-induced in one and due to disease progression in the other. CONCLUSION: Bilateral pallidal DBS resulted in significant and sustained improvement in dystonia and moderate improvement in parkinsonism. Pallidal DBS represents an important treatment option for XPD for the management of motor symptoms.

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.

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 Parkinson's 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 Parkinson's 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.

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 Parkinson's disease onset. This study quantifies dyskinesia risks for different Parkinson's onset ages in a patient population treated at the Parkinson's Disease Research, Education, and Clinical Center at the San Francisco Veterans Affairs Medical Center. Medical records were reviewed to determine age of Parkinson's 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 Parkinson's, 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 Parkinson's therapy. Drug studies for Parkinson's disease should also take age of Parkinson's onset into account when analyzing dyskinesia outcomes.

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.

Whole-body tremulousness: isolated generalized polymyoclonus.

BACKGROUND: Acquired generalized repetitive myoclonus may be mistaken for tremor. Distinguishing myoclonus has etiologic and therapeutic implications. OBJECTIVE: To describe isolated generalized polymyoclonus and the outcomes of etiologic evaluations at the time of diagnosis. DESIGN: Computer search of the Mayo Movement Neurophysiology Laboratory database and medical records linkage system. SETTING: Department of Neurology, Mayo Clinic. PATIENTS: Nineteen adults with generalized repetitive myoclonus confirmed using surface electromyography (burst duration <50 milliseconds), and other neurologic features minimal or absent. INTERVENTIONS: Treatment of myoclonus and underlying causes. MAIN OUTCOME MEASURES: Clinical presentation and underlying etiologies. RESULTS: We identified 19 patients with isolated generalized polymyoclonus resembling whole-body tremor. Onset was most often subacute (12 patients), mean symptom duration was 1.8 years, and mean age at onset was 55 years. Referral diagnoses or patient complaints were tremor, tremulousness, or shaking in all but 5 patients. All the patients had repetitive myoclonus of all limbs, impairing gait in 14 patients. Surface electromyography confirmed nonperiodic muscle burst durations of less than 50 milliseconds, typical of myoclonus. Clinical and serologic screening for cancer and autoimmunity revealed metastatic breast cancer in 2 patients (1 positive for ganglionic acetylcholine receptor antibody) and antibody profiles implicating neurologic autoimmunity in 3 patients (CRMP-5 IgG or neuronal voltage-gated potassium channel antibodies). Medications known to occasionally trigger myoclonus (opioids, selective serotonin reuptake inhibitors, and a serotonin-norepinephrine reuptake inhibitor) were being taken by 7 patients. Myoclonus resolved after discontinuation of selective serotonin reuptake inhibitor therapy in 1 patient; drug discontinuation was declined and follow-up was inadequate in the other 6. CONCLUSIONS: Isolated whole-body tremulousness should raise the suspicion of generalized polymyoclonus, confirmed using routine surface electromyography. Recognition is important because the differential diagnosis includes autoimmunity and drug-induced myoclonus.

Respiratory insufficiency as the primary presenting symptom of multiple-system atrophy.

BACKGROUND: Respiratory stridor, sleep-disordered breathing, and respiratory insufficiency are part of the clinical spectrum of multiple-system atrophy (MSA). We have encountered cases where these were presenting symptoms, with the diagnosis of MSA being initially unrecognized. OBJECTIVE: To describe cases in which breathing difficulties were the initial and primary manifestation of MSA. DESIGN: Database review from January 1, 1996, through October 31, 2005. SETTING: Mayo Clinic, Rochester, Minn. PATIENTS: All patients diagnosed as having MSA, cross-referenced for apnea, hypopnea, or hypoventilation. On review, we included only cases in which respiratory dysfunction was the primary initial clinical event in MSA, excluding equivocal cases. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Characteristics and clinical course of patients. RESULTS: Six cases were identified in which substantial respiratory insufficiency occurred as an early, presenting symptom of MSA. Three patients had been examined emergently for acute respiratory distress before the ultimate diagnosis of MSA; the other 3 patients were diagnosed as having obstructive sleep apnea unresponsive to therapy, with bilateral vocal cord paralysis found on ear, nose, and throat examination. Stridor was noted early in the course in all. All patients required tracheostomy, and all eventually developed features consistent with probable MSA. CONCLUSIONS: Multiple-system atrophy may occasionally present as primary respiratory failure or dysfunction, with initially mild motor and autonomic symptoms. Otherwise unexplained central respiratory failure, bilateral vocal cord paralysis, stridor, or refractory central sleep apnea should prompt consideration of MSA.

Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid.

N-acetyl cysteine (NAC) supports the synthesis of glutathione (GSH), an essential substrate for fast, enzymatically catalyzed oxidant scavenging and protein repair processes. NAC is entering clinical trials for adrenoleukodystrophy, Parkinson's disease, schizophrenia, and other disorders in which oxidative stress may contribute to disease progression. However, these trials are hampered by uncertainty about the dose of NAC required to achieve biological effects in human brain. Here we describe an approach to this issue in which mice are used to establish the levels of NAC in cerebrospinal fluid (CSF) required to affect brain neurons. NAC dosing in humans can then be calibrated to achieve these NAC levels in human CSF. The mice were treated with NAC over a range of doses, followed by assessments of neuronal GSH levels and neuronal antioxidant capacity in ex vivo brain slices. Neuronal GSH levels and antioxidant capacity were augmented at NAC doses that produced peak CSF NAC concentrations of ≥50 nM. Oral NAC administration to humans produced CSF concentrations of up to 10 µM, thus demonstrating that oral NAC administration can surpass the levels required for biological activity in brain. Variations of this approach may similarly facilitate and rationalize drug dosing for other agents targeting central nervous system disorders.

Cerebrospinal fluid concentrations of N-acetylcysteine after oral administration in Parkinson's disease.

INTRODUCTION: Depletion of neuronal glutathione may contribute to the pathogenesis of Parkinson's disease (PD). N-acetylcysteine (NAC) can restore neuronal glutathione levels, but it has not been established whether NAC can cross the blood-brain barrier in humans. METHODS: Twelve patients with PD were given oral NAC twice daily for 2 days. Three doses were compared: 7 mg/kg, 35 mg/kg, and 70 mg/kg. NAC, cysteine, and glutathione were measured in the cerebrospinal fluid (CSF) at baseline and 90 min after the last dose. Cognitive and motor functions were assessed pre- and post-NAC administration using the Montreal Cognitive Assessment (MoCA) and the Unified Parkinson's Disease Rating Scale part III motor subscore (UPDRS-III). RESULTS: Oral NAC produced a dose-dependent increase in CSF NAC concentrations (p < 0.001), with the highest dose producing a CSF concentration of 9.26 ± 1.62 µM. There were no significant adverse events. NAC had no acute effect on motor or cognitive function. CONCLUSION: Orally administered NAC produces biologically relevant CSF NAC concentrations at doses that are well tolerated. The findings support the feasibility of NAC as a potential disease-modifying therapy for PD.

Pallidal stimulation for Holmes tremor: clinical outcomes and single-unit recordings in 4 cases.

OBJECT: Holmes tremor (HT) is characterized by irregular, low-frequency (< 4.5 Hz) tremor occurring at rest, with posture, and with certain actions, often affecting proximal muscles. Previous reports have tended to highlight the use of thalamic deep brain stimulation (DBS) in cases of medication-refractory HT. In this study, the authors report the clinical outcome and analysis of single-unit recordings in patients with medication-refractory HT treated with globus pallidus internus (GPi) DBS. METHODS: The authors retrospectively reviewed the medical charts of 4 patients treated with pallidal DBS for medication-refractory HT at the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center. Clinical outcomes were measured at baseline and after surgery using an abbreviated motor-severity Fahn-Tolosa-Marin (FTM) tremor rating scale. Intraoperative microelectrode recordings were performed with patients in the awake state. The neurophysiological characteristics identified in HT were then also compared with characteristics previously described in Parkinson's disease (PD) studied at the authors' institution. RESULTS: The mean percentage improvement in tremor motor severity was 78.87% (range 59.9%-94.4%) as measured using the FTM tremor rating scale, with an average length of follow-up of 33.75 months (range 18-52 months). Twenty-eight GPi neurons were recorded intraoperatively in the resting state and 13 of these were also recorded during contralateral voluntary arm movement. The mean firing rate at rest in HT was 56.2 ± 28.5 Hz, and 63.5 ± 19.4 Hz with action, much lower than the GPi recordings in PD. GPi unit oscillations of 2-8 Hz were prominent in both patients with HT and those with PD, but in HT, unlike PD, these oscillations were not suppressed by voluntary movement. CONCLUSIONS: The efficacy of GPi DBS exceeded that reported in prior studies of ventrolateral thalamus DBS and suggest GPi may be a better target for treating HT. These clinical and neurophysiological findings help illuminate evolving models of HT and highlight the importance of cerebellar-basal ganglia interactions.

Effect of frequency on subthalamic nucleus deep brain stimulation in primary dystonia.

BACKGROUND: Subthalamic nucleus deep brain stimulation (DBS) is an alternative target choice for treating primary dystonia, but little is known about the most effective programming parameters. OBJECTIVE: Here we prospectively evaluate the effect of low versus high frequency subthalamic nucleus DBS in patients with predominantly cervical or upper extremity primary dystonia. METHODS: Seven patients were stimulated at low frequency stimulation (60 Hz) for the first three months and then switched to high frequency stimulation (130 Hz) until month six. Severity of dystonia was determined by a blinded rater (unaware of the patient's pre or post-operative status) who scored the Burke Fahn Marsden dystonia rating scale movement score (BFMDRS-M) and the Toronto Western Spasmodic Torticollis Rating Scale severity score (TWSTRS-S) preoperatively, three, six, and twelve months post-surgery. RESULTS: Patients had a lower mean improvement of 16.6% in BFMDRS-M and 9.5% in TWSTRS-S at three months using low frequency stimulation compared to a 52.3% (p = 0.018) and 45.2% (p = 0.028), respectively, noted at six months using high frequency stimulation. At 12 months (using 130 Hz), the BFMDRS-M and TWSTRS-S improved by 51.8% (p = 0.022) and 56% (p = 0.034). Patients developed transient dyskinesia (during low and high frequency stimulation) which improved with programming adjustments. CONCLUSION: This study offers further support of the effectiveness of subthalamic nucleus DBS in the treatment of primary dystonia and finds that high frequency stimulation was more effective than low frequency stimulation.

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.

Pharmacist's role in a Parkinson's disease and movement disorders clinic.

PURPOSE: The expanding role of a clinical pharmacist at a Veterans Affairs (VA) out-patient clinic for patients with Parkinson's disease (PD) and movement disorders is described. SUMMARY: San Francisco VA Medical Center added a clinical pharmacist to the multi-disciplinary team serving patients at an outpatient clinic operated by its Parkinson's Disease Research, Education and Clinical Center (PADRECC). During the first six months after joining the clinic team, the pharmacist met with 131 patients and made a total of 69 drug therapy recommendations that were implemented by neurologists, clinical nurse specialists, and other PADRECC providers. The results of a retrospective chart review suggested that in about 21% of the cases evaluated, the pharmacist's recommendations contributed to an improved medical outcome or the resolution of a medical problem. Anonymous surveys indicated that clinic providers (n = 33) and patients (n = 20) were satisfied with the pharmacist's services. Using a five-point Likert scale (scores ranged from 1 for "strongly disagree" to 5 for "strongly agree") that they had more time to devote to other clinic responsibilities with the pharmacist present in the clinic (mean score, 4.79); patients indicated that they had an improved understanding of their medications after speaking with the pharmacist (mean score, 4.88). CONCLUSION: A clinical pharmacist's regular involvement in an outpatient PD and movement disorders clinic has been well received by patients and clinic providers. The study results suggest that the pharmacist has made important contributions in areas such as therapeutic problem solving and medication education while freeing up providers for other responsibilities.

Epilepsy, sleep disturbances, and psychiatric consequences.

Neurologic impairment after TBI causes serious morbidity for patients and their families. Prior articles have discussed headache and memory impairment. In this article, epilepsy, sleep disturbances, and psychiatric consequences will be covered. People who have suffered traumatic brain injury are at risk for any of these disturbances, and each person will have a constellation of neurologic symptoms spanning the spectrum from no difficulty in any area to symptoms in each of these areas.

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.

Orthostatic myoclonus: a contributor to gait decline in selected elderly.

BACKGROUND: We encountered 15 patients with a newly recognized clinical phenomenon that we term orthostatic myoclonus. We conducted a retrospective chart review to better understand the clinical context and importance of this phenomenon. OBJECTIVE: To describe the clinical picture of orthostatic myoclonus. METHODS: The Mayo Clinic Rochester Movement Disorders Laboratory database was searched for all patients diagnosed electrophysiologically with orthostatic myoclonus (2002 through 2006). Medical records and laboratory data of all patients were retrospectively reviewed. RESULTS: Fifteen patients with orthostatic myoclonus were identified, all seniors (64 to 81 years). Seven of the patients had a CNS degenerative disorder and two had a systemic illness known to be associated with myoclonus. In the remaining six patients no known CNS disorder contributed to the phenomenon. The onset of orthostatic myoclonus was accompanied by complaints of leg jerking or observed leg jerking in 13 of 15 patients during upright posture. An insidious deterioration of gait that was often described as "apraxia" or "gait initiation difficulty" accompanied the myoclonus in 13 of 15 patients. Clinicians frequently suspected normal pressure hydrocephalus or orthostatic tremor syndrome. Surface EMG studies revealed short duration myoclonic bursts that occurred predominately with the assumption of an upright posture. Some patients improved on clonazepam. CONCLUSIONS: Orthostatic myoclonus is a unique clinical and physiologic phenomenon that accompanies a slowly progressive and eventually disabling gait disorder in the elderly. This phenomenon often arises in the company of more widespread CNS disease.