Treatment of multiple system atrophy using intravenous immunoglobulin.

BACKGROUND: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA. METHODS: This was a single-arm interventional, single-center, open-label pilot study. Interventions included monthly infusions of the IVIG preparation Privigen®, dose 0.4 gram/kg, for 6 months. Primary outcome measures evaluated safety and secondary outcome measures evaluated preliminary efficacy of IVIG. Unified MSA Rating Scale (UMSARS) was measured monthly. Quantitative brain imaging using 3T MRI was performed before and after treatment. RESULTS: Nine subjects were enrolled, and seven (2 women and 5 men, age range 55-64 years) completed the protocol. There were no serious adverse events. Systolic blood pressure increased during IVIG infusions (p<0.05). Two participants dropped out from the study because of a non-threatening skin rash. The UMSARS-I (activities of daily living) and USMARS-II (motor functions) improved significantly post-treatment. UMSARS-I improved in all subjects (pre-treatment 23.9 ± 6.0 vs. post-treatment 19.0±5.9 (p=0.01). UMSARS-II improved in 5 subjects, was unchanged in 1 and worsened in 1 (pre-treatment 26.1±7.5 vs. post-treatment 23.3±7.3 (p=0.025). The MR imaging results were not different comparing pre- to post-treatment. CONCLUSIONS: Treatment with IVIG appears to be safe, feasible and well tolerated and may improve functionality in MSA. A larger, placebo-controlled study is needed.

Limbic and motor function comparison of deep brain stimulation of the zona incerta and subthalamic nucleus.

BACKGROUND: Psychiatric and neuropsychological side effects of subthalamic nucleus (STN) stimulation have been increasingly recognized. Most programming regimens focus on contacts 0 and 1, whereas contact 3, which often is located near or in the zona incerta (ZI), is usually not used. The question of whether ZI stimulation may limit limbic effects has not been answered. OBJECTIVE: To examine the effects of short-term stimulation near or in the ZI (contact 3) compared with stimulation of the STN using standard trajectories and targeting as measured by limbic and motor functions. METHODS: Motor and limbic functions of 11 patients with STN DBS were assessed with the Unified Parkinson Disease Rating Scale-3, structured gait video analysis, Visual Analog Scale mood scales, task testing of impulsivity, and facial recognition under routine STN programming and under stimulation in or near the ZI. Postoperative magnetic resonance imaging confirmed the location of contact 3 near or in the ZI. RESULTS: Data analysis with repeated-measures analysis of variance revealed that motor scores remained stable with both stimulation settings, with specific improvements in finger taps (P = .02) and rapid alternating movements (P = .03) in ZI stimulation. Stimulation near or in the ZI led to a decrease in self- reported anxiety and depression (P = .03 for both) and an improvement in fear recognition (P = .02). CONCLUSION: We provide preliminary evidence that stimulation in or near the ZI results in maintained motor function while improving self-reported depression and anxiety in patients with bilateral STN DBS. Stimulation in or near the ZI may provide a useful programming setting for patients prone to psychiatric side effects.

Localization of the subthalamic nucleus in Parkinson disease using multiunit activity.

BACKGROUND: Refinement of the subthalamic nucleus (STN) coordinates using intraoperative microelectrode recordings (MER) is routinely performed during deep brain stimulation (DBS) surgeries in Parkinson disease (PD). The commonly used criteria for electrophysiological localization of the STN are qualitative. The goal of this study was to validate quantitative STN detection algorithm (QD) derived from the multi-unit activity in a prospective setting. METHODS: Ten PD patients underwent STN DBS surgery. The MUA was obtained by removing large spikes close to microelectrode using wavelet method and integrating the 500-2000Hz band in the power spectral density. The qualitative intraoperative mapping of the STN using MER (IOM) versus QD was compared using Bland-Altman and Pearson's correlation analysis. RESULTS: The clinical efficacy was confirmed in all subjects. The mean difference between IOM and QD of the dorsal/ventral border was 0.31±0.84/0.44±0.47mm. Using Bland-Altman statistic, only 2/36 (5.6%) differences (one for the dorsal border and one for the ventral border) were out of ±2 sd line of measurement differences. Correlation between dorsal border/ventral border positions obtained by IOM and QD was 0.79, p<0.0001/0.91, p<0.0001. CONCLUSION: Both methods are in reasonable agreement and are strongly correlated. The QD gives objective coordinates of the STN borders at high precision and may be more accurate than IOM. Prospective blinded comparative studies where the DBS leads will be placed using either QD or IOM are warranted.

Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme.

PURPOSE: Cilengitide, an inhibitor of alphavbeta3 and alphavbeta5 integrin receptors, demonstrated minimal toxicity and durable activity across a wide range of doses administered to adults with recurrent glioblastoma multiforme (GBM) in a prior phase I study. The current multicenter phase II study was conducted to evaluate the activity and safety of cilengitide in GBM patients at first recurrence. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive either 500 or 2,000 mg of cilengitide twice weekly on a continuous basis. Patients were assessed every 4 weeks. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included PFS, overall survival (OS), and radiographic response, as well as quality-of-life and pharmacokinetic assessments. RESULTS: Eighty-one patients were enrolled, including 41 on the 500-mg arm and 40 on the 2,000-mg arm. The safety profile of cilengitide was excellent, with no significant reproducible toxicities observed on either arm. Antitumor activity was observed in both treatment cohorts but trended more favorably among patients treated with 2,000 mg, including a 6-month PFS of 15% and a median OS of 9.9 months. CONCLUSION: Cilengitide monotherapy is well tolerated and exhibits modest antitumor activity among recurrent GBM patients. Additional studies integrating cilengitide into combinatorial regimens for GBM are warranted.

Dopamine agonists induce episodes of irresistible daytime sleepiness.

We assessed the prevalence and risk factors for irresistible daytime sleepiness (IDS) in a cohort of patients with Parkinson's disease (PD) treated with dopamine agonists. Seventy consecutive PD patients on dopamine agonists were interviewed. IDS was experienced by 24 patients (34.3%). Fifty percent of the pramipexole patients, 15.4% of the pergolide patients, 23.1% of the ropinirole patients and the 2 patients on bromocriptine experienced IDS. Patients who experienced IDS were younger (p = 0.009). Nineteen patients had IDS while driving, 3 sustained a motor vehicle crash. Daytime somnolence (p = 0.05) and early arousals (p = 0.001) were risk factors and daytime napping (p = 0.007) and benzodiazepines (p = 0.006) were protective. Improvement was achieved by changing the dosing schedule, the amount of agonist per dose, discontinuing the agonist or accommodating the sleepiness. We conclude that dopamine agonists are commonly implicated in IDS.