ABSTRACT
BACKGROUND: Programming deep brain stimulation in dystonia is difficult because of the delayed benefits and absence of evidence-based guidelines. Therefore, we evaluated the efficacy of a programming algorithm applied in a double-blind, sham-controlled multicenter study of pallidal deep brain stimulation in dystonia. METHODS: A standardized monopolar review to identify the contact with the best acute antidystonic effect was applied in 40 patients, who were then programmed 0.5 V below the adverse effect threshold and maintained on these settings for at least 3 months, if tolerated. If no acute effects were observed, contact selection was based on adverse effects or anatomical criteria. Three-year follow-up data was available for 31 patients, and five-year data for 32 patients. The efficacy of the algorithm was based on changes in motor scores, adverse events, and the need for reprogramming. RESULTS: The mean (±standard deviation) dystonia motor score decreased by 73 ± 24% at 3 years and 63 ± 38% at 5 years for contacts that exhibited acute improvement of dystonia (n = 17) during the monopolar review. Contacts without acute benefit improved by 58 ± 30% at 3 years (n = 63) and 53 ± 31% at 5 years (n = 59). Interestingly, acute worsening or induction of dystonia/dyskinesia (n = 9) correlated significantly with improvement after 3 years, but not 5 years. CONCLUSIONS: Monopolar review helped to detect the best therapeutic contact in approximately 30% of patients exhibiting acute modulation of dystonic symptoms. Acute improvement, as well as worsening of dystonia, predicted a good long-term outcome, while induction of phosphenes did not correlate with outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT00142259.
ABSTRACT
Two-pore domain K(+) channels, a recently discovered family of ion channels with a unique membrane topology, have been shown to be critically involved in cell death. We here address the functional role of TASK3 (TWIK-related acid-sensitive K(+) channel, KCNK9) in human glioblastoma in vitro and in vivo. Human glioma cell lines (n = 5) as well as glioma specimens (n = 5) constitutively express TASK3 mRNA and protein. The functional impact of the potassium channel on cell survival was investigated using a medium with high (25 mM) extracellular potassium over 7 days. Using flow cytometric assessment, we show that under these culture conditions 97 +/- 0.76% of all glioma cells survived. Application of the TASK channel opener isoflurane (1 vol%) resulted in a 30 +/- 4% reduction of cell survival in different glioma cell lines. Simultaneous application of isoflurane and the TASK channel blockers bupivacaine (20 microM) and spermine (500 microM) completely reversed this effect. Our results demonstrate the expression of TASK3 in glioma cells in vitro and in vivo and provide a direct link between the TASK3 channel function and glioma cell survival. This implies that TASK3 channels may possibly represent a novel molecular target for the treatment of this type of cancer.
