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Noninvasive Ventilation for ALS Improves Survival and Quality of Life By: Dee Rapposelli Noninvasive ventilation (NIV) has been shown to ameliorate respiratory impairment, which, as the disease worsens, is often responsible for death in patients with amyotrophic lateral sclerosis (ALS). Its use, however, is uncommon, and its overall value in improving quality of life and survival has been debated. Findings of a randomized controlled study by a team from the University of Newcastle upon Tyne, UK, may shift clinicians' attitudes about the intervention. The team, led by Honorary Clinical Lecturer Stephen C. Bourke, MD, and Professor of Respiratory Medicine G. John Gibson, MDaeboth from the University of Newcastle upon Tyneaeand Pamela J. Shaw, MD, professor of neurology at Sheffield University, found that NIV provided a survival advantage that was significantly better than standard care and improved quality of life even in patients with severe bulbar impairment. The researchers pointed out that median survival for patients using NIV who had normal or moderately impaired bulbar function was 205 days, whereas median survival for comparable patients receiving riluzole (Rilutek, Aventis) for symptomatic amelioration of ALS has been reported in the literature to range from 60 to 90 days. In addition, the findings, published in the February issue of Lancet Neurology, challenged the reasoning of "many physicians caring for patients" with ALS who, according to the researchers, "are concerned that NIV could prolong suffering in a distressing and disabling condition." Symptom control and quality-of-life measures, in fact, were improved in those patients who received NIV in the British study (Table). Indeed, "quality-of-life measures not only showed improvement, but quality of life was maintained for most of the period of extended survival," reported Bourke in a communication with Applied Neurology. The team studied a cohort of 92 patients who were assessed every 2 months and randomly assigned to receive either NIV (n = 22) or standard care (n = 19) when orthopnea with maximum inspiratory pressure of less than 60% was predicted or when symptomatic hypercapnia occurred. Standard care consisted of riluzole, vitamins C and E, vaccination against influenza and pneumonia, physical aids such as bed raisers and percutaneous endoscopic gastrostomy tubes if needed, and other interventions. Outcomes were measured by the Short Form-36 mental component summary, the Sleep Apnea Quality of Life Index, and the Chronic Respiratory Disease Questionnaire. The average age of patients was 63 years, and the average duration of disease was 2 years. Overall median survival was 219 days for patients receiving NIV and 171 for patients receiving standard care. "In well-motivated patients, substantially longer survival on NIV has been shown," Bourke added, referring to an earlier study, published in Neurology in 2003. That study showed a median survival of 512 days for such patients. Although NIV did not confer a survival advantage for patients with severe bulbar impairment in the current study, quality-of-life outcomes were significantly better for these patients if they received NIV than if they received standard care. Is NIV economically feasible? An American study published last August in BMC Health Services Research demonstrated that the intervention would be cost-effective if NIV, begun at the time of diagnosis, facilitated a health-related quality-of-life improvement of 13.5%. The study, authored by researchers from the departments of Neurology and Health Management and Policy at the University of Michigan in Ann Arbor, further suggested that the intervention might maintain its cost-effectiveness even if its use achieved a health-related quality-of-life improvement rate of as low as 6.8%. The authors based their study on analysis of clinical and economic events of 80 theoretic patients with ALS. Methodology included a Markov process probability theory that, informed by the clinical literature on ALS, allowed patients to segue through disease progression. For more information, see: -Bourke SC, Tomlinson M, Williams TL, et al. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 2006;5:140-147. -Bourke SC, Bullock RE, Williams TL, et al. Non-invasive ventilation in ALS: indications and effects on quality of life. Neurology. 2003;61:171-177. -Gruis KL, Chernew ME, Brown DL. The cost-effectiveness of early noninvasive ventilation for ALS patients. BMC Health Serv Res. 2005;5:58. The article is available online at www.biomedcentral.com/ 1472-6963/5/58 (full text can be accessed from this Web page). New, Improved Neural Stimulator May Be on the Horizon By: Dee Rapposelli A nerve stimulator designed to improve on the Cyberonics VNS Therapy System has been developed by a team of engineers from the University of Pittsburgh with the help of a group of local high school science teachers. Like the currently available vagus nerve stimulator, the Radio Frequency-powered Neural Stimulator-or RFNS-would be indicated for epilepsy and depression. Like the VNS Therapy System, it transmits a specifically defined current and is implanted under the skin of the neck, but implantation requires 1 surgical incision rather than 2. The technology dispenses with invasive tunneling from the shoulder to the neck and uses an external battery. These elements may ameliorate some of the adverse effects associated with the VNS Therapy System, specifically hoarseness and risk of infection and adhesions. In addition, because the device uses an external battery, the RFNS may require fewer surgical interventions for maintenance than the VNS Therapy System. The RFNS includes a receiving component that is implanted under the skin of the neck and an external powering component at the same site that can be hidden in a lapel, for example. The team, which included Marlin Mickle, PhD, director of both the university's Radio Frequency Identification Center for Excellence and John A. Swanson Institute for Technical Excellence; Michael Lovell, PhD, associate dean for research at the School of Engineering and director of the John A. Swanson Institute for Technical Excellence; Robert Sclabassi, MD, PhD, director of the Center for Clinical Neurophysiology; and Steven Hackworth, PhD, a graduate in electrical engineering, was joined by 4 high school science teachers whose participation was funded by a National Science Foundation program. They took a deep-brain stimulation (DBS) device developed by Mickle, Lovell, and Hackworth that uses radio frequency technology to treat patients with Parkinson disease and related disorders, modified it, and applied it to the management of epileptic seizures. The challenge in developing the RFNS from the DBS model, explained Mickle, was to convert radio frequency energy into a constant current source rather than a constant voltage source, the latter of which was required by the DBS technology. "In DBS, you want to guarantee a particular voltage across 2 electrodes. The current, however, may vary according to the resistances of the tissue. VNS, however, needs a constant current source. To go from DBS radio frequency-based technology to VNS radio frequency technology, you have to figure out how to change a voltage source to a current source," explained Mickle. This, he said, was the challenge for the high school science teachers. "We set it up, but they did most of the technical work," said Mickle. The Pittsburgh team tested their DBS and RFNS devices in a number of ways but did not test the devices in living persons-a job left to the company licensing the technology, which would be tasked with conducting clinical trials and applying for FDA approval. The DBS device has already been licensed, according to Mickle. As for the RFNS, Mickle notes that "people are lining up for it." Pigment Epithelial Cells as Parkinson Disease Treatment By: Dee Rapposelli A double-blind placebo-controlled trial of human retinal pigment epithelial (RPE) cell implantation for the treatment of Parkinson disease (PD) has just begun after a small pilot study showed that the procedure improved motor symptoms in patients with PD. The mechanism of action is the levodopa produced by the cells. The cells were harvested from the eyes of organ donors postmortem, cultured, attached to gelatin microcarriers, and embedded via stereotactic intrastriatal implantation in the postcommissural putamen contralateral to the more affected side of the body in 6 patients with PD. Preclinical studies guided optimal dose requirements for efficacy and safety. The total number of RPE cells, delivered as 2 separated deposits of 25 microL each at 5 target points, was approximately 325,000. Findings at 24 months follow-up suggested that the procedure contributed to significant improvements in off- and on-state motor activity, activities of daily living, and quality-of-life measures. Improvements in dyskinesias were modest. Essentially, the implants provided a durable source of levodopa, avoiding some of the adverse effects of long-term oral treatment with the dopamine precursor, such as "on/off" motor fluctuations caused by treatment-associated intermittent dopaminergic stimulation. The microcarrier acted as a support matrix for the RPE cells, without which they would undergo apoptosis. The citation for the study, which appears in the December 2005 issue of Archives of Neurology, is Stover NP, Bakay RA, Subramanian R, et al. Intrastriatal implantation of human retinal pigment epithelial cells attached to microcarriers in advanced Parkinson disease. Arch Neurol. 2005;62: 1833-1837. Increasing Nogo-66 Receptor Levels May Be a Good Go for Lessening Amyloid Plaque By: Dee Rapposelli Tweaking expression of a protein receptor of a myelin-derived axon outgrowth inhibitor may reduce amyloid-beta (Abeta) deposition, according to researchers from the Yale University School of Medicine in New Haven, CT, and BiogenIdec Inc in Cambridge, MA. The Nogo-66 receptor (NgR), which plays a role in axon regeneration and determines whether and how axons will grow after traumatic injury, appears to influence Abeta plaque production. Observing that aberrant NgR-mediated axonal sprouting occurs near Abeta deposits in the brains of persons with Alzheimer disease (AD), the Yale researchers studied the relationship between the NgR and Abeta. Using murine models of AD, the team, headed by Stephen Strittmatter, MD, a professor in the departments of neurology and neurobiology at Yale, found that NgR and Abeta bind to each other. The team went on to explore how NgR influenced Abeta production. "We demonstrated that decreasing the level of Nogo receptor causes more amyloid-beta to build up in the brain. Conversely, higher levels of Nogo receptor reduced the concentration of beta-amyloid," commented Strittmatter. The findings suggest that NgR may be a therapeutic target for modifying AD progression. The report appears in the February issue of the Journal of Neuroscience. The citation is Park JH, Gimbel DA, Grandpre T, et al. Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition. J Neurosci. 2006;26:1386-1395. Nerve Cell Production Restored in Mouse Model of Down Syndrome By: Dee Rapposelli Therapeutic stimulation of the Hedgehog (Hh) protein signaling pathway, shown to be impaired in the trisomic brain, encourages nerve growth in newborn mouse models of Down syndrome. The clinical implication is that the delayed and inadequate development of brain size in persons with Down syndrome may one day be treatable. Researchers from Johns Hopkins University School of Medicine first studied brain growth of trisomic and euploid newborn mice, documenting and comparing brain size at 7 developmental points from birth to adulthood (birth and days 6, 14, 24, 28, 35, and "adult"). They found that the brains of trisomic mice were the same size as those of euploid mice at birth but were significantly smaller by day 6 and remained smaller compared with brains of euploid mice throughout development. By day 6, the density of granule cell neurons (GNC) in the cerebellar internal granule layer of trisomic mice was significantly less than that of euploid mice. The cause of this compromised development was traced to a malfunction in GNC mitogenic response mediated by the Hh protein signaling pathway. The researchers reasoned that if they therapeutically stimulated the Hh pathway, GNC expression and mitosis might be enhanced. "We injected 20 mg/g of the Hh pathway agonist, SAG1.1, into newborn trisomic and euploid pups in a triolein vehicle," the researchers explained in their article, which appears in the January 31 issue of the Proceedings of the National Academy of Sciences U S A. The treatment resulted in a restoration of both GCP and mitotic cells to euploid levels by day 6. The researchers added that a trend toward increased GCP and mitotic GCP also was seen in euploid mice that were treated with SAG1.1. The citation for this study is Roper RJ, Baxter LL, Saran NG, et al. Defective cerebellar response to mitogenic Hedgehog signaling in Down's syndrome mice. Proc Natl Acad Sci U S A. 2006;103:1452-1456.

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