Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Multifocal Motor Neuropathy

Multifocal motor neuropathy (MMN) was first described in 1988 as a purely motor neuropathy affecting multiple motor nerves. The diagnosis was based entirely on demonstrating electrophysiological evidence of a conduction block (CB) that selectively affected motor axons, with sparing of sensory axons even through the site of motor CB. Subsequently, a similar disorder was reported but with absence of demonstrable CB on routine nerve conduction studies and there is still some debate as to whether MMN without CB is related to MMN. MMN is thought to be an inflammatory neuropathy related to an immune attack on motor nerves. The conventional hypothesis is that the primary pathology is segmental demyelination, but recent research raises the possibility of a primary axonopathy. Anti-GM1 antibodies can be found in some patients but it is unclear whether these antibodies are pathogenic. Intravenous immunoglobulin is the mainstay of treatment but other immunosuppressive treatments can also be effective

Recurrent orthostatic numbness with carotid stenosis and beta-blocker use

Results:The episodes began when the patient was placed on twice a day 50 mg dose of Lopresor. The patient presented with stereotypic, recurrent, transient numbness involving his entire right arm. Every such episode occurred on changing from a supine or sitting posture into an upright one, lasted less than a minute in duration, and resolved rapidly when the patient became supine again. They increased in frequency when the dose was increased first to 75 mg twice a day and then to 100 mg twice a day, with the patient having daily episodes on admission. Lopresor was discontinued and the patient\u27s symptoms resolved.AdverseEffects:1 patient had recurrent orthostatic numbness.AuthorsConclusions:Anti-hypertensive medications can uncover otherwise asymptomatic carotid disease and alter the course of patient management by precipitating surgical intervention. Conversely, one could argue that these medications should be used cautiously in patients with known high-grade stenosis even in the absence of significant orthostatic hypotension. The TIA [transient ischemic attack] reported here is a classical example of a perfusion failure TIA. These TIAs are frequently associated with severe carotid stenosis and signify distal insufficiency.FreeText:The patient\u27s admission orthostatic measurements were: supine blood pressure (BP) 117/69, pulse 63; standing BP 108/61, pulse 59. Subsequent orthostatic measurements were: supine BP 142/82, pulse 69; standing BP 139/84, pulse 84. Brain magnetic resonance imaging was unremarkable. Ultrasound showed high-grade stenosis of the left internal carotid artery (ICA). Intracranial magnetic resonance angiogram showed stenosis of the A1 segment of the left anterior cerebral artery (ACA). Cerebral angiogram confirmed severe stenosis of the left ICA with a string sign. The left sided injection filled very few branches of the left middle cerebral artery. The left ACA filled from the right via the anterior communicating artery.Patients:1 patient, a 59 year old man. Dropout due to side effect.TypeofStudy:Recurrent orthostatic numbness associated with Lopresor. A case report.DosageDuration:50 mg bid (=100 mg daily) increased first to 75 mg bid (=150 mg daily) and then to 100 mg bid (=200 mg daily). Duration not stated

Response to oral supplementation in copper deficiency myeloneuropathy

Neurological manifestations due to copper deficiency include ataxic myeloneuropathy that resembles subacute combined degeneration due to B12 deficiency. We report our experience in the treatment of 10 patients with copper deficiency myeloneuropathy and conclude that copper supplementation leads to stabilization rather than improvement in the neurological deficits. © 2008 by Lippincott Williams & Wilkins