April 30, 2014April 8, 2014Free AccessTypical and Atypical Initial Presentations of Neuromyelitis Optica: A Retrospective Study (P4.008)Juebin Huang, Burhan Chaudhry, Kimberly McDonald, V Vedanarayanan, Colette Parker, James Corbett, and Robert HerndonAuthors Info & AffiliationsApril 8, 2014 issue82 (10_supplement)https://doi.org/10.1212/WNL.82.10_supplement.P4.008 Letters to the Editor

Background: We aimed to evaluate effects of gender on efficacy and safety of intramuscular (IM) interferon beta (IFNβ)-1a in patients with relapsing–remitting MS (RRMS) or clinically isolated syndromes (CIS) characteristic of early MS. Methods: Pooled data from 1406 (1027 women; 379 men) patients enrolled in five clinical studies of IM IFNβ-1a were analyzed. One analysis examined data for all patients treated with IM IFNβ-1a from all studies. Separate analyses were conducted of pooled IM IFNβ-1a-treated groups from all studies and pooled IFNβ-1a-treated and placebo-treated patients from the placebo-controlled studies. Outcome measures included time to first relapse, annualized relapse rate, time to disability progression, number of gadolinium-enhanced lesions, adverse events, laboratory evaluations, and neutralizing antibodies. Results: All efficacy assessments indicated similar treatment effects of IM IFNβ-1a in men and women with no significant treatment-by-gender interactions. Women reported more headaches, urinary tract infections, and depression in the analysis; however, these were also common in women who received placebo. Men reported more frequent flu-like symptoms in the placebo-controlled studies only. There were no other differences in the safety profile of IM IFNβ-1a between men and women. Conclusions: We conclude that no significant gender-related differences were found in the efficacy and safety of IM IFNβ-1a in patients with RRMS or CIS.

Uncontrollable episodes of emotional expression occur in a variety of neurological conditions. This emotional disinhibition syndrome is characterized by episodes of crying or laughing that are. unrelated to or out of proportion to the eliciting stimulus. This syndrome is common among patients with amyotrophic lateral sclerosis, multiple sclerosis, stroke, and traumatic brain injury and a variety of terms and definitions have been used to describe it. The confusing nomenclature has been a barrier to understanding, diagnosis, and treatment of this disorder. The authors propose a unifying term, involuntary emotional expression disorder (IEED), and provide diagnostic criteria for this disorder.

Even with all the newer diagnostic tools, including MRI with multiple sequences, evoked potentials, CSF studies, and so forth, multiple sclerosis remains a clinical diagnosis. In the past it was, to a large extent, a wastebasket diagnosis. Since we really could not do much about it, if our diagnosis was wrong it really didn't matter a great deal. Now, with an increasing number of effective therapies and with good therapies for some of the MS mimics, accurate diagnosis is a must. In addition to the cost of treatment, many of the current treatments such as Mitoxantrone (Novantrone) are not benign and we should not subject our patients to unnecessary harmful therapies.

Uncontrollable episodes of emotional expression occur in a variety of neurological conditions. This emotional disinhibition syndrome is characterized by episodes of crying or laughing that are unrelated to or out of proportion to the eliciting stimulus. This syndrome is common among patients with amyotrophic lateral sclerosis, multiple sclerosis, stroke, and traumatic brain injury and a variety of terms and definitions have been used to describe it. The confusing nomenclature has been a barrier to understanding, diagnosis, and treatment of this disorder. The authors propose a unifying term, involuntary emotional expression disorder (IEED), and provide diagnostic criteria for this disorder.

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNβ-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNβ-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNβ-1a-Avonex 30 mg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNβ-1a-Avonex in the phase III trial. Serum levels of IFNβ antibodies were measured every six months using a screening enzyme-linked immunosorbent assay (ELISA) followed by an antiviral cytopathic effect assay to detect neutralizing antibodies (NAbs) in serum samples positive on ELISA. The incidence of adverse events and laboratory test results assessed safety. Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 IFNβ-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNβ-naïve. At baseline, 281 patients were negative for IFNβ antibodies (NAb-). NAbs (titre≥ 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNβ-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNβ-1a-Avonex were NAb+ at baseline. Thirty-nine of 49 patients who had been on Betaseron and were NAb+ had titres <100; 36 of these 39 seroconverted to NAb-while on IFNβ-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres ≥ 100; five remained NAb+ during six years on IFNβ-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNβ-1a-Avonex during the clinical trial were NAb+ with titres <100 at baseline; four seroconverted to NAb-, with a median time of two to three years. Six patients who had been on IFNβ-1a-Avonex had NAb titres ≥100; five of these remained NAb+ at six years. No patient with a NAb titre >1000 seroconverted to NAb-, whether initially treated with IFNβ-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNβ-1a-Avonex was associated with a low incidence of NAbs and was well tolerated for up to eight years. Further, the results indicate that persistence of NAbs is dependent on titre and IFNβ product.

Mitoxantrone is a synthetic anthracenedione recently approved by the FDA for the treatment of worsening relapsing-remitting (RR), secondary progressive (SP), and progressive relapsing (PR) multiple sclerosis (MS). In experimental allergic encephalomyelitis (EAE), mitoxantrone prevented the development of the signs and decreased the frequency of relapses in relapsing EAE. Early pilot trials using mitoxantrone were carried out using vastly different dosage regimens and patient populations, which may have resulted in conflicting results. Subsequent trials of mitroxantrone in patients with active inflammatory forms of MS suggested a profound effect in decreasing relapse rates, enhancing lesion frequency, and progression of disability. These results were later confirmed in a large, randomized, double-blind trial in patients with either worsening RRMS or SPMS. Treatment with mitoxantrone brought about statistically significant decreases in relapse rates, progression of disability, gadolinium-enhancing, and new lesions on T2-weighted MRI. Although mitoxantrone is generally well tolerated, it is associated with a variety of potential toxicities. Therefore, its use should probably be restricted to those patients with a suboptimal response to high-dose interferon therapy or those with rapidly progressive disease from onset.

Multiple sclerosis (MS) is an immune-mediated neurologic disease in which acute inflammatory events early in the disease course contribute to subsequent neurologic disability. The early relapsing inflammatory phase is followed by a progressive degenerative phase in which the frequency of acute inflammatory attacks diminishes but progressive loss of neurologic function continues. Current immune therapies are most effective in suppressing the acute inflammatory events that characterize the earlier stages of disease. Optimal suppression of these inflammatory events is likely to have the best potential for delaying or preventing loss of axons and decline in neurologic function. In view of these considerations, and because MS is a heterogeneous disease and response to disease-modifying agents (DMA) varies across individuals, it is important to identify suboptimal responders as early as possible to allow therapeutic modification while the opportunity to avert future loss of function remains. At present, no criteria for identifying suboptimal responders have been validated. In January 2004, a group of neurologists from 16 MS centers in the United States met to develop a consensus on criteria for defining suboptimal response for use in compelling clinical situations and to prompt clinical studies to validate the efficacy of these criteria. Consensus criteria included relapse rates of either 1/year or unchanged from pretreatment rates, incomplete recovery from multiple attacks, evolution of polyregional neurologic involvement, recurrent brainstem or spinal cord lesions, and cumulative loss of neurologic function sufficient to disrupt daily activities. The panel then considered the use of mitoxantrone for patients with worsening MS and a suboptimal response to DMA therapy.

Secondary progressive multiple sclerosis is a relentlessly progressive, usually ascending, disease process. Once secondary progression begins, regardless of how long the disease was present before secondary progression began, patients appear to progress at a uniform rate. Recent studies show that it responds poorly to medications effective in relapsing remitting disease, although these drugs decrease relapses and have a substantial effect on lesions seen on magnetic resonance imaging. Disruption of axonal transport is known to occur in demyelinated fibers. Synapses, vacated when axons are destroyed, cause sprouting in surviving terminal axons, resulting in metabolic overload in the terminal axons. This noninflammatory process would not be expected to be altered by current disease-altering therapies.

The new international panel guidelines for diagnosis of multiple sclerosis (MS) raised a number of concerns regarding their use and application, particularly in relation to their impact on treatment issues and options. As a result, a consensus panel composed primarily of North American neurologists with inclusion of several members from the International Panel was convened in Fort Worth, Texas, November 30 to December 2, 2001, to discuss these concerns, resulting in the following consensus statement regarding the guidelines and their appropriate use. (Int J MS Care. 2002; 4: 170–173)