Imbalance in multiple sclerosis: a result of slowed spinal somatosensory conduction.

Balance problems and falls are common in people with multiple sclerosis (MS) but their cause and nature are not well understood. It is known that MS affects many areas of the central nervous system that can impact postural responses to maintain balance, including the cerebellum and the spinal cord. Cerebellar balance disorders are associated with normal latencies but reduced scaling of postural responses. We therefore examined the latency and scaling of automatic postural responses, and their relationship to somatosensory evoked potentials (SSEPs), in ten people with MS and imbalance and ten age-, sex-matched, healthy controls. The latency and scaling of postural responses to backward surface translations of five different velocities and amplitudes, and the latency of spinal and supraspinal somatosensory conduction, were examined. Subjects with MS had large, but very delayed automatic postural response latencies compared to controls (161 +/- 31 ms vs. 102 +/- 21 ms, p < 0.01) and these postural response latencies correlated with the latencies of their spinal SSEPs (r = 0.73, p < 0.01). Subjects with MS also had normal or excessive scaling of postural response amplitude to perturbation velocity and amplitude. Longer latency postural responses were associated with less velocity scaling and more amplitude scaling. Balance deficits in people with MS appear to be caused by slowed spinal somatosensory conduction and not by cerebellar involvement. People with MS appear to compensate for their slowed spinal somatosensory conduction by increasing the amplitude scaling and the magnitude of their postural responses.

Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

Multiple sclerosis mimics.

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.

Defining and diagnosing involuntary emotional expression disorder.

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.

Medical hypothesis: why secondary progressive multiple sclerosis is a relentlessly progressive illness.

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.

Differentiation of neuromyelitis optica from multiple sclerosis on spinal magnetic resonance imaging.

In order to examine the accuracy of magnetic resonance imaging (MRI)-based diagnosis of neuromyelitis optica (NMO) versus multiple sclerosis (MS), we performed a retrospective, rater-blinded review of 29 cases of NMO and 30 cases of MS using the criteria of long (more than three vertebral levels), continuous lesions with a central cord location for NMO and more peripheral and patchy lesions for MS. Using these criteria, two raters were able to distinguish the two conditions with a good degree of confidence, particularly when the imaging was performed at the time of an acute cord attack. The sensitivity and specificity for diagnosis of NMO were 86.2% and 93.3%, respectively, for Rater A and 96.4% and 78.6%, respectively, for Rater B, with a kappa value of 0.72. Thus there are significant differences in lesion characteristics that allow the distinction on spinal cord imaging between MS and NMO with a moderately high degree of confidence. The location of the lesion as evident on MRI of the spine can be regarded as a distinguishing diagnostic feature between MS and NMO.

Eight-year immunogenicity and safety of interferon beta-1a-Avonex treatment in patients with multiple sclerosis.

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNbeta-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNbeta-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 IFNbeta-1a-Avonex 30 microg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNbeta-1a-Avonex in the phase III trial. Serum levels of IFNbeta 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 IFNbeta-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNbeta-naïve. At baseline, 281 patients were negative for IFNbeta antibodies (NAb-). NAbs (titre > or = 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNbeta-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNbeta-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 IFNbeta-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres > or = 100; five remained NAb+ during six years on IFNbeta-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNbeta-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 IFNbeta-1a-Avonex had NAb titres > or = 100; five of these remained NAb+ at six years. No patient with a NAb titre > 1000 seroconverted to NAb-, whether initially treated with IFNbeta-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNbeta-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 IFNbeta product.

Review of mitoxantrone in the treatment of multiple sclerosis.

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.