Utility of nerve ultrasound in ulnar neuropathy with abnormal non-localizing electrophysiology in diabetes mellitus.

We studied the utility of ultrasound in the diagnostic workup of ulnar neuropathy with abnormal non-localizing electrophysiology (NL-UN) in patients with diabetes. Eighteen ulnar nerves (15 patients) were scanned from wrist to mid-upper arm. Ultrasound showed: (a) focal nerve enlargement at the elbow (8/18 nerves), either alone (6) or superimposed upon diffuse nerve abnormality (2); (b) diffuse nerve enlargement without focal abnormality (8/18); (c) segmental abnormality in upper-arm or forearm without extrinsic nerve compression (2/18). This study shows a pivotal role for ultrasound in the classification of NL-UN in patients with diabetes, which can facilitate critical therapeutic decisions.

A comparative audit of anticardiolipin antibodies in oligoclonal band negative and positive multiple sclerosis.

It has been suggested that multiple sclerosis (MS) patients with positive anticardiolipin antibodies (ACLA) have some atypical features, including absent oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). Our aim was to compare the frequencies of ACLA and related laboratory and clinical features in OCB negative (OCB-) and positive (OCB+) MS patients. We compared 41 OCB- patients attending a MS Clinic in a tertiary referral center, with 206 OCB+ patients. ACLA, anti-beta2-glycoprotein and other autoantibodies, lupus anticoagulant and coagulation markers were measured. We found a higher frequency of ACLA in OCB- patients, 18/41 versus 33/206 in OCB+ patients (P<0.0001). OCB- patients had more progressive MS than OCB+ subjects. There were no differences in age, sex, Expanded Disability Status Scale (EDSS) score, antiphospholipid syndrome symptoms between the groups. ACLA+ MS patients were more frequently in the OCB- group. Although this may suggest that they represent a special subgroup of MS, no other clinical or laboratory findings distinguish the groups. Although OCB- MS patients may be thought to be less active immunologically, this study shows they have more frequently ACLA than OCB+ patients. OCB- MS patients in our cohort do not appear to have a more benign form of MS, as has previously been suggested.

Cerebral atrophy and disability in relapsing-remitting and secondary progressive multiple sclerosis over four years.

Pathology and magnetic resonance imaging (MRI) studies have provided evidence of widespread axonal loss and reductions of cerebral and spinal cord volume in multiple sclerosis (MS). Atrophy measures on MRI may be a useful surrogate marker of worsening disability in MS, but the published studies are of relatively short duration. Change in brain volume (atrophy) was measured over a four-year period in 20 patients with relapsing-remitting (RR) and 18 with secondary progressive (SP) MS using three-dimensional (3D) MRI acquired during treatment trials of interferon-beta-1a (Rebif). Brain parenchymal and lateral ventricle volume changes were determined and correlated with clinical measures. Over four years, brain parenchymal volume (BPV) decreased in RRMS and SPMS patients by 0.9% (P = 0.006) and 0.3% (P = 0.118), respectively, and the lateral ventricle volumes increased by 15% (P < 0.0001) and 13% (P < 0.0001), respectively. In RRMS patients both lateral ventricle volume (r = 0.63, P = 0.004) and BPV change (r = -0.47, P = 0.037) were related to disability change, as measured by the Expanded Disability Status Scale. Even though a small study and despite the possible confounding effects of interferon treatment, this study demonstrated an association between measures of cerebral atrophy and worsening disability. The data also provides evidence that brain atrophy can be detected early in the disease course and central white matter atrophy as reflected by ventricle enlargement appears to be a continuous process.

A controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

Long-Term Cost Effectiveness of Interferon-beta-1a in the Treatment of Relapsing-Remitting Multiple Sclerosis : An Econometric Model.

OBJECTIVE: To evaluate the cost effectiveness of subcutaneous interferon-beta-1a (IFNbeta-1a) 44mug three times weekly in relapsing-remitting multiple sclerosis (RRMS) using an econometric model. METHODS: Data on RRMS patients treated with IFNbeta-1a 22 or 44mug subcutaneously three times weekly or placebo for up to 4 years were obtained from the Prevention of Relapses and disability by Interferon-beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study. The area under the Expanded Disability Status Scale (EDSS) score-time curve was used as a measure of disability and the effectiveness of therapy was expressed as EDSS-months of disability prevented. Costs were calculated for the UK and France, and results were projected to 10 and 20 years using a time series regression model. RESULTS: Over 10 years, treatment with IFNbeta-1a 44mug subcutaneously three times weekly prevented 121 EDSS-months of additional disability at a cost of Euros (euro)732 each (year of costing 2000). Over 20 years, 321 EDSS-months were saved at a cost of euro359 per month (year of costing 2000). CONCLUSION: This analysis indicated that IFNbeta-1a 44mug subcutaneously three times weekly is cost effective in RRMS and that treatment becomes increasingly cost effective over time.

T1 relaxation time mapping of white matter tracts in multiple sclerosis defined by diffusion tensor imaging.

T(1) relaxation time (T(1)) is a quantitative magnetic resonance measure that enables a global evaluation of white matter disease in multiple sclerosis (MS). We aimed to investigate whether mapping of T(1) values in critical white matter tracts, defined by diffusion tensor (DT) imaging, could provide a stronger surrogate marker of disability. 25 patients with relapsing-remitting MS and 14 healthy controls were imaged with a dual-echo T(2)-weighted sequence. Whole brain T(1) maps were acquired using a multi-slice inversion recovery sequence and DT images generated from a spin-echo, echo-planar diffusion weighted sequence. Trajectories were defined to follow the course of white matter fibre tracts in the pyramidal pathways and corpus callosum. T(1) values were sampled along these trajectories. Total white matter T(1) was sampled by defining white matter masks on axial slices of the T(1) maps. Median T(1) in the pyramidal tracts, corpus callosum and total white matter of MS patients was significantly longer than in controls (p < 0.0001). Median pyramidal tract T(1) correlated significantly with the pyramidal Kurtzke Functional Systems Score (r = 0.64, p = 0.0007) and the Expanded Disability Status Scale (r = 0.55, p = 0.005). By contrast, no correlation with disability was observed for corpus callosum T(1) or total white matter T(1). Our findings show that quantifying pathology within the pyramidal tracts, by utilizing T(1), provides a strong correlate of disability compared with the overall white matter burden of disease. Pyramidal tract T(1) may also provide an objective, sensitive measure for monitoring the progression of motor deficits and disability.

White matter T(1) relaxation time histograms and cerebral atrophy in multiple sclerosis.

T(1) relaxation time (T(1)) provides a quantitative magnetic resonance imaging (MRI) parameter for evaluating tissue damage in the brain. We aimed to measure T(1) in the white matter of patients with multiple sclerosis (MS) and study relationships with cerebral atrophy, T(2) lesion load and clinical parameters. Twenty-six patients with relapsing-remitting MS and sixteen healthy controls were scanned with dual-echo T(2)-weighted, 3-dimensional (3-D) magnetization-prepared rapid acquisition gradient echo and whole brain, multi-slice inversion recovery (IR) sequences. White matter masks were defined on axial T(1) map slices using semi-automated seed growing and normalized 'total white matter' T(1) histograms generated. Atrophy data was obtained using the Cavalieri method of modern design stereology. T(2) lesion volume was also determined using seed growing.T(1) histogram-derived measures (median, peak height, peak position and standard deviation) in MS patients were significantly different (p < 0.0001) from controls. Median T(1) correlated significantly with supratentorial (r = 0.42, p = 0.036), lateral ventricle (r = 0.55, p = 0.004), and T(2) lesion volumes (r = 0.84, p < 0.0001), but not with clinical parameters. Total white matter T(1) provides a robust, quantitative measure of global disease burden in MS, and also correlates significantly with cerebral atrophy. Serial studies are required to determine its potential role as a surrogate marker of disease progression.

Antibody-mediated suppression of Vbeta5.2/5.3(+) T cells in multiple sclerosis: results from an MRI-monitored phase II clinical trial.

The objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM-027 in a baseline versus treatment magnetic resonance imaging-monitored study. Expansion of Vbeta5.2/5.3(+) T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM-027 depleted these cells in peripheral blood and, in parallel, T-cell MBP reactivity and IFN-gamma expression were reduced. We studied 59 patients with relapsing-remitting MS (47 on ATM-027 and 12 on placebo) stratified for HLA-DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T-cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow-up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM-027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run-in, active lesions were found in 78.7% (37/47) of patients treated with ATM-027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm(3) at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon-gamma messenger RNA, and decreased T-cell reactivity to several myelin antigens were found in ATM-027 treated patients. In conclusion, consistent suppression of Vbeta 5.2/5.3(+) T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.