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Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

We performed a cross-sectional, “bottom-up” observational study of resource use, costs, and quality of life in patients with multiple sclerosis (MS) in Germany. Six centers participated in the study. Patients were asked to complete a questionnaire, and a total of 737 patients returned it (response rate 66%). The questionnaire provided information on all resource consumption, medical, and nonmedical, work absence, informal care related to their MS, and quality of life (EuroQol). Simultaneously, medical charts were also abstracted for a subsample of 202 patients for comparison between answers in the questionnaires and registered data. Levels of disability were assessed using the Expanded Disability Status Scale. The mean age of the cohort was 41.9±14.1 years (disease onset 33.4), mean EDSS score 4.4 (range 1.0–9.5), and mean utility measured by EQ-5D 0.552±0.331). Mean total cost per patient and year was 65,400 DM, adjusted for use of interferons, which was higher in this sample than the current average use in Germany. When this cost is extrapolated to an estimated patient population of 120,000, total costs to society are estimated at 7.85 billion DM. Direct costs represented 57.5%, informal care accounted for 12.1% and indirect costs amounted to 42.5%. Public payers pay for an estimated 24,800 DM per patient or 38% of total costs. All types of costs (direct, informal care, indirect) increased with increasing disability, while utilities decreased.

Objective To assess the clinical and histologic effects of an intraarticular application of low-dose (noncytotoxic) liposomal clodronate in established antigen-induced monarthritis (AIA) in rabbits. Methods AIA was monitored by assessments of joint swelling, C-reactive protein levels, and radiographic changes in 17 NZW rabbits for 8 weeks during the course of weekly intraarticular injections of liposomal clodronate (0.145 mg/injection, low dose) or “empty” liposomes. The contralateral knee was injected with liposome buffer alone as the control. End-point analyses included macroscopic joint examination, immuno- and TUNEL staining, Safranin O staining/microspectrophotometry, and tumor necrosis factor α (TNFα) convertase enzyme (TACE) inhibition assay. Results Liposomal clodronate–treated rabbits showed a reduction and delay in joint swelling during the first 3 injections. Expression of matrix-bound (solubilized) TNFα, lining cell hyperplasia, and levels of RAM-11+ macrophages were low in the synovium of the liposomal clodronate treatment group, but the proportion of apoptotic lining cells was not affected. The radiologic score was low at the end of weeks 2 and 4, but at 8 weeks, no difference, compared with controls, was found in pannus formation or in the extent of joint erosion; also, joint swelling was higher than before initiation of treatment. Injections of liposomal clodronate prevented cartilage proteoglycan loss, which was significant in the superficial zone only. TACE activity was not inhibited by clodronate. Conclusion Liposomal clodronate had temporary antiinflammatory and antierosive effects on established AIA in rabbits. Over the long-term, the loss of cartilage proteoglycans was halted. This observed treatment effect may be related to the inhibition of TNFα production and processing in the synovium.

Background: A pathological classification has been developed of early active multiple sclerosis (MS) lesions that reveals four patterns of tissue injury: I—T cell/macrophage associated; II—antibody/complement associated; III—distal oligodendrogliopathy, and IV—oligodendrocyte degeneration in the periplaque white matter. Mechanisms of demyelination in early MS may differ among the subgroups. Previous studies on biopsied MS have lacked clinicopathological correlation and follow up. Critics argue that observations are not generalisable to prototypic MS. Objective: To describe the clinicopathological characteristics of the MS Lesion Project biopsy cohort. Methods: Clinical characteristics and disability of patients with pathologically confirmed inflammatory demyelinating disease (excluding ADEM) classified immunopathologically (n = 91) and patients from the Olmsted County MS prevalence cohort (n = 218) were determined. Results: Most patients who underwent biopsy and had pathologically proved demyelinating disease ultimately developed definite (n = 70) or probable (n = 12) MS (median follow up 4.4 years). Most had a relapsing remitting course and 73% were ambulatory (EDSS ⩽4) at last follow up. Nine patients remained classified as having an isolated demyelinating syndrome at last follow up. Patients with different immunopathological patterns had similar clinical characteristics. Although presenting symptoms and sex ratios differed, the clinical course in biopsy patients was similar to the prevalence cohort. Median EDSS was Conclusions: Most patients undergoing biopsy, who had pathologically confirmed demyelinating disease, were likely to develop MS and remain ambulatory after a median disease duration of 4.4 years. The immunopathological patterns lacked specific clinical correlations and were not related to the timing of the biopsy. These data suggest that pathogenic implications derived largely from MS biopsy studies may be extrapolated to the general MS population.

Multiple sclerosis is characterized morphologically by the key features demyelination, inflammation, gliosis and axonal damage. In recent years, it has become more evident that axonal damage is the major morphological substrate of permanent clinical disability. In our study, we investigated the occurrence of acute axonal damage determined by immunocytochemistry for amyloid precursor protein (APP) which is produced in neurones and accumulates at sites of recent axon transection or damage. The numbers of APP-positive axons in multiple sclerosis lesions were correlated with the disease duration and course. Most APP-positive axons were detected within the first year after disease onset, but acute axonal damage was also detected to a minor degree in lesions of patients with a disease duration of 10 years and more. This effect was not due to the lack of active demyelinating lesions in the chronic disease stage. Late remyelinated lesions (so-called shadow plaques) did not show signs of axon destruction. The number of inflammatory cells showed a decrease over time similar to that of the number of APP-positive axons. There was a significant correlation between the extent of axon damage and the numbers of CD8-positive cytotoxic T cells and macrophages/microglia. Our results indicate that a putative axon-protective treatment should start as early as possible and include strategies preventing T cell/macrophage-mediated axon destruction and leading to remyelination of axons.

The present study investigated the fate of macrophages in peripheral nerves undergoing Wallerian degeneration, especially their disappearance from the injured nerves after phagocytosis of axonal and myelin debris. Wallerian degeneration was induced in adult male C57Bl/6 mice by transecting the right sciatic nerve. Five days after transection, the male sciatic nerves were transplanted into female recipient mice by placing them exactly parallel to the host sciatic nerves. Nerves of the female recipient mice were also transected to induce breakdown of the blood–nerve barrier in the host animal. Apoptosis was assessed by morphological, immunohistochemical (activated caspase-3), and molecular (DNA fragmentation) methods in transplanted, recipient, and in control nerves. A subpopulation of macrophages within the degenerating nerves died locally by apoptosis in each experiment. The fate of the male macrophages within the transplanted nerves and the host organism was investigated byin situhybridization with a Y-chromosome-specific DNA probe (145SC5).In situhybridization specifically stained cells within the transplanted male nerve. Y-chromosome-positive cells were detected not only inside the transplanted nerve, but also inside the female host nerve, the perineurial tissue, the local perineurial blood vessels, draining lymph nodes and the spleen of the female host, suggesting hematogenous as well as lymphatic elimination of macrophages from the injured nerve. These data indicate that local apoptosis and systemic elimination via circulation to the local lymph nodes and the spleen are involved in the disappearance of macrophages from the injured peripheral nervous system.

Background and Purpose —Activation of endothelial cells is a consequence of cerebral ischemia and leads to the expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin, which can be released into the blood. This study aimed to define the kinetics of soluble adhesion molecule serum levels after cerebral ischemia and their correlation with the extent of neurological deficits, clinical outcome, and infarct volume as measured on CT scans. Methods —Plasma levels of soluble (s) ICAM-1, sVCAM-1, and sE-selectin were repeatedly determined by ELISA in 38 patients during a period of 14 days after acute cerebral ischemia. Results —Soluble adhesion molecule levels demonstrated considerable variability. Overall, concentrations revealed characteristic and significant changes after completed strokes but not after transient ischemic attacks. In patients with completed stroke (n=26) but not in patients with transient ischemic attacks (n=12), sICAM-1 peaked within 24 hours ( P =0.04), sVCAM-1 reached a maximum after 5 days ( P =0.02), and sE-selectin levels decreased after 5 days ( P =0.002). There was no clear-cut correlation of soluble adhesion molecule levels with infarct volume or clinical disability. The initial increase of sE-selectin levels was higher in more disabled patients ( P =0.02). sICAM-1 levels were higher in patients with signs of infection (n=9; P =0.03). Conclusions —As a result of large interindividual variability influenced by ischemia-independent factors, soluble adhesion molecules are not reliable candidates as surrogate markers in acute cerebral ischemia. The characteristic profile of individual soluble adhesion molecules after completed stroke supports prior hypotheses of their involvement in the pathogenesis of acute cerebral ischemia, but this needs to be clarified in detail.