Clyde Markowitz

Rituximab in Relapsing-Remitting Multiple Sclerosis : A 72-Week, Open-Label, Phase I Trial

We evaluated the safety, tolerability, pharmacodynamics, and activity of B‐cell depletion with rituximab in patients with relapsing‐remitting multiple sclerosis, receiving two courses of rituximab 6 months apart, and followed for a total of 72 weeks. No serious adverse events were noted; events were limited to mild‐to‐moderate infusion‐associated events, which tended to decrease with subsequent infusions. Infections were also mild or moderate, and none led to withdrawal. Fewer new gadolinium‐enhancing or T2 lesions were seen starting from week 4 and through week 72. An apparent reduction in relapses was also observed over the 72 weeks compared with the year before therapy. Ann Neurol 2008

Treatment of Susac syndrome with gamma globulin and corticosteroids

Susac syndrome is a rare vasculopathy characterized by visual, hearing, and cognitive dysfunction. Optimal treatment is unknown, but many patients require chemotherapy to control disease activity. We describe two patients with Susac syndrome and their response to intravenous immune globulin (IVIg) and corticosteroids. Both patients improved following acute treatment with IVIg and intravenous methylprednisolone (IVMP), and no further relapses were observed. One patient showed significant improvement in hearing and MRI lesions shortly following acute treatment. Treatment with IVIg and corticosteroids provides a therapeutic option that avoids the toxicities of chemotherapy and suggests the possible importance of pathologic antibodies in the pathogenesis of Susac syndrome.

An Approach to Comparing Accuracies of Two Flair MR Sequences in the Detection of Multiple Sclerosis Lesions in the Brain in the Absence of Gold Standard

RATIONALE AND OBJECTIVESnThe purpose of this study was to present a new methodology to compare accuracies of two imaging fluid attenuated inversion recovery (FLAIR) magnetic resonance sequences in detection of multiple sclerosis (MS) lesions in the brain in the absence of ground truth, and to determine whether the two sequences, which differed only in echo time (TE), have the same accuracy.nnnMATERIALS AND METHODSnWe acquired FLAIR images at TE(1) = 90 ms and TE(2) = 155 ms from 46 patients with MS (24-69 years old, mean 45.8, 15 males) and 11 healthy volunteers (23-54 years old, mean 37.1, 6 males). Seven experienced neuroradiologists segmented lesions manually on randomly presented corresponding TE(1) and TE(2) images. For every image pair, a surrogate ground truth for each TE was generated by applying probability thresholds, ranging from 0.3 to 0.5, to the weighted average of experts segmentations. Jackknife alternative free-response receiver operating characteristic analysis was used to compare experts performance on TE(1) and TE(2) images, using successively the TE(1)- and TE(2)-based ground truths.nnnRESULTSnSupratentorially, there were significant differences in relative accuracy between the two sequences, ranging from 8.4% to 12.1%. In addition, we found a higher ratio of false positives to true positives for the TE(2) sequence using the TE(2) ground truth, compared to the TE(1) equivalent. Infratentorially, differences in the relative accuracy did not reach statistical significance.nnnCONCLUSIONnThe presented methodology may be useful in assessing the value of new clinical imaging protocols or techniques in the context of replacing existing ones, when the absolute ground truth is not available, and in determining changes in disease progression in follow-up studies. Our results suggest that the sequence with shorter TE should be preferred because it generates relatively fewer false positives. The finding is consistent with results of previous computer simulation studies.

Multiple Sclerosis and Other Demyelinating Diseases

Multiple sclerosis (MS) is the most common idiopathic demyelinating disease of the central nervous system (CNS). Although partially effective treatments are now available, MS represents a major target for research into the development of disease-modifying therapies that specifically focus on the neuroimmune pathways of myelin and tissue damage that currently are incompletely understood. Multiple sclerosis is considered to be an example of development of autoimmunity to self-antigens within the CNS through multiple initiating events that include infections and other environmental factors. The direct or indirect induction of immune responses against CNS antigens includes chemotaxis of T cells, B cells, and monocytes, and production of immunoglobulin responses, each of which can act as an effector of myelin damage that occurs in distinct histological patterns. Because a specific cause for MS has not been identified, much MS research has focused on CNS immune responses triggered by unidentified insults that in turn trigger inflammation-mediated cascades of myelin and cellular damage that are likely relevant to other neurodegenerative diseases. This chapter discusses current the epidemiology, etiology, pathophysiology, animal models, virus models and recent advances in the neuroimmunology of MS from the perspective of the potential for development of newer therapies for MS and other inflammatory CNS diseases.