Fred D. Lublin

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis.

Management of patients receiving interferon beta-1b for multiple sclerosis Report of a consensus conference*

Article abstract-Results of a double-blind, placebo-controlled study in ambulatory patients with relapsing-remitting MS showed that interferon beta-1b reduced the rate of exacerbations by one-third compared with placebo and limited new disease activity in the brain as evidenced by MRI. Interferon beta-1b, administered subcutaneously at a dosage of 0.25 mg (8 million IU) every other day is indicated for the treatment of ambulatory patients with relapsing-remitting MS. Interferon beta-1b may help a wider range of patients, but it should be prescribed only for patients with a diagnosis of clinically definite or laboratory-supported definite MS. The decision to treat a patient with interferon beta-1b should be individualized; that is, based on each patients clinical presentation and course of MS. The most common adverse effects include (1) injection-site reactions and (2) flulike symptoms, which are generally manageable and usually abate after the first few months of treatment. Spasticity may increase. Patients with severe depression or suicidal ideation should be monitored carefully, and symptomatic treatment should be pursued. Interferon beta-1b is contraindicated in pregnant and nursing women. Interferon beta-1b is effective in reducing the progression of total disease burden as seen on MRI in patients with MS. Its use is relatively straightforward and generally does not require alteration in the symptomatic treatment of MS. Patient education and support remain the mainstays of maintaining compliance through the early phases of therapy. NEUROLOGY 1996;46: 12-18

Linomide in relapsing and secondary progressive MS: Part II: MRI results

Objective: To determine the safety and efficacy of roquinimex (linomide) in the management of relapsing-remitting and secondary progressive MS as monitored by MRI. Background: Preclinical studies and several short term randomized trials of linomide suggested clinical and MRI-measured benefits with acceptable risk for closely followed MS patients. Methods: The North American Linomide Trial formally screened 853 individuals for relapsing or secondary progressive, clinically definite MS; recent disease activity or progression; and an Expanded Disability Status Scale score at entry of 3.0 to 6.5 inclusive. MRI was obtained on 811 subjects at pre-enrollment, 718 cases at enrollment, and then at three monthly intervals until the trial was prematurely terminated for unacceptable toxicity. Results: Enhancement was found on 40.2% of 718 entry scans. Statistically robust correlations were found between clinical demographic data and several entry MRI measures including CSF volume, a reflection of brain atrophy. Assessment of the effect of treatment on MRI-measured disease was limited by early trial termination. However, active treatment for 3 months reduced the proportion of patients with one or more enhancements. An exploratory analysis suggested that 2.5 mg was the most active of three doses tested in limiting the total volume of enhanced tissue, the proportion of MRI-defined lesions designated as “black holes,” and by a novel MRI composite disease measure. Conclusions: The short term signature of the effect of linomide on MRI-measured aspects of the disease suggests that safer drugs of this class might be useful in the management of MS. The use of a composite index of the heterogeneous nature of the pathology of MS as captured by MRI may have merit as an outcome measure in clinical trials.

The PROMiSe trial: baseline data review and progress report

The PRO MiSe trial is a multinational, multicentre, double-blind, placebo -controlled trial evaluating the effects of glatiramer acetate treatment over 3 years in patients with primary progressive multiple sclerosis (PPMS). A total of 943 patients were enrolled, and all those remaining on-study had completed at least 24 months as of O ctober 2002. Baseline clinical and MRI character istics and select correlations are reported here. A total of 3.9% of patients exhibited confirmed relapse over 1904 patient-years of exposure, indicating success of efforts to exclude relapsing MS types. O f the 26.3% of patients who have prematurely withdrawn from the study, only 36% discontinued after meeting the study primary endpoint of disease progression. The progression rate in patients in the low Expanded Disability Status Scale (EDSS) stratum (3.0-5.0) observed thus far is markedly lower than the 50% annual progression rate estimate used for determining size and statistical power of the trial; progression was observed in 16.1% of patients with 12 months of study exposure. These early findings raise some concern about the ability of the trial to demonstrate a significant treatment effect, and suggest that the short-term natural history of PPMS may not be as aggressive as previously assumed.

The cellular response of JC virus T-antigen-induced brain tumor implants to a Murine intra-ocular model

In order to define the immunologic response to central nervous system tumors in a controlled fashion, we compared xenogeneic, allogeneic and syngeneic transplants of JC virus-induced neural tumor cell aggregates implanted into anterior ocular chambers of mice. Semiquantitative assessment of the level of leukocyte common antigen (CD45) of the transplants by immunohistochemistry was used to gauge rejection. Reticulin staining was used to monitor vascularization. Immunoreactivity to the viral oncoprotein, T-antigen, was confirmed by immunohistochemistry and immunoprecipitation/Western blot analysis. The results demonstrated that transplants were viable at all time-points and developed vascularization as early as three days after transplantation. Xenotransplants, 13-days post-transplantation, and allogeneic transplants, 25 days post-transplantation were infiltrated with polymorphonuclear leukocytes. Fewer CD45 positive cells were demonstrated in syngeneic transplants. High levels of JCV T-antigen stimulated rejection in syngeneic transplants. These results establish a model for further investigation of the natural and induced immunologic response to central nervous system tumors.

Chapter 2 Clinical Features and Subtypes of Multiple Sclerosis

Publisher Summary This chapter describes clinical features and subtypes of multiple sclerosis (MS). MS is a disorder of the immune system with an impact on the central nervous system (CNS) and thus can produce any constellation of symptoms and signs that might occur from a lesion or lesions in areas of the brain, spinal cord, and optic nerves. Symptoms and signs in MS reflect primarily—but not exclusively—white-matter involvement, although the body of data implicating neuronal injury is growing. Variability of signs and symptoms—in type and in timing—is a hallmark of MS. A constellation of clinical problems, some more frequently seen than others, occur in the disease, generally different in different individuals and different over time in the same individual. Although specific signs and symptoms may not be attributable to specific pathological conditions, the clinical features of MS are best understood in the context of the knowledge of the neurophysiological and neuropathological consequences of inflammatory, primarily demyelinating, disease.

Quantitative functional MRI of the visual cortex as a function of luminance contrast at 1.5 T

Examined the BOLD signal changes in primary visual cortex as a function of luminous contrast at 1.5 T in 4 normals and 2 patients with multiple sclerosis (MS) disease. Echo planar T2* weighted BOLD imaging experiments were performed using a 1.5 T Imager. Ten axial slices through the calcarine fissure were obtained. The imaging series consisted of alternations between a 20-second epoch of dark screen (rest) and a 20-second epoch of a flickering checkerboard (activation) repeated 6 times. Each imaging series utilized a stepwise, graded increase of eight different luminance contrast levels. A paired t-test was used to compare the control condition with each activation condition. The data shows a linear trend in the number of fMRI activated voxels within the visual cortex with increasing luminous contrast in normals and MS patients. This study demonstrates quantifiable changes in BOLD signal and a linear increase in activated voxels within the primary visual cortex with increasing luminous contrast.