E. J. Orav

Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: Final report of the Northeast Cooperative Multiple Sclerosis Treatment Group

Previous studies reported that a 2- to 3-week course of IV cyclophosphamide plus adrenocorticotropic hormone (ACTH) induction can temporarily halt progressive MS for a period of 12 months in the majority of patients treated, after which reprogression occurs. The Northeast Cooperative Multiple Sclerosis Treatment Group was formed to determine whether outpatient pulse cyclophosphamide therapy could affect reprogression and whether there were differences between a modified induction regimen and the previously published regimen. Two hundred fifty-six progressive MS patients were randomized into four groups to receive IV cyclophosphamide/ACTH via the previously published versus a modified induction regimen, with or without outpatient IV cyclophosphamide boosters (700 mg/m2 every other month for 2 years). There were blinded evaluations performed every 6 months. Results demonstrate that (1) there were no differences between the modified and the published induction regimens either in terms of initial stabilization or subsequent progression; (2) without boosters, the majority of patients continued to progress; and (3) in patients receiving boosters, there was a statistically significant benefit at 24 months and 30 months (p = 0.04). Time to treatment failure after 1 year was also significantly prolonged in the booster versus the nonbooster group (p = 0.03). Age was the most important variable that correlated with response to therapy in that amelioration of disease progression occurred primarily in patients 40 years of age or younger. Boosters had a significant benefit on time to treatment failure in patients ages 18 to 40, p = 0.003, but not in patients ages 41 to 55, p = 0.97. In addition, patients with primary progressive MS had a poorer prognosis at 12 months than patients with secondarily progressive MS (p = 0.04). Our findings (1) support a role for immunosuppression in the treatment of MS, (2) begin to identify variables that may explain differences between studies of immunosuppression with cyclophosphamide in progressive MS, and (3) suggest that intermittent pulse therapy is an important method for the treatment of progressive MS and perhaps for earlier stages of MS as well.

Disease steps in multiple sclerosis : a longitudinal study comparing Disease Steps and EDSS to evaluate disease progression

Clinical assessment of outcome in Multiple Sclerosis (MS) patients is problematic since the disease can affect different aspects of the central nervous system and follow a variable course. Recently, we developed Disease Steps, a simple approach for evaluating disease progression. Previously, we found that Disease Steps was easy to use, had uniformly distributed scores and low inter-rater variability. Our current objective was to test the long-term use of Disease Steps together with the most widely utilized clinical outcome measure in MS, the Expanded Disability Status Scale (EDSS) in assessing clinical progression. Over 4 years, 804 patients were classified using both EDSS and Disease Steps. Each patient was assessed at least twice. Follow-up results included annual status and time-to-event analysis examining median staying times within a level of Disease Steps or EDSS. We found that the two scales behaved similarly and correlated strongly with each other. For both Disease Steps and EDSS, patients with milder levels of disability and relapsing-remitting disease demonstrated a higher likelihood of changing scores over time and shorter median staying times compared to more disabled, chronic progressive patients. These findings have important implications for patient selection in clinical trials and for the design of future measurements of clinical outcome in MS. Furthermore, Disease Steps may serve as a simple, practical tool for the nonspecialty neurologist to follow patients over time and serve as a guide in therapeutic decision making. Our findings further document the general progressive nature of MS when a large cohort is followed in an MS specialty clinic over time.

Longitudinal MRI in multiple sclerosis: Correlation between disability and lesion burden

We followed 18 multiple sclerosis patients clinically and with repeated brain MRIs with and without gadolinium for over 1 year. Clinical evaluations included scoring on the Kurtzke Expanded Disability Status Scale (EDSS) and the Ambulation Index (AI) scale. There was a significant correlation between the change in EDSS or AI and the change in number of lesions on MRI and between cumulative number of lesions on MRI and cumulative change in EDSS or AI. Our findings support the validity of MRI as a measure of clinical activity and potentially as an objective quantitative outcome measure for assessing response to therapy.

Double‐blind study of true vs. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis

We enrolled 116 patients in a multicenter, randomized, double-blind controlled trial of an 8-week course of 11 plasma exchange (PE) treatments in exacerbations of MS. The control group received sham PE, and both groups received identical treatment with IM ACTH and oral cyclophosphamide. Serum IgG decreased in the PE and sham treatment groups by 76% versus 22% by treatment 5, and by 64% versus 14% by treatment 11. PE also produced significant reductions in IgA, IgM, C3, and fibrinogen. PE patients had moderately enhanced improvement at 2 weeks relative to the sham group. PE patients with relapsing/remitting disease had significantly enhanced improvement at 4 weeks and there was also an increased improvement at 12 months, although this latter effect disappeared when we analyzed relapsing/remitting patients as a separate subgroup. Life table analysis showed the median time to recover preattack disability status was shorter in PE- than in sham-treated relapsing/remitting patients (4 vs. 13 weeks), a result confirmed by raw disability status scores in which there was recovery to their average preattack disability score by 3 months. PE given with ACTH plus cyclophosphamide enhances recovery from an exacerbation of disease in relapsing/remitting patients, although we observed no clear long-term benefits.

Changes in serum levels of ICAM and TNF-R correlate with disease activity in multiple sclerosis

Objective: To study the change in serum levels of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble tumor necrosis factor receptors (sTNF-Rs) in MS patients in relation to clinical disease activity and changes on brain MRI. Background: Circulating forms of adhesion molecules or soluble receptors may be released from cells as a consequence of activation and may be useful markers for inflammation. Methods: During a prospective longitudinal study over 1 year, 40 patients with MS underwent frequent imaging of the brain (22 MR images per patient) at the time of blood sampling as well as monthly neurologic examinations, and scoring on Kurtzke’s Expanded Disability Status Scale (EDSS) and ambulation index (AI). Results: Patients with relapsing–progressive disease had the highest levels of sICAM-1 whereas patients with progressive disease had the highest levels of sTNF-Rs. Fluctuations in sICAM-1 correlated with the occurrence of attacks in patients with relapsing and relapsing–progressive disease. In patients with relapsing–progressive MS, an increase in sICAM-1 level preceded the appearance of new gadolinium (Gd) enhancing lesions on MRI. In patients with progressive disease, an increase in sTNF-R p55 level preceded the appearance of new Gd enhancing lesions on MRI, whereas a decrease in sICAM-1 levels correlated with the appearance of new Gd enhancing lesions. Conclusions: These results demonstrate a linkage between sICAM-1 and sTNF-R levels and disease activity in MS. Furthermore, patients with progressive disease appear to have a different immunologic stage of disease in which immune changes are tightly linked with changes on MRI. The demonstration of a correlation in individual patients between immunologic events and changes in disease activity has implications for monitoring patients undergoing treatment and for monitoring disease progression.

Correlation of Magnetic Resonance Imaging With Immune and Clinical Measures in 45 MS Patients Receiving 20 to 24 MRI Scans Each Over a 1 ‐Year Period: 1

‘ “Works in Progress” is a feature of the Scientific Program of the American Academy of Neurology Annual Meeting. It focuses on current ongoing neuroscience research. Works i n Progress posters are selected on the basis of scientific merit, timeliness, and anticipated interest to the membership. Key aspects of the research had to have been conducted afcer October 11, 1994, and had to have been currently in progress. The posters were displayed during the Scientific Program a t this year’s annual meeting and are reproduced here i n abstract form.