Donald E. Goodkin

Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis

The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with clinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including “monosymptomatic” disease suggestive of MS, disease with a typical relapsing‐remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as “clinically definite” and “probable MS” are no longer recommended. The outcome of a diagnostic evaluation is either MS, “possible MS” (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or “not MS.”

Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis

Background: Interferon beta is an effective treatment for relapsing multiple sclerosis(MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment. Objectives: To determine the incidence and biological significance of NAB to interferon beta-1a (IFN-β-1a; Avonex; Biogen, Cambridge, MA) in MS patients. Methods: A two-step assay for NAB to IFN-β-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-β-1a, and from patients in an ongoing open-label study of IFN-β1a. The biological significance of NAB to IFN-β-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and β-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-β-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-β-1a with the incidence in MS patients who had used only IFN-β-1b. Results: In patients in the open-label study, development of NAB to IFN-β-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in β-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-β-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-β-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-β-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-β-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. Conclusions: NAB directed against IFN-β have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-β is significantly greater with IFN-β-1b therapy compared with IFN-β-1a therapy. Treatment decisions in MS patients treated withIFN-β should take into account development of NAB.

A longitudinal study of brain atrophy in relapsing multiple sclerosis

Objective: To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of interferon β-1a (Avonex). Methods: All subjects had mild to moderate disability, with baseline expanded disability status scores ranging from 1.0 to 3.5, and at least two relapses in the 3 years before study entry. Atrophy measures included third and lateral ventricle width, brain width, and corpus callosum area. Results: Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years. Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years. Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width. Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement. Conclusion: In patients with relapsing MS and only mild to moderate disability, significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions. Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.

Neuropsychological effects of interferon β-1a in relapsing multiple sclerosis

Cognitive dysfunction is common in multiple sclerosis (MS), yet few studies have examined effects of treatment on neuropsychological (NP) performance. To evaluate the effects of interferon β‐1a (IFNβ‐1a, 30 μg administered intramuscularly once weekly [Avonex]) on cognitive function, a Comprehensive NP Battery was administered at baseline and week 104 to relapsing MS patients in the phase III study, 166 of whom completed both assessments. A Brief NP Battery was also administered at 6‐month intervals. The primary NP outcome measure was 2‐year change on the Comprehensive NP Battery, grouped into domains of information processing and learning/memory (set A), visuospatial abilities and problem solving (set B), and verbal abilities and attention span (set C). NP effects were most pronounced in cognitive domains vulnerable to MS: IFNβ‐1a had a significant beneficial effect on the set A composite, with a favorable trend evident on set B. Secondary outcome analyses revealed significant between‐group differences in slopes for Brief NP Battery performance and time to sustained deterioration in a Paced Auditory Serial Addition Test processing rate, favoring the IFNβ‐1a group. These results support and extend previous observations of significant beneficial effects of IFNβ‐1a for relapsing MS. Ann Neurol 2000;48:885–892

Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of Depression in multiple sclerosis

This study compared the efficacy of 3 16-week treatments for depression in 63 patients with multiple sclerosis (MS) and major depressive disorder (MDD): individual cognitive-behavioral therapy (CBT), supportive-expressive group therapy (SEG). and the antidepressant sertraline. Significant reductions were seen from pre- to posttreatment in all measures of depression. Intent-to-treat and completers analyses using the Beck Depression Inventory (BDI; A. T. Beck, C. H. Ward. M. Medelson. J. Mock, & J. Erbaugh, 1961) and MDD diagnosis found that CBT and sertraline were more effective than SEG at reducing depression. These results were largely supported by the BDI-18, which eliminates BDI items confounded with MS. However, the Hamilton Rating Scale for Depression (M. Hamilton, 1960) did not show consistent differences between treatments. Reasons for this inconsistency are discussed. These findings suggest that CBT or sertraline is more likely to be effective in treating MDD in MS compared with supportive group treatments.

The psychosocial impact of multiple sclerosis: exploring the patient's perspective.

This study examined subjective patient experiences of the psychosocial consequences of multiple sclerosis (MS). Fifty patients were interviewed regarding the effects MS had on their lives and interpersonal relationships. These statements were collated and administered with a 5-point Likert scale to 94 MS patients. The responses were subjected to factor analysis. Three areas of subjective patient experience of the psychosocial consequences of MS emerged: demoralization, benefit-finding, and deteriorated relationships. Of particular interest was benefit-finding, which included a deepening of relationships, enhanced appreciation of life, and an increase in spiritual interests. Although benefit-finding was related to adaptive coping strategies such as positive reappraisal and seeking social support, it was unrelated to depression and was related to higher levels of anxiety and anger. These findings indicate that benefit-finding is a substantial and poorly understood part of the illness experience for MS patients.

Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis

Background and Objective: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-la (IFNβ-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as≥1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance. Methods: Post hoc analyses related to disability outcomes using data collected during the double-blind, placebo-controlled phase III clinical trial. Results: (1) Clinical efficacy related to disability did not depend on the definition of disability progression. A significant benefit in favor of IFNβ-1a was observed when ≥2.0 point worsening from baseline EDSS was required or when worsening was required to persist for ≥1.0 year. (2) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFNβ-1a recipients who reached the primary study outcome. (3) Significantly fewer IFNβ-1a recipients progressed to EDSS milestones of 4.0 (relatively severe impairment) or 6.0(unilateral assistance needed to walk). (4) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFNβ-1a treatment. Conclusions: The primary clinical outcome for the IFNβ-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFNβ-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.

Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis.

OBJECTIVE To 1) compare monthly serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of MMP-type 1 (TIMP-1) in patients with relapsing-remitting MS (RRMS) versus healthy controls and 2) determine the relationship among monthly serum levels of MMP-9 and TIMP-1 and MRI activity. BACKGROUND Activated T-cells and macrophages secrete MMPs that may facilitate their migration across vascular subendothelial basement membranes into the CNS. The serum concentration of MMP-9 is reported to be higher in patients with RRMS than healthy controls. METHODS Monthly evaluations including gadolinium-enhanced (Gd+) brain MRI and measures of serum MMP-9 and TIMP-1 were performed for up to 15 months in 24 patients with RRMS and for up to 4 months in 10 controls. RESULTS Serum MMP-9 but not TIMP-1 levels are elevated in RRMS patients compared to healthy controls (p = 0.025, p = 0.61). In a univariate analysis, high MMP-9 and low TIMP-1 levels precede appearance of new Gd+ lesions (respectively; odds ratio = 3.3, p = 0.008; odds ratio = 2.2, p = 0.086). In a multivariate analysis, in comparison to months when MMP-9 is low and TIMP-1 high, MRI scans obtained the month following high MMP-9 and low TIMP-1 serum concentrations are more likely to report new Gd+ lesions (p = 0.0006, odds ratio = 21.5). CONCLUSION An increase in the activity of matrix metalloproteinase-9 (MMP-9) relative to tissue inhibitor of MMP-type 1 (TIMP-1) may be related to formation of new MS lesions, suggesting that serum levels of MMP-9 and TIMP-1 may be surrogate markers of disease activity in relapsing-remitting MS.

Telephone-administered cognitive-behavioral therapy for the treatment of depressive symptoms in multiple sclerosis.

This study examined the efficacy of an 8-week telephone-administered cognitive-behavioral therapy (CBT) for the treatment of depressive symptomatology in multiple sclerosis (MS) patients. The treatment, Coping with MS (CMS), included a patient workbook designed to structure the treatment, provide visual aids, and help with homework assignments. Thirty-two patients with MS, who scored at least 15 on the Profile of Mood States Depression-Dejection scale, were randomly assigned to either the telephone CMS or to a usual-care control (UCC) condition. Depressive symptomatology decreased significantly in the CMS condition compared with the UCC condition. Furthermore, adherence to interferon beta-1a, a disease-modifying medication for the treatment of MS, was significantly better at the 4-month follow-up among patients who received CMS as compared with those in the UCC condition.

A serial study of new MS lesions and the white matter from which they arise

Objective: To compare MS normal-appearing white matter (NAWM) where new gadolinium-enhancing (Gd+) lesions do and do not arise. Methods: A total of 22 relapsing-remitting MS patients and 11 healthy control subjects completed as many as 12 monthly brain MRI sessions. Quantitative measures of gadolinium enhancement (GDR), water proton density (PDN), water proton T2 relaxation time constants (T2), magnetization transfer ratio (MTR), and T1-weighted signal intensity (T1N) were followed serially in healthy control and MS NAWM. Results: A total of 129 new Gd+ lesions were identified in 11 patients. PDN, T2, MTR, and T1N were diffusely abnormal in MS NAWM. NAWM regions in which new Gd+ lesions arose have increased GDR, PDN, and T2, and reduced MTR and T1N compared with contralateral homologous NAWM regions in which no new Gd+ lesions arose. Differences between these NAWM regions preceded lesion appearance for at least several months. After lesions became visible, GDR returned to baseline within 2 months, and PDN and MTR had larger residual abnormalities than T2 or T1N. Conclusions: Quantitative MRI measures are diffusely abnormal in MS NAWM. These measures are, on average, more abnormal in NAWM regions in which new Gd+ lesions arise. After the appearance of Gd+ lesions, measures of PDN and MTR may provide more appealing markers of relatively irreversible tissue damage than measures of T2 and T1N.