Biomedical subjects
Publications and source records attributed to D E Goodkin.
About 350,000 persons in the United States have multiple sclerosis, and primary care physicians are often called on to provide symptomatic therapy for these patients. We review our current pharmacologic approach to the management of multiple sclerosis exacerbations and the symptoms of spasticity, fatigue, bladder and bowel involvement, neurobehavioral complaints, pain syndromes, dystonic spasms, and tremor and ataxia.
A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic. Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients' Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity. We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.
The design and conduct of a randomized, double-blinded, placebo-controlled, multicenter, phase III study of recombinant interferon beta-1a (IFN-beta-1a) as treatment for exacerbating-remitting MS are described, as are baseline characteristics of the study population. The purpose of the study was to determine if 6.0 x 10(6) IU (30 micrograms) of IFN-beta-1a, administered by weekly intramuscular (i.m.) injections, was effective in delaying the onset of sustained disability. The primary outcome measure was time to onset of treatment failure, defined as a worsening on the Kurtzke Expanded Disability Status Scale (EDSS) of greater than or equal to 1.0 point compared with baseline, persisting for at least 6 months. An intent-to-treat design was used. The primary outcome measure was analyzed using the Mantel-Cox log-rank statistic and Kaplan-Meier survival curves. Secondary outcomes included quantitative measures of upper and lower extremity function, neuropsychological test performance, functional and quality of life assessments and several measures derived from annual brain MRI studies. Entry criteria included prestudy exacerbation rates of at least 0.67 per year and EDSS scores of 1.0-3.5. A total of 301 MS patients were randomly assigned to receive weekly i.m. injections of IFN-beta-1a or placebo. The average age of the study population at entry was 37 years; 92% were Caucasian and 73% were women. The mean prestudy disease duration was 6.5 years, mean prestudy exacerbation rate was 1.2 per year and the mean EDSS score was 2.3. The randomization yielded well-balanced treatment arms. Various aspects of the study are discussed, including: (1) the decision to focus study design on sustained disability; (2) the rationale for the treatment regimen; (3) measures taken to assure the reliability of the primary outcome measure; and (4) a description of the secondary outcome measures.
Cognitive impairment affects 40 to 70% of patients with multiple sclerosis (MS), but its occurrence cannot be predicted from knowledge of the individual patient's age, level of physical disability, duration of disease, disease type, or performance on standard mental status examinations. To evaluate the usefulness of a brief screening battery, the Screening Examination for Cognitive Impairment (SEFCI), 103 community-dwelling MS patients and 32 healthy normal controls received the SEFCI and a 2-hour battery of other neuropsychological tests chosen for their sensitivity to the cognitive impairments most often observed in MS. Performance on the SEFCI correctly identified 86% of the patients with impairment on any of the 11 measures from the longer battery, 100% of the patients with impairments in at least three cognitive domains, and 90% of the patients without cognitive impairment. Because the SEFCI is sensitive, specific, and easily administered and scored, it should aid the physician in deciding whether to refer an MS patient for a complete evaluation.
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OBJECTIVES: To determine the frequency of serum cobalamin (Cbl) deficiency and to clarify the biologic importance of low screening Cbl levels in patients with multiple sclerosis (MS) and idiopathic myelopathy (MYL). BACKGROUND: A significant association between Cbl metabolism and MS has been postulated based on the observations that patients with MS have lower serum Cbl levels, higher unsaturated Cbl binding capacities, and a higher prevalence of macrocytosis than do normal controls. Whether such observations have biologic importance as documented by abnormal accumulation of metabolites that would result from Cbl deficiency has not yet been determined. METHODS: Serum Cbl and folate levels were determined in 208 consecutively evaluated patients seen in an outpatient MS clinic setting during a 7-month period. Necessary blood samples were obtained for 165 of these patients. One hundred twenty-five patients had clinically definite MS, 31 had clinically probable MS, and nine had MYL. Serum methylmalonic acid (MMA) and homocysteine (HCY) concentrations, which rise in biologically severe Cbl deficiency, were subsequently determined in all patients whose Cbl levels were lower than 301 pg/mL. RESULTS: A Cbl level lower than 301 was found in 32 of 156 patients with either clinically definite MS or clinically probable MS but in none of the patients with MYL. Elevated MMA or HCY levels were found in seven of 32 patients with either clinically definite MS or clinically probable MS, six of whom had an elevated HCY level and one of whom had elevated HCY and MMA levels. CONCLUSIONS: Despite the observation that 32 (19.4%) of 165 of these patients with MS and MYL had screening Cbl levels less than 301 pg/mL, only seven (4.2%) of 165 had elevated MMA or HCY levels. The frequency of biologically severe Cbl deficiency in these patients with MS and MYL was very low.
During the past year, two new agents have been demonstrated to be of value in multiple sclerosis. The first agent, a form of recombinant interferon beta (Betaseron; Berlex Labs, Cedar Knolls, NJ), is effective in reducing relapses and also prevent accumulation of brain lesions over time, but has no demonstrated effect on the accumulation of disability over time. The second agent, methylprednisolone (Solumedrol; The Upjohn Co., Kalamozoo, MI), administered in megadose pulses over several days and followed by an oral prednisone taper, reduces the conversion rate of patients with optic neuritis to multiple sclerosis by approximately 50% over 2 years compared with placebo or oral prednisone alone. The mechanisms by which these agents exert their benefits are incompletely understood, but both have complex, relatively widespread effects on the immune systems. The demonstration of efficacy for both of these agents represent landmarks in the search for an effective treatment for multiple sclerosis; both agents seem to provide prophylaxis against future relapses, and methylprednisolone seems to delay the development of the disease. Their introduction into the clinical environment will undoubtedly have a profound effect on the day-to-day care of multiple sclerosis patients as well as the designs of future basic and clinical research. Other new therapies that have substantial potential for benefit in multiple sclerosis but require further definitive study include intramuscular copolymer 1 for relapsing disease and low-dose oral methotrexate and booster doses of intravenous cyclophosphamide for chronic progressive disease.
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Corticosteroids, corticotropin, azathioprine, cyclophosphamide, and IFN-beta 1b have each had a substantial effect on the care of patients with multiple sclerosis and the design of subsequent clinical trials of experimental therapeutics for MS. The use of MRI scanning and more sensitive clinical outcome measures will possibly enable us to complete clinical trials in a fraction of the time required for earlier trials. The release of Betaseron, which favorably alters the attack rate in ambulatory patients with relapsing-remitting MS has brought a sense of renewed optimism to patients with MS, their families, and their care providers. New promising therapies for chronic progressive MS and biologic products possibly capable of enhancing the effects of IFN-beta 1b in patients with relapsing MS are setting the stage for additional important therapeutic advances in this disease.
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OBJECTIVE: To present a detailed description of (1) the study design of this ongoing trial, (2) advantages of using a composite outcome variable instead of multiple individual outcome measures, (3) treatment group characteristics at baseline, and (4) observed short-term methotrexate (MTX) toxicity. DESIGN: Randomized, double-masked, placebo-controlled intervention study. SETTING: Referral-based outpatient multidisciplinary multiple sclerosis (MS) clinic. PATIENTS: Participation offered to all clinically definite chronic progressive multiple sclerosis (CPMS) patients attending clinic ages 21 to 60, disease duration > 1 year, Expanded Disability Status Scale (EDSS) score 3.0 to 6.5 (ambulatory with moderate disability). Patients first stratified by EDSS 3.0 to 5.5 and 6.0 to 6.5, then randomized to MTX or placebo treatment. INTERVENTION: Weekly oral low-dose (7.5 mg) MTX or identical-appearing placebo for 2 years followed by a 1-year observation period. MAIN OUTCOME MEASURES: Sample size calculations undertaken prior to enrolling patients based upon a composite outcome variable consisting of designated change in any of the following functional measures: (1) EDSS, (2) Ambulation Index (AI), (3) Box and Block Test (BBT), and (4) 9-Hole Peg Test (9HPT). RESULTS: (1) Treatment group characteristics were comparable at baseline, (2) no patient has been withdrawn for adverse effects or lost to follow-up, (3) no significant short-term MTX toxicity has been observed. CONCLUSIONS: (1) The use of a composite outcome measure in the design of MS clinical trials is a promising alternative to multiple individual outcome measures that are relatively insensitive to detecting clinical change, (2) low-dose oral weekly MTX does not appear to be associated with significant short-term toxicity in CPMS. Conclusions regarding therapeutic efficacy of MTX in MS must await completion of this clinical trial.
Magnetic resonance imaging (MRI) may demonstrate disease activity in a number of ways in patients with multiple sclerosis. Newly appearing MRI lesions, gadolinium-enhancing lesions, and enlargement of preexisting lesions are frequently taken as evidence of disease activity. Furthermore, serial MRI studies have been stated to be more sensitive than repeated neurologic examinations in detecting disease activity. We assessed the validity of using lesion enlargement as a measure of disease activity by repeatedly measuring the area of all MRI lesions in four patients with multiple sclerosis. The size-frequency distribution in all patients was similar, with 80% of the lesions measuring less than 0.67 cm2. The median coefficient of variation for three successive lesion measurements was inversely related to lesion area, ranging from 22.6% for the more common smaller lesions (less than 0.67 cm2) to 12.1% for larger lesions. Based on these coefficients of variation, a change in a particular lesion exceeding 45.2% for a baseline lesion smaller than 0.67 cm2 and 24.2% for a baseline lesion greater than or equal to 0.67 cm2 should be required to exclude a change due to measurement variability. It remains necessary to determine the number of lesions that must change when multiple lesions are present in the baseline MRI to reliably exclude chance occurrence when establishing MRI-evident disease activity. Guidelines for determining these criteria are presented, as are the limitations inherent in the statistical model employed to make these determinations.
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We determined inter- and intrarater Kurtzke Expanded Disability Status Scale (EDSS) scoring agreement for four trained examining physicians who evaluated 10 clinically stable multiple sclerosis patients. These patients had previously been determined to have EDSS scores of 1.0 to 3.5 and were scheduled to participate in a funded clinical trial of intramuscular recombinant interferon-beta. Intrarater reliability was greater than interrater reliability for scoring the EDSS and all of its component functional systems scores (FSS). Specifically, individual examiners were able to reproduce three serial examination scores on the same patient on the same day (intrarater agreement) within 1.0 EDSS or 2.0 individual FSS points. Reproducible scoring across examiners (interrater agreement), however, could only be accomplished within 1.5 EDSS or 3.0 individual FSS points. Additionally, the interrater scoring variability in our patients is greater than that previously reported for patients with higher EDSS scores. We conclude that clinical trials that employ the EDSS as an outcome measure of treatment efficacy should include inter- and intrarater agreement data for all examining physicians. Most importantly, studies using a single examining physician to evaluate individual patients throughout the course of a clinical trial will require less change in the EDSS to reliably measure disease activity than will studies using more than one examining physician to evaluate individual patients throughout the trial.
The efficacy of azathioprine in the treatment of multiple sclerosis was assessed by meta-analysis of the results of all published blind, randomised, controlled trials. 793 patients were enrolled in 5 double-blind and 2 single-blind studies. After 1 year of treatment, the increase in Kurtzke disability status score was no different in treated and control groups, but at 2 years there was a small difference (-0.22; 95% confidence interval [CI] -0.43, 0.003) in favour of azathioprine treatment; this difference was sustained, but not increased, after 3 years. The probability of freedom from any relapse during 1, 2, and 3 years' treatment was significantly greater in the azathioprine-treated group (relative odds over 3 years 1.97; 95% Cl 1.27, 3.04), but it is debatable whether the slight clinical benefits of azathioprine outweigh its side-effects.