A phase II study of i.v. methylprednisolone in secondary-progressive multiple sclerosis.

OBJECTIVE: To compare the tolerability and efficacy of two doses of i.v. methylprednisolone in patients with secondary-progressive MS. METHODS: I.v. methylprednisolone administered in high or low dose every other month for up to 2 years to 108 patients with secondary-progressive MS. RESULTS: No significant difference in efficacy with the primary outcome, a comparison of the proportions of patients in each treatment group who experienced sustained progression of disability. A relative treatment effect was detected with the high-dose regimen as measured by the preplanned secondary analysis, a comparison of time to onset of sustained progression of disability. Drug-related adverse events were observed more frequently in high-dose recipients but serious drug-related adverse events were uncommon, and cessation of study drug was only required in one patient. CONCLUSION: The results of the secondary analysis of this study suggest that a phase III trial of corticosteroids for secondary-progressive MS is warranted.

Tissue plasminogen activator-assisted surgical excision of subfoveal choroidal neovascularization in age-related macular degeneration: a randomized, double-masked trial.

OBJECTIVE: To determine whether lysing subretinal fibrin with tissue plasminogen activator (t-PA) before excising subfoveal choroidal neovascularization improves visual acuity in patients with age-related macular degeneration. DESIGN: Randomized, double-masked trial. PARTICIPANTS: Eighty eyes of 80 patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration were studied. INTERVENTION: Each eye underwent pars plana vitrectomy and received a subretinal injection of t-PA or balanced salt solution (BSS) before the neovascular membrane was excised. Preoperative and postoperative protocol refraction, ophthalmic examination, color photography, and fluorescein angiography were performed in all 80 eyes. MAIN OUTCOME MEASURES: Visual acuity and fluorescein angiographic evidence of leakage after 1 year. RESULTS: Visual acuity did not differ between the t-PA group (n = 40) and the BSS group (n = 40), and median best-corrected visual acuity was 20/320 for both groups (P = 0.38). Changes in visual acuity from baseline were also equal, with a median loss of 1 line in each group (P = 0.78). Patients whose initial visual acuity was 20/250 or less were more likely to improve by 2 or more lines (P = 0.01) and less likely to lose 2 or more lines (P < 0.001). Patients with choroidal neovascularization of at least 4 disc areas were more likely to improve by 2 or more lines (P = 0.02) and less likely to lose 2 or more lines (P < 0.001). After 1 year, choroidal neovascularization was present in seven of the t-PA eyes and in eight of the BSS eyes (P = 0.78). CONCLUSIONS: With current surgical techniques, the use of t-PA before surgical excision of subfoveal choroidal neovascularization is of no visual or anatomic benefit to patients with age-related macular degeneration.

Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs.

We monitored 56 patients with chronic progressive multiple sclerosis (MS) who participated in a clinical trial of weekly, low-dose oral methotrexate with annual gadolinium-enhanced MRIs of the brain (Gd + MRI). Not of these patients had clinical exacerbations during the 8 months preceding study entry. We also monitored 35 of the patients with serial Gd + MRIs every 6 weeks for 6 months. We observed a treatment effect, measured by absolute change in T2-weighted total lesion area (T2W-TLA), in the cohort that completed 6-week scans. We found change in T2W-TLA in this cohort to be significantly related to sustained change in performance on the nine-hold peg test but not to sustained change on the Expanded Disability Status Scale. Gadolinium enhancement of lesions on 6-week and annual scans was uncommon. Prestudy exacerbation frequency appears to be an important consideration in designing future clinical trials in patients with secondary and primary progressive MS.

Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis.

Interferon-beta decreases the relapse rate, relapse severity, progression of neurological disability, and development of new brain lesions observed with brain magnetic resonance imaging in relapsing-remitting multiple sclerosis patients. The mechanism of action of this effect is presently unknown. This study was based on the hypothesis that immunoregulatory effects of interferon-beta may underlie its demonstrated clinical efficacy. The objective of the study was to determine the effect of interferon-beta-1a on the expression of interleukin-10, a cytokine that strongly inhibits cell-mediated immune responses. Interferon-beta-1a induced accumulation of interleukin-10 messenger RNA and protein secretion by cultured peripheral blood mononuclear cells. The observed in vitro effects were similar for healthy control subjects and multiple sclerosis patients. Intramuscular injections of interferon-beta-1a increased serum levels of interleukin-10 at 12 and 24 hours following the injection. Greater increases were induced with 12 x 10(6)-IU than 6 x 10(6)-IU injections. The effect of interferon-beta-1a was relatively specific for interleukin-10, as treatment with interferon-beta-1a did not result in accumulation of transforming growth factor-beta messenger RNA. Upregulation of interleukin-10 represents a possible mechanism of action of interferon-beta's therapeutic effect in relapsing-remitting multiple sclerosis, and has implications for therapy of other autoimmune diseases.

The Ohio Bicycle Injury Study.

To understand bicycle injuries and determine how to prevent them, we designed prospectively a descriptive study of bicycle-crash-related admissions in July 1993 to 10 major Ohio hospitals that admit child trauma patients. All patients studied were under the age of 16. In the 52 cases (38 male, 73%), impact with another vehicle accounted for 23 (44%) crashes. Of these crashes, only three (13%) were caused by definite motor vehicle operator error, and all 20 (87%) of the remaining motor vehicle-bicycle collisions were caused by bicyclist error, including 10 (43%) caused by bicyclists failing to yield properly at an intersection. Head injuries were the primary cause of morbidity in 29 (56%) cases. No child was wearing a bicycle helmet at the time of the crash. Efforts to reduce childhood morbidity from bicycle-related crashes should focus on helmet education and safe riding skills.

Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis.

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.

Low-dose (7.5 mg) oral methotrexate for chronic progressive multiple sclerosis. Design of a randomized, placebo-controlled trial with sample size benefits from a composite outcome variable including preliminary data on toxicity.

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.

Screening for the detection of coronary artery disease by using the exercise tolerance test in a preventive medicine population.

We designed this study to identify patients with coronary artery disease (CAD), employing the exercise tolerance test, and to develop further criteria for ordering the exercise tolerance test in the preventive medicine population of the Cleveland Clinic Foundation. During 1987-1988 1,930 patients not known to have CAD were referred from the Department of Preventive Medicine for exercise tolerance tests as part of their periodic physical exams. We hypothesized that age was a major risk factor and ordered most (86.4%) tests on this basis: at age 40 and every two years after age 50. Twenty-five cases of CAD (25/1,930 or 1.3%) were found. One of 297 women was found to have CAD (0.3%). Seventeen patients were treated surgically and eight medically. Using age as an indication for testing detected 23 of 25 cases (92%). We compared the group with normal or nondiagnostic exercise tolerance tests and presumed not to have CAD (1,905 patients, median age 48) with the group with CAD (25 patients, median age 59). Age greater than 40, a total cholesterol level over 240 mg/dL, triglyceride level over 250 mg/dL, a total cholesterol to high-density lipoprotein ratio greater than 4.5, and a history of chest pain of any type were all significantly related to the presence of CAD. Testing men older than forty with two or more CAD risk factors, as has been recommended, would have resulted in finding five of the 25 cases (20%). Testing only patients who complained of any type of chest discomfort would have resulted in detecting 14 of the 25 cases (56%).(ABSTRACT TRUNCATED AT 250 WORDS)

Intracavernous injection therapy: analysis of results and complications.

Experience with 100 patients who used intracavernous injection therapy with a combination of papaverine with or without phentolamine for 29 months is analyzed in detail. The largest group of patients had vasculogenic erectile failure (56%). At the end of followup 50% of the patients were no longer performing injection. Those who discontinued injection therapy were slightly older and had more vasculogenic erectile failure. The nonfibrotic complications were mild in all instances and did not result in discontinuation of injection therapy. These complications consisted of small hematomas in 20.9% of the patients, mild discomfort in 13.6% and mild liver enzyme abnormalities in 9.8%. No episode of priapism or infection occurred during therapy. Fibrotic complications consisted of nodules or plaques, and correlated significantly with the number of months on injection and the number of injections. At 12 months the fibrotic complication rate was 31 +/- 8.6%. Our study suggests caution regarding the long-term complication rate of intracavernous injection therapy with these compounds and underscores the importance of routine followup examinations. While injection therapy is an effective form of treatment for erectile failure, it is not a satisfactory alternative for many patients and is associated with a significant fibrotic complication rate.

Effect of empiric antiarrhythmic therapy in resuscitated out-of-hospital cardiac arrest victims with coronary artery disease.

The effect of empiric antiarrhythmic therapy with quinidine and procainamide on long-term mortality was examined in 209 patients with coronary artery disease resuscitated after out-of-hospital cardiac arrest. The antiarrhythmic agent used was determined by the patient's private physician without knowledge of the study ambulatory electrocardiogram. Of the 209 patients, procainamide was prescribed in 45 (22%), quinidine in 48 (23%) and no antiarrhythmic therapy in 116 (55%). Digoxin therapy was initiated in 101 patients. The 2-year total survival rate for the quinidine, procainamide and nontreated patients was 61, 57 and 71% (p less than 0.05), and for sudden death was 69, 69 and 89% (p less than 0.01), respectively. These observations suggest that empiric antiarrhythmic therapy in survivors of out-of-hospital cardiac arrest did not affect total mortality and was associated with an increased frequency of sudden death.

Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer.

Specimens from 84 radical cystectomies for bladder carcinoma performed between January 1984 and July 1986 were reviewed to characterize the involvement of the prostate with transitional cell carcinoma. Whole-mount sectioning of the prostate was performed at 4 mm. intervals and processed in the same manner as radical prostatectomy specimens. A total of 36 patients (43 per cent) had transitional cell carcinoma of the prostate: 94 per cent of these had prostatic urethra involvement and 6 per cent had a normal prostatic urethra but transitional cell carcinoma was present in the periurethral structures. In situ prostatic duct or acini, ejaculatory duct and seminal vesicle involvement occurred, respectively, in 67, 8 and 17 per cent of the patients with prostatic involvement. Of the patients with prostatic involvement 39 per cent had stromal invasion (22 per cent focal and 17 per cent diffuse invasion). The incidence of carcinoma in situ of the bladder neck or trigone (59 per cent), previous intravesical chemotherapy (59 per cent) and ureteral carcinoma (79 per cent) was significantly increased in patients with prostatic involvement. In patients with carcinoma in situ of the trigone or bladder neck, or in whom previous intravesical chemotherapy treatments have failed prostatic involvement should be suspected so that this disease can be detected before stromal invasion occurs.

Survival experience following Nd:YAG laser photoresection for primary bronchogenic carcinoma.

We followed the course of 47 consecutive patients with inoperable primary bronchogenic carcinoma who underwent palliative neodymium-yttrium-aluminum-garnet laser photoresection (YPR) between September 1983 and September 1986. Of these 47, 35 (74.5 percent) underwent both radiation therapy (XRT) and YPR. The survival of these 35 patients (median survival, 304 days) was compared with that of 58 who underwent only palliative palliative XRT (median survival, 253 days) from 1981 to 1983, when YPR was not yet available at our institution. There was no significant difference in overall survival (p = 0.17). A significant increase in survival (p = 0.04) was seen in 15 patients who underwent emergency palliative YPR as the initial therapeutic intervention compared with 11 patients who received emergency palliative XRT but would have received YPR had it been available at that time. A trend toward increased survival was also shown in patients who underwent endobronchial radiation therapy in addition to YPR and XRT.

Clinical characteristics and survival experience of out-of-hospital cardiac arrest victims without coronary heart disease.

Of 270 patients successfully resuscitated from out-of-hospital cardiac arrest, 16% had no evidence of coronary heart disease. In these 43 patients, other forms of heart disease were found in 81% (35/43): cardiomyopathy in 18 patients, valvular disease in six, congenital heart disease in two, and primary arrhythmia in nine. Seven patients had evidence of only pulmonary disease and one had pancreatitis as his precipitating event. Nineteen of the 43 patients (44%) had serum potassium less than 3.6 mEq l-1 in the initial blood sample after cardiac arrest. One- and two-year mortalities were 30% and 43%, respectively, for the group, which is similar to one-year (20%) and two-year (35%) mortalities of the 227 resuscitated patients with coronary heart disease. Patients who survive a sudden death experience and who have no evidence of coronary artery disease are a unique but heterogeneous group who usually have identifiable cardiac or pulmonary disease.

Predictive survival models for resuscitated victims of out-of-hospital cardiac arrest with coronary heart disease.

Resuscitated victims of cardiac arrest with coronary heart disease represent a group of patients with an accelerated mortality rate. Among 227 such patients in our follow-up study, 20% had died at 1 year and 50% were dead in slightly over 3 years. Predictors of death were related to use of digitalis, elevated blood urea nitrogen, cerebral vascular accident, previous myocardial infarction, and age. In a subset of 103 patients in whom ambulatory electrocardiographic recordings were available within 3 months of the arrest event, the presence of complexity and high-frequency ventricular premature beats (VPBs) (greater than or equal to 25/hr) were added to the mortality predictors of digitalis and diuretic therapy and elevated blood urea nitrogen. An almost equal number of patients died suddenly and nonsuddenly. Predictors of sudden death were treatment with quinidine and paired VPBs. Occurrence of arrhythmias was an important addition to the previous mortality predictors related to left ventricular dysfunction.