Glycaemic control and risk of incident urinary incontinence in women with Type 1 diabetes: results from the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.

AIMS: To study the impact of glycaemic control on urinary incontinence in women who participated in the Diabetes Control and Complications Trial (DCCT; 1983-1993) and its observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC; 1994-present). METHODS: Study participants were women who completed, at both years 10 (2003) and 17 (2010) of the EDIC follow-up, the urological assessment questionnaire (UroEDIC). Urinary incontinence was defined as self-reported involuntary leakage of urine that occurred at least weekly. Incident urinary incontinence was defined as weekly urinary incontinence present at EDIC year 17 but not at EDIC year 10. Multivariable regression models were used to examine the association of incident urinary incontinence with comorbid prevalent conditions and glycaemic control (mean HbA1c over the first 10 years of EDIC). RESULTS: A total of 64 (15.3%) women with Type 1 diabetes (mean age 43.6 ± 6.3 years at EDIC year 10) reported incident urinary incontinence at EDIC year 17. When adjusted for clinical covariates (including age, DCCT cohort assignment, DCCT treatment arm, BMI, insulin dosage, parity, hysterectomy, autonomic neuropathy and urinary tract infection in the last year), the mean EDIC HbA1c was associated with increased odds of incident urinary incontinence (odds ratio 1.03, 95% CI 1.01-1.06 per mmol/mol increase; odds ratio 1.41, 95% CI 1.07-1.89 per % HbA1c increase). CONCLUSIONS: Incident urinary incontinence was associated with higher HbA1c levels in women with Type 1 diabetes, independent of other recognized risk factors. These results suggest the potential for women to modify their risk of urinary incontinence with improved glycaemic control. (Clinical Trials Registry no: NCT00360815 and NCT00360893).

Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications.

AIMS: The Michigan Neuropathy Screening Instrument (MNSI) is used to assess distal symmetrical peripheral neuropathy in diabetes. It includes two separate assessments: a 15-item self-administered questionnaire and a lower extremity examination that includes inspection and assessment of vibratory sensation and ankle reflexes. The purpose of this study was to evaluate the performance of the MNSI in detecting distal symmetrical peripheral neuropathy in patients with Type 1 diabetes and to develop new scoring algorithms. METHODS: The MNSI was performed by trained personnel at each of the 28 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications clinical sites. Neurologic examinations and nerve conduction studies were performed during the same year. Confirmed clinical neuropathy was defined by symptoms and signs of distal symmetrical peripheral neuropathy based on the examination of a neurologist and abnormal nerve conduction findings in ≥ 2 anatomically distinct nerves among the sural, peroneal and median nerves. RESULTS: We studied 1184 subjects with Type 1 diabetes. Mean age was 47 years and duration of diabetes was 26 years. Thirty per cent of participants had confirmed clinical neuropathy, 18% had ≥ 4 and 5% had ≥ 7 abnormal responses on the MNSI questionnaire, and 33% had abnormal scores (≥ 2.5) on the MNSI examination. New scoring algorithms were developed and cut points defined to improve the performance of the MNSI questionnaire, examination and the combination of the two. CONCLUSIONS: Altering the cut point to define an abnormal test from ≥ 7 abnormal to ≥ 4 abnormal items improves the performance of the MNSI questionnaire. The MNSI is a simple, non-invasive and valid measure of distal symmetrical peripheral neuropathy in Type 1 diabetes.

Biomedical risk factors for decreased cognitive functioning in type 1 diabetes: an 18 year follow-up of the Diabetes Control and Complications Trial (DCCT) cohort.

AIMS/HYPOTHESIS: In patients with type 1 diabetes, there has been concern about the effects of recurrent hypoglycaemia and chronic hyperglycaemia on cognitive function. Because other biomedical factors may also increase the risk of cognitive decline, this study examined whether macrovascular risk factors (hypertension, smoking, hypercholesterolaemia, obesity), sub-clinical macrovascular disease (carotid intima-media thickening, coronary calcification) and microvascular complications (retinopathy, nephropathy) were associated with decrements in cognitive function over an extended time period. METHODS: Type 1 diabetes patients (n = 1,144) who had completed a comprehensive cognitive test battery at entry into the Diabetes Control and Complications Trial were re-assessed at a mean of 18.5 (range: 15-23) years later. Univariate and multivariable models examined the relationship between cognitive change and the presence of micro- and macrovascular complications and risk factors. RESULTS: Univariate modelling showed that smoking history was modestly associated with decrements in learning, memory, spatial information-processing and psychomotor efficiency; hypertension was associated with only psychomotor slowing. Multivariable modelling demonstrated that HbA(1c) level, and retinal and renal complications were each independently associated with decrements in psychomotor efficiency. In contrast, no macrovascular risk factors were significant after correcting for multiple comparisons. No interactions were found between these predictors and sex, severe hypoglycaemic events or presence of the APOE ε4 allele. CONCLUSIONS/INTERPRETATION: In relatively healthy, middle-aged adults with type 1 diabetes who had been followed for an average of 18.5 years, long-term metabolic control and microvascular factors are independently associated with a decline in cognitive function specifically affecting measures of psychomotor efficiency. TRIAL REGISTRATION: ClinicalTrials.gov NCT00360893.

The associations of apolipoprotein E and angiotensin-converting enzyme polymorphisms and cognitive function in Type 1 diabetes based on an 18-year follow-up of the DCCT cohort.

AIMS: Specific polymorphisms of the apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) genes appear to increase risk for Alzheimer's disease and cognitive dysfunction in the general population, yet little research has examined whether genetic factors influence risk of cognitive dysfunction in patients with Type 1 diabetes. The long-term follow-up of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) population provides an opportunity to examine if specific genetic variations in APOE and ACE alter risk for cognitive decline. METHODS: Neurocognitive function in Type 1 diabetic subjects from the DCCT/EDIC study was assessed at DCCT entry and re-assessed approximately 18 years later, using a comprehensive cognitive test battery. Glycated haemoglobin (HbA(1c)) and the frequency of severe hypoglycaemic events leading to coma or seizures were measured over the 18-year follow-up. We determined whether the APO epsilon4 and ACE intron 16 indel genotypes were associated with baseline cognitive function and with change over time, and whether they conferred added risk in those subjects experiencing severe hypoglycaemic events or greater glycaemic exposure. RESULTS: None of the APOE or ACE polymorphisms were associated with either baseline cognitive performance or change in cognition over the 18-year follow-up. Moreover, none of the genotype variations altered the risk of cognitive dysfunction in those subjects with severe hypoglycaemic episodes or high HbA(1c). CONCLUSIONS: In this sample of young and middle-aged adults with Type 1 diabetes, APO epsilon4 and ACE D alleles do not appear to increase risk of cognitive dysfunction.

Urinary tract infections in women with type 1 diabetes mellitus: survey of female participants in the epidemiology of diabetes interventions and complications study cohort.

PURPOSE: We determined the prevalence of and risk factors for urinary tract infection in women with type 1 diabetes, and compared the prevalence of cystitis to that in nondiabetic women. MATERIALS AND METHODS: Women enrolled in the Epidemiology of Diabetes Interventions and Complications study were surveyed at year 10 as part of the Uro-EDIC study to assess the prevalence of cystitis and pyelonephritis in the preceding 12 months. Multivariate logistic regression models including measures of glycemic control and vascular complications of type 1 diabetes were used for risk factor analyses. The prevalence of cystitis in Uro-EDIC women was compared to that in a nondiabetic subset of women participants in the National Health and Nutrition Examination Survey III (NHANES III). RESULTS: A total of 550 women participated in the Uro-EDIC survey. The prevalence of cystitis and pyelonephritis in the preceding 12 months was 15% and 3%, respectively. Duration of diabetes, hemoglobin A1C, retinopathy, neuropathy, nephropathy, composite vascular complication score and intensive glycemic therapy during the Diabetes Control and Complications Trial, and Diabetes Control and Complications Trial cohort were not associated with cystitis or pyelonephritis. Sexual activity was associated with increased cystitis risk (adjusted OR 8.28; 95% CI 1.45, 158.32; p = 0.01). The adjusted prevalence of cystitis was 19.1% in Uro-EDIC women and 23.1% in NHANES III participants (adjusted OR 0.78; 95% CI 0.51, 1.22; p = 0.28). CONCLUSIONS: In Uro-EDIC women sexual activity rather than measures of diabetes control and complications was the main risk factor for urinary tract infection. The prevalence of cystitis was similar to that in nondiabetic women participants in NHANES III.

Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT).

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy of type 1 diabetes mellitus reduces the risk of development and progression of microvascular complications. The Epidemiology of Diabetes Interventions and Complications (EDIC) study assessed whether these benefits persisted after the end of DCCT. Results for the adolescent DCCT cohort are reported here. STUDY DESIGN: Of the DCCT adolescent cohort (n = 195), 175 participated in EDIC, 151 had fundus photography, and 156 had albumin excretion rate measured at year 3 or 4. The odds of progression of retinopathy and albuminuria from closeout of the DCCT until EDIC year 4 were assessed. RESULTS: In contrast to the 7.4 years of the DCCT, during which mean hemoglobin A(1c) levels were significantly lower with intensive therapy than conventional therapy (8.06% vs 9.76%; P <.0001), the subsequent first 4 years of EDIC had mean hemoglobin A(1c) levels that were similar between the former intensive and the former conventional groups (8.38% vs 8.45%). However, the prevalence of worsening of 3 steps or more in retinopathy and of progression to proliferative or severe nonproliferative retinopathy were reduced by 74% (P <.001) and 78% (P <.007), respectively, in the former intensive therapy group compared with the former conventional group. CONCLUSIONS: These findings provide further support for the DCCT recommendation that most adolescents with type 1 diabetes receive intensive therapy aimed at achieving glycemic control as close to normal as possible to reduce the risk of microvascular complications.

Increased small dense LDL and intermediate-density lipoprotein with albuminuria in type 1 diabetes.

OBJECTIVE: This population study examines the relationship between LDL density and persistent albuminuria in subjects with type 1 diabetes at the end of the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: Subjects were classified as persistently normoalbuminuric (albumin excretion rate [AER] < 30 mg/d, n = 1,056), microalbuminuric (AER > or = 30-299 mg/day, n = 80), and macroalbuminuric (AER = 300 mg/day, n = 24) based on the last two AER measures. RESULTS: Triglyceride (P < 0.01) and LDL cholesterol (P < 0.01) levels were higher in macroalbuminuric subjects compared with normoalbuminuric subjects. Cholesterol distribution by density-gradient ultracentrifugation showed an increase in intermediate-density lipoprotein (IDL) and a shift in peak LDL from buoyant toward more dense particles with progressive albuminuria. In the entire group, there was a significant negative correlation between the peak buoyancy of LDL particles and albuminuria (r = -0.238, P < 0.001, n = 1,160). This correlation persisted in the normoalbuminuric DCCT group (r = -0.138, P < 0.001, n = 1,056). CONCLUSIONS: As albuminuria increases in subjects with type 1 diabetes, dyslipidemia occurs with an increase in IDL and dense LDL that may lead to increased cardiovascular disease.

Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial.

The relationships between long-term intensive control of glycemia and indicators of skin collagen glycation (furosine), glycoxidation (pentosidine and N(epsilon)-[carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 diabetes from the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30-32% lower furosine, 9% lower pentosidine, 9-13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P < 0.006-0.001) and also of the secondary intervention cohort (P < 0.015-0.001) with the exception of CML and acid-soluble collagen. Age- and duration-adjusted collagen variables were significantly associated with the HbA1c value nearest the biopsy and with cumulative prior HbA1c values. Multiple logistic regression analyses with six nonredundant collagen parameters as independent variables and various expressions of retinopathy, nephropathy, and neuropathy outcomes as dependent variables showed that the complications were significantly associated with the full set of collagen variables. Surprisingly, the percentage of total variance (R2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and from 14 to 51% with conventional treatment. These associations generally remained significant even after adjustment for HbA1c, and, most unexpectedly, in conventionally treated subjects, glycated collagen was the parameter most consistently associated with diabetic complications. Continued monitoring of these subjects may determine whether glycation products in the skin, and especially the early Amadori product (furosine), have the potential to be predictors of the future risk of developing complications, and perhaps be even better predictors than glycated hemoglobin (HbA1c).

Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial.

CONTEXT: Intensive treatment of type 1 diabetes results in greater weight gain than conventional treatment. OBJECTIVE: To determine the effect of this weight gain on lipid levels and blood pressure. DESIGN: Randomized controlled trial; ancillary study of the Diabetes Control and Complications Trial (DCCT). SETTING: Twenty-one clinical centers. PARTICIPANTS: The 1168 subjects enrolled in DCCT with type 1 diabetes who were aged 18 years or older at baseline. INTERVENTION: Randomized to receive either intensive (n = 586) or conventional (n = 582) diabetes treatment with a mean follow-up of 6.1 years. MAIN OUTCOME MEASURES: Plasma lipid levels and blood pressure in each treatment group categorized by quartile of weight gain. RESULTS: With intensive treatment, subjects in the fourth quartile of weight gain had the highest body mass index (BMI) (a measure of weight adjusted for height), blood pressure, and levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B compared with the other weight gain quartiles with the greatest difference seen when compared with the first quartile (mean values for the highest and lowest quartiles: BMI, 31 vs 24 kg/m2; blood pressure, 120/77 mm Hg vs 113/73 mm Hg; triglyceride, 0.99 mmol/L vs 0.79 mmol/L [88 mg/dL vs 70 mg/dL]; LDL-C, 3.15 mmol/L vs 2.74 mmol/L [122 mg/dL vs 106 mg/dL]; and apolipoprotein B, 0.89 g/L vs 0.78 g/L; all P<.001). In addition, the fourth quartile group had a higher waist-to-hip ratio; more cholesterol in the very low density lipoprotein, intermediate dense lipoprotein, and dense LDL fractions; and lower high-density lipoprotein cholesterol and apolipoprotein A-I levels compared with the first quartile. Baseline characteristics were not different between the first and fourth quartiles of weight gain with intensive therapy except for a higher hemoglobin A1c in the fourth quartile. Weight gain with conventional therapy resulted in smaller increases in BMI, lipids, and systolic blood pressure. CONCLUSIONS: The changes in lipid levels and blood pressure that occur with excessive weight gain with intensive therapy are similar to those seen in the insulin resistance syndrome and may increase the risk of coronary artery disease in this subset of subjects with time.

Visual symptoms after optic neuritis. Results from the Optic Neuritis Treatment Trial.

As part of the Optic Neuritis Treatment Trial, vision-specific quality-of-life data were collected on the patients at their 6-month visits. The purpose of this study was to determine the types of visual tasks in day-to-day living in which patients have difficulty and to compare the patients' subjective assessment of visual impairment with measurements of visual acuity, contrast sensitivity, mean deviation, and color vision. The questionnaire was completed by 382 (87%) of the 438 patients who had 6-month study visits. Associations between ophthalmic test scores and self-reported vision were examined using both a summary problem index and selected individual items. Although a substantial percentage of the patients (63%) indicated that vision had not recovered to normal in the affected eye, the reported visual deficits generally were mild. For most of the visual tasks of daily living, patients reported little or no problem. Among the 215 patients who perceived their vision at 6 months to be somewhat or much worse than it was before optic neuritis, 20% had normal results on none of the four visual function tests, 14% had normal results on one of the four tests, 23% had two of four, 23% had three of four, and 20% had normal results on all four. Reported visual symptoms 6 months after optic neuritis generally were mild. When patients were symptomatic, the four visual function tests often did not detect abnormality. This finding supports previous reports that visual deficits are frequently perceived even when vision testing is normal.

Contrast sensitivity and other vision tests in the optic neuritis treatment trial.

PURPOSE: To determine the intercorrelation, prevalence of abnormality, and incremental detection value of vision tests in optic neuritis. METHODS: We calculated the linear correlation of paired vision tests and prevalence of abnormal test values from baseline and six-month measurements of Snellen visual acuity, Pelli-Robson contrast sensitivity, Humphrey Field Analyzer mean deviation, and Farnsworth-Munsell 100-hue color vision in 438 patients entered in the Optic Neuritis Treatment Trial from 1988 to 1991. The incremental detection value of nonvisual acuity tests was defined as their frequency of abnormality when visual acuity was 20/20 or better. RESULTS: All four vision-test results were highly intercorrelated at baseline and at six months. At baseline, contrast sensitivity had the highest prevalence of abnormality, but all vision tests were so often abnormal that differences were not clinically relevant. At six months, when visual recovery had occurred, contrast sensitivity was most often abnormal (2.2 X visual acuity; 1.8 X mean deviation; 1.5 X Farnsworth-Munsell 100-hue color vision test); when contrast sensitivity, mean deviation, or Farnsworth-Munsell 100-hue color vision was normal, visual acuity was 20/25 or better in 98% of patients. CONCLUSIONS: The high intercorrelation of four vision tests suggests that optic neuritis affects a broad range of visual functions. Among non-visual acuity tests, Pelli-Robson contrast sensitivity proved to be a particularly practical and sensitive indicator of visual dysfunction in optic neuritis.

Levels of lipoprotein(a), apolipoprotein B, and lipoprotein cholesterol distribution in IDDM. Results from follow-up in the Diabetes Control and Complications Trial.

Levels of lipoprotein(a) [Lp(a)], apolipoprotein (apo) B, and lipoprotein cholesterol distribution using density-gradient ultracentrifugation were measured as part of a cross-sectional study at the final follow-up examination (mean 6.2 years) in the Diabetes Control and Complications Trial. Compared with the subjects in the conventionally treated group (n = 680), those subjects receiving intensive diabetes therapy (n = 667) had a lower level of Lp(a) (Caucasian subjects only, median 10.7 vs 12.5 mg/dl, respectively; P = 0.03), lower apo B (mean 83 vs. 86 mg/dl, respectively; P = 0.01), and a more favorable distribution of cholesterol in the lipoprotein fractions as measured by density-gradient ultracentrifugation with less cholesterol in the very-low-density lipoprotein and the dense low-density lipoprotein fractions and greater cholesterol content of the more buoyant low-density lipoprotein. Compared with a nondiabetic Caucasian control group (n = 2,158), Lp(a) levels were not different in the intensive treatment group (median 9.6 vs. 10.7 mg/dl, respectively; NS) and higher in the conventional treatment group (9.6 vs. 12.5 mg/dl, respectively; P < 0.01). No effect of renal dysfunction as measured by increasing albuminuria or reduced creatinine clearance on Lp(a) levels could be demonstrated in the diabetic subjects. Prospective follow-up of these subjects will determine whether these favorable lipoprotein differences in the intensive treatment group persist and whether they influence the onset of atherosclerosis in insulin-dependent diabetes.

Reproducibility of a comprehensive diet history in the Diabetes Control and Complications Trial. The DCCT Research Group.

OBJECTIVE: To evaluate the reproducibility of a modified Burke-type diet history within the context of a long-term, randomized, 29-center clinical diabetes study. DESIGN: Diet histories were collected by trained interviewers at the end of years 1 and 2 after subjects were randomly assigned to the intensive treatment group or the conventional treatment group. Mean daily intakes of energy, protein, carbohydrate, total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, cholesterol, and dietary fiber were calculated for each treatment group at each time period. SUBJECTS: The study population consisted of 139 subjects in the intensive treatment group and 128 subjects in the conventional treatment group. Ages ranged from 13 to 39 years; groups included men and women. Distribution by age, sex, race, proportion of smokers, weight reported as percent ideal body weight, and duration of IDDM were similar in both groups. STATISTICAL METHODS: Differences in nutrient intake between the conventional and intensive treatment groups at each time period were tested for significance using the Wilcoxon rank-sum test. The Wilcoxon paired differences test was used to assess changes between time periods within treatment groups. Linear agreement between repeated administrations of the diet history was evaluated using Pearson's correlation coefficient, and the extent of within-subject reproducibility was assessed by intraclass correlation. RESULTS: No statistically significant differences in energy and nutrient intakes were observed between the two groups at either year 1 or year 2. Within each treatment group, energy and nutrient intake differences between times were not statistically significant. Correlation coefficients between years 1 and 2 ranged from .51 for dietary fiber to .72 for dietary cholesterol; within-subject reproducibility was slightly higher. APPLICATIONS: These results demonstrate long-term reproducibility for the meal-based diet history in the DCCT population.

The use of bioelectrical impedance analysis (BIA) to estimate body composition in the Diabetes Control and Complications Trial (DCCT).

Although weight gain often accompanies intensive treatment regimens designed to achieve near-normal glycemia in insulin-dependent diabetes mellitus (IDDM), body composition (BC) has not been well studied. Bioelectrical impedance analysis (BIA) is a safe, rapid, and non-invasive method of assessing BC but has not been utilized widely in IDDM. Data from 46 adults with IDDM were used to develop a regression model estimating fat-free body mass (FFM) from bioimpedance measurements obtained using a proximal electrode placement. Reference values of FFM were determined by dual x-ray absorptiometry (DXA). A model using the ratio of height squared to the minimum resistance of 4 limb-lead combinations (H2/R), total body weight, and a weight-gender interaction achieved a high level of accuracy (R2 = 0.982, residual standard deviation = 1.43 kg), while studies of 10 subjects before and after a light meal found no short-term effect of glycemia on measured BIA variables. BIA will therefore be used in combination with waist-to-hip ratios to study the composition and distribution of the increased weight associated with intensive therapy in the DCCT.

The course of visual recovery after optic neuritis. Experience of the Optic Neuritis Treatment Trial.

PURPOSE: To define the time course of visual recovery after optic neuritis and factors predictive of this course in the patients enrolled in the Optic Neuritis Treatment Trial. METHODS: The cohort for this study consisted of the 438 patients who completed the 6-month follow-up visit. Visual acuity was measured at baseline and at seven follow-up visits during the first 6 months. Factors predictive of recovery were evaluated with univariate and multivariate statistical tests. RESULTS: Visual recovery was rapid in all three treatment groups. In almost all patients, regardless of treatment group and initial severity of visual loss, improvement began within the first month. Among the 278 patients with baseline visual acuity of 20/50 or worse, all patients improved at least one line of visual acuity, and all except six improved at least three lines, during the 6-month follow-up period. Baseline visual acuity was the best predictor of the 6-month visual acuity outcome (P = 0.0001). Older age was statistically associated with a slightly worse outcome (P = 0.02), but this appeared to be of no clinical importance. CONCLUSIONS: In most patients with optic neuritis, visual recovery is rapid. The only factor of value in predicting the visual outcome is initial severity of visual loss. However, even when initial loss is severe, visual recovery is still good in most patients. Patients not following the usual course of visual recovery should be considered atypical. For such patients, further investigation in regard to etiology of the visual loss may be appropriate.

The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group.

BACKGROUND: Optic neuritis is often the first clinical manifestation of multiple sclerosis, but little is known about the effect of corticosteroid treatment for optic neuritis on the subsequent risk of multiple sclerosis. METHODS: We conducted a multicenter study in which 389 patients with acute optic neuritis (and without known multiple sclerosis) were randomly assigned to receive intravenous methylprednisolone (250 mg every six hours) for 3 days followed by oral prednisone (1 mg per kilogram of body weight) for 11 days, oral prednisone (1 mg per kilogram) alone for 14 days, or placebo for 14 days. Neurologic status was assessed over a period of two to four years. The patients in the first group were hospitalized for three days; the others were treated as outpatients. RESULTS: Definite multiple sclerosis developed within the first two years in 7.5 percent of the intravenous-methyl-prednisolone group (134 patients), 14.7 percent of the oral-prednisone group (129 patients), and 16.7 percent of the placebo group (126 patients). The adjusted rate ratio for the development of definite multiple sclerosis within two years in the intravenous-methylprednisolone group was 0.34 (95 percent confidence interval, 0.16 to 0.74) as compared with the placebo group and 0.38 (95 percent confidence interval, 0.17 to 0.83) as compared with the oral-prednisone group. The beneficial effect of the intravenous-steroid regimen appeared to lessen after the first two years of follow-up. Signal abnormalities on magnetic resonance imaging (MRI) of the brain were a strong indication of risk for the development of definite multiple sclerosis (adjusted rate ratio in patients with three or more lesions, 5.53; 95 percent confidence interval, 2.41 to 12.66). The beneficial effect of treatment was most apparent in patients with abnormal MRI scans at entry. CONCLUSIONS: In patients with acute optic neuritis, treatment with a three-day course of high-dose intravenous methylprednisolone (followed by a short course of prednisone) reduces the rate of development of multiple sclerosis over a two-year period.

Glomerular filtration rate measurements in clinical trials. Modification of Diet in Renal Disease Study Group and the Diabetes Control and Complications Trial Research Group.

To assess the utility and precision of GFR measurements in multicenter trials, the test performance and variability of GFR were analyzed in 2,250 patients enrolled in 44 clinical centers participating in either the Modification of Diet in Renal Disease (MDRD) Study or the Diabetes Control and Complications Trial (DCCT). GRF was measured as the renal clearance of [125I]iothalamate after an sc injection without epinephrine. The studies used similar protocols for obtaining blood and urine, training clinical center staff, and processing specimens in central laboratories. The performance of GFR measurements, assessed from adherence to protocol and quality control analyses, was excellent. The variability among the four clearance periods (intratest coefficient of variation [CV]) was acceptable; the median intratest CV for GFR was 9.4% in the MDRD Study and 11.7% in the DCCT. The pattern of decline in serum counts was better approximated by an exponential rather than a linear relationship. The cause of the intratest variability in GFR measurements was explored by univariate and multivariate analysis. The intratest CV was highest at the extremes of GFR. Among patients with a high GFR (> 90 mL/min per 1.73 m2), most of whom were participants in the DCCT, the higher intratest GFR was due, in part, to a systematic decline in GFR during the test. Among patients with a very low GFR (< 13 mL/min per 1.73 m2), technical difficulties in urine collections contributed substantially to the higher intratest CV. Other patient characteristics, including age, gender, weight, serum glucose, renal diagnosis, and use of diuretics, were not strongly correlated with the intratest CV. The precision of GFR measurements was assessed from the variability from measurement to measurement (interest CV). Among MDRD Study subjects, in whom two measurements of GFR were performed over a 3-month interval, the median interest CV was relatively low (6.3%) and was only weakly related to the intratest CV. Thus, GFR measurements are reasonably precise, even if the intratest CV is high. Given the relatively high intratest CV that is characteristic of GFR measurements, the estimate of GFR in an individual is more precise if multiple clearance periods, rather than a single period, are included. Similarly, the estimate of mean GFR for a population is also more precise if multiple clearance periods are included. In conclusion, by the use of standardized methods, an acceptable precision of GFR results can be obtained in multicenter trials. The same methods can be applied in clinical practice.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain magnetic resonance imaging in acute optic neuritis. Experience of the Optic Neuritis Study Group.

OBJECTIVE: Changes in the brain on magnetic resonance images are common in patients with optic neuritis even when there is no other clinical evidence of multiple sclerosis. The current study was designed to determine systematically the prevalence of brain abnormalities on magnetic resonance images in the patients entered into the Optic Neuritis Treatment Trial. DESIGN: Prospective multicenter clinical trial. SETTING: Referral centers. PATIENTS AND METHODS: Brain magnetic resonance images from 418 patients with acute optic neuritis (77% women; mean age, 32.0 years) were evaluated at a central reading center with the use of a standardized classification system (ranging from 0 for normal to IV for most extensive changes). RESULTS: Of the scans, 40.9% were classified as grade 0, 10.8% as grade I, 9.1% as grade II, 6.7% as grade III, and 32.5% as grade IV. For patients with isolated (monosymptomatic) optic neuritis, 26.7% had two or more lesions. CONCLUSIONS: We found a lower prevalence of brain magnetic resonance imaging abnormalities in isolated optic neuritis than previous studies have reported. This likely is due to our study having a higher degree of standardization of patient inclusion criteria, which limited patient selection bias.

Optic neuritis treatment trial. One-year follow-up results.

OBJECTIVE: To determine the efficacy of corticosteroids as treatment for acute demyelinative optic neuritis after completion of 1 year of patient follow-up in the Optic Neuritis Treatment Trial. DESIGN: Randomized placebo controlled multicenter clinical trial. SETTING: Fifteen university or hospital-based centers throughout the United States. PATIENTS: Four hundred fifty-seven patients with acute demyelinative optic neuritis between 18 and 46 years of age. INTERVENTION: Either intravenous methylprednisolone sodium succinate (250 mg every 6 hours) for 3 days followed by oral prednisone (1 mg/kg per day) for 11 days, oral prednisone (1 mg/kg per day) for 14 days, or oral placebo for 14 days. The first two regimens were followed by a short taper of corticosteroid therapy. MAIN OUTCOME MEASURES: Visual acuity, visual field, contrast sensitivity, and color vision. RESULTS: Visual acuity at 1 year was 20/40 or better in 95% of the placebo group, 94% of the intravenous group, and 91% of the oral prednisone group. Comparing each corticosteroid group with the placebo group, there were no statistically significant differences in the distributions of any of the four measures of visual function. Patients in the oral prednisone group suffered a higher rate of new attacks of optic neuritis than patients in either of the other two groups. CONCLUSIONS: The visual benefit from treating acute optic neuritis with intravenous followed by oral corticosteroids is short term, limited to an accelerated rate of recovery. The decision whether to prescribe this regimen for optic neuritis, or to prescribe no treatment, must be made for each patient on an individual basis. Oral prednisone alone, in the dose range used in the Optic Neuritis Treatment Trial, should not be prescribed.