Optic Neuritis Treatment Trial
In Multiple Sclerosis

Purpose
To describe the health-related quality of life, measured with the National Eye Institute Visual Function Questionnaire (NEI-VFQ), of patients several years after the onset of Optic Neuritis.

According to their Neurologic and Visual status; to assess the relationship between the NEI-VFQ subscales and clinical measures of Visual function; and to assess the internal consistency reliability of the NEI-VFQ subscales.

Methods
The NEI-VFQ was administered to 244 patients 5 to 8 years after treatment for an episode of acute Optic Neuritis as part of the Optic Neuritis Treatment Trial.

Visual Acuity, Visual Field, Contrast Sensitivity, and Color Vision were measured at the same time as questionnaire completion.

Results
The NEI-VFQ scores generally were lower than those reported for a disease-free group.

Reported dysfunction was greater when Multiple Sclerosis was present and when Visual Acuity was abnormal, supporting the construct validity of the NEI-VFQ.

Rank correlations between the NEI-VFQ subscales and clinical measures of Visual function were moderate at best. Internal consistency reliability was generally high for most of the NEI-VFQ subscales.

Conclusions
These findings add support to the use of the NEI-VFQ as a valuable measure of self-reported Visual Impairment.

Objective
To assess the 5-year Visual course, including the incidence of recurrent Optic Neuritis, in 454 patients enrolled in the Optic Neuritis Treatment Trial.

Methods
Five-year follow-up vision testing, which included measures of Visual Acuity, Contrast Sensitivity, Visual field, and Color Vision, was completed for 397 (87%) of the 454 patients.

Results
Visual function test results in the eyes that experienced Optic Neuritis at study enrollment (affected Eyes) were normal or only slightly abnormal after 5 years in most patients; the results did not significantly differ by treatment group (P=.37 for Visual Acuity).

The Visual Acuity in the affected Eyes was 20/25 or better in 87%, 20/25 to 20/40 in 7%, 20/50 to 20/190 in 3%, and 20/200 or worse in 3%.

The recurrence of Optic Neuritis in either Eye occurred in 28% of the patients and was more frequent in patients with Multiple Sclerosis (P=.001) and in patients without Multiple Sclerosis who were in the Prednisone treatment group (P=.004).

Most Eyes with a recurrence retained normal or almost normal Visual function.

Conclusions
Most patients retained good to excellent vision in the 5 years following an attack of Optic Neuritis, even if the Optic Neuritis recurred.

Recurrences were more frequent in patients with Multiple Sclerosis and in those treated with Oral Prednisone alone.

The completion of the 5-year follow-up by the Optic Neuritis Treatment Trial cohort has not altered our management recommendations based on the results we reported earlier.

Purpose
We sought to characterize the DysChroMatopsia of Optic Neuritis, to determine the type and severity of Color Defect present and its relation to Central Vision and Spatial Acuity.

To examine changes in this DysChroMatopsia over time, and to determine the applicability of Kollner's rule to patients with Optic Neuritis.

Methods
We analyzed the raw data on Color Vision performance as assembled within the Optic Neuritis Treatment Trial (ONTT).

The ONTT was designed to evaluate GlucoCorticoids as a treatment for Acute DeMyelinating Optic Neuritis and to allow long-term outcome and natural history analyzes.

Between July 1, 1988 and June 30, 1991, 488 patients were enrolled in this trial. All patients underwent extensive Neurologic and Ophthalmologic Examinations including standardized testing of Visual Function that included testing of Color Vision.

The ONTT population thus afforded a unique opportunity to characterize acquired DysChroMatopsias in a large, homogenous, well-characterized cohort of patients with Optic Neuritis.

We used quantitative analysis of FM-100 scores from this patient cohort to determine the severity of the DysChroMatopsia, the selectivity of the DysChroMatopsia (polarity of errors) and the type of DysChroMatopsia (axis of confusion) by employing quadrant analysis of FM-100 scores.

Results
The results of high-and low-selectivity analyzes of the FM-100 data showed that during the acute phase of Optic Neuritis, blue/yellow, red/ green, and non-selective Color Defects occurred; among patients with pure defects, blue/yellow defects were more frequent than red/green defects.

At 6 months after the acute event, however, analyzes showed that red/green defects were more common than blue/yellow defects. Among patients with selective Color Defects both acutely and at 6 months, the defect was as likely to change over time as remain the same.

The likelihood of persistent DysChroMatopsia at 6 months was related to the severity of initial Central Acuity Loss, but the type of DysChroMatopsia present (red/green versus blue/yellow) was not.

Conclusions
Our results suggest that at the time of the acute attack of Optic Neuritis, the majority of selective color defects were blue/yellow defects.

Whereas at 6 months, more of the selective defects were red/green defects, though both types of defects (as well as nonselective defects) were seen acutely and at 6 months.

Despite the rigorous inclusion criteria of the ONTT, the large number of patients we studied, correlation of Color Vision with Visual Acuity, and longitudinal follow up, this study showed that no single type of Color Defect was consistently associated with Optic Neuritis. DeMyelinating Optic Neuritis does not obey Kollner's rule.

Moreover, the type of defect present changed in some patients over the course of recovery. Thus, the type of defect may not even be consistent in individual patients as they recover.

The type of defect appeared to be related to Spatial Vision at the time of the test, but the type of defect present at 6 months was not related to the severity of the initial Visual Loss.

Therefore, in evaluating Color defects associated with Optic Neuritis, the level of Central Visual Function must be considered.

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
• 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.

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.

The objective of our study was to assess the 5-year risk of and prognostic factors for the development of Clinically Definite Multiple Sclerosis (CD/MS) following Optic Neuritis.

In a prospective cohort study design, 388 patients, who did not have Probable or Definite MS at study entry enrolled in the Optic Neuritis Treatment Trial between 1988 and 1991, and were followed for the development of CD/MS.

The 5-year cumulative probability of CD/MS was 30% and did not differ by treatment group. Neurologic Impairment in the patients who developed CD/MS was generally mild.

Brain MRI performed at study entry was a strong predictor of CD/MS, with the 5-year risk of CD/MS ranging from 16% in the 202 patients with no MRI lesions to 51% in the 89 patients with three or more MRI lesions.

Independent of Brain MRI, the presence of prior nonspecific Neurologic symptoms was also predictive of the development of CD/MS.

Lack of Pain, the presence of Optic Disk swelling, and mild Visual Acuity Loss were features of the Optic Neuritis associated with a low risk of CD/MS among the 189 patients who had no Brain MRI lesions and no history of Neurologic symptoms or Optic Neuritis in the fellow Eye.

The 5-year risk of CD/MS following Optic Neuritis is highly dependent on the number of lesions present on Brain MRI.

However, even a normal Brain MRI does not preclude the development of CD/MS. In these patients with no Brain MRI lesions, certain clinical features identify a subgroup with a particularly low 5-year risk of CD/MS.

Objective
To determine the incidence of side effects from short-term GlucoCorticoid therapy prescribed for treatment of Optic Neuritis in the Optic Neuritis Treatment Trial.

Design & Setting
Randomized, placebo-controlled, multicenter clinical trial. Fifteen university or hospital-based centers throughout the United States.

Patients
A total of 457 patients between the ages of 18 and 46 years with acute DeMyelinative Optic Neuritis were studied.

Interventions

1. IntraVenous MethylPrednisolone (250 mg every 6 hours) for 3 days while hospitalized
   • followed by Oral Prednisone (1 mg/kg per day) for 11 days
2. Oral Prednisone (1 mg/kg per day) for 14 days
3. Oral placebo for 14 days

Results
Only two patients experienced major side effects, Psychotic Depression in one and Acute Pancreatitis in the other.

Both of these patients were from the IntraVenous MethylPrednisolone group and both of the side effects resolved without Sequela.

Patients in both groups receiving active drugs more often reported sleep disturbances, mood change, stomach upset, and facial flushing and gained more weight during the treatment period than patients in the placebo group (P < .001 for each comparison).

Conclusions
Although minor side effects are common, short-term GlucoCorticoid therapy in young, healthy adults is relatively safe.

Because of the infrequency of serious side effects, outpatient administration of high-dose IntraVenous GlucoCorticoids may be feasible.

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 & Setting
Prospective multicenter clinical trial and referral centers.

Patients & Methods
Brain MRI 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
• 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 MRI 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.

Objective
To identify factors associated with a high and low risk of developing Multiple Sclerosis after an initial episode of Optic Neuritis.

Methods
Three hundred eighty-eight patients who experienced acute Optic Neuritis between July 1, 1988, and June 30, 1991, were followed up prospectively for the development of Multiple Sclerosis. Consenting patients were reassessed after 10 to 13 years.

Results
The 10-year risk of Multiple Sclerosis was 38% (95% confidence interval, 33%-43%).

Patients (160) who had 1 or more typical lesions on the baseline Magnetic Resonance Imaging (MRI) scan of the Brain had a 56% risk; those with no lesions (191) had a 22% risk (P < .001, log rank test).

Among the patients who had no lesions on MRI, male gender and Optic Disc swelling were associated with a lower risk of Multiple Sclerosis.

As was the presence of the following atypical features for Optic Neuritis: no light perception Vision; absence of Pain; and Ophthalmoscopic findings of severe Optic Disc Edema, PeriPapillary Hemorrhages, or Retinal exudates.

Conclusions
The 10-year risk of Multiple Sclerosis following an initial episode of acute Optic Neuritis is significantly higher, if there is a single Brain MRI lesion; higher numbers of lesions do not appreciably increase that risk.

However, even when Brain lesions are seen on MRI, more than 40% of the patients will not develop clinical Multiple Sclerosis after 10 years. In the absence of MRI lesions, certain demographic and clinical features seem to predict a very low likelihood of developing Multiple Sclerosis.

This natural history information is a critical input for estimating a patient's 10-year Multiple Sclerosis risk and for weighing the benefit of initiating prophylactic treatment at the time of Optic Neuritis or other initial DeMyelinating events in the Central Nervous System.

Purpose
To assess visual function more than 10 years after an episode of Optic Neuritis in patients enrolled in the Optic Neuritis Treatment Trial (ONTT).

Design
Longitudinal follow-up of a randomized clinical trial.

Methods
Vision testing included measures of Visual Acuity, Contrast Sensitivity, and Visual Field. Quality of life was assessed with the National Eye Institute Visual Function Questionnaire.

Results
Examinations were completed on 319 patients. In most patients, Visual Function Test results in the eyes that experienced Optic Neuritis at study entry ("affected Eyes") were normal or only slightly abnormal after 9.9 to 13.7 years.

Visual Acuity in the affected Eyes was >or=20/20 in 74%, 20/25 to 20/40 in 18%, < 20/40 to 20/200 in 5%, and < 20/200 in 3%.

On average, Visual Function was worse in patients with Multiple Sclerosis (MS) than in those without MS. Recurrent Optic Neuritis in either Eye occurred in 35% of patients.

Such attacks were more frequent in patients with MS (P < .001). The National Eye Institute Visual Function Questionnaire scores were lower when Visual Acuity was abnormal and when MS was present.

Conclusions
Most patients retained good to excellent Vision more than 10 years after an attack of Optic Neuritis. Recurrences were more frequent in patients with MS.

Background
Participants enrolled in the Optic Neuritis Treatment Trial have been observed for more than a decade to assess the relationship between Optic Neuritis and the development of Clinically Definite Multiple Sclerosis.

Objective & Design
To assess Neurologic disability 10 to 12 years after an initial episode of Optic Neuritis. Longitudinal follow-up of a clinical trial.

Setting
Fourteen Optic Neuritis Treatment Trial clinical centers performed standardized Neurologic Examinations, including an assessment of Neurologic disability.

Participants & Main Outcome Measures
One hundred twenty-seven patients who had developed Clinically Definite Multiple Sclerosis. Functional Systems Scale and Expanded Disability Status Scale.

Results
The disability of most patients was mild, with 65% of patients having an Expanded Disability Status Scale score lower than 3.0.

The degree of Disability appeared to be unrelated to whether the baseline Magnetic Resonance Imaging scan was lesion-free or showed lesions (P =.51).

Among patients with baseline lesions, the degree of disability was unrelated to the number of lesions that were present on the scan (P =.14).

Two patients died owing to severe Multiple Sclerosis, one of whom had no lesions revealed on the baseline scan.

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 (IV) 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:
1.   7.5 percent of the IV-Methyl-Prednisolone group (134 patients)
2. 14.7 percent of the oral-Prednisone group (129 patients)
3. 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 IV-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 IV-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 IV MethylPrednisolone (followed by a short course of Prednisone) reduces the rate of development of Multiple Sclerosis over a two-year period.