Optic Neuritis In Multiple Sclerosis

Objective
To determine whether the Optic Neuritis Treatment Trial (ONTT) results have altered the practice patterns of Ophthalmologists and Neurologists.

Design & Participants
Mail survey of a random sample of 987 Ophthalmologists and 900 Neurologists practicing in the United States were mailed a questionnaire.

That inquired into decision-making with regard to management of Optic Neuritis before and after the publication of the ONTT results.

Main Outcome Measures
Responses received from 202 Ophthalmologists and 244 Neurologists, a response rate of 47%.

Results
Following the ONTT reports, nearly all Ophthalmologists and Neurologists have reduced their use of Oral Prednisone alone, substituting a regimen that includes IntraVenous MethylPrednisolone.

A large proportion of practitioners in both specialties mistakenly believe that IntraVenous MethylPrednisolone treatment improves final Visual outcome.

Only 7% of Neurologists and 36% of Ophthalmologists (P = 0.0001) are adhering to the ONTT suggestion to use Magnetic Resonance Imaging as a basis for initiating treatment.

Conclusions
The ONTT has led to a dramatic reduction in the use of Oral Prednisone without a preceding course of IntraVenous MethylPrednisolone in the treatment of acute Optic Neuritis.

Ophthalmologists and Neurologists have changed some of their practices without fully understanding the results of the ONTT.

Background And Methods
The use of CorticoSteroids to treat Optic Neuritis is controversial. At 15 clinical centers, we randomly assigned 457 patients with acute Optic Neuritis to receive:

1. Oral Prednisone
   • (1 mg per kilogram of body weight per day) for 14 days
2. IntraVenous MethylPrednisolone (1 g per day) for 3 days,
   • followed by Oral Prednisone (1 mg per kilogram per day) for 11 days; or
3. Oral Placebo for 14 days.

Visual function was assessed over a six-month follow-up period.

Results
Visual function recovered faster in the group receiving IntraVenous MethylPrednisolone than in the Placebo group; this was particularly true for the reversal of Visual-Field Defects (P = 0.0001).

Although the differences between the groups decreased with time, at six months the group that received IntraVenous MethylPrednisolone still had slightly better Visual Fields (P = 0.054), Contrast Sensitivity (P = 0.026), and Color Vision (P = 0.033) but not better Visual Acuity (P = 0.66).

The outcome in the Oral-Prednisone group did not differ from that in the Placebo group.

In addition, the rate of new episodes of Optic Neuritis in either Eye was higher in the group receiving Oral Prednisone, but not the group receiving IntraVenous MethylPrednisolone, than in the Placebo group (relative risk for Oral Prednisone vs. Placebo, 1.79; 95 percent confidence interval, 1.08 to 2.95).

Conclusions
Intravenous MethylPrednisolone followed by Oral Prednisone speeds the recovery of Visual Loss due to Optic Neuritis and results in slightly better Vision at six months.

Oral Prednisone alone, as prescribed in this study, is an ineffective treatment and increases the risk of new episodes of Optic Neuritis.

• Comment in: N Engl J Med 1992 Feb 27;326(9):634-5

Background
A randomized, controlled clinical trial was conducted in 1991 to compare an IntraVenous megadose of MethylPrednisolone with a control drug (Mecobalamin) for treating acute idiopathic Optic Neuritis.

Cases
Sixty-six cases from 22 clinical centers throughout Japan were examined to evaluate the treatment on Visual function parameters, such as Visual Acuity, Visual Field, Color Vision, Contrast Sensitivity, and Critical Flicker Frequency.

Observations
The MethylPrednisolone pulse treatment group showed faster recovery of Visual function, particularly the Visual Acuity at 1 week (P<.05).

Humphrey field analyzer mean deviation at 3 weeks (P<.05), and Color Vision at 1 week (P<.05).

Recovery of contrast sensitivity at several different spatial frequencies was significant in the pulse treatment group at 1 (P<.01), 2 (P<.05), and 4 weeks (P<.05) after the start of treatment.

Visual function test results at 12 weeks and 1 year were essentially the same in the two treatment groups.

Side effects appeared more frequently in the pulse treatment group than in the control (P<.05).

Conclusions
Pulse treatment does not appear effective for idiopathic Optic Neuritis.

Even though Visual function in the pulse treatment group of this trial recovered more quickly during the initial phase compared to the controls.

More effective and specific treatment should be established for Optic Neuritis.

Objective
To assess the efficacy of Oral high-dose MethylPrednisolone in Acute Optic Neuritis (ON).

Background
It has been determined that oral high-dose MethylPrednisolone is efficacious in attacks of MS.

Methods
A total of 60 patients with symptoms and signs of ON with a duration of less than 4 weeks and a Visual Acuity of 0.7 or less were randomized to treatment with placebo (n = 30) or oral MethylPrednisolone (n = 30; 500 mg daily for 5 days, with a 10-day tapering period).

Visual function was measured and symptoms were scored on a Visual Analog Scale (VAS) before treatment and after 1, 3, and 8 weeks.

Primary efficacy measures were Spatial Vision and VAS scores the first 3 weeks (analysis of variance with baseline values as the covariate), and changes in Spatial Vision and VAS scores after 8 weeks. A significance level of p < 0.0125 was employed.

Results
The VAS score ( p = 0.008) but not the Spatial Visual function ( p = 0.03) differed in MethylPrednisolone and Placebo-treated patients during the first 3 weeks.

After 8 weeks the improvement in VAS scores ( p = 0.8) and spatial Visual function ( p = 0.5) was comparable with MethylPrednisolone and Placebo-treated patients.

A post hoc subgroup analysis suggested that patients with more severe baseline Visual deficit and patients treated early after onset of symptoms had a more pronounced response to treatment.

The risk of a new DeMyelinating attack within 1 year was unaffected by treatment. No serious adverse events were seen.

Conclusion
Oral high-dose MethylPrednisolone treatment improves recovery from ON at 1 and 3 weeks, but no effect could be demonstrated at 8 weeks or on subsequent attack frequency.

Neurology #52 April 1999
Copyright © 1999 by the American Academy of Neurology. All rights reserved

Optic Neuritis is an acute inflammation of the Optic Nerve. It is a common manifestation of Multiple Sclerosis; it may be the initial expression or occur later in the course of the disease.

Approximately 15-20% of cases of Definite Multiple Sclerosis present with Optic Neuritis; another 40% will suffer an attack at some point.

When Optic Neuritis occurs without antecedent signs of Multiple Sclerosis, Magnetic Resonance Imaging (MRI) of the Brain frequently reveals characteristic signal abnormalities of White Matter, and analysis of CerebroSpinal fluid often shows OligoClonal Bands.

Optic Neuritis has been considered a forme fruste of Multiple Sclerosis.

To establish the value of Visual Evoked Potentials (VEPs) for monitoring disease evolution, we undertook a population-based study of 90 untreated patients 12 to 57 years of age (median, 32 years) at the onset of Optic Neuritis (ON) and after 2, 4, 12, and 52 weeks.

Optic Neuritis was MonoSymptomatic (AMON) in 58 patients and part of the Clinically Definite Multiple Sclerosis (CD/MS) in 32 patients.

The VEP was abnormal in Eyes with acute ON in 69 (77%) of 90 patients at onset and in 80 (89%) of 90 patients at one or more of the follow-up sessions.

In eyes with acute ON, normalization of an initially abnormal VEP was observed during 1-year follow-up in 13 (19%) of 69 patients.

At onset of ON, VEP was abnormal in 35% of the clinically unaffected Eyes.

By parametric analysis of variance, the latencies (P = 0.0058), the amplitudes (P = 0.0298), and the combined VEP scores (P = 0.0345) in the eyes with acute ON were significantly associated with the time after onset.

The latencies were influenced by the presence of CD/MS (P = 0.0033), whereas the amplitudes were influenced by Visual Acuity (P = 0.0000).

When Visual Acuity was included in a multifactor model, the time after onset was, however, not significantly associated with the amplitude (P = 0.8826).

The mean latency of the VEPs in eyes with acute ON was significantly shorter in AMON than in ON as part of CD/MS.

This study provides evidence that VEP abnormality is often transitory, and that VEP often normalizes during follow-up.

The diagnostic yield is increased by repeating VEP in the spontaneous course of acute ON. Visual Evoked Potential is a sensitive tool for revealing SubClinical lesions.

We evaluated the risk of developing Clinically Definite Multiple Sclerosis (CD/MS) after an acute attack of isolated Optic Neuritis (ON) in 112 patients, in relation to demographic and paraclinical findings.

Patients were examined by Brain MRI, CSF analysis, and multiple Evoked Potentials (EPs); 10 were lost to follow-up, and the other 102 were enrolled in a prospective study (follow-up duration 6. 3 +/- 2.2 years).

Of these, 37 (36.3%) developed CD/MS after a mean interval of 2.3 +/- 1.6 years.

The risk of developing CD/MS was:
• 13% after 2 years
• 30% after 4 years
• 37% after 6 years
• 42% after 8 and 10 years

Gender, age, and season of ON onset did not affect the risk. MS occurred in 37 of 71 patients (52.1%) with one MRI lesion or more; no patient with a normal MRI developed the disease.

MS developed more frequently in patients with Intrathecal IgG synthesis than in those without (43% vs. 28%), but the difference was not statistically significant.

Multiple EPs showed a slight predictive value only including SomatoSensory EPs of the lower limb.

Multiple Sclerosis was mild in most cases (EDSS 2.2 +/- 1.9). The EDSS was less than 4 in 32 cases (86%), between 4 and 6 in 2 (5%), higher than 6.5 in 3 (8%).

Purpose
To assess whether a correlation exists between Optic Nerve Fiber Layer (NFL) thickness and the Retinal or Visual pathway function in Multiple Sclerosis (MS) patients previously affected by Optic Neuritis.

Methods
Fourteen patients with a diagnosis of definite MS were examined. All had been affected by Optic Neuritis (MSON) with complete recovery of Visual Acuity (14 Eyes included in study).

These were compared with 14 Eyes from 14 age-matched control subjects. NFL thickness was measured by Optical Coherence Tomography (OCT).

Three different measurements in each quadrant (Superior, Inferior, Nasal, and Temporal) were taken and averaged.

The data in all quadrants (12 values averaged) were identified as NFL Overall, whereas the data obtained in the Temporal quadrant only (3 values averaged) were identified as NFL Temporal.

Retinal and Visual pathway function was assessed by simultaneously recording Pattern ElectroRetinoGrams (PERGs) and Visual Evoked Potentials (VEPs) using high-contrast (80%) checkerboard stimuli subtending 15 minutes and 60 minutes of the Visual arc (min arc) and reversed at the rate of two reversals per second.

Results
In MSON Eyes there was a significant (P < 0.01) reduction in NFL thickness in both NFL Overall and NFL Temporal evaluations compared with the values observed in control Eyes.

PERG, (15-min arc checks) and VEP (15-min arc and 60-min arc checks), showed a significant (P < 0.01) delay in latency and reduction in amplitude.

NFL Overall and NFL Temporal values were significantly correlated (P < 0.01) to the PERG P50 latency and P50 to N95 amplitude recorded with 15-min arc checks.

No correlations (P > 0.01) between NFL values and the other ElectroPhysiological data (PERG recorded with 60-min arc checks and VEP recorded with 15-min arc and 60-min arc checks) were found.

Conclusions
There is a correlation between PERG changes and NFL thickness in MS patients previously affected by Optic Neuritis, but there is no correlation between VEP changes and NFL thickness.

Visual disturbances are common in Multiple Sclerosis (MS) and often a result of Acute DeMyelinating Optic Neuropathy. Careful examination of MS patients, who have never suffered Optic Neuritis, may also reveal Asymptomatic Visual Loss.

This type of silent disease activity was investigated by Computerized Resolution Perimetry, which has the potential to reflect the percentage of functional Retino-Cortical Neural Channels.

The time of onset and the evolution of Asymptomatic Visual Loss was investigated. One approach was to retrospectively select patients who never had suffered Acute Optic Neuritis from a closely monitored MS population and re-examine them again.

Sixteen patients were identified and Vision was evaluated during a period of 5.5-9 years of follow-up and compared with that in 14 healthy controls.

The mean channel percentage of the MS group was 89 +/- 19 % (SD) on entry into the study, compared with 110 +/- 15% (SD) of controls (p < 0.003).

At termination of the study the mean percentage was essentially unchanged both in MS patients (87 +/- 21%, SD) and controls (110 +/- 19%, SD).

The second approach was to test a group of 7 patients with MS or strongly suspected MS, with the same method, in close connection with their first clinical exacerbation. All cases lacked Visual symptoms and none had previously had Acute Visual Loss.

Again, virtually all performed subnormally in the Vision Tests, and to the same degree as in the first group of patients. Results were compared with those obtained from 25 MS patients who had experienced one or more attacks of Optic Neuritis.

Compared with controls the loss of functional Retino-Cortical Neural Channels was 20% in patients without a previous history of Optic Neuritis and 30 % in patients who previously had experienced Optic Neuritis.

We conclude that Asymptomatic Visual Loss seems to be a universal feature of MS and has a substantial impact on the Visual Pathways, that it is present already at the time of clinical onset of the disease.

And, that any progression thereafter is slow enough to elude detection during several years of follow-up.