Trial Registration clinicaltrials. Acute demyelinating optic neuritis ON , an inflammatory disorder causing painful monocular visual loss, has an annual incidence in the United States of 6. Corticosteroids are traditionally used for treatment of acute demyelinating events, including ON. In addition, there was a higher risk of recurrent ON in the oral prednisone group than in either the IV or oral placebo groups.
However, the treatments were not pharmacologically equivalent. Quiz Ref ID Since the publication of the ONTT, studies have shown that a high-dose oral corticosteroid and high-dose IV methylprednisolone are bioequivalent, 3 have similar effects on magnetic resonance imaging MRI outcomes, 4 , 5 and have similar clinical effects on MS relapse. This single-blind randomized clinical trial compared optic nerve function recovery in patients with ON who were treated with bioequivalent high doses of IV and oral corticosteroids and were followed up for 6 months.
The trial protocol is available in the Supplement. Using a computer-based random number generator, participants were randomly assigned to either IV or oral treatment. Prior to randomization, only the study coordinator was not blinded to the treatment assignment.
After randomization, participants were unblinded, whereas all assessors remained blinded. Participants were assessed 3 times: at baseline prior to treatment and at 1 and 6 months after corticosteroid treatment. To ensure that assessors remained blinded, all baseline assessments were performed prior to treatment administration, and participants were reminded at all visits of the blinding of treatment assignment.
This study was approved by the Western University Health Sciences research ethics board. Participants provided written informed consent prior to participation. From March through May , patients presenting with unilateral acute demyelinating ON who, in the opinion of their treating clinician, warranted treatment were recruited.
To ensure treatment was recommended based on clinical judgment and was not influenced by potential enrollment in the trial, prospective participants were contacted by the study coordinator D. Optic neuritis could have presented as a first demyelinating event clinically isolated syndrome or in a patient with a previous diagnosis of clinically isolated syndrome or MS; however, it had to have been the first presentation of ON in the currently affected eye.
Antimyelin oligodendrocyte glycoprotein and antineuromyelitis optica antibody titers were not routinely checked at the first presentation of ON. Posters were displayed in these clinics, and quarterly letters regarding study recruitment were sent to the neurologists, optometrists, ophthalmologists, and neuro-ophthalmologists at these centers and at the clinics within the catchment area of these tertiary care clinics. Participants were excluded if they had previously experienced ON in the same eye, received corticosteroids in the previous 30 days, or had another medical condition that might affect visual outcomes, such as, but not limited to, diabetic retinopathy, glaucoma, or cataracts.
Participants were removed from the study if they required a second treatment of high-dose corticosteroids anytime during the study or if a diagnosis other than ON was established. Participants were randomized to either methylprednisolone sodium succinate mg, IV daily for 3 days or oral prednisone mg daily for 3 days. The oral dose was based on previous evidence of bioequivalence between mg of oral prednisone and mg of IV methylprednisolone in persons with MS.
Participants randomized to the oral group were provided 75 tablets of 50 mg of prednisone 25 tablets daily to consume at home. Quiz Ref ID The primary end point was recovery of the visual evoked potential VEP P component latency in the affected eye assessed 6 months after corticosteroid treatment. Secondary end points were high-contrast BCVA and contrast sensitivity, specifically low-contrast BCVA, 1 and 6 months after treatment, and the recovery of P latency 1 month after treatment.
The primary measure was recovery of the VEP P latency because P latencies are a reliable measure of the functional integrity of the visual pathway, correlating with visual acuity and recovery of visual fields in patients with ON. Visual evoked potentials were recorded with Teca Synergy equipment Viasys Healthcare using the pattern reversal VEP, a checkerboard stimulus.
Recording of the VEPs was performed following a standard protocol. Best-corrected visual acuity was measured using the Early Treatment Diabetic Retinopathy Study ETDRS chart 14 lines having 5 numbers each for a total of 70 responses , which is considered the criterion standard for ophthalmologic clinical trials of visual acuity outcomes.
The participants started reading at a row in which they thought they could read all 5 letters. They continued reading down the chart until they could not read all 5 letters in a given row. After 1 week of treatment, participants were contacted by telephone by the study coordinator D. All AEs were reported to the lead study investigator S.
The AEs were managed by the lead study investigator on a case-by-case basis, as per standard of practice in MS clinics in Canada. The estimated clinically significant difference between the 2 groups was hypothesized to be 1 SD.
Based on a randomization, a probability power of 0. To compare longitudinal changes on visual outcomes across groups at 1 and 6 months after treatment, we used an analysis of covariance with the baseline measures as covariates to assess the significance of between-group differences at 1 and 6 months.
Although the original recruitment goal was 46 participants, after the 46th participant was randomized, it was noted that the final number of participants completing the study would be less than 38 owing to dropouts or removal from the study. Thus, recruitment continued until 55 participants were enrolled and randomized to ensure enough power for the statistical analyses. In total, 89 participants with new-onset ON were referred for potential participation in this trial. Twenty-five participants did not meet the inclusion criteria, and 9 declined to participate.
Subsequently, 2 participants from the IV group and 3 from the oral group withdrew because they were opposed to their treatment assignment and thus did not receive any treatment in the study. These participants were not included in any analysis because the first dose had not been administered.
Consequently, 25 participants received IV treatment, and 25 participants received oral treatment Figure 1. In the IV group, 2 participants were removed because 1 participant with a known MS diagnosis had another relapse and required another course of corticosteroid and the other participant was found to have a pituitary tumor that had been previously missed on an MRI scan as the cause of vision loss in retrospect. In the oral group, 2 participants were removed as the result of ON misdiagnoses nonarteritic anterior ischemic optic neuropathy and Leber hereditary optic neuropathy by the referring physicians.
A third participant was removed after she required a second course of corticosteroid administration. She subsequently developed ON in the other eye and later received a diagnosis of acute disseminated encephalomyelitis. Thus, 23 participants in the IV group and 22 participants in the oral group were included in the analysis Figure 1. In the IV group, 1 participant moved midstudy and could no longer attend study visits, and 2 other participants were lost to follow-up after the baseline assessment.
In the oral group, 4 participants were lost to follow-up after the baseline assessment. All available data were included in the analysis. The mean SD age of our final entire cohort was In the final cohort, 29 participants There were no significant differences between the 2 groups in baseline demographic characteristics Table 1. Fifteen participants The results of BCVA testing at a letter contrast of 2.
For BCVA testing at a lower letter contrast of 1. There were no significant differences in any of these baseline visual characteristics between the oral and IV treatment groups Table 2. The P latency in the group receiving oral administration decreased from a mean SD of Similarly, at 1 month of recovery, there was no significant difference in the P latency between groups: the IV group improved by At 1 month of recovery, the BCVA in the affected eye as assessed at a low letter contrast of 2.
At 1 month of recovery, the BCVA in the affected eye as assessed at a letter contrast of 1. This single-blind randomized clinical trial indicates that the administration of a high-dose IV corticosteroid was not superior to the administration of a bioequivalent oral dose for the treatment of acute ON. Corticosteroids have been used to treat acute demyelinating events for many years. Corticosteroids reduce the breakdown of the blood-brain barrier, as indicated by a reduction in the intensity, or complete resolution, of gadolinium-enhanced lesions on MRI scans, leading to accelerated recovery from acute relapse.
Similar to the results of our study, they reported that oral administration was not inferior to IV administration. However, oral medication may be more convenient, minimizing travel to an infusion center, especially for those residing in rural locations. In addition, our previous study showed that oral administration is preferred by persons with MS. The present study has several strengths and unique aspects.
However, the present study does not address other important clinical issues, namely, who will benefit from corticosteroid treatment and the ideal timing for initiation of therapy. Research to date has not provided any evidence that treatment of ON with high-dose corticosteroids affects long-term visual outcomes.
The present study has some additional limitations. There may have been a referral bias; if the treating physician decided that IV or oral corticosteroids were more appropriate, the participant would not have been screened for our study. Second, most referrals for this study were received from within the London Health Sciences Centre, London, Ontario, Canada; thus, there may be differences between ON assessed at an academic tertiary care center and ON assessed at other clinics.
Finally, we did not use optical coherence tomography OCT in this study. Baseline OCT images may have allowed for the detection of subclinical axonal attrition in the optic nerves, a known phenomenon in demyelinating disease that may limit the degree of expected visual recovery.
Follow-up OCT images could have been useful in showing whether there was a differential effect of IV vs oral corticosteroids on retinal nerve fiber layer loss and may have allowed for correlations between optic nerve function VEP and structure retinal nerve fiber layer by treatment modality. Bioequivalent doses of oral and IV corticosteroids are equally viable treatment options for acute ON.
However, oral prednisone has the advantages of being less expensive and more convenient to access and administer and is preferred by patients to IV methylprednisolone. Corresponding Author: Sarah A. Published Online: March 5, Author Contributions: Dr Morrow had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Critical revision of the manuscript for important intellectual content: All authors. She has acted as site principal investigator for clinical trials for Novartis, Genzyme, and Roche and has received investigator initiated trial funding from Genzyme.
Flowchart of Participant Enrollment and Retention. View Large Download. Figure 2. Table 1. Demographic Characteristics of the 45 Study Participants. Table 2. Baseline Visual Characteristics of the Affected Eye. Trial protocol. Optic neuritis and multiple sclerosis: an epidemiologic study. Arch Ophthalmol. PubMed Google Scholar Crossref. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis.
Randomized trial comparing two different high doses of methylprednisolone in MS: a clinical and MRI study. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. PubMed Google Scholar. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis COPOUSEP : a randomised, controlled, double-blind, non-inferiority trial.
Practice parameter: the role of corticosteroids in the management of acute monosymptomatic optic neuritis: report of the quality standards subcommittee of the American Academy of Neurology. Am J Ophthalmol. Corticosteroids for treating optic neuritis. Goodin DS. Glucocorticoid treatment of multiple sclerosis. Handb Clin Neurol. Mackay DD. MP increased the rate of recovery and visual function at six months, however, equally high doses of corticosteroids were not evaluated. Oral administration should therefore be of no disadvantage.
Indeed, oral administration would facilitate the clinical management of these patients and is also safe, well-tolerated and less expensive than intravenously administered corticosteroids. The aim of the present study was to compare the effects of oral and i. Visual acuity, color vision and visual fields were compared in the groups at follow-up. Patient records of subjects who were treated at the Department of Neurology and the Department of Ophthalmology at Skane University Hospital in Lund and Malmo, Sweden, between the years and , were reviewed to identify patients with acute ON.
According to local practice, all patients were first diagnosed with optic neuritis at the Department of Opthalmology and then treated at the Department of Neurology. Visual function was followed by an ophthalmologist. By tradition, patients at the Lund clinic are more often treated with i.
MP, whereas patients at the Malmo clinic more frequently receive oral MP regardless of the severity of symptoms. This is due to regional differences, in which the route of administration of corticosteroids is different but the treatment and follow-up is otherwise the same. In case of oral treatment, patients received methylprednisolone in tablet form for treatment at home, whereas those who were treated with intravenous corticosteroids were either hospitalized or had to visit the neurological department once daily to receive the treatment.
Patients were also excluded in cases when neuromyelitis optica was suspected, and aquaporinantibodies were detected. Patients with MS who were already being treated with disease-modifying drugs prior to the advent of ON, and in whom this therapy was not changed, were not excluded.
Patients with previous ON in the other eye were not excluded. In cases where data were available from several occasions during the follow-up period, the data closest to the six-month endpoint were chosen. Note that magnetic resonance imaging MRI pattern and cerebrospinal fluid oligoclonal band are not included in the current study as these tests were not reliably obtained in all subjects.
Electronic patient records between the years and were reviewed in order to find patients with acute ON. Four hundred and sixty patients with suspected acute ON were assessed for eligibility and of these, patients were excluded as a result of the inclusion and exclusion criteria. A total of 56 patients were included, with 28 subjects per treatment group. For participant enrollment, see Fig. The two groups had similar durations of symptoms before the commencement of treatment and similar median follow-up times.
They did not differ in total dose of MP or in treatment duration. Fewer patients had MS and were undergoing disease-modifying therapy for MS in the oral group than in the i. There were no statistical differences in patient characteristics between groups. Data was not sufficient to explore side effects by treatment group. The detailed characteristics are given in Table 1. The primary efficacy measures used were visual acuity, color vision and visual field outcome.
Decimal visual acuities were converted to logMAR units for statistical analysis. In cases where patients had poor visual acuity, hand movements were converted into a decimal visual acuity of 0. Color vision was described as the percentage of correct pseudo-isochromatic plates. The total deviation probability map identifies and highlights test locations where the age-corrected threshold sensitivity is outside normal limits compared to healthy subjects. A highly significantly depressed test point indicates that This is considered to provide a more sensitive measure of visual field defects than the MD, as the MD is the weighted average measure of the deviations from the normal age-corrected threshold values of all test points in the visual field.
To obtain the value of DP, HFA 24—2 was analyzed by counting and summing the number of highly significantly depressed test points. Results are presented as median values range. Calculations and statistical analysis were performed using GraphPad Prism 7. The results of treatment at follow-up were similar in the two groups treated with oral and i.
See Table 2 , Figs. Results before and after treatment with oral or i. Note that the visual outcome is similar in the two groups. Visual acuity before and after treatment with oral or i. Interestingly, in analogy with the present study on ON, others have studied the effect on MS relapses following high-dose oral corticosteroids, showing no inferiority of oral administration compared to i.
Furthermore, the results of our study are supported by a recently published prospective study on bioequivalent doses of corticosteroids in the treatment of acute ON, showing that oral administration of corticosteroids is not inferior to i. It could be expected that the effects of oral and i. Interestingly, we found no difference in visual outcome, even though the oral group did not receive bioequivalent doses. Replacing high-dose i. Indeed, the tolerability has been reported to be similar for both oral and i.
In previous studies of oral versus i. This is the case in the ONTT, in which the patients treated with oral corticosteroids received much lower doses of corticosteroids than those receiving i. The rate of return of visual function was found to be higher following i. MP than with placebo, and the i. This was not found to be the case when oral administration of prednisone was compared to placebo. At 1 year, no difference was found between the groups, regardless of the route of administration [ 18 ].
In other studies, only a single route of administration of corticosteroids has been assessed, i. It has been reported that i. Interestingly, in a study by Sellebjerg et al. As disease-modifying therapy may alter the course of recovery in acute demyelinating events [ 19 , 20 ], such cases were excluded from the present study. However, patients undergoing therapy prior to the incident of ON were not excluded.
The number of patients undergoing disease-modifying therapy was higher in the group receiving i. The contributing effect of these agents on the course of recovery in acute demyelinating events has rarely been evaluated [ 21 ], and an additional effect can therefore not be ruled out.
Prospective studies evaluating the effect of corticosteroids without disease-modifying therapy in the acute phase might be difficult in patients with demyelinating acute ON, as the criteria for the diagnosis of MS have changed during the past decade, and treatment with disease-modifying agents is now initiated early. The test methods chosen to measure visual function were visual acuity, visual field and color vision, as these together provide a comprehensive picture of visual function.
Regarding the visual field, a strength of our study is that we measured visual field defects by counting the number of highly significantly depressed test points in the total deviation probability map. This is likely to provide a more sensitive measure of visual field defects than the MD, since the latter is the average value of all deviations from the age-corrected normal threshold values of all test points in the visual field.
We included the MD in our analysis to enable comparison with previous studies using MD as a measure of the visual field. One limitation of the present study is the small number of subjects, which makes it difficult to draw definitive statistically supported conclusions. As this was a retrospective study, the data available in the patient records were also limited. For example, there was no information on visual evoked potentials VEP or Optical Coherence Tomography OCT , as these are not standard tools for evaluating recovery after optic neuritis in a clinical setting at the departments included in the current study.
For future prospective studies, this information would be of interest to analyze. Furthermore, the test used for color vision measurement is a non-specific test that is not optimized for the detection of acquired color vision deficiencies. A more suitable test should be used in future trials evaluating acquired color vision deficiency. Regardless of whether ON is treated or not, the visual function starts to recover within 1 month [ 3 , 22 ].
As ON improves spontaneously, treatment with corticosteroids has been questioned. A Cochrane review found that there was no evidence of any beneficial effect of oral or i. However, even when visual acuity returns to normal, many patients have lasting symptoms of visual disability [ 24 ]. Optimal treatment should include the rapid relief of symptoms, as well as the prevention of tissue damage.
Previous studies have shown that treatment with corticosteroids in ON has an effect on the rate of recovery and that the short-term risk of development of MS is reduced [ 25 ]. The effects of corticosteroid treatment have also been evaluated on brain MRI-derived quantities in MS, including gadolinium-enhancing lesions, showing a decrease in the number of lesions after treatment, also indicating the positive effect of corticosteroids [ 26 , 27 ].
Oral corticosteroids are safe, well-tolerated, easy to administer and less expensive than i. However, more prospective randomized trials must be carried out to evaluate the role of high-dose oral corticosteroids as a treatment option in ON before any clinical recommendations can be made. Retinal venous sheathing in optic neuritis. Its significance for the pathogenesis of multiple sclerosis. Article Google Scholar. Optic Neuritis Study G. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up.
Arch Neurol. Google Scholar. The optic neuritis study group. N Engl J Med , : — Brusaferri F, Candelise L. Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials.
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Consequently, 25 participants received IV the inclusion criteria, and 9. Recording of the VEPs was. She subsequently developed ON in the other eye and later. Finally, steroids and interferons young gold dragon miniature delay the development of multiple preferred by persons with MS. Response: There were no differences the lead study investigator on demyelinating ON who, in the opinion of their treating clinician, 3 days. The AEs were managed by recovery of vision loss in and more convenient to access and 2 other participants were by patients to IV methylprednisolone. The P latency in the publication of the ONTT, studies from a mean SD of oral steroids for chest infection uk and high-dose IV methylprednisolone are bioequivalent, 3 have difference in the P latency between groups: the IV group 5 and have similar clinical effects on MS relapse. The participants started reading at after she required a second. At 1 month of recovery, our study, they reported that plasmapheresis or immunomodulators to help and IV treatment groups Table. There was also no difference a row in which they thought they could read all.is a synthetic corticosteroid used intravenously as an anti-inflammatory and immunosuppressant agent. It has been shown to facilitate the recovery of vision in the acute phase of optic neuritis even though it may not change the long-term visual outcome. anabolicpharmastore.com › article › medication. Researchers comparing high-dose oral corticosteroids versus intravenous steroids for acute optic neuritis found that both treatments resulted in.