The
Optic
Neuritis Treatment Trial
Implications for Clinical
Practice
the 1950s, physicians have debated the value of Since corticosteroids for optic neuritis. controlled studies have demonstrated effi¬ as a
treatment
Although no
cacy, corticosteroids are commonly prescribed during the acute phase of the disorder. To resolve the contro¬ versy around the therapeutic role of corticosteroids in optic neuritis, the Optic Neuritis Treatment Trial
(ONTT) was developed.
Between July 1,1988, and June 30,1991,457 patients entered into the trial. Based on the study's entry criteria, the ONTT results are applicable to the treat¬ ment of patients between ages 18 and 46 years who are examined within 8 days of the onset of visual symptoms of a first attack of demyelinative optic neuritis. The baseline characteristics of the patients in the trial were reported in a recent issue of the Archives. ' Each patient enrolled in the ONTT was randomly assigned to one of three treatment regimens: (1) intra¬ venous methylprednisolone sodium succinate (250 mg every 6 hours for 3 days) followed by oral prednisone (1 mg/kg per day for 11 days), (2) oral prednisone (1 mg/kg per day for 14 days), or (3) oral placebo (for 14 days). Each oral regimen was followed by a short taper con¬ sisting of 20 mg on day 15 and 10 mg on days 16 and 18. were
RESULTS OF TREATMENT TRIAL
As recently reported in the New England Journal of Medicine,2 most patients in all three treatment groups had good recovery of vision. After 6 months' follow-up, the median visual acuity in each group was 20/16 in the study eye, with fewer than 10% of patients in each group having visual acuity in the study eye of 20/50 or worse.
Among patients treated with a 3-day course of intra¬ methylprednisolone followed by an 11-day course of oral prednisone, visual function recovered considerably faster than it did in patients receiving the placebo, particularly during the first 2 weeks of followup. Although the differences between groups lessened over time, visual function at 6 months was still slightly venous
better in the group receiving intravenous medication. The benefit of the intravenous regimen was most ap¬ parent in patients whose visual acuity at study entry was worse than 20/40 in the study eye. Oral prednisone alone did not improve recovery rate or visual outcome at 6-month follow-up. Unexpectedly, patients in this group suffered a higher rate of new attacks of optic neuritis in either eye than did patients in the other two groups. TREATMENT RECOMMENDATIONS
The typical course of untreated, acute, demyelinative optic neuritis is one of improvement to normal or near-normal vision. Based on the ONTT results, oral prednisone alone, administered in standard doses, con¬ fers no beneficial effect and should not be prescribed. Therapeutic options that should be considered in¬ clude (1) a 3-day course of intravenous methylpredniso¬ lone followed by an 11-day course of oral prednisone, and (2) no treatment. A decision must be made on a patient-by-patient basis, with the risks and costs of treatment being weighed against the potential bene¬ fits. When the presenting visual loss is mild, treatment probably is not beneficial. However, when visual acuity within the first 8 days of symptom onset is worse than 20/40, treatment may benefit the patient. For some patients, treatment, with the potential for recovery of normal or near-normal vision about 2 weeks earlier than with no treatment, may be of value; for others, it may not. The small beneficial effect of treatment noted after 6 months' follow-up may be only marginally signif¬ icant. However, because optic neuritis can recur and can presumably cause additional damage with each re¬ currence, limiting optic nerve damage, albeit slightly, with treatment may be justified. In the ONTT, intravenous corticosteroids were ad¬ ministered four times per day in a hospital setting. Because side effects of treatment were generally mild, outpatient administration may be feasible. No data are available pertaining to the efficacy of treatment of optic
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 05/20/2015
neuritis with one or two daily intravenous injections. Such a regimen would enhance the feasibility of outpa¬ tient treatment. Likewise, no data are available re¬ garding the adequacy of a regimen limited to 3 days of intravenous administration of corticosteroids without a subsequent course of oral prednisone. THE IMPORTANCE OF CLINICAL TRIALS
Clinical trials have provided much of the knowledge we have gained in the last 40 years regarding the effica¬ cy of treatments of various medical conditions. The National Eye Institute has been a leader among the many branches of the National Institutes of Health in promoting the value of multicenter, controlled, clinical trials. In very few conditions is the natural history of a disease so well defined and the outcome of intervention so evident that the benefits as well as the adverse effects of a treatment can be determined without a control group and randomization of treatment assign¬ ments. With a disorder such as optic neuritis, the effica¬ cy of treatment can only be determined in a multicenter study, which allows recruitment of a sufficiently large number of patients. With an insufficient sample size, reseachers too often draw erroneous conclusions about a treatment's value.
The 0 NTT's
finding that oral prednisone was not only ineffective, but also was associated with an in¬ creased rate of new attacks of optic neuritis is testimo¬
ny to the value of clinical trials. As Thomas Chalmers has so aptly stated, "One has only to review the grave¬ yard of discarded therapies to discover how many pa¬ tients might have benefited from being assigned to a
control group."3 Such is the case for oral prednisone. Based on results of the ONTT, it is time to stop treating acute demyelinative optic neuritis with oral pred¬ nisone. RoyW. Beck, MD Optic Neuritis Study Group Tampa, Fla The ONTT
was
Bethesda, Md.
supported in part by the
National
References 1. Optic Neuritis Study Group. The clinical profile of optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol.
1991;109:1673-1678. 2. Beck RW, Cleary PA, Anderson MA,
et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992;326:581-588. 3. Chalmers TC. Prophylactic treatment of Wilson's disease. N Engl J Med. 1968;278:911-912.
From the Archives of the Archives A look at the past.
.
Eye Institute,
.
In November 1927, Charlie Chiarelli, an Italian boy, nearly 4 years old, was admitted to Bellevue Hospital, and was assigned to the eye service because of marked exophthalmos. On seeing him, I recognized him immediately as a patient whom I had examined at Mount Sinai Hospital about three months before, through the courtesy of Dr Isadore Goldstein. Fortu¬ nately, the diagnosis of Schüller's disease (or Christian's disease) had been made at Mount Sinai Hospital before I saw the case, for I was unfamiliar with the striking syndrome presented and should not have been able to classify it. The case in its earlier stages has been reported by Dr Louis Hausman and Dr Walter Bromberg in the Archives ofNeurology and Psychiatry.
Pronounced exophthalmos was the most striking clinical feature in the reported cases, but seemingly the attention of ophthalmologists has not been called to the condition by descrip¬
tions in the literature on the eyes. Moreover, no reference can be found to an antemortem orbital dissection in a case demonstrating the syndrome, and so for the first time I can report surgical exploration of the orbit in a living victim of this rare and important disease and definitely establish the cause of the extreme proptosis. Source: Wheeler JM. Exophthalmos associated with diabetes insipidus and large defects in the bones of the skull. Arch Ophthalmol. 1931;5:1. Edited by Julie Foreman, Associate Editor
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 05/20/2015
Optic
Neuritis Treatment Trial
Implications for Clinical
Practice
the 1950s, physicians have debated the value of Since corticosteroids for optic neuritis. controlled studies have demonstrated effi¬ as a
treatment
Although no
cacy, corticosteroids are commonly prescribed during the acute phase of the disorder. To resolve the contro¬ versy around the therapeutic role of corticosteroids in optic neuritis, the Optic Neuritis Treatment Trial
(ONTT) was developed.
Between July 1,1988, and June 30,1991,457 patients entered into the trial. Based on the study's entry criteria, the ONTT results are applicable to the treat¬ ment of patients between ages 18 and 46 years who are examined within 8 days of the onset of visual symptoms of a first attack of demyelinative optic neuritis. The baseline characteristics of the patients in the trial were reported in a recent issue of the Archives. ' Each patient enrolled in the ONTT was randomly assigned to one of three treatment regimens: (1) intra¬ venous methylprednisolone sodium succinate (250 mg every 6 hours for 3 days) followed by oral prednisone (1 mg/kg per day for 11 days), (2) oral prednisone (1 mg/kg per day for 14 days), or (3) oral placebo (for 14 days). Each oral regimen was followed by a short taper con¬ sisting of 20 mg on day 15 and 10 mg on days 16 and 18. were
RESULTS OF TREATMENT TRIAL
As recently reported in the New England Journal of Medicine,2 most patients in all three treatment groups had good recovery of vision. After 6 months' follow-up, the median visual acuity in each group was 20/16 in the study eye, with fewer than 10% of patients in each group having visual acuity in the study eye of 20/50 or worse.
Among patients treated with a 3-day course of intra¬ methylprednisolone followed by an 11-day course of oral prednisone, visual function recovered considerably faster than it did in patients receiving the placebo, particularly during the first 2 weeks of followup. Although the differences between groups lessened over time, visual function at 6 months was still slightly venous
better in the group receiving intravenous medication. The benefit of the intravenous regimen was most ap¬ parent in patients whose visual acuity at study entry was worse than 20/40 in the study eye. Oral prednisone alone did not improve recovery rate or visual outcome at 6-month follow-up. Unexpectedly, patients in this group suffered a higher rate of new attacks of optic neuritis in either eye than did patients in the other two groups. TREATMENT RECOMMENDATIONS
The typical course of untreated, acute, demyelinative optic neuritis is one of improvement to normal or near-normal vision. Based on the ONTT results, oral prednisone alone, administered in standard doses, con¬ fers no beneficial effect and should not be prescribed. Therapeutic options that should be considered in¬ clude (1) a 3-day course of intravenous methylpredniso¬ lone followed by an 11-day course of oral prednisone, and (2) no treatment. A decision must be made on a patient-by-patient basis, with the risks and costs of treatment being weighed against the potential bene¬ fits. When the presenting visual loss is mild, treatment probably is not beneficial. However, when visual acuity within the first 8 days of symptom onset is worse than 20/40, treatment may benefit the patient. For some patients, treatment, with the potential for recovery of normal or near-normal vision about 2 weeks earlier than with no treatment, may be of value; for others, it may not. The small beneficial effect of treatment noted after 6 months' follow-up may be only marginally signif¬ icant. However, because optic neuritis can recur and can presumably cause additional damage with each re¬ currence, limiting optic nerve damage, albeit slightly, with treatment may be justified. In the ONTT, intravenous corticosteroids were ad¬ ministered four times per day in a hospital setting. Because side effects of treatment were generally mild, outpatient administration may be feasible. No data are available pertaining to the efficacy of treatment of optic
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 05/20/2015
neuritis with one or two daily intravenous injections. Such a regimen would enhance the feasibility of outpa¬ tient treatment. Likewise, no data are available re¬ garding the adequacy of a regimen limited to 3 days of intravenous administration of corticosteroids without a subsequent course of oral prednisone. THE IMPORTANCE OF CLINICAL TRIALS
Clinical trials have provided much of the knowledge we have gained in the last 40 years regarding the effica¬ cy of treatments of various medical conditions. The National Eye Institute has been a leader among the many branches of the National Institutes of Health in promoting the value of multicenter, controlled, clinical trials. In very few conditions is the natural history of a disease so well defined and the outcome of intervention so evident that the benefits as well as the adverse effects of a treatment can be determined without a control group and randomization of treatment assign¬ ments. With a disorder such as optic neuritis, the effica¬ cy of treatment can only be determined in a multicenter study, which allows recruitment of a sufficiently large number of patients. With an insufficient sample size, reseachers too often draw erroneous conclusions about a treatment's value.
The 0 NTT's
finding that oral prednisone was not only ineffective, but also was associated with an in¬ creased rate of new attacks of optic neuritis is testimo¬
ny to the value of clinical trials. As Thomas Chalmers has so aptly stated, "One has only to review the grave¬ yard of discarded therapies to discover how many pa¬ tients might have benefited from being assigned to a
control group."3 Such is the case for oral prednisone. Based on results of the ONTT, it is time to stop treating acute demyelinative optic neuritis with oral pred¬ nisone. RoyW. Beck, MD Optic Neuritis Study Group Tampa, Fla The ONTT
was
Bethesda, Md.
supported in part by the
National
References 1. Optic Neuritis Study Group. The clinical profile of optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol.
1991;109:1673-1678. 2. Beck RW, Cleary PA, Anderson MA,
et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992;326:581-588. 3. Chalmers TC. Prophylactic treatment of Wilson's disease. N Engl J Med. 1968;278:911-912.
From the Archives of the Archives A look at the past.
.
Eye Institute,
.
In November 1927, Charlie Chiarelli, an Italian boy, nearly 4 years old, was admitted to Bellevue Hospital, and was assigned to the eye service because of marked exophthalmos. On seeing him, I recognized him immediately as a patient whom I had examined at Mount Sinai Hospital about three months before, through the courtesy of Dr Isadore Goldstein. Fortu¬ nately, the diagnosis of Schüller's disease (or Christian's disease) had been made at Mount Sinai Hospital before I saw the case, for I was unfamiliar with the striking syndrome presented and should not have been able to classify it. The case in its earlier stages has been reported by Dr Louis Hausman and Dr Walter Bromberg in the Archives ofNeurology and Psychiatry.
Pronounced exophthalmos was the most striking clinical feature in the reported cases, but seemingly the attention of ophthalmologists has not been called to the condition by descrip¬
tions in the literature on the eyes. Moreover, no reference can be found to an antemortem orbital dissection in a case demonstrating the syndrome, and so for the first time I can report surgical exploration of the orbit in a living victim of this rare and important disease and definitely establish the cause of the extreme proptosis. Source: Wheeler JM. Exophthalmos associated with diabetes insipidus and large defects in the bones of the skull. Arch Ophthalmol. 1931;5:1. Edited by Julie Foreman, Associate Editor
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 05/20/2015
