Literature Commentary

In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the; following 6 articles: 1. Morrow SA, Fraser JA, Day C, Bowman D, Rosehart H, Kremenchutzky M, Nicolle M. Effect of treating acute optic neuritis with bioequivalent oral vs intravenous corticosteroids: a randomized clinical trial. JAMA Neurol. 2018;75:690-696. 2. Saxena R, Singh D, Sharma M, James M, Sharma P, Menon V. Steroids versus no steroids in nonarteritic anterior; ischemic optic neuropathy: a randomized controlled trial. Ophthalmology. 2018;125:1623-1627. 3. Lee PH, Liang CC, Huang SF, Liao HT. The outcome analysis of traumatic facial nerve palsy treated with systemic steroid therapy. J Craniofacial Surg. 2018,29:1842-1847. 4. Schultheiss M, Härtig F, Spitzer MS, Feltgen N, Spitzer B, Hüsing J, Rupp A, Ziemann U, Bartz-Schmidt KU, Poli S. Intravenous thrombolysis in acute central retinal artery occlusion-a prospective interventional case series. PLoS One. 2018;13:e0198114. 5. Dale GH, Petersen T, Bacher Svendsen K, Christensen T, Houen G, Bek T. Time to steroid treatment in severe acute optic neuritis. Brain Behav. 2018 Jun 22 (epub ahead of print). 6. Bilyk JR, Murchison AP, Leiby BT, Sergott RC, Eagle RC, Needleman L, Savino PJ. The utility of color duplex ultrasonography in the diagnosis of giant cell arteritis: a prospective, masked study (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc. 2018;115:T9.

Literature Commentary Section Editors: Mark L. Moster, MD M. Tariq Bhatti, MD Literature Commentary In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the following 6 articles: 1. Morrow SA, Fraser JA, Day C, Bowman D, Rosehart H, Kremenchutzky M, Nicolle M. Effect of treating acute optic neuritis with bioequivalent oral vs intravenous corticosteroids: a randomized clinical trial. JAMA Neurol. 2018;75:690-696. 2. Saxena R, Singh D, Sharma M, James M, Sharma P, Menon V. Steroids versus no steroids in nonarteritic anterior ischemic optic neuropathy: a randomized controlled trial. Ophthalmology. 2018;125:1623-1627. 3. Lee PH, Liang CC, Huang SF, Liao HT. The outcome analysis of traumatic facial nerve palsy treated with systemic steroid therapy. J Craniofacial Surg. 2018,29:1842-1847. 4. Schultheiss M, Härtig F, Spitzer MS, Feltgen N, Spitzer B, Hüsing J, Rupp A, Ziemann U, Bartz-Schmidt KU, Poli S. Intravenous thrombolysis in acute central retinal artery occlusion-a prospective interventional case series. PLoS One. 2018;13:e0198114. 5. Dale GH, Petersen T, Bacher Svendsen K, Christensen T, Houen G, Bek T. Time to steroid treatment in severe acute optic neuritis. Brain Behav. 2018 Jun 22 (epub ahead of print). 6. Bilyk JR, Murchison AP, Leiby BT, Sergott RC, Eagle RC, Needleman L, Savino PJ. The utility of color duplex ultrasonography in the diagnosis of giant cell arteritis: a prospective, masked study (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc. 2018;115:T9. Morrow SA, Fraser JA, Day C, Bowman D, Rosehart H, Kremenchutzky M, Nicolle M. Effect of treating acute optic neuritis with bioequivalent oral versus intravenous corticosteroids: a randomized clinical trial. JAMA Neurol. 2018;75:690-696 Importance: Intravenous (IV) administration of corticosteroids is the standard of care in the treatment of acute optic neuritis. However, it is uncertain whether a bioequivalent dose of corticosteroid administered orally, which may be more cost-efficient and convenient for patients, is as effective as IV administration in the treatment of acute optic neuritis. Objective: To determine whether recovery of vision after treatment of acute optic neuritis with a high-dose IV corticosteroid is superior to that with a bioequivalent dose of an oral corticosteroid. Design, Setting, and Participants: This single-blind (participants unblinded) randomized clinical trial with 6-month follow-up was conducted at a single tertiary care center in London, Ontario, Canada. Participants were enrolled from March 2012 to May 2015, with the last participant's final visit occurring November 2015. Patients aged 18-64 years presenting within 14 days of acute optic neuritis onset, without any recovery at time of randomization and without history of optic neuritis in the same eye, were screened. Inclusion criteria included best-corrected visual acuity (BCVA) of 20/40 or worse and corticosteroids deemed required by treating physician. In total, 89 participants were screened; 64 were eligible, but 9 declined to participate. Thus, 55 participants were enrolled and randomized. Primary analysis was unadjusted and according to the intention-to-treat principle. Interventions: Participants were randomized 1:1 to the IV methylprednisolone (MP) sodium succinate (1,000-mg) or oral prednisone (1,250-mg) group. Main Outcomes and Measures: Primary outcome was recovery of the latency of the P100 component of the visual Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 531-537 evoked potential (VEP) at 6 months. Secondary outcomes were the P100 latency at 1 month and BCVA as assessed with Early Treatment Diabetic Retinopathy Study letter scores on the alphabet chart and scores on low-contrast letters at 1 and 6 months. Results: Of 55 randomized participants, the final analyzed cohort comprised 23 participants in the IV and 22 in the oral treatment groups. The mean (SD) age of the cohort was 34.6 (9.5) years, and there were 28 women (62.2%). At 6 months' recovery, P100 latency in the IV group improved by 62.9 ms (from a mean [SD] of 181.9 [53.6] to 119.0 [16.5] ms), and the oral group improved by 66.7 ms (from a mean [SD] of 200.5 [67.2] to 133.8 [31.5] ms), with no significant difference between groups (P = 0.07). Similarly, no significant group difference was found in the mean P100 latency recovery at 1 month. For BCVA, recovery between the groups did not reach statistical significance at 1 month or 6 months. In addition, improvements in low-contrast (1.25% and 2.5%) BCVA were not significantly different between treatment groups at 1 or 6 months' recovery. Conclusions and Relevance: This study finds that bioequivalent doses of oral corticosteroids may be used as an alternative to IV corticosteroids to treat acute optic neuritis. COMMENTS If you recall, Mark, in the March 2016 issue of Literature Commentary we discussed the COPOUSEP trial comparing oral (po) to intravenous methylprednisolone (IVMP) for the treatment of multiple sclerosis (MS) relapses, which showed no difference between the 2 steroid regimens. Now, we have this superiority study that looked to determine 531 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary whether IVMP had greater efficacy than high-dose po prednisone in patients with optic neuritis. It is a bit misleading, when you read the abstract that states 55 patients were enrolled and randomized. In fact, only 45 patients (23 in the IV group and 22 in the bymouth group) were actually treated and included in the final analysis. All patients were enrolled within 2 weeks of symptom onset with a visual acuity of 20/40 or worse. Patients received either 1,000 mg/day of IVMP for 3 days or 1,250 mg/day of po prednisone for 3 days. No steroid taper was given for either group. The primary outcome was the VEP P100 latency. As expected, at 6 months, both groups had a significant mean improvement in the P100 latency (62.9-ms IV group vs 66.7=-ms by-mouth group), with no statistically significant advantage for either. In addition, the final visual outcome with high-contrast sensitivity or low-contrast sensitivity acuity testing was no different at 6 months. I have several observations that I would like to highlight: 1. Sample size was small. 2. Single-blinded study. The patients were not blinded to treatment. I found this design interesting and wonder why the investigators did not do a double-dummy study? I think it would have been quite easy to do with each patient receiving both IV and po treatment but with one group receiving po placebo and the other receiving IV placebo. 3. Po prednisone group took 25 pills a day. That is a lot of pills! 4. No comment was made on the frequency of recurrent optic neuritis between the 2 groups. As you know the optic neuritis treatment trial found a 2-fold higher incidence of recurrent optic neuritis in the po prednisone group at a dose of 1 mg/kg/day as compared to the IVMP and po placebo groups. 5. Relatively high percentage of men (37.8%) enrolled in the study. Optic neuritis (idiopathic or MS associated) is typically thought of as a disease of women. 6. Anti-aquaporin 4 and anti-myelin oligodendrocyte glycoprotein antibody status was not assessed. I would not be surprised if some of these patients, especially those with profound visual loss or long segment optic nerve enhancement on MRI were positive for one of these antibodies. This obviously could skew the results. In my mind, the role of po vs IV corticosteroids in the treatment of acute inflammatory demyelinating optic neuritis is no longer an issue. Based on this study, despite its limitations and other similar studies such as the COPOUSEP trial, highdose po prednisone is equivalent to IVMP. I have to admit that I have not used high-dose po prednisone for my patients with optic neuritis and when I treat I favor outpatient IVMP. I have heard from some of my MS patients who have taken high-dose po prednisone that it was a bit tough on their stomachs. In this study, more patients in the po group (n = 8) had gastrointes532 tinal adverse events than the IV group (n = 5). I am curious Mark, what has been your practice regarding prescribing steroids for patients with optic neuritis? -M. Tariq Bhatti, MD Tariq, I agree with many of your concerns. However, I think that the follow-up was too brief (only 6 months) to accurately assess for recurrences of optic neuritis. Also, I do not see that this trial is different demographically from other MS populations. Typically, the breakdown is 2/3 women and 1/3 men, and this trial is only a few percentage points away from that. To answer your question, I usually treat with IV steroids. However, if a patient has difficulty obtaining IV treatment then I do prescribe po steroids at 1,250 mg daily. This has occurred a handful of times and without adverse events. Our MS specialists more frequently use the by-mouth treatment. -Mark L. Moster, MD Saxena R, Singh D, Sharma M, James M, Sharma P, Menon V. Steroids versus no steroids in nonarteritic anterior ischemic optic neuropathy: a randomized controlled trial. Ophthalmology. 2018;125:1623- 1627. Purpose: To examine the role of oral steroid therapy in the treatment of nondiabetic cases of acute nonarteritic anterior ischemic optic neuropathy (NAAION). Design: Randomized double-blind clinical trial. Participants: Thirty-eight patients with acute nondiabetic NAAION divided into 2 arms of 19 patients each. One arm constituted the cases and the other constituted the controls. Methods: Cases received oral steroid therapy and were designated the steroid group, whereas controls received placebo and were designated the nonsteroid group. Bestcorrected visual acuity (BCVA), visual evoked response (VER), and optical coherence tomography (OCT) were performed at baseline, 1 month, 3 months, and 6 months after recruitment into the trial. Main Outcome Measures: BCVA, VER, and retinal nerve fiber layer changes on OCT. Results: Both groups showed significant improvement in BCVA, VER latency, and resolution of disc edema on OCT parameters over 6 months. Final outcome showed no statistically significant difference regarding visual acuity, although VER was better in the steroid group (P = 0.011). BCVA, VER amplitude, and VER latency (P = 0.02, P = 0.02, and P = 0.04, respectively) showed a greater percentage improvement in the steroid group, which also saw a faster resolution of disc edema on OCT (1-month follow-up). Conclusions: Oral steroids in acute NAAION did not improve the visual acuity significantly at 6 months. However, they improved resolution of disc edema significantly and enabled a greater improvement in VER parameters. This subtle benefit of oral steroids in NAAION is clinically unimportant and does not provide support for its use. Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 531-537 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary COMMENTS Of the list of neuro-ophthalmic controversies, I think it is safe to say that the role of steroids in the treatment of nonarteritic anterior ischemic optic neuropathy (NAION) is close to the top. Within that context, I would be remiss if I did not mention Dr. Sohan Hayreh's NAION steroid study that has garnered a lot of attention (1,2). First, let me give kudos to the Editor-In-Chief of Ophthalmology, Stephen McLeod, MD, for publishing a negative-result clinical trial. Second, it is quite impressive that 1 institution (in India) recruited 38 NAION patients within 17 months. This was a double-blind, placebo-controlled trial that randomized patients with NAION to receive either oral (po) prednisolone or po placebo within 1 month of the onset of visual loss. All patients in the by-mouth prednisolone group were started on 80 mg/day for 2 weeks followed by a taper that lasted 65 days. A total of 38 patients were randomized equally into the 2 groups. The baseline demographics of the 2 groups were similar. However, the steroid group had a slightly worse baseline logMAR visual acuity (1.0 steroid group vs 0.8 placebo group). No patients with diabetes mellitus were enrolled. The primary outcome was BCVA at 6 months. Both groups showed an improvement in final visual acuity with a median logMAR visual acuity of 0.6 in the placebo group and 0.5 in the steroid group. Although the percentage change in vision over time was better in the steroid group compared with the placebo group (P = 0.02), the final visual acuity at 6 months was not statistically significant (P = 0.78). Patients in the steroid group had faster resolution of their optic disc edema at 1 month, but overall, the speed of recovery was noted to be similar between the 2 groups. I had a bit of a difficult time grasping the visual acuity data and had to use the visual acuity conversion chart because unlike in the ischemic optic neuropathy decompression trial, the visual acuity data were recorded using the logMAR scale, and the outcome was not presented as a percentage of lines improved-worsened. Is the issue of steroids in NAION a foregone conclusion now or do we as a neuro-ophthalmology community need to spend the energy, time, and money to do a bigger NAION steroid study? What say you, Mark? -M. Tariq Bhatti, MD 1. Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol. 2008;246:1029-1046. 2. Lee AG, Biousse V. Should steroids be offered to patients with nonarteritic anterior ischemic optic neuropathy? J Neuroophthalmol. 2010;30:193-198. Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 531-537 Tariq, I say that this study does not lead to any foregone conclusions that steroids do not work in NAION. On the contrary, before this article, I was comfortable with my assessment of the literature, my understanding of the mechanism of action of steroids, and past clinical experience that steroids would not be helpful. However, despite the conclusion of the authors that steroids did not improve visual acuity significantly, the data suggest otherwise. There was a statistically significant difference in improvement of visual acuity in treated vs untreated that the authors claim is not clinically significant. In Snellen acuity measurements, the treated group improved from 20/200 to 20/63 and the untreated group improved from 20/159 to 20/80. I am not comfortable in calling that clinically insignificant. In addition, there was statistically significant improvement in VER latency and amplitude in the treated vs untreated group. The median time to presentation was 12 days without mention of time until treatment. Perhaps, treatment within just a few days of presentation would have shown more benefit. I commend the authors for performing a double-blind clinical trial, and, for me, there is enough to warrant a larger trial. The cost for an outpatient trial of steroids vs placebo would be very reasonable. A final thought on what the authors call a limitation of their study, which is the exclusion of patients with diabetes. I actually see this as a benefit because there would have been a possibility of mistakenly including patients with diabetic papillopathy who often have a better visual outcome than patients with NAION. -Mark L. Moster, MD Lee PH, Liang CC, Huang SF, Liao HT. The outcome analysis of traumatic facial nerve palsy treated with systemic steroid therapy. J Craniofac Surg. 2018,29:1842-1847. Purpose: Although facial nerve palsy is uncommon after a blunt craniofacial injury, it will result in functional and aesthetic disability if full recovery is not achieved. Currently, the management is still controversial and mainly through systemic steroid therapy or surgical decompression. However, current studies mainly focus on the surgical intervention, and only a few of these studies discuss the details of the steroid treatments. Thus, the purpose of this study is to analyze possible prognosis factors of systemic steroid in managing traumatic facial nerve palsy after a blunt craniofacial injury retrospectively. Methods: During the period from May 2005 to April 2015 at Chang Gung Memorial Hospital, a total of 26 patients who suffered from post-traumatic facial nerve palsy receiving steroid therapy were enrolled in the study. All the patient's charts were reviewed, recorded, and analyzed 533 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary including the general data, temporal bone fracture type, hospital courses, trauma-related data from emergency department records, and initial and final facial nerve palsy grading. The facial nerve palsy was graded using the House-Brackmann (HB) system; the final HB Grade I was set as full recovery. Results: The outcome showed steroid therapy onset within 24 hours (odds ratio [OR] = 10.111; 95% confidence interval [CI] = 1.597-64.005; P = 0.014) and steroid therapeutic duration for longer than 14 days (OR = 11.571; 95% CI = 1.172-114.262; P = 0.036) possessed a significantly better recovery rate. Conclusion: This study recommends applying steroids within 24 hours once post-traumatic facial palsy occurs, and the therapy should persist longer than 14 days. COMMENTS For those who take trauma call or are involved in the care of patients with facial trauma, this article is for you! The authors did a 10-year retrospective chart review of patients who suffered facial nerve palsy due to blunt trauma. Twenty-six patients treated with steroids were analyzed to determine the prognostic factors of systemic steroids in the management of blunt traumatic facial nerve paralysis. Many factors were analyzed including patient demographics, initial House-Brakmann (HB) grade, onset of facial palsy, pattern of fracture, duration of treatment, and clinical signs and symptoms of trauma. Patients received varying regimens of systemic steroids. Based on a multivariate analysis, steroid therapy initiated within 24 hours, and steroid therapy duration of greater than 14 days was associated with a better chance of full recovery. No patient with an HB grade of 6 (complete facial palsy) had full recovery compared with nearly 50% of patients with HB grade of 2-5 achieving full recovery. There are many limitations of this study with some of the obvious being a retrospective design, selection bias, no standardized steroid regimen, and no control group. The authors tried to compare the results of their steroid treated group with 6 observation patients, none of whom enjoyed full recovery. I found it curious that although the authors state toward the end of the introduction- ".. patients with delayed-onset or incomplete palsy were normally treated with systemic steroids.. However, there is still lack of a high-level, evidence-based study to backup this recommendation."- their study did not accomplish that at all. -M. Tariq Bhatti, MD Tariq, I agree with your assessment of the limitations of this study. As it turns out, the patients that received observation had much milder palsies to begin with (HB of grades 2-3 compared with an average grade of 4.42 in the patients treated with steroids), so that it would not be an adequate control group for comparison. 534 Despite the limitations, it seems that treatment within 24 hours and for 14 days makes sense until we have better data. -Mark L. Moster, MD Schultheiss M, Härtig F, Spitzer MS, Feltgen N, Spitzer B, Hüsing J, Rupp A, Ziemann U, BartzSchmidt KU, Poli S. Intravenous thrombolysis in acute central retinal artery occlusion- a prospective interventional case series. PLoS One. 2018;13:e0198114 Background: No evidence-based therapy exists for nonarteritic central retinal artery occlusion (NA-CRAO). Retinal ischemic tolerance is low; irreversible damage occurs within 4 hours of experimental NA-CRAO. In previous randomized trials evaluating intra-arterial or intravenous thrombolysis (IVT) in NA-CRAO, only one patient was treated this early. In December 2013, the Departments of Neurology and Stroke and Ophthalmology at University Hospital Tuebingen, Germany, decided to treat patients using IVT within 4.5 hours of NA-CRAO, the therapeutic window established for ischemic stroke. Materials and Methods: Consecutive NA-CRAO patients with severe visual loss received IVT after exclusion of intracranial hemorrhage. Follow-up was conducted at Day 5 (d5) and Day 30 (d30). Visual outcomes were compared with the conservative standard treatment (CST) arm of the EAGLE trial. Results: Until August 2016, 20 patients received IVT within 4.5 hours after NA-CRAO with a median onset-totreatment time of 210 minutes (IQR 120-240). Visual acuity improved from baseline mean logarithm of the minimum angle of resolution 2.46 ± 0.33 (SD) (light perception) to 1.52 ± 1.09 (Snellen equivalent: 6/200) at d5 (P = 0.002) and 1.60 ± 1.08 (Snellen equivalent: 6/240) at d30. Compared with the EAGLE CST-arm, functional recovery to reading ability occurred more frequently after IVT: 6/20 (30%) vs 1/39 (3%) at d5 (P = 0.005) and at d30 5/20 (25%) vs 2/37 (5%) (P = 0.045). Two patients experienced serious adverse events (1 angioedema and 1 bleeding from an abdominal aortic aneurysm) but recovered without sequelae. Conclusions: IVT within 4.5 hours after symptom onset may represent an effective treatment of NA-CRAO. Randomized trials are warranted to evaluate efficacy and safety of early IVT in acute NA-CRAO. COMMENTS The original enthusiasm for thrombolytic therapy for CRAO was quashed when the EAGLE study results were published. However, there has been much criticism of that study, and numerous articles have suggested that thrombolytic therapy may be helpful in CRAO. Schultheiss et al looked at 20 patients treated within 4.5 hours of Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 531-537 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary presentation and found improvement compared with the control arm of the EAGLE study. Although this study has limitations, I certainly agree with the call for a prospective, randomized, placebo-controlled trial with initiating treatment within 4.5 hours of presentation. -Mark L. Moster, MD A while back I had coauthored an article on thrombolytic therapy for CRAO (1). I think the comments in that article still hold true today: In the event that future randomized studies unambiguously and convincingly demonstrate the efficacy and safety of thrombolytic therapy in CRAO, ophthalmologists and health care providers should consider the following issues and potential hurdles to the successful implementation of thrombolytic therapy as a standardized treatment for CRAO: 1. Development of an organizational infrastructure that facilitates the well-tolerated administration of intravenous thrombolytic therapy, intra-arterial thrombolytic therapy, or both in a timely manner. 2. A systematic institutional approach with the integral involvement of ophthalmologists, stroke specialists, emergency physicians, and neuroradiologists. 3. Development of a specific thrombolytic therapy protocol to maximize benefit and minimize complications. 4. A consensus on who will be responsible for the administration of intravenous thrombolytic therapy (e.g., emergency physician, ophthalmologist, neurologist, etc.). Currently, most hospitals allow emergency physicians to administer intravenous thrombolytic therapy for an acute ischemic stroke, a situation that may not necessarily be appropriate for patients with CRAO. 5. The medicolegal ramifications of thrombolytic therapy associated with CRAO. 6. Lack of public awareness of CRAO resulting in a delay in seeking medical care. To overcome this problem, it will require extensive public education and awareness programs. 7. The large financial cost of thrombolytic therapy. In a recent study involving 1,379 patients with CRAO, Suri et al (2) showed the mean hospital cost of not receiving thrombolytic therapy was dramatically less than the hospital cost of thrombolytic therapy ($14,500 vs $32,500- 37,800, respectively). -M. Tariq Bhatti, MD 1. Hazin R, Dixon JA, Bhatti MT. Thrombolytic therapy in central retinal artery occlusion: cutting edge therapy, standard of care therapy, or impractical therapy? Curr Opin Ophthalmol. 2009;20:210-218. 2. Suri MF, Nasar A, Hussein HM, Divani AA, Qureshi A. Intraarterial thrombolysis for central retinal artery occlusion in United States: Nationwide In-patient Survey 2001-2003. J Neuroimaging. 2007;17:339-343. Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 531-537 Dale GH, Petersen T, Bacher Svendsen K, Christensen T, Houen G, Bek T. Time to steroid treatment in severe acute optic neuritis. Brain Behav. 2018 Jun 22 (epub ahead of print) Objectives: Steroid treatment can accelerate visual recovery in patients with optic neuritis (ON), but it is unknown whether the timing of the start of treatment influences the outcome. The main purpose of this observational study was to assess the effect of early onset steroid treatment of ON on visual prognosis and retinal morphology. Methods: Forty-nine patients with acute mild/moderate (n = 21) or severe (n = 28) ON, and an equal number of healthy controls were enrolled. Patients with severe ON either received early-onset steroid treatment (initiated within 1 week of presentation with visual loss) (n = 9), late-onset treatment (initiated after 1 week) (n = 13), or no treatment (n = 6). Visual function and retinal morphology were studied after 6 and 12 months. Results: All measures of visual function had improved after 6 months (P # 0.03) in the 3 groups with severe ON. This was not the case for Rayleigh match setting range (SR) in the nontreated group (P = 0.24), or for SR (P = 0.08) and latency to P100 of visual evoked potential (P = 0.08) in the late-onset treated group. After 12 months, further improvement occurred in the nontreated and late-treated groups, but not in the early-treated group. Macular retinal nerve fiber layer (mRNFL) and ganglion cell plus inner plexiform layer had decreased significantly (P # 0.001) in all 3 groups with severe ON after 6 months. After 12 months, only mRNFL had further significantly decreased and only in the late-onset treated group (P = 0.02). Conclusion: The beneficial effects of early-onset steroid treatment of ON are limited to a few months, whereas the long-term prognosis is independent of the timing of treatment. COMMENTS This study compared the visual results of early steroid treatment (,1 week), late treatment (.1 week), or no treatment in patients with ON. The time of treatment of optic neuritis with steroids was determined by the logistics of referral for treatment rather than a prospective attempt at treatment earlier or later than 7 days. Those not treated was because of patient preference or contraindication. Earlyonset treatment resulted in earlier visual recovery than lateronset treatment, and both resulted in earlier recovery than no treatment. What is not mentioned in the study, however, is how much earlier or later than 7 days each group was treated. In contrast to some previous studies, patients with steroid treatment did not achieve a better clinical outcome or better optical coherence tomography parameters. Limitations include small sample size and the inclusion of first time as well as recurrent cases of ON. Also, there is no information on the average time to treatment for either the early or late group in this study. 535 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary This article reinforces what we have learned from previous studies, especially the Optic Neuritis Treatment Trial (ONTT). That is, steroids hasten recovery but proffer no long-term visual benefit in patients with ON. This study offered to date on whether steroids can delay future demyelinating events. -Mark L. Moster, MD I have to be honest: I am not really sure whether I gained any new knowledge given the solid body of evidence already published on the role of steroids in the treatment of ON. I understand that there may not have been a study that looked at the timing of initiating steroid treatment for ON. I was disappointed that the authors did not specify exactly when the 12 patients in the delayed group (.1 week) received treatment. As you know, the ONTT enrolled all patients within 8 days of visual symptom onset. It seems to me the designers of the ONTT were already aware of the benefit of early steroid treatment. -M. Tariq Bhatti, MD Bilyk JR, Murchison A, Leiby BT, Sergott RC, Eagle RC, Needleman L, Savino PJ. The utility of color duplex ultrasonography in the diagnosis of giant cell arteritis: a prospective, masked study (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc. 2018;115:T9 Purpose: To evaluate the diagnostic yield and concordance of color duplex ultrasound (CDU) of the superficial temporal artery (STA), temporal artery biopsy (TAB), and American College of Rheumatology (ACR) criteria in the diagnosis of giant cell arteritis (GCA). Methods: Prospective, masked study of all patients evaluated in 1 institution suspected of having GCA. All patients with a suspected diagnosis of GCA were admitted for pulsed intravenous corticosteroids. Patients underwent serologic work-up, and ACR criteria were documented. All patients had a CDU and TAB performed within 3 days of initiation of systemic corticosteroid therapy. Main outcome measure: concordance of CDU and TAB. Secondary outcome measures: concordance between unilateral and bilateral CDU and TAB by side and segment, concordance between TAB and ACR criteria, and statistical analysis of serologic markers for GCA. Results: The diagnosis of biopsy-proven GCA was found in 14 of 71 (19.7%) patients. The sensitivity of CDU compared with the reference standard of TAB ranged between 5.1% and 30.8% depending on the signs studied on CDU and correlation of specific TAB parameters. Of the serologic studies, a platelet count threshold of 400,000 mL had the highest positive (18.32) and lowest negative (0.37) likelihood ratios (LRs) for a diagnosis of GCA. Conclusion: In this study, CDU showed minimal value in diagnosing GCA compared with TAB. There was poor correlation between CDU results and ACR criteria for GCA. The threshold platelet count had higher positive and negative 536 predictive values for GCA than CDU and is a useful serologic marker for GCA COMMENTS Color duplex ultrasound (CDU) has been proposed by some to be a sensitive and specific test for the diagnosis of giant cell arteritis (GCA). Often, when I have residents from neurology or medicine rotating on my service, and we discuss potential GCA patients, I am questioned about foregoing temporal artery biopsy (TAB) and using ultrasound instead, based on previous literature. However, I have not found CDU helpful in either ruling in or ruling out GCA. With that in mind, I chose to review this study performed by my colleagues at Wills, which served as Dr. Jurij Bilyk's American Ophthalmological Society thesis. This prospective, masked trial comprised a typical cohort of 71 patients with GCA. Forty-nine percent had vision loss, 20% had headache, 16% had blurred vision, and 16% had diplopia. The study hypothesis was that CDU would correlate with TAB results in the diagnosis of GCA. Bilateral TABs were performed by experienced oculoplastic surgeons and interpreted by an ocular pathologist with a vast experience in interpreting TABs. CDU studies were performed by an experienced certified ultrasonographer and interpreted by a radiologist specializing in vascular ultrasonography. The parameters looked for were the "halo" sign, stenosis and/or occlusion, and the CDU results were correlated to TAB results by patient, side, and 2-cm segments of the artery. Twenty-percent of 71 patient biopsies were positive for GCA. There was a discordance rate of 1.6% between sides. Unlike most previous studies on the subject, the authors reported likelihood ratios (LRs) regarding the usefulness of CDU in GCA. Briefly, an LR uses both sensitivity and specificity to calculate the usefulness of a diagnostic test to either rule in (positive LR) or rule out (negative LR) a disease. Depending on the parameters studied, the positive LRs ranged between 2.20 and 3.06, whereas the negative LRs ranged between 0.81 and 0.91; neither of these ranges effectively ruled in or ruled out GCA by CDU. The area under the receiver operating characteristic curve also was poor, ranging between 0.54 and 0.58. Based on these analyses, CDU was not helpful in diagnosing or excluding GCA in this study. Previous studies mention "biopsy-negative GCA" patients who were successfully diagnosed by CDU. In this study, all TAB-negative patients were quickly tapered off steroids, and none of those had progressive visual loss, which would have been expected if they truly had GCA. Interestingly, there was no statistical difference in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) between TAB-positive or TAB-negative patients. This is likely explained by the fact that patients chosen for TAB often have elevated ESR and CRP. Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 531-537 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary However, platelet counts and interleukin-6 levels were greater in TAB positive patients. This study confirms my clinical impression that TAB is still the "gold standard" for diagnosing GCA. -Mark L. Moster, MD Let me commend Dr. Bilyk et al on a very comprehensive study which contains a great deal of excellent information. While at Duke, I was approached by someone in the vascular laboratory regarding using CDU in GCA. I explained to them that, in my opinion, using CDU to make the diagnosis of GCA in lieu of a TAB was not standard of care here in the United States. Interestingly, when I was in England recently giving a talk on GCA, the utility of CDU was discussed, and apparently in Europe, it is widely accepted as a diagnostic tool for GCA (1). This study confirms what you already said, Mark, which is that TAB remains the gold standard for diagnosing GCA. Moster and Bhatti: J Neuro-Ophthalmol 2018; 38: 531-537 I think we all understand that TAB is not 100% sensitive for GCA, but I really like what the authors said about a "gold standard:" in the strictest sense, a gold standard test would have 100% sensitivity and specificity for a given disease, a combination that does not exist in medicine. A less rigid definition of a gold standard is a modality that, albeit imperfect, is the best test available to diagnose a given pathology and is usually referred to as the "reference standard." As noted in the article, Peter Savino has pointed out that any new test that attempts to supplant the accepted reference standard as "the new gold standard" for a specific diagnosis must exceed the sensitivity and specificity of the older test. -M. Tariq Bhatti, MD 1. Landau K, Savino PJ, Gruber P. Diagnosing giant cell arteritis: is ultrasound enough? J Neuroophthalmol. 2013;33:394-400. 537 Copyright © North American Neuro-Ophthalmology Society. 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