Literature Commentary

In this issue of JNO Drs. M. Tariq Bhatti and Mark L. Moster discuss the following 6 articles: 1. Dinah Zur, Michaella Goldstein, Barequet D, Oron Y, Elkayam O, Karni A, Wilf-Yarkoni A, Regev K, Habot- Wilner Z. Susac's syndrome-A new ocular finding and disease outcome. Eye (Lond). 2021. doi: 10.1038/ s41433-021-01464-7. Epub ahead of print. 2. Durbant E, Radoi C, Garcia T, Denoyer A, Arndt C. Intravitreal triamcinolone injections in non-arteritic anterior ischemic optic neuropathy-A retrospective report. J Fr Ophtalmol. 2021;44:777-785. 3. Cavanaugh MR, Blanchard LM, McDermott M, Lam BL, Tamhankar M, Feldon SE. Efficacy of Visual Retraining in the Hemianopic Field after Stroke: Results of a Randomized Clinical Trial. Ophthalmology. 2021;128:1091- 1101. 4. Czihal M, Lottspeich C, Köhler A, Prearo I, Hoffmann U, Priglinger SG, Mackert MJ. Transocular sonography in acute arterial occlusions of the eye in elderly patients: Diagnostic value of the spot sign. PLoS One. 2021;16:e0247072. 5. Ailani J, Lipton RB, Goadsby PJ, Guo H, Miceli R, Severt L, Finnegan M, Trugman JM; ADVANCE Study Group. Atogepant for the Preventive Treatment of Migraine. N Engl J Med. 2021;385:695-706. 6. Engelter ST, Traenka C, Gensicke H, Schaedelin SA, Luft AR, Simonetti BG, Fischer U, Michel P, Sirimarco G, Kägi G, Vehoff J, Nedeltchev K, Kahles T, Kellert L, Rosenbaum S, von Rennenberg R, Sztajzel R, Leib SL, Jung S, Gralla J, Bruni N, Seiffge D, Feil K, Polymeris AA, Steiner L, Hamann J, Bonati LH, Brehm A, De Marchis GM, Peters N, Stippich C, Nolte CH, Christensen H, Wegener S, Psychogios MN, Arnold M, Lyrer P; TREAT- CAD investigators. Aspirin vs. anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, rand- omised, non-inferiority trial. Lancet Neurol. 2021;20:341-350.

Literature Commentary Section Editors: Mark L. Moster, MD M. Tariq Bhatti, MD Literature Commentary In this issue of JNO Drs. M. Tariq Bhatti and Mark L. Moster discuss the following 6 articles: 1. Dinah Zur, Michaella Goldstein, Barequet D, Oron Y, Elkayam O, Karni A, Wilf-Yarkoni A, Regev K, HabotWilner Z. Susac’s syndrome—A new ocular finding and disease outcome. Eye (Lond). 2021. doi: 10.1038/ s41433-021-01464-7. Epub ahead of print. 2. Durbant E, Radoi C, Garcia T, Denoyer A, Arndt C. Intravitreal triamcinolone injections in non-arteritic anterior ischemic optic neuropathy—A retrospective report. J Fr Ophtalmol. 2021;44:777–785. 3. Cavanaugh MR, Blanchard LM, McDermott M, Lam BL, Tamhankar M, Feldon SE. Efficacy of Visual Retraining in the Hemianopic Field after Stroke: Results of a Randomized Clinical Trial. Ophthalmology. 2021;128:1091– 1101. 4. Czihal M, Lottspeich C, Köhler A, Prearo I, Hoffmann U, Priglinger SG, Mackert MJ. Transocular sonography in acute arterial occlusions of the eye in elderly patients: Diagnostic value of the spot sign. PLoS One. 2021;16:e0247072. 5. Ailani J, Lipton RB, Goadsby PJ, Guo H, Miceli R, Severt L, Finnegan M, Trugman JM; ADVANCE Study Group. Atogepant for the Preventive Treatment of Migraine. N Engl J Med. 2021;385:695–706. 6. Engelter ST, Traenka C, Gensicke H, Schaedelin SA, Luft AR, Simonetti BG, Fischer U, Michel P, Sirimarco G, Kägi G, Vehoff J, Nedeltchev K, Kahles T, Kellert L, Rosenbaum S, von Rennenberg R, Sztajzel R, Leib SL, Jung S, Gralla J, Bruni N, Seiffge D, Feil K, Polymeris AA, Steiner L, Hamann J, Bonati LH, Brehm A, De Marchis GM, Peters N, Stippich C, Nolte CH, Christensen H, Wegener S, Psychogios MN, Arnold M, Lyrer P; TREATCAD investigators. Aspirin vs. anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol. 2021;20:341–350. Dinah Zur, Michaella Goldstein, Barequet D, Oron Y, Elkayam O, Karni A, Wilf-Yarkoni A, Regev K, HabotWilner Z. Susac’s syndrome—A new ocular finding and disease outcome. Eye (Lond). 2021. doi: 10.1038/s41433-021-01464-7. Epub ahead of print. Background: Susac syndrome, a rare autoimmune vasculo-occlusive disease, may pose a diagnostic challenge and result in a devastating ocular and systemic outcome. Our study identifies a new retinal finding and evaluates disease outcome. We aimed to assess clinical and imaging findings, systemic manifestations, and disease outcome in patients with ocular Susac syndrome under immunosuppressive/immunomodulation therapies. Methods: Retrospective tertiary center study including patients with a diagnosis of Susac syndrome with .12 months followup. Medical record review including ocular, neurological and auditory clinical and imaging findings, and treatment modalities. Main outcome measures were clinical manifestations and disease outcome. Results: Seven patients (14 eyes) with a mean age of 34.1 years were included. Mean follow-up was 31.9 months (12.4–72.4). All had bilateral ocular disease. Retinal microaneurysms, a new ocular finding, were demonstrated in 5 patients and persisted at the final visit. In 5 eyes, they further extended during follow-up. All were treated with immunosuppressive drugs and 5/7 additional immunomodulation therapy. At last examination, best-corrected visual Moster and Bhatti: J Neuro-Ophthalmol 2021; 41: 553-559 acuity was .20/40 in all eyes, 1/10 eyes had visual field deterioration, no eye had active ocular disease, all patients achieved neurological stability, and 1 patient had auditory deterioration. Conclusion: Retinal microaneurysms, a new ocular finding in Susac syndrome, were present in most of our patients, indicating ischemic retinal damage. Immunosuppressive and immunomodulation therapies seem to be highly effective in the control of disease activity. COMMENTS In this retrospective case series of 14 eyes in 7 patients with Susac Syndrome (SS) followed for more than 12 months, the authors report what they believe to be a new or novel finding of retinal microaneurysms (MAs) on intravenous fluorescein angiography (IVFA). The mean age of the patients was 34 years (range, 20–44 years) with 57% being women. The diagnosis of SS was made based on the criteria set by the European Susac Consortium. Six of 7 patients were treated with an immunosuppressive medication. The details of the ocular findings are well documented and there are some nice figures of the IVFA. At presentation, all 7 patients had bilateral ocular disease and all patients had extramacular branch retinal artery occlusion and peripheral retinal arteriolar occlusion on IVFA. One eye 553 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary in 1 patient had retinal MA on presentation but on followup, 8 eyes in 5 patients were noted to have new retinal MAs. These retinal MAs were noted in both ischemic and nonischemic areas involving the posterior pole or peripheral retina. None of the MAs were found to leak on IVFA. I asked Dr. Robert Egan his thoughts on this paper and this is what he had to say “I’ve seen this finding before. When I lecture on SS, I mention it with the caveat that retinal microaneurysms can be seen with any chronic retinal ischemic disease, not just SS, and therefore is not a pathognomonic finding of the illness. I did not mention it in my diagnosis and treatment paper in the JNO for that reason; and in our paper that same year we had noted it but also focused on the retinal collaterals which I do think is likely a pathognomonic finding. I think that this is the important caveat.” In keeping with what Dr. Egan said, I am not sure if the term “new” or “novel” that the authors used to describe the retinal MAs is correct. Maybe it would have been more appropriate to have used the term “unrecognized” or “underreported.” —M. Tariq Bhatti, MD I’m glad that this finding was published so that we do not need to seek alternative diagnoses when seeing a patient with SS and retinal MAs. —Mark L. Moster, MD Durbant E, Radoi C, Garcia T, Denoyer A, Arndt C. Intravitreal triamcinolone injections in nonarteritic anterior ischemic optic neuropathy—A retrospective report. J Fr Ophtalmol. 2021;44:777–785 Background: Nonarteritic anterior ischemic optic neuropathy (NAION) is a common cause of vision loss, but no treatment has demonstrated its efficiency. A preliminary study showed an improvement on the visual acuity (VA) in a group of patients who received intravitreal administration of triamcinolone acetonide (IVTA) vs. a nontreated group. In the present series, the visual outcome of IVTA in NAION was evaluated on a larger group of patients. Methods: This retrospective, unmasked and nonrandomized study took place at Reims University Hospital between 2009 and 2017. The data of consecutive patients presenting with isolated optic disc edema characteristic of recent NAION (,1 month of visual acuity loss) were included. After informed consent, a single intravitreal injection of filtrated 4 mg/0.1 mL triamcinolone acetonide were administered. Twenty-seven control patients chose not to be injected and therefore served as controls. LogMar visual acuity (VA), VA rating (VAR) (1 line = 0.1LogMAR = 5 VAR letters), retinal nerve fiber layer thickness assessed by OCT and static visual field were evaluated at presentation, after 7 days, after 3 months, and after 6 months. Results: Sixty-eight patients with NAION were evaluated. Forty-one received IVTA, 29 were injected within 15 days 554 after the onset of symptoms and 12 after 15 days. There was a higher proportion of patients improving VA of 2 lines or more (10 or more VAR letters) in the injected group (49%) compared with the noninjected group (11%, P = 0.019). Among the patients injected before 15 days, the proportion improving for 2 lines or more (55% vs 11%, respectively, P = 0.013) and for 3 lines or more (45% vs 11%, respectively, P = 0.035) were significantly higher than in the noninjected group. Also, comparing the VA at presentation with the VA after 6 months in the injected eyes, it improved significantly (P = 0.003) and also in the subgroup injected within 15 days (P = 0.0007), but not in the injected group after 15 days (P = 0.801). Visual field improvement was only observed in the subgroup of patients injected within 15 days with a significant improvement of the mean deviation (dB) within 6 months (P = 0.015). Conclusions: This follow-up study confirms the results of the previous series displaying an apparent benefit of intravitreal steroids injected in the acute phase of NAION. Only patients receiving IVTA within 15 days from onset of NAION have a significant improvement of VA and visual field during the follow-up period of 6 months. COMMENTS As you know Mark, despite the phase 2/3 study of intravitreal QPI-1007, a small-interfering RNA, for the treatment of nonarteritic anterior ischemic optic neuropathy (NAION) being extended, disappointingly, it was eventually halted because of lack of efficacy (1). Therefore, in many ways we are back to square one in establishing a proven effective therapy for NAION. In this retrospective case series that took place over 7 years, 29 patients with NAION underwent intravitreal administration of triamcinolone acetonide (IVTA) within 30 days of symptom onset. Visual acuity (VA) improvement was the primary outcome and was compared with a cohort of 27 control patients. All patients had optic disc edema and were white. Age of the patients ranged from 59 years to 91 years. The IVTA group was subdivided into those that were injected ,15 days (n = 29) and $15 days (n = 12). At 6 months, $ 2 lines of VA improvement was 49% in the IVTA group compared to 11% in the cohort group. In those patients that received IVTA within 15 days, 55% had .2 lines of VA improvement compared with 33% of the cohort (P = 0.013). However, there was no statistically significant difference in VA improvement in the $15-day IVTA cohort vs. the control cohort (P = 0.801). Let me point out something that I think is important and that was mentioned by the authors. If we compare the $3 lines, VA improvement between those patients that received IVTA within 15 days to the nonsurgical cohort of the Ischemic Optic Neuropathy Decompression Trial (IONDT) (2), the numbers are basically the same (45% vs 42.7%, respectively). I also found it interesting that only 11% of the control cohort had $3 lines of VA improvement, which certainly would favor a positive treatment effect. Moster and Bhatti: J Neuro-Ophthalmol 2021; 41: 553-559 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary I was very disappointed to find that there was no dedicated section or detailed discussion on the periprocedure and long-term complications of IVTA. All that is mentioned is that 2 patients underwent cataract surgery after IVTA. Finally, nowhere in the paper could I find the number of patients with lines of VA worsening. Table 4 presents the mean VA variation between presentation and at 6 months in LogMAR, but frankly it was a bit difficult to interpret. —M. Tariq Bhatti, MD REFERENCES 1. Available at: https://www.clinicaltrialsregister.eu/ctrsearch/trial/2015-003079-31/results. Accessed March 1, 2021. 2. Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. The Ischemic Optic Neuropathy Decompression Trial Research Group. JAMA. 1995;273:625–632. This study has many limitations. It is retrospective, unrandomized and the subjects and examiners were unmasked to the treatment. As the authors point out, 35% of treated patients and only 13% of untreated patients had diabetes. This, combined with the unknown status of the macula before or at the time of the NAION may mean that the VA improvements were because of treatment of diabetic macular edema. Alternatively, some of the patients may have had diabetic papillopathy and not NAION. There was also no standardized controlled measurement of VA. The lack of any difference in retinal nerve fiber layer and the similar results to the control group in the IONDT raises further concern. To consider this a possible treatment, a much better study is required. —Mark L. Moster, MD Cavanaugh MR, Blanchard LM, McDermott M, Lam BL, Tamhankar M, Feldon SE. Efficacy of Visual Retraining in the Hemianopic Field after Stroke: Results of a Randomized Clinical Trial. Ophthalmology. 2021;128:1091–1101 Purpose: To evaluate the efficacy of motion discrimination training as a potential therapy for stroke-induced hemianopic visual field defects. Design: Clinical trial. Participants: Forty-eight patients with stroke-induced homonymous hemianopia (HH) were randomized into 2 training arms: intervention and control. Patients were between 21 and 75 years old and showed no ocular issues at presentation. Methods: Patients were trained on a motion discrimination task previously evidenced to reduce visual field deficits, but not in a randomized clinical trial. Patients were randomized with equal allocation to receive training in their sighted or Moster and Bhatti: J Neuro-Ophthalmol 2021; 41: 553-559 deficit visual fields. Training was performed at home for 6 months, consisting of repeated visual discriminations at a single location for 20–30 minutes daily. Study staff and patients were masked to training type. Testing before and after training was identical, consisting of Humphrey visual fields (Carl Zeiss Meditech), macular integrity assessment perimetry, OCT, motion discrimination performance, and visual quality-of-life questionnaires Main Outcome Measures: Primary outcome measures were changes in perimetric mean deviation (PMD) on Humphrey Visual Field Analyzer in both eyes. Results: Mean PMDs improved over 6 months in deficittrained patients (mean change in the right eye, 0.58 dB; 95% confidence interval, 0.07–1.08 dB; mean change in the left eye 0.84 dB; 95% confidence interval, 0.22– 1.47 dB). No improvement was observed in sightedtrained patients (mean change in the right eye, 0.12 dB; 95% confidence interval, 20.38 to 0.62 dB; mean change in the left eye, 0.10 dB; 95% confidence interval, 20.52 to 0.72 dB). However, no significant differences were found between the alternative training methods (right eye, P = 0.19; left eye, P = 0.10). Conclusions: To date, no widely accepted therapy is available to treat HH. This study evaluated the efficacy of a promising potential treatment, visual perceptual training. We failed to find a difference between treatment training within the deficit field and control training within the sighted field when performed in a home environment. COMMENTS It is difficult when I see patients with a HH and explain to them that there is really not much I can do for them in improving the visual field defect. This randomized control trial evaluated the efficacy of in-home computer-based direction discrimination training in patients with HH from cerebral stroke. Three academic centers recruited 48 patients (46 completed the study) with the primary outcome being the change in perimetric mean deviation (PMD) on Humphrey Visual Field Analyzer. Secondary outcomes included optical coherence tomography metrics, microperimetry, and quality of life (QOL). Twenty-five patients underwent training of the deficit hemifield and 23 patients underwent training of the sighted hemifield, which served as the control group. Over 6 months, each patient performed 300 discriminations daily on average for 30 minutes for a minimum of 5 days per week. The specific task given was to discriminate the vertical direction of the stimulus relative to the horizontal meridian. Task difficulty was modified based on the degree of angle between the direction of motion and the horizontal meridian. In primary outcome, the mean PMD in the deficit field-trained cohort had improved (0.58 dB right eye and 0.84 dB left eye), but not in the sight field-trained cohort (0.12 dB right eye and 0.10 dB left eye). However, the difference between the 2 groups was not statistically different. 555 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Here are some interesting points I want to mention: • Industry sponsored • Powered based on 60 patients • On average, neither group reached the target training level • The sight field-trained cohort had improvement in QOL but not the deficit field-trained cohort • Visual field testing was variable among many of the patients • OCT ganglion cell layer analysis demonstrated transsynaptic retrograde degeneration. The authors pointed out that aside from being a randomized controlled study, a major strength of the trial was that it was a “real world test” using outcome measures routinely done in the clinical setting. —M. Tariq Bhatti, MD It is disappointing but expected that the formal visual field would not change in these patients. However, somewhat based on prior positive results in some functions with visual training (1), I would have expected some improvement in quality-of-life measures. —Mark L. Moster, MD 1. Ong YH, Brown MM, Robinson P, Plant GT, Husain M, Leff AP. Read-Right: a “web app” that improves reading speeds in patients with hemianopia. J Neurol. 201;259:2611–2615. Czihal M, Lottspeich C, Köhler A, Prearo I, Hoffmann U, Priglinger SG, Mackert MJ. Transocular sonography in acute arterial occlusions of the eye in elderly patients: Diagnostic value of the spot sign. PLoS One. 2021;16:e0247072 Background: To characterize the diagnostic yield of the spot sign in the diagnostic workup of acute arterial occlusions of the eye in elderly patients. Methods: Clinical characteristics of consecutive patients aged $50 years with acute central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), or anterior ischemic optic neuropathy (AION) were recorded. Videos of transocular sonography were assessed for the presence of the spot sign by 2 blinded readers. Group comparisons were made between CRAO-patients with and without the spot sign. Two experienced cardiovascular physicians allocated CRAO-cases to a presumed etiology, without and with knowledge on the presence/absence of the spot sign. Results: One-hundred-twenty-three patients were included, 46 of whom suffered from CRAO. A spot sign was seen in 32 of 46 of patients with CRAO and in 7 of 23 patients with BRAO. Interobserver agreement was excellent (Cohen’s kappa 0.98). CRAO-patients with the spot sign significantly more frequently had a medical history of cardiovascular disease (62.8 vs 21.4%, P = 0.03) and left heart valve pathologies (51.9 vs 10%, P = 0.03). The spot sign was not found 556 in any of the 3 patients with CRAO secondary to cranial giant cell arteritis. The assumed CRAO etiology differed in 37% of cases between 2 cardiovascular physicians, regardless whether transocular sonography findings were known or not. Conclusion: The spot sign is a simple sonographic finding with excellent interobserver agreement, which proofs the embolic nature of CRAO, but does not allow exact attribution of the underlying etiology. COMMENTS The “spot sign” is a hyperechoic, sharply delineated structure in optic nerve or nearby retina seen on transocular sonography that is caused by an embolus. This paper describes the presence or absence of the spot sign in 123 consecutively examined patients with central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), or anterior ischemic optic neuropathy (AION). The spot sign was present in 70% of 46 CRAO patients, 30% of 23 BRAO patients and none of 54 AION patients. One of the findings was that none of the patients diagnosed with giant cell arteritis (GCA) had a spot sign. This included 27 AION and 3 CRAO patients. Two cardiologists blinded to the results of the ultrasound reviewed the patient records and decided whether there was cardiovascular disease. In patients with CRAO, with a spot sign, 63% had cardiovascular disease and 52% had left sided heart disease. Without a spot sign, 21% had cardiovascular disease and 10% had left heart disease. After they were unblinded and told the ultrasound results, they diagnosed more with embolic disease. An interesting finding was that atrial fibrillation (Afib) was found in 17% of CRAO, 13% of BRAO and 24% of AION patients. However, new onset Afib was only seen in 3 patients—a GCA patient with AION, a GCA patient with CRAO and one other CRAO patient. Four patients with CRAO presented on the day they became symptomatic. All 4 had a spot sign. This raises the possibility that some of the other patients would have had a spot sign if studied earlier. A large limitation of the study is that the vascular workups were variable and at the discretion of the treating internist. So echocardiograms, carotid ultrasounds and electrocardiograms were not routinely performed. Also the 2 cardiologists disagreed on the diagnosis in 37% of patients. In addition, the study was retrospective and patients were not followed after the initial evaluation. Orbital color Doppler has been performed for years at Wills Eye Hospital and years ago my colleagues first reported that 31% of patients with CRAO had an embolus noted at the optic disc (1), many fewer than in the current study. This paper saw no spot sign in 27 patients with NAION. We have occasionally seen the spot sign in NAION patients, reported in a poster at the NANOS Amelia Island meeting in 2020 (2). Moster and Bhatti: J Neuro-Ophthalmol 2021; 41: 553-559 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary The authors propose to add simple transocular B-mode sonography to the standard diagnostic workup in CRAO. Transocular B-mode sonography can be performed as a pointof-care test in the emergency department, can be easily learned, is highly reproducible, and requires only a short examination time. I agree, we find orbital color Doppler very useful, with findings in some patients suggestive of GCA, ruling out GCA in patients with an embolus and guiding a work-up in those patients with an embolus —Mark L. Moster, MD Yes, first I agree that calling it what it is, an embolus, is much better than a “spot sign.” Second, we mainly use the orbital color doppler to help distinguish NAION from GCA with arteritic AION by looking for more global ischemia in GCA than just the posterior ciliary arteries. When we see an embolus, we have ruled out GCA and we do a workup with carotid ultrasound, echocardiogram (transthoracic ± transesophageal) and prolonged cardiac rhythm monitoring. Based on our finding an embolus in NAION patients, we do think that embolic NAION, although rare, is more common than has been reported. —Mark L. Moster, MD 1. Foroozan R, Savino PJ, Sergott RC. Embolic central retinal artery occlusion detected by orbital color Doppler imaging. Ophthalmology. 2002;109:744–747; discussion 747–748. 2. Srinivasan A, Moster ML, Debusk AA, Sergott RC. Orbital Color Doppler Imaging Detects Central Retinal Artery Emboli in Patients with Ischemic Optic Neuropathy. Poster 204, NANOS Annual Meeting, Amelia Island, Fl, March 2020. I see that you are now engaged in self-promotion! You went from a Mayomance to a Willsmance. The “spot sign” is a very interesting finding, but I wish someone would have come up with a better name that rhymes, maybe something like “embolus diagnosis.” Here are a few of my thoughts. I would have like to have known how many of the CRAO and BRAO patients had a visible embolus on examination. The diagnosis of GCA did not rely on a temporal artery biopsy. I am not an ultrasound expert by any stretch of the imagination, but it was my understanding that a strong signal (echorich) is indicative of calcification and fibrous tissue. If that is the case, does that mean the spot sign represents a calcific embolus? I thought that calcific emboli are more often because of cardiac valvular disease and cholesterol emboli indicative of carotid artery disease (1). This would go along with what the authors found: “patients with the spot sign more frequently had a medical history of cardiovascular disease (62.8 vs 21.4%, P = 0.03), and these patients also had a significantly higher rate of left heart valve pathologies (51.9 vs 10%, P = 0.03), mainly of the aortic valve.” My clinical experience has been that visible retinal emboli are more often cholesterol. I wonder what the carotid artery ultrasound signal characteristic would have compared to the transocular B-mode sonography. A couple of questions for you Mark. If your group noted a spot sign in some patients with NAION, do you believe that NAION is more often embolic in etiology than presumed to be? Are you recommending patients with AION and a positive spot sign undergo a carotid ultrasound and echocardiogram? —M. Tariq Bhatti, MD 1. Miller NR. Embolic causes of transient monocular visual loss. Ophthalmol Clin Am. 1996;9:359–380. Moster and Bhatti: J Neuro-Ophthalmol 2021; 41: 553-559 Ailani J, Lipton RB, Goadsby PJ, Guo H, Miceli R, Severt L, Finnegan M, Trugman JM; ADVANCE Study Group. Atogepant for the Preventive Treatment of Migraine. N Engl J Med. 2021;385:695–706 Background: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine. Methods: In a phase 3, double-blind trial, we randomly assigned adults with 4–14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D). Results: A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the 4 groups. The changes from baseline across 12 weeks were 23.7 days with 10-mg atogepant, 23.9 days with 30-mg atogepant, 24.2 days with 60-mg atogepant, and 22.5 days with placebo. The mean differences from placebo in the change from baseline were 21.2 days with 10-mg atogepant (95% confidence interval [CI], 21.8 to 20.6), 21.4 days with 30-mg atogepant (95% CI, 21.9 to 20.8), and 21.7 days with 60-mg atogepant (95% CI, 22.3 to 21.2) (P , 0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9%–7.7% across atogepant doses) and nausea (4.4%–6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10mg atogepant group. Conclusions: Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. 557 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary COMMENTS The involvement of neuro-ophthalmologists in migraine treatment spans a spectrum of being leaders in the headache field to total noninvolvement. However, we all see and diagnose migraine and need familiarity with the treatment modalities. Hence, my review of this article. Calcitonin gene-related peptide (CGRP) is involved in migraine—blood levels increase during an attack and infusion of CGRP induces migraine. Injected monoclonal antibodies are approved for preventative therapy and oral CGRP antagonists (gepants) to abort acute migraine attacks. The CGRP-related treatments have just been approved in the past 3 years and are the first medications specifically designed to treat migraines in contrast to prior preventative treatments, such as anticonvulsants, antidepressants, and antihypertensives. This paper, reports the results of the ADVANCE trial which studied daily oral atogepant in 3 different doses to prevent migraine attacks. This was a phase 3, multicenter, double-blind, randomized, placebo, controlled trial of 10 mg, 30 mg, 60 mg or placebo over 12 weeks. The primary outcome was the change from baseline in the mean number of migraine days per month across the 12-week treatment period. The baseline number of days was 7.4–7.9 in the 4 groups. The results were a decrease in migraine days compared with placebo with better results with increasing doses. The best result was with 60 mg with a decrease of 4.2 days/month compared with placebo of 2.5 days/month, similar findings to the injectable monoclonal antibodies. The percentage of participants with a reduction of at least 50% in the 3-month average of the mean number of migraine days per month was 60.8% for the 60-mg dose of atogepant, compared with 29.0% for placebo. Atogepant is now in the FDA approval process and if approved will be a welcome new alternative for the treatment of patients with migraine. —Mark L. Moster, MD I do not treat migraine and defer that to “brainy doctors” like you Mark. What I wonder is how atogepant would fair in a head-to-head trial to some of the standard preventative migraine therapies? It will also be interesting to see what the cost of this medicine will be. As you know the current injectable CGRPs on the market cost approximately $5,000-$6,000 per year. —M. Tariq Bhatti, MD Tariq, what do you think it is worth to a patient with severe migraine to have 50 fewer days of migraine per year? —Mark L. Moster, MD 558 Engelter ST, Traenka C, Gensicke H, Schaedelin SA, Luft AR, Simonetti BG, Fischer U, Michel P, Sirimarco G, Kägi G, Vehoff J, Nedeltchev K, Kahles T, Kellert L, Rosenbaum S, von Rennenberg R, Sztajzel R, Leib SL, Jung S, Gralla J, Bruni N, Seiffge D, Feil K, Polymeris AA, Steiner L, Hamann J, Bonati LH, Brehm A, De Marchis GM, Peters N, Stippich C, Nolte CH, Christensen H, Wegener S, Psychogios MN, Arnold M, Lyrer P; TREAT-CAD investigators. Aspirin vs. anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, noninferiority trial. Lancet Neurol. 2021;20:341– 350 Background: Cervical artery dissection is a major cause of stroke in young people (aged ,50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines—based on available evidence from mostly observational studies—suggest using aspirin. If proven to be noninferior to vitamin K antagonists, aspirin may be preferable, because of its ease of use and lower cost. We aimed to test the noninferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection. Methods: We did a multicentre, randomised, open-label, noninferiority trial in 10 stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalized ratio [INR] 2$0–3$0) for 90 days. Randomization was computergenerated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major hemorrhage, or death) and MRI outcomes (new ischemic or hemorrhagic brain lesions) in the perprotocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Noninferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460. Results: Between Sept 11, 2013 and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI -4 to 21], noninferiority P = 0$55). Thus, noninferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischemic Moster and Bhatti: J Neuro-Ophthalmol 2021; 41: 553-559 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial hemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group. Conclusion: Our findings did not show that aspirin was noninferior to vitamin K antagonists in the treatment of cervical artery dissection. COMMENTS When I grew up (debatable), all cervical dissections were treated with anticoagulation. Over time, many of the stroke specialists and neuro-ophthalmologists have moved over to treating with antiplatelet agents, mainly based on the CADISS (Cervical Artery Dissection in Stroke Study), which showed no difference in efficacy of antiplatelet and anticoagulant drugs at preventing stroke and death in patients with symptomatic carotid and vertebral artery dissection. However, stroke was rare in both groups, much rarer than reported in prior studies and a significant number of dissections could not be confirmed radiographically by the central imaging reading center. The current study tested the noninferiority of aspirin (ASA) to oral anticoagulation with vitamin K antagonists. It was a 10center, randomized, open-label study in Europe. Patients were randomized to ASA 300 mg vs phencrocoumon, acenocoumarol or warfarin with a target INR or (2.0–3.0). The primary outcome was a composite of clinical and MRI outcomes at 14 days and clinical outcomes at 90 days and included stroke, hemorrhage or death. Ninety-one patients were in the ASA group and 82 in the anticoagulation group. The bottom line is that noninferiority of ASA was not shown. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI –4 to 21], noninferiority Moster and Bhatti: J Neuro-Ophthalmol 2021; 41: 553-559 P = 0$55). Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial hemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group and 26 in the vitamin K antagonist group Although the trial did not analyze outcomes by clinical presentation, all but 1 who had a primary outcome had a stroke or MRI lesion at baseline. The authors point out that the superiority of oral anticoagulants has not been established, because this study was not powered to do so. What does that mean for me as a clinical neuroophthalmologist? I now am not sure that ASA is as good as anticoagulation, but am reassured that the risk of stroke is lower than I thought with a patient presenting with isolated Horner syndrome and a negative MRI. I will still treat that patient as an emergency with immediate referral to a stroke center and allow them to decide the best treatment. Unfortunately, this study did not evaluate non vitamin K antagonist oral anticoagulants. —Mark L. Moster, MD We discussed the CADISS study in the September 2019 issue of Literature Commentary. It is important to note that both this study and CADISS were not randomized controlled trials therefore, the results do not classify as Class I evidence. I agree that it has not been established that anticoagulation is better than ASA. So, in many ways, we are back to the original question: ASA or anticoagulation? But at the end of the day, like you, I treat an acute (0– 30 days) cervical artery dissection as a medical emergency and refer the patient immediately to either the emergency room or a stroke center. —M. Tariq Bhatti, MD 559 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.