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. Adderley NJ, Subramanian A, Nirantharakumar K, Yiangou A, Gokhale KM, Mollan SP, Sinclair AJ. Association between idiopathic intracranial hypertension and risk of cardiovascular diseases in women in the United Kingdom. JAMA Neurol. [published ahead of print July 8, 2019] doi: 10.1001/jamaneurol.2019.1812. 2. Touze R, Gravellier B, Rolla-Bigliani C, Touitou V, Shotar E, Lenck S, Boch AL, Degos V, Sourour NA, Clarencon F. Occlusion rate and visual complications with flow-diverter stent placed across the ophthalmic artery's origin for carotid-ophthalmic aneurysms: a meta-analysis. Neurosurgery. [published ahead of print June 19, 2019] doi: 10.1093/neuros/nyz202. 3. Petzold A, Woodhall M, Khaleeli Z, Tobin WO, Pittock SJ, Weinshenker BG, Vincent A, Waters P, Plant GT. Aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in immune-mediated optic neuritis at long-term follow-up. J Neurol Neurosurg Psychiatry. 2019;90:1021-1026. 4. Stiebel-Kalish H, Hellmann MA, Mimouni M, Paul F, Bialer O, Bach M, Lotan I. Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Neurol Neuroimmunol Neuroinflamm. 2019;6:e572. 5. Piquet AL, Khan M, Warner JEA, Wicklund MP, Bennett JL, Leehey MA, Seeberger L, Schreiner TL, Paz Soldan MM, Clardy SL. Novel clinical features of glycine receptor antibody syndrome: a series of 17 cases. Neurol Neuroimmunol Neuroinflamm. 2019;6:e592. 6. D'Antona L, McHugh JA, Ricciardi F, et al. Association of intracranial pressure and spontaneous retinal venous pulsation. JAMA Neurol. [published ahead of print September 9, 2019] doi: 10.1001/jamaneurol.2019.2935.

Literature Commentary: Double Feature - Take Two! 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. Adderley NJ, Subramanian A, Nirantharakumar K, Yiangou A, Gokhale KM, Mollan SP, Sinclair AJ. Association between idiopathic intracranial hypertension and risk of cardiovascular diseases in women in the United Kingdom. JAMA Neurol. [published ahead of print July 8, 2019] doi: 10.1001/jamaneurol.2019.1812. 2. Touzé R, Gravellier B, Rolla-Bigliani C, Touitou V, Shotar E, Lenck S, Boch AL, Degos V, Sourour NA, Clarençon F. Occlusion rate and visual complications with flow-diverter stent placed across the ophthalmic artery's origin for carotid-ophthalmic aneurysms: a meta-analysis. Neurosurgery. [published ahead of print June 19, 2019] doi: 10.1093/neuros/nyz202. 3. Petzold A, Woodhall M, Khaleeli Z, Tobin WO, Pittock SJ, Weinshenker BG, Vincent A, Waters P, Plant GT. Aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in immune-mediated optic neuritis at long-term follow-up. J Neurol Neurosurg Psychiatry. 2019;90:1021-1026. 4. Stiebel-Kalish H, Hellmann MA, Mimouni M, Paul F, Bialer O, Bach M, Lotan I. Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Neurol Neuroimmunol Neuroinflamm. 2019;6:e572. 5. Piquet AL, Khan M, Warner JEA, Wicklund MP, Bennett JL, Leehey MA, Seeberger L, Schreiner TL, Paz Soldan MM, Clardy SL. Novel clinical features of glycine receptor antibody syndrome: a series of 17 cases. Neurol Neuroimmunol Neuroinflamm. 2019;6:e592. 6. D'Antona L, McHugh JA, Ricciardi F, et al. Association of intracranial pressure and spontaneous retinal venous pulsation. JAMA Neurol. [published ahead of print September 9, 2019] doi: 10.1001/jamaneurol.2019.2935. Adderley NJ, Subramanian A, Nirantharakumar K, Yiangou A, Gokhale KM, Mollan SP, Sinclair AJ. Association between idiopathic intracranial hypertension and risk of cardiovascular diseases in women in the United Kingdom. JAMA Neurol. [published ahead of print July 8, 2019] doi: 10.1001/ jamaneurol.2019.1812. Importance: Cardiovascular disease (CVD) risk has not been previously evaluated in a large matched cohort study in idiopathic intracranial hypertension (IIH). Objectives: To estimate the risk of composite cardiovascular events, heart failure, ischemic heart disease (IHD), stroke/ transient ischemic attack (TIA), Type 2 diabetes, and hypertension in women with idiopathic intracranial hypertension and compare it with the risk in women, matched on body mass index (BMI) and age, without the condition, and to evaluate the prevalence and incidence of IIH. Design, Setting, and Participants: This population-based matched controlled cohort study used 28 years of data, from January 1, 1990, to January 17, 2018, from The Health Improvement Network, an anonymized, nationally representative electronic medical records database in the United Kingdom. All female patients aged 16 years or older were eligible for inclusion. Female patients with IIH (n = 2,760) were included and randomly matched with up to 10 control patients (n = 27,125) by BMI and age. Main Outcomes and Measures: Adjusted hazard ratios (aHRs) of cardiovascular outcomes were calculated using 122 Cox regression models. The primary outcome was a composite of any CVD (heart failure, IHD, and stroke/TIA), and the secondary outcomes were each CVD outcome, Type 2 diabetes, and hypertension. Results: In total, 2,760 women with IIH and 27,125 women without IIH were included. Age and BMI were similar between the 2 groups, with a median (interquartile range) age of 32.1 (25.6-42.0) years in the exposed group and 32.1 (25.7-42.1) years in the control group; in the exposed group, 1,728 women (62.6%) were obese, and in the control group, 16,514 women (60.9%) were obese. Higher absolute risks for all cardiovascular outcomes were observed in women with IIH compared with control patients. The aHRs were as follows: composite cardiovascular events, 2.10 (95% confidence interval [CI], 1.61-2.74; P , 0.001); heart failure, 1.97 (95% CI, 1.16-3.37; P = 0.01); IHD, 1.94 (95% CI, 1.27-2.94; P = 0.002); stroke/TIA, 2.27 (95% CI, 1.61-3.21; P , 0.001); Type 2 diabetes, 1.30 (95% CI, 1.07-1.57; P = 0.009); and hypertension, 1.55 (95% CI, 1.30-1.84; P , 0.001). The incidence of IIH in female patients more than tripled between 2005 and 2017, from 2.5 to 9.3 per 100 000 person-years. Similarly, IIH prevalence increased in the same period, from 26 to 79 per 100 000 women. Incidence increased markedly with BMI higher than 30. Conclusions and Relevance: Idiopathic intracranial hypertension in women seemed to be associated with a 2-fold increase in CVD risk; change in patient care to modify risk factors for CVD may reduce long-term morbidity for women with IIH and warrants further evaluation. Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 122-129 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! COMMENTS If you are like me Mark, whenever I am seeing a patient with IIH, I discuss the risk of visual loss and the importance of weight loss in treating the disease. In addition, I briefly discuss the benefit of losing weight in terms of overall health. When I first saw this article, I was surprised to read that IIH is associated with CVD and had not been previously studied. This population-based matched controlled cohort study performed in the United Kingdom (UK), enrolled 2,760 women with IIH and 27,125 controls without IIH. The control group was matched to age (within 1 year), gender, and body mass index (BMI, within 2 kg/ m2). The primary outcome was any CVD, defined as heart failure, IHD, stroke, or transient ischemic attack (TIA). Secondary outcomes included each of the CVD items separately, Type 2 diabetes mellitus, and hypertension. The covariates identified based on biological plausibility were age, BMI, social deprivation, smoking status, current lipid-lowering medication prescription, migraine, and baseline cardiometabolic conditions. The 2 groups were evenly matched aside from more patients with IIH were either smokers or ex-smokers and had higher rates of migraine, CVD, and hypertension. In addition to the crude HR, the adjusted HR was calculated using the following models: • Adjusted for age, BMI (continuous), Townsend deprivation quintile, and smoking status. • Adjusted for age, BMI (continuous), Townsend deprivation quintile, smoking status plus current (up to 65 days before index date) lipid-lowering drug prescription, and baseline hypertension and diabetes. • Adjusted for age, BMI (continuous), Townsend deprivation quintile, smoking status plus current (up to 65 days before index date) lipid-lowering drug prescription, and baseline hypertension and diabetes plus migraine. • Adjusted for age, BMI (continuous), Townsend deprivation quintile, smoking status plus current (up to 65 days before index date) lipid-lowering drug prescription, and baseline IHD, heart failure, stroke/TIA, and hypertension. • Adjusted for age, BMI (continuous), Townsend deprivation quintile, and smoking status plus current (up to 65 days before index date) lipid-lowering drug prescription, and baseline IHD, heart failure, stroke/TIA, and diabetes. All adjusted HR models showed an increased risk of composite CVD, as well as each separate CVD item. Table 2 provides all the HRs as well as the P values. In terms of composite CVD, the adjusted HR (Model 1) was 2.10 (95% CI of 1.61-2.73, P , 0.001). Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 122-129 The prevalence of IIH increased from 26 per 100,000 in 2005 to 79 per 100,000 in 2017 and the incidence increased from 2.5 per 100,000 in 2005 to 9.3 per 100,000 in 2017. There was no surprise that the increase incidence correlated with increasing BMI. The incidence was highest in patients in the most-deprived Townsend quintile (i.e., lowest socioeconomic status). There are several limitations of the study that need to be highlighted. This was a study performed in the United Kingdom, therefore extrapolating to other areas of the world such as the United States should be made with caution. The authors also listed database inaccuracy, fluctuating BMI, lack of information regarding physical activity, surveillance bias, and medication exposure as potential limitations. The authors attempt to explain the increase risk of CVD in patients with IIH independent of BMI by suggesting ".a complex disease characterized by systemic metabolic dysregulation. Centripetal fat accumulation is key in determining the risk of metabolic syndrome and CVD." I think it is important that we recognize that more studies such as this are needed to confirm an increased risk of CVD in patients with IIH. I commend the authors on a very nice study, but as often happens, there are many unanswered questions such as the following: • Is there a link, if any, to exposure of medications (e.g., nonsteroidal anti-inflammatory drugs and opioid-based analgesics)? • What is the risk of CVD with the use of intracranial pressure lowering medications (i.e., acetazolamide), cerebrospinal fluid diversion procedures, or venous sinus stenting? • Does the risk of CVD decrease in those patients who lose weight loss? • What is the underlying pathophysiology of this apparent increase risk of CVD? -M. Tariq Bhatti, MD I agree with you, Tariq, in expecting an increase risk of CVD in IIH patients based on obesity but not a further increase in risk beyond that caused by the obesity. These results of a greater than 2-fold increase in risk are intriguing. One of the theoretical causes proposed is that IIH patients have a state of androgen excess and androgen excess is a vascular risk factor. What we don't yet know is whether treating IIH with any modality (e.g., weight loss, acetazolamide, shunts, sheath fenestrations, venous stents, or bariatric surgery) will mitigate this excess CVD risk in these patients. I would point out that even the finding in the study of a doubling of the risk still leaves the population of IIH patients at a relatively low risk for CVD. Finally, what really is concerning to me is the 3-fold increase in incidence of IIH between 2005 and 2017. -Mark L. Moster, MD 123 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! Touzé R, Gravellier B, Rolla-Bigliani C, Touitou V, Shotar E, Lenck S, Boch AL, Degos V, Sourour NA, Clarençon F. Occlusion rate and visual complications with flow-diverter stent placed across the ophthalmic artery's origin for carotid-ophthalmic aneurysms: a meta-analysis. Neurosurgery. [published ahead of print June 19, 2019] pii: nyz202. doi: 10.1093/neuros/nyz202. Background: Flow-diverter stents (FDSs) have recently gained acceptance for the treatment of intracranial aneurysms, especially for carotid-ophthalmic aneurysms (COAs). However, complications have been reported after coverage of side branches, especially the ophthalmic artery (OA). Objective: To evaluate, through a meta-analysis, the occlusion rate and the ophthalmic complications after treatment of COA by FDS. Methods: We reviewed on MEDLINE via PubMed, Embase via Ovid, and Cochrane central database via CENTRAL. We included all case series with at least 15 patients and clinical trials about flow diversion of aneurysms close to the OA's origin. Among these studies, we only included articles with aneurysm occlusion rate and rate of new ophthalmic symptoms. Results: We included 16 studies with 913 COA treated by FDSs and covering the OA with a mean follow-up of 16.4 months. The random-effect modeling analysis concerning the overall rate of new ophthalmic complications, after FDS deployment covering the OA, was 3.0% (95% confidence interval [CI] 1.0-6.0). There was medium-high heterogeneity in the study reports P , 0.01, I2 = 70.2% (50.4%; 82.1%). We were not able to statistically explain this heterogeneity with the performed analysis, which could be related to the design of the included studies. We found an overall aneurysm occlusion rate of 85.0% (95% CI 80.0- 89.0). Conclusion: Our meta-analysis found a high aneurysm occlusion rate (85%) and low rate of iatrogenic visual complications, with only 3.0% of new visual symptoms, after treatment of COA by FDS. either cobalt-chrome or nitinol alloy as well as radiopaque wires. A meta-analysis was performed on 913 patients in 16 studies (minimum of 15 patients) to determine the occlusion rate of OA aneurysms and new visual complications. Only studies that had no pretreatment visual loss were included. The frequency of new "ophthalmic complications" (the reason I use the quotation marks is explained below in the paragraph regarding limitation of the study) was 3% (95 CI, 1-6). The frequency of complications among the 16 studies was large ranging from 0% to 38%. The overall patency of the OA after FDS placement was 90% (95% CI, 86-93) and the total rate of aneurysm occlusion (complete or near complete) was 85% (95% CI, 80-89). For comparison, the authors referenced a meta-analysis that compared visual outcome between clipping, coiling, and flow diversion of paraclinoid aneurysms. The frequency of post-treatment visual dysfunction was 1%, 0% and 0%, respectively (2). The exact mechanism of visual disturbance from FDS is not entirely clear. The authors suggest 2 reasons: fugax amaurosis and retinal emboli. There are substantial limitations of this meta-analysis. None of the studies were prospective, there was significant heterogeneity of study design, and the visual data was, well to put it mildly, not very good. In fact, only 1 of the 16 studies had systematic objective visual data! I think we as neuro-ophthalmologists need to get it together and do a study of FDS and OA aneurysms. -M. Tariq Bhatti, MD 1. Schmidt GW, Oster SF, Golnik KC, Tumialán LM, Biousse V, Turbin R, Prestigiacomo CJ, Miller NR. Isolated progressive visual loss after coiling of paraclinoid aneurysms. AJNR Am J Neuroradiol. 2007;28:1882-1889. 2. Silva MA, See AP, Dasenbrock HH, Patel NJ, Aziz-Sultan MA. Vision outcomes in patients with paraclinoid aneurysms treated with clipping, coiling, or flow diversion: a systematic review and meta-analysis. Neurosurg Focus. 2017;42:E15. COMMENTS Endovascular embolization of intracranial aneurysms has become a very popular treatment modality. During the heyday of coiling (late 1990s and early 2000s), we learned a lot about the deleterious effects of coiling aneurysms adjacent to critical neuro-ophthalmic structures. For example, in 2007, there was a very nice case series published that described visual loss in the setting of endovascular coil embolization of paraclinoid or OA aneurysms (1). More recently, FDSs have become part of the treatment armamentarium of intracranial aneurysms. Unlike coil embolization, that requires entry of the coils into the aneurysm sac, FDS is placed over the neck of the aneurysm resulting in isolation of the aneurysm sac from the parent vessel. The stents are flexible woven fibers composed of 124 Tariq, this is one of the most ridiculous articles I've ever read. To amplify on the limitations you've identified, after beginning with a review of 367 articles and excluding 328 "nonrelevant" articles, they were left with 39 articles to review. Eighteen had no visual information, and 5 were small case series, so they were left with 16 studies which found approximately 3% visual complications. However, in these 16 studies, 7 studies were without objective visual outcome (only listing complications as reported by the patient), 8 studies with visual objective outcome only in those who had visual complaints, and only 1 study with systematic visual examinations. The one study with routine visual examinations had a 39.1% complication rate, including retinal emboli and optic atrophy (1). So they've taken one decent article and diluted it with 15 articles that don't Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 122-129 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! even address the issue and come out with a low complication rate. Would you believe the 3% on their meta-analysis? I have to agree with you that we need to have a study where we in neuro-ophthalmology "get it together" with our interventional colleagues to figure out the true complication rate from FDS in the OA! -Mark L. Moster, MD 1. Rouchaud A, Leclerc O, Benayoun Y, Saleme S, Camilleri Y, D'Argento F, Boncoeur MP, Robert PY, Mounayer C. Visual outcomes with flow-diverter stents covering the ophthalmic artery for treatment of internal carotid artery aneurysms. AJNR Am J Neuroradiol. 2015;36:330-336. Petzold A, Woodhall M, Khaleeli Z, Tobin WO, Pittock SJ, Weinshenker BG, Vincent A, Waters P, Plant GT. Aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in immune-mediated optic neuritis at long-term follow-up. J Neurol Neurosurg Psychiatry. 2019;90:1021-1026 Objectives: To re-evaluate serum samples from our 2007 cohort of patients with single-episode-isolated optic neuritis (SION), recurrent-isolated ON (RION), chronic relapsing inflammatory optic neuropathy (CRION), multiple sclerosisassociated ON (MSON), and neuromyelitis optica (NMO). Methods: We re-screened 103/114 patients with available serum on live cell-based assays (CBA) for aquaporin-4 (AQP4)-M23-IgG and myelin-oligodendrocyte glycoprotein (MOG)-a1-IgG. Further testing included oligoclonal bands, serum levels of glial fibrillar acidic and neurofilament proteins and S100B. We show the impact of updated serology on these patients. Results: Reanalysis of our original cohort revealed that AQP4-IgG seropositivity increased from 56% to 75% for NMO, 5%-22% for CRION, 6%-7% for RION, 0%-7% for MSON, and 5%-6% for SION. MOG-IgG1 was identified in 25% of RION, 25% of CRION, 10% of SION, 0% of MSON, and 0% of NMO. As a result, patients have been reclassified incorporating their autoantibody status. Presenting visual acuity was significantly worse in patients who were AQP4IgG seropositive (P = 0.034), but there was no relationship between antibody seropositivity and either ON relapse rate or visual acuity outcome. Conclusions: The number of patients with seronegative CRION and RION has decreased due to improved detection of autoantibodies over the past decade. It remains essential that the clinical phenotype guides both antibody testing and clinical management. Careful monitoring of the disease course is key when considering whether to treat with prophylactic immune suppression. many neurological diseases. The evolution of detecting these autoimmune Abs has improved over time allowing the discovery of novel Abs. In addition, the accuracy of detecting these Abs has increased thereby reintroducing the value of previously known autoimmune Abs. The goal of this retrospective study was to re-assess the serum samples of 103 patients with SION, RION, chronic relapsing optic neuritis (CRION), multiple sclerosis optic neuritis, and neuromyelitis optica optic neuritis (NMOON) that 10 years previously were negative or positive for NMOimmunoglobulin G (IgG)1. The serum samples were reevaluated using a live CBA for aquaporin-4 (AQP4)-IgG and also tested for MOG-IgG1 using a CBA. In the interval of 10 years, 10 patients developed definite multiple sclerosis (MS), 5 that initially had MSON, 2 with SION, and 2 with RION. One patient with RION developed CRION. One patient with SION was found to have an optic nerve sheath meningioma. I put together the table below to show the antibody status of the serum samples between 2007 and 2017: As a result of the CBA, the number of patients in each classification changed in the following manner: • MSON: 28 to 26 • SION: 41 to 35 • RION: 17 to 12 • CRION: 19 to 12 • NMOON: 9 to 19 The overall detection of autoantibody seropositivity increased from 8% to 23%, and 11 patients were found to have MOG optic neuritis. The seropositivity of CRION patients increased from 5% to 38%, and 25% were found to be MOG-IgG1 positive. This article reinforces the concept that CBAs improved the sensitivity of detecting autoimmune Abs, and for me, I will consider re-testing all my patients who were seronegative based on non-CBAs. Also, for all my optic neuritis patients who I order autoimmune Abs, I make sure it is based on a CBA technique. If you will indulge me Mark for a moment, and without appearing to be self-promoting, I would like to bring to your attention a recent editorial of sorts that Dr John J. Chen and I, along with our autoimmune-multiple sclerosis colleagues at Mayo Clinic, published in the Survey of Ophthalmology discussing optic neuritis in the era of biomarkers (1). -M. Tariq Bhatti, MD COMMENTS 1. Chen JJ, Pittock SJ, Flanagan EP, Lennon VA, Bhatti MT. Optic neuritis in the era of biomarkers. Surv Ophthalmol. 2019. (epub ahead of print). doi: 10.1016/j.survophthal.2019.08.001. Biomarkers, in particular autoimmune antibodies (Abs), have become a very valuable instrument in the diagnosis of This article is one of many that is helping to improve the care of patients with optic neuritis. Identifying those with Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 122-129 125 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! Antibody Status MSON (n/%) SION (n/%) RION (n/%) CRION (n/%) NMO (n/%) NMO-IgG1 (2007) AQP4-IgG (2017) MOG-IgG1 (2017) 0/28 (0%) 2/27 (7%) 0/9 (9%) 2/41 (5%) 2/34 (6%) 4/40 (10%) 1/17 (6%) 1/16 (7%) 4/16 (25%) 1/19 (5%) 4/18 (22%) 3/12 (25%) 5/9 (56%) 6/8 (75%) 0/7 (0%) MOG and AQP4 antibodies will help further define the phenotypes associated with these antibodies and allow more specific and accurate therapy. In your excellent article in Survey of Ophthalmology, you recommend antibody testing in patients with atypical ON. However, there is a discussion in the neuroophthalmologic community considering whether patients with even typical ON should be evaluated with laboratory test results for NMO, MOG, or other disorders. Because the clinical picture of NMO and MOG antibody syndromes are still being defined, I think it may not be unreasonable to test those patients with typical ON presentations as well. -Mark L. Moster, MD Stiebel-Kalish H, Hellmann MA, Mimouni M, Paul F, Bialer O, Bach M, Lotan I. Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Neurol Neuroimmunol Neuroinflamm. 2019;6:e572 Objective: To investigate whether visual disability which is known to accumulate by poor recovery from optic neuritis (ON) attacks can be lessened by early treatment, we investigated whether the time from symptom onset to high-dose intravenous methylprednisolone (IVMP) affected visual recovery. Methods: A retrospective study was performed in a consecutive cohort of patients after their first aquaporin-4 (AQP4)IgG or myelin oligodendrocyte glycoprotein (MOG)-IgG-ON. Best-corrected visual acuity (BCVA) in ON eyes at 3 months (BCVA 3 months) was correlated with time to IVMP (days). In cases of bilateral ON, 1 eye was randomly selected. Results: A total of 29 of 37 patients had ON (27 AQP4seropositive neuromyelitis optica spectrum disorder and 9 MOG-IgG-ON), 2 of whom refused treatment. Of the 27 patients included, 10 presented later than 7 days from onset. The median BCVA 3 months of patients treated .7 days was 20/100 (interquartile range 20/100-20/200). Patients treated .7 days had an odds ratio (OR) of 5.50 (95% CI 0.88-34.46, P = 0.051) of failure to regain 0.0 logMAR vision (20/20) and an OR of 10.0 (95% CI 1.39- 71.9) of failure to regain 0.2 logMAR vision (20/30) (P = 0.01) compared with patients treated within 7 days. ROC analysis revealed that the optimal criterion of delay in IVMP initiation was #4 days, with a sensitivity and specificity of 71.4% and 76.9%, respectively. Conclusions: In this retrospective study of ON with AQP4 and MOG-IgG, even a 7-day delay in IVMP initiation was 126 detrimental to vision. These results highlight the importance of early treatment for the long-term visual recovery in this group of patients. A prospective, multicenter study of the effects of timing of IVMP is currently underway. Classification of Evidence: This study provides Class IV evidence that hyperacute treatment of AQP4 and MOG-ON with IVMP increases the chance for good visual recovery (20/20 vision), and that even a greater than 7-day delay in treatment is associated with a higher risk for poor visual recovery. COMMENTS This study shows Class IV evidence that there is a better outcome with IVMP treatment when performed in less than 7 days than when it is greater than 7 days for patients with neuromyelitis optica (NMO) or MOG-related disease. Limitations of the study include the small number of patients, lack of long-term follow-up, and the retrospective nature of the study. Therefore, these results need to be confirmed with stronger data. However, with the current results, it may be difficult to perform a prospective study with a delayed treatment arm because of the poorer visual outcome noted in this study. A change to my clinical practice that I've made recently is that all patients with ON now get a recommendation for IVMP. The previous thinking was based on the Optic Neuritis Treatment Trial (ONTT) results, which did not show any benefit to visual outcome, so that patients with normal brain MRI were not recommended IVMP. However, without knowing NMO or MOG status at presentation and now evidence of better outcome with early treatment for these disorders, I am treating all new ON patients with IVMP early on. -Mark L. Moster, MD Know that I still love you Mark, but I completely disagree with you that every ON patient needs to be treated with IVMP just because the serological status is not known. If the brain MRI findings are compatible with MS, I don't feel the need to proceed with a workup or urgently treat the visual loss with IVMP. If one was to just consider the odds of what type of ON a patient has based on epidemiology, idiopathic ON and multiple sclerosis ON are far more common than NMO-ON or MOG-ON (1). This would mean that you would be giving IVMP to a substantial number of patients who based on the ONTT would not benefit Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 122-129 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! in terms of final visual outcome. Ideally, if medical insurance companies were aligned with our clinical practice, all patients suspected of NMO-ON or MOG-ON would get the blood test with the simple click of a mouse or stroke of a computer key with no questions asked. But even if we were able to get the MOG and NMO antibodies on every ON patient, often it takes several days for the test to come back. So, what does one do? For me, there are several clinical and paraclinical clues to "atypical" ON that would compel me to use IVMP immediately: • Severe visual acuity impairment (,20/200 or worse) • Prominent optic disc edema • Chiasmal, perineural, or long segment optic nerve enhancement on MRI • Central nervous system demyelinating lesions on MRI not consistent with MS • Unusual clinical symptoms such as hiccups, nausea, or vomiting -M. Tariq Bhatti, MD 1. Rubiera M, Río J, Tintoré M, Nos C, Rovira A, Téllez N, Montalban X. Neuromyelitis optica diagnosis in clinically isolated syndromes suggestive of multiple sclerosis. Neurology. 2006;66:1568-1570. I think most neuro-ophthalmologists would agree with you, Tariq, and you may certainly be right about whom to treat with IVMP. Nonetheless, one of the contributors to the "art of medicine" is our ability to modify our treatment strategies in light of new information in the literature and our new clinical experiences. So, the conversation continues. -Mark L. Moster, MD Piquet AL, Khan M, Warner JEA, Wicklund MP, Bennett JL, Leehey MA, Seeberger L, Schreiner TL, Paz Soldan MM, Clardy SL. Novel clinical features of glycine receptor antibody syndrome: A series of 17 cases. Neurol Neuroimmunol Neuroinflamm. 2019;6:e592 Objective: To describe novel clinical features of GlyRa1IgG-positive patients. Methods: Patients with a positive serum GlyRa1-IgG were identified during a 2-year period from July 2016 to December 2018 at 2 academic centers and followed prospectively. All patients in this series were evaluated in the Neuroimmunology and Autoimmune Neurology clinics at the University of Utah or the University of Colorado. Results: Thirteen of 17 patients had phenotypes more typically associated with glutamic acid decarboxylase (GAD65) antibody syndromes, consisting of stiff-person syndrome (SPS) with parkinsonism or cerebellar signs. One patient with parkinsonism had a presentation similar to rapidly progressive multiple system atrophy with severe dysautonoMoster and Bhatti: J Neuro-Ophthalmol 2020; 40: 122-129 mia. Ten of 17 patients had various visual symptoms including visual snow, spider web-like images forming shapes and 3-dimensional images, palinopsia, photophobia, visual hallucinations, synesthesia, and intermittent diplopia. Three of 17 patients presented with primarily autoimmune epilepsy accompanied by psychiatric symptoms. Conclusions: Clinicians should consider testing for GlyR antibodies in GAD65 antibody-negative or low positive GAD65 antibody patients with SPS-like presentations, especially in the setting of atypical features such as visual disturbances, parkinsonism, or epilepsy. COMMENTS I chose this article because it is about a diagnosis and laboratory test that I have not yet considered in my practice. This is a descriptive series of 17 patients who had glycine receptor antibodies, some who also had antiGAD65 antibodies. For the most part, they presented similarly to patients with the antiGAD65 syndrome of SPS, parkinsonism, and cerebellar signs. However, other manifestations included autoimmune epilepsy and psychiatric symptoms. Of interest to us in neuro-ophthalmology, 10 of the 17 patients (59%) had prominent visual disturbances. Although there were many patients with visual symptoms, each patient had a unique visual symptom and no clear visual syndrome emerges. For instance, in the 17 patients, the following were seen: • Palinopsia, 3 patients • Photophobia, 3 patients • Diplopia, 3 patients • Hallucinations, 2 patients • Visual field constriction, 2 patients One patient each had visual snow, synesthesia, metamorphopsia, and oscillopsia. One had an abnormal electroretinogram and one a delayed visual evoked potential, but there is no mention of whether others received these tests. Many of the symptoms mimicked migraine aura, but the symptoms were persistent rather than intermittent. In contrast to some previous reports suggesting a better response to immunotherapy in patients with GlyR antibodies than GAD65 patients, the patients in this series did not predictably improve and many progressed despite treatments with intravenous immunoglobulin, plasma exchange, rituximab, or other immunosuppressant therapies. What I learned from this article is that in patients presenting with visual symptoms in association with a syndrome otherwise consistent with a GAD65 antibody syndrome, I should check glycine receptor antibodies. Similar to other neurologic antibody-induced syndromes (e.g., neuromyelitis optic spectrum disorder, myelin oligodendrocyte-associated disorder), further testing of many patients will better characterize the phenotypic syndrome expected with these antibodies. 127 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! -Mark L. Moster, MD Thank you for bringing this autoimmune antibody and its associated spectrum disorders and clinical features to my attention. Like you, this was not on my clinical radar. There are so many new autoimmune/paraneoplastic antibodies being described that it is really difficult to keep up with them all. Aside from this article, we could have also discussed several other articles that were recently published describing newly discovered autoantibodies.1,2 -M. Tariq Bhatti, MD 1. Zekeridou A, Kryzer T, Guo Y, Hassan A, Lennon V, Lucchinetti CF, Pittock S, McKeon A. Phosphodiesterase 10A IgG: a novel biomarker of paraneoplastic neurologic autoimmunity. Neurology. 2019;93:e815-e822. 2. Mandel-Brehm C, Dubey D, Kryzer TJ, O'Donovan BD, Tran B, Vazquez SE, Sample HA, Zorn KC, Khan LM, Bledsoe IO, McKeon A, Pleasure SJ, Lennon VA, DeRisi JL, Wilson MR, Pittock SJ. Kelch-like protein 11 antibodies in seminomaassociated paraneoplastic encephalitis. N Engl J Med. 2019;381:47-54. D'Antona L, McHugh JA, Ricciardi F, et al. Association of intracranial pressure and spontaneous retinal venous pulsation. JAMA Neurol. [published ahead of print September 9, 2019] doi: 10.1001/jamaneurol.2019.2935. Importance: A convenient and reliable method for noninvasive intracranial pressure assessments is desirable to reduce the need for invasive procedures (e.g., intracranial pressure monitoring and lumbar punctures) and allow clinicians to identify and treat patients with intracranial hypertension in a timely manner. Objective: To determine whether infrared video assessment of spontaneous retinal venous pulsation is associated with intracranial pressure and is a valid tool to indicate the presence or absence of raised intracranial pressure in patients without papilledema. Design, Setting, and Participants: A single-center prospective study was conducted at a tertiary referral center between January 2017 and May 2018. Patients consecutively admitted for clinically indicated elective 24-hour invasive intracranial pressure monitoring had ophthalmic review including infrared video recording of their spontaneous venous pulsation. Two neuro-ophthalmologists, who were masked to the intracranial pressure monitoring results, independently graded the spontaneous venous pulsation (Grade 0-3). Analysis began in June 2018. Main Outcomes and Measures: The association between simultaneously recorded intracranial pressure and spontaneous venous pulsation (binary variable: present/ absent) assessed through retinal infrared video recordings was evaluated using a multiple linear regression model. Results: Of 105 patients, the mean (SD) age was 39 (14) years, and 79 (75%) were women. The mean (SD) simultaneous intracranial pressure was 1 (5) mm Hg for 91 pa- 128 tients (86.7%) with spontaneous venous pulsations and 13 (14) mm Hg for 14 patients (13.3%) without spontaneous venous pulsations. A multiple linear regression model adjusted for 7 potential confounders confirmed a statistically significant association between intracranial pressure and spontaneous venous pulsation (b = 29.1; 95% confidence interval [CI], 213.7 to 24.6; P , 0.001; adjusted R2 = 0.42). Conclusions and Relevance: The absence of spontaneous venous pulsation on retinal infrared video recordings is significantly associated with higher levels of intracranial pressure and should raise the suspicion of intracranial hypertension. COMMENTS In August 2019, McHugh JA et al published in JNO online the use of infrared video recordings using the Spectralis (Heidelberg Engineering, Franklin, MA) optical coherence tomography (OCT) to assess presence of retinal spontaneous venous pulsations (SVPs) (1). Here is a link to a video example (http://links.lww.com/ WNO/A378). What is really nice in the video is that one can see SVPs not just on the optic disc but throughout the retina. In that article, they found that using this technique, 99% of normals can be seen to have SVPs. In the current study, they attempt to use this technique to correlate the magnitude of SVP with intracranial pressure (ICP). Using a grading system proposed by both Drs. Tom Hedges in 1994 (2), they graded absent SVPs as grade 0, up to 33% change in diameter (Grade 1), 33%-66% change in diameter (Grade 2), greater than 66% change in diameter (Grade 3). This was simultaneously correlated with ICP in patients admitted for ICP monitoring for symptoms suggestive of intracranial hypertension, shunt malfunction, or other cerebrospinal fluid dynamics disorders whose fundi did not show papilledema, and neuroimaging did not clearly indicated elevated ICP. Although they did not see SVPs at the slit lamp in 50% of the patients in this study, they did see at least a grade 1 SVP on the infrared video in 87% of patients. In addition, they found a statistically significant correlation of SVP grade and ICP. Limitations of the study identified by the authors include the lack of portability of the Spectralis OCT requiring the patient to sit up in an office and the low numbers of patients without SVPs in this population. Another limitation I see is that most of the patients had low ICP in the study. The average ICP was 1 mm Hg (1.36 cm H2O) in those with SVPs and 13 mm Hg (18 cm H20) in those without SVPs. Despite this limitation, this study may bring us one step closer to having a noninvasive way of evaluating ICP. -Mark L. Moster, MD Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 122-129 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! 1. McHugh JA, DʼAntona L, Toma AK, Bremner FD. Spontaneous venous pulsations detected with infrared videography. J Neuroophthalmol. 2019. (epub ahead of print). doi: 10.1097/ WNO.0000000000000815. 2. Hedges TR Jr, Baron EM, Hedges TR III, Sinclair SH. The retinal venous pulse: its relation to optic disc characteristics and choroidal pulse. Ophthalmology. 1994;101:542-547. It seems so long ago, but in the September 2017 Literature Commentary, we discussed the article by Swanson et al on the use of OCT in detecting elevated ICP (1). At that time you said ". we still have a long way to go for a noninvasive correlate of ICP in real time," I think this still holds true and I don't think in my humble opinion this method studied by the authors will get us there. I noticed the discussion was very short, and I would have liked the authors to have expanded on their results more. There were several things that I found curious about the Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 122-129 study. First, no definition was provided about what was considered a high ICP. Second, 86.7% of the patients did not have optic disc edema or papilledema. Third, yes, there was a correlation between SVP grade and ICP, but what does that mean in practice? Fourth, if you look at Figure 1 and the CI bar for the Grade 0 cohort, there were patients with normal ICP. I wonder, how many of those 14 patients had normal ICP? -M. Tariq Bhatti, MD 1. Swanson JW, Aleman TS, XuW, Ying GS, PanW, Liu GT, Lang SS, Heuer GG, Storm PB, Bartlett SP, Katowitz WR, Taylor JA. Evaluation of optical coherence tomography to detect elevated intracranial pressure in children. JAMA Ophthalmol. 2017;135:320-328. 129 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.