Literature Commentary: Double Feature - Take Two! (pt 2)

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. Lambru G, Rantell K, Levy A, Matharu MS. A prospective comparative study and analysis of predictors of SUNA and SUNCT. Neurology. 2019;93:e1127–e1137. 2. Gruener AM, Poostchi A, Carey AR, Eberhart CG, Henderson AD, Chang JR, McCulley TJ. Association of giant cell arteritis with race. JAMA Ophthalmol. [published ahead of print August 8, 2019] doi: 10.1001/jamaophthalmol.2019.2919. 3. Ferro JM, Coutinho JM, Dentali F, Kobayashi A, Alasheev A, Canhão P, Karpov D, Nagel S, Posthuma L, Roriz JM, Caria J, Frässdorf M, Huisman H, Reilly P, Diener HC; RE-SPECT CVT Study Group. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurol. [published ahead of print September 3, 2019] doi: 10.1001/jamaneurol.2019.2764. 4. Meer E, Shindler KS, Yu Y, VanderBeek BL. Adherence to clinical trial supported evaluation of optic neuritis. Ophthalmic Epidemiol. 2019;5:321–328. 5. Park KA, Min JH, Oh SY, Kim BJ. Idiopathic third and sixth cranial nerve neuritis. Jpn J Ophthalmol. 2019;63:337–343. 6. Waters P, Fadda G, Woodhall M, et al. Serial anti–myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes. JAMA Neurol. [published ahead of print September 23, 2019] doi: 10.1001/jamaneurol.2019.2940. Lambru G, Rantell K, Levy A, Matharu MS. A prospective comparative study and analysis of predictors of SUNA and SUNCT. Neurology. 2019;93:e1127–e1137. Objective: Despite the similar phenotypes, comparison between short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with autonomic features (SUNA) has hitherto not been possible due to the dearth of studies validating the phenotype of SUNA. Therefore, these 2 syndromes have been kept separate in the International Classification of Headache Disorders. The aim of this study is to characterize and compare the clinical phenotypes of large clinicbased cohorts of patients with SUNA and SUNCT. Methods: The clinical phenotype of consecutive patients with SUNA identified from a single specialist headache center in the United Kingdom between 2007 and 2012 was studied and compared to that of patients with SUNCT. Results: Sixty-three patients with SUNA (18 male, 28.6%) and 70 patients with SUNCT (32 male, 35.7%) were included. The demographic and clinical characteristics of patients with SUNA were similar to those of patients with SUNCT. Ptosis and rhinorrhea were predictors of SUNCT. The corresponding odds ratios (ORs) (95% confidence interval [CI]) were 3.79 (1.64– 8.77, P = 0.002) and 2.46 (1.09–5.59, P = 0.031), respectively. The presence of spontaneous-only attacks was a predictor for SUNA (OR 2.58 [1.10–6.05], P = 0.029). Conclusions: No major clinical differences have emerged between SUNCT and SUNA, bar the fact that SUNCT is characterized by more prominent cranial autonomic features and triggerability. We propose that the 2 disorders be placed 130 together in a single diagnostic category for which new diagnostic criteria are proposed. COMMENTS Mark, as my guru, I know you would never judge me, so I am going to tell you a couple of things that I have never told anybody before. First, I had no idea that the short-lasting unilateral neuralgiform headache attacks with autonomic features (SUNA) existed. Second, I can’t recall making a diagnosis of short-lasting unilateral neuralgiform headache attacks with conjunctival injection (SUNCT). So, to make me a better neuro-ophthalmologist, I chose to discuss this article that aimed to describe and compare the clinical characteristics of SUNA and SUNCT, which are categorized as separate disorders in the International Classification of Headache Disorders-3 (ICHD-3, Table 1). This was a retrospective series of patients with SUNA (n = 63) and SUNCT (n = 70) seen at one institution (Queen Square Institute of Neurology in London, UK). The first thing that struck me about this article was the impressive number of patients identified from a single institution study for what is an uncommon condition. All patients were identified in a prospective fashion between the years of 2007 and 2012 and they all completed a “comprehensive standardized semistructured questionnaire.” The authors found that SUNCT was more often associated with prominent cranial autonomic features (e.g., ptosis, eyelid Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 130-137 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! TABLE 1. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with autonomic features (SUNA) 3.3 Short-lasting unilateral neuralgiform headache attacks 3.3.1 short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) 3.3.2 short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) Description: Attacks of moderate or severe, strictly unilateral head pain lasting seconds to minutes, occurring at least once a day and usually associated with prominent lacrimation and redness of the ipsilateral eye. Diagnostic criteria: A. At least 20 attacks fulfilling criteria B–D B. Moderate or severe unilateral head pain, with orbital, supraorbital, temporal, and/or other trigeminal distribution, lasting for 1–600 seconds and occurring as single stabs, series of stabs, or in a sawtooth pattern C. At least one of the following 5 cranial autonomic symptoms or signs, ipsilateral to the pain: 1. conjunctival injection and/or lacrimation 2. nasal congestion and/or rhinorrhoea 3. eyelid edema 4. forehead and facial sweating 5. miosis and/or ptosis D. Occurring with a frequency of at least one a day E. Not better accounted for by another ICHD-3 diagnosis Note: 1. During part, but less than half, of the active time course of 3.3 shortlasting unilateral neuralgiform headache attacks, attacks may be less frequent. Comments: Longer-duration attacks are characterized by multiple stabs or a saw-tooth pain pattern. Two subtypes of 3.3 short-lasting unilateral neuralgiform headache attacks are recognized: 3.3.1 shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and 3.3.2 short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). 3.3.1 SUNCT may be a subform of 3.3.2 SUNA, although this requires further study. Meanwhile, each is classified as a separate subtype, described below. 3.3.1 SUNCT and 3.3.2 SUNA can usually be triggered without a refractory period. This is in contrast to 13.1.1 trigeminal neuralgia, which usually has a refractory period after each attack. Diagnostic criteria: A. Attacks fulfilling criteria for 3.3 short-lasting unilateral neuralgiform headache attacks, and criterion B below B. Both of the following, ipsilateral to the pain: 1. conjunctival injection 2. lacrimation (tearing) Comments: The literature suggests that the most common mimic of 3.3.1 SUNCT is a lesion in the posterior fossa. Patients have been described in whom there is overlap between 3.3.1 SUNCT and 13.1.1 trigeminal neuralgia. Differentiation is clinically complex. Such patients should receive both diagnoses. Patients with both 3.3.1 SUNCT and 3.1 cluster headache have been reported; the pathophysiological significance of this overlap is yet to be determined. A. Attacks fulfilling criteria for 3.3 short-lasting unilateral neuralgiform headache attacks, and criterion B below B. Not more than one of the following, ipsilateral to the pain: 1. conjunctival injection 2. lacrimation (tearing) Adapted from: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018 Jan;38(1):1–211. Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 130-137 131 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! edema, miosis, rhinorrhea, nasal blockage, and aural fullness), but only ptosis and rhinorrhea were statistically significant. Also, SUNCT was more frequently associated with a triggering factor (52.4% for SUNA vs 67.1% for SUNCT, P = 0.029). Aside from these 2 findings, there were no other distinguishing clinical characteristics between SUNCT and SUNA. As a result, the authors suggest combining SUNA and SUNCT into one disorder termed SUNA with the following criteria: A. At least 20 attacks of unilateral head pain fulfilling criteria B–E B. Occurring over the orbital, supraorbital, temporal, and/ or other trigeminal distribution C. Pain has at least 3 of the following 4 characteristics: 1. Attacks lasting 1–600 seconds 2. Moderate or severe intensity 3. Stabbing, sharp, electric shock–like, or shooting in quality 4. Precipitated by innocuous stimuli to the affected side of the face D. At least one of the following cranial autonomic symptoms or signs, ipsilateral to the pain: 1. 2. 3. 4. 5. Conjunctival injection and/or lacrimation Nasal congestion and/or rhinorrhea Eyelid edema Forehead and facial sweating Miosis and/or ptosis E. No refractory period follows attacks triggered by the innocuous stimuli to the affected side of the face F. Not better accounted for by another ICHD-3 diagnosis An obvious limitation of this study is correctly identifying these 2 disorders, although the authors stated “appropriate investigations were undertaken” to exclude other diseases that could mimic SUNA or SUNCT. Based on this study and what is written in the ICHD-3 (“3.3.1 SUNCT may be a subform of 3.3.2 SUNA, although this requires further study”), it seems to me that it is time to join these 2 diseases together in harmonious bliss, much like us Mark. —M. Tariq Bhatti, MD Tariq, I’m glad you didn’t tell others first, because it’s all “TMI.” I like this article because it makes sense. However, we really don’t know if these 2 groups are the same disease or if even there are many different disorders within these 2 groups. The challenge is that there are no diagnostic tests or biomarkers for these headache disorders and they are classified on the clinical manifestations. Highlighting the potential lack of accuracy in classifying patients into a particular diagnosis is the authors’ claim that they excluded patients who responded to indomethacin or to treatments for cluster headache. 132 Although the authors’ proposal makes sense, until there is a reliable biomarker to say for sure what the patient has, it will be up to a panel of headache specialists to decide whether to combine or separate these. As for us living in bliss together, remember, as Thomas Gray said, “ignorance is bliss.” —Mark L. Moster, MD Gruener AM, Poostchi A, Carey AR, Eberhart CG, Henderson AD, Chang JR, McCulley TJ. Association of giant cell arteritis with race. JAMA Ophthalmol. [published ahead of print August 8, 2019] doi: 10.1001/jamaophthalmol.2019.2919. Importance: Giant cell arteritis (GCA) is the most common vasculitis in adults and is associated with significant morbidity and mortality. Its incidence has been carefully studied in white populations, yet its relevance among other racial and ethnic groups is less well known. Objective: To examine the incidence of biopsy-proven GCA (BP-GCA) in a tertiary care center–based population with a sizeable proportion of black patients. Design, Setting, and Participants: This retrospective cohort study identified all patients who underwent temporal artery biopsy (TAB) from July 1, 2007, through September 30, 2017, using the electronic medical record system at the Johns Hopkins Wilmer Eye Institute. Associations between self-reported race, sex, and age were explored and compared with all other patients attending the hospital over the same period. Data were analyzed from November 1, 2017, through July 31, 2018. Main Outcomes and Measures: Estimated incidence rates of BP-GCA in black and white patients. Results: Among 586 patients who underwent TAB (mean [SD] age, 70.5 [11.1] years; age range, 32–103 years; 423 [72.2%] women), 167 (28.5%) were black, 382 (65.2%) were white, and 37 (6.3%) were other or unknown. Of 573 individuals aged 50 years and older, 92 (16.1%) had BP-GCA, 14 were black (8.4% of all black patients undergoing testing), and 75 were white (19.6% of all white patients undergoing testing). Crude annual incidence rates for BP-GCA were 2.9 (95% CI, 1.3–5.5) per 100 000 for black and 4.2 (95% CI, 3.0–5.6) per 100 000 for white patients within the study population. Population-adjusted age- and sex-standardized incidence rates were 3.1 (95% CI, 1.0–5.2) and 3.6 (95% CI, 2.5– 4.7) per 100,000 for black and white patients, respectively (difference, 0.5; 95% CI, 21.7 to 2.7; P = 0.70). The incidence rate ratio was 1.9 in women compared with men (95% CI, 1.1–3.4; P = 0.03) but was not significant in white compared with black patients (1.2; 95% CI, 0.6–2.4; P = 0.66). Conclusions and Relevance: In our cohort, BP-GCA occurred more commonly in women, but rates were similar between races. These findings do not seem to support the conclusion that GCA occurs more frequently in white compared with black patients. Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 130-137 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! COMMENTS I took a double take when I saw this study and continue to think about it. The reason being that this is not what has been reported in the literature regarding giant cell arteritis (GCA) and its associated racial predilection (higher incidence in white patients compared to black patient), and not in alignment with my clinical experience. The authors retrospectively reviewed the temporal artery biopsy (TAB) results of 586 patients over a 10-year period (2007–2017) at John Hopkins Health System. Sixty-five percent of the TABs were performed on white patients and 28.5% were performed on black patients. Of the 573 TABs performed in patients over the age of 50 years, 16.1% (n-92) were positive, with 8.4% (n = 14) among black patients and 19.6% (n = 75) among white patients. The crude incidence rate (calculated by using the number of incident cases as the numerator and patients of the corresponding sex and age groups seen at John Hopkins Heath System as the denominator) of TAB-positive GCA was 2.9/100,000 for black patients and 4.2/100,000 for white patients. Populationadjusted age- and sex-standardized rates for black patients and white patients were 3.1/100,000 and 3.6/100,000, respectively. The authors concluded that there is no race disparity in GCA. I am not going to dispute the absolute numbers but what I do question is the method of how the population-based incidence was derived. I can’t determine what exactly the authors used in terms of the population numbers. The 2010 United States (US) consensus was applied but does that represent the entire US, the state of Maryland, or the city of Baltimore? Even with this specified, I don’t think it fixes the problem, the reason being that Johns Hopkins is not the only tertiary care center in Baltimore and there is no proof that all patients included in the study resided in the US, let alone Baltimore. The editorial that accompanied the article briefly discussed this issue by stating “This comparison was derived from an area with a higher percentage of residents who self-identify as black compared with other studies, but the composition of their population was not described. Their use of the US Census data rather than their local racial distribution raises a concern about the accuracy of their results and their interpretations.” (1) The editorial goes on to say “Although the authors’ methods are imperfect, the studies that had previously established a low incidence of GCA in black patients were also flawed in design.” To me, 2 wrongs don’t make a right. In my mind, a true population-based study requires evaluating a group of patients within a well-defined region with an established number of residents. An example of such a group is from the Rochester Epidemiology Project (REP). Now granted this database is heavily weighted Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 130-137 toward whites because of the region of the country it represents, the advantage of the REP is that it is a systematic electronic health database that includes all patients from Olmsted county (2). Finally, several years ago we looked at the 10-year results of 204 TABs performed at Duke University Medical Center from 2000 to 2009. We didn’t apply our numbers to the US census nor did we perform a population-based study but the absolute numbers were the following and, as you can see, more TABs were performed on white patients and more often the TAB was positive in white patients (3): Total TAB cohort (n = 204) B B Pathologically confirmed: 49 (24%) Pathologically suggestive: 12 (5.9%) Black patients B TAB performed: 52 (25.4%) (i) Pathologically confirmed: 3 (5.7%) (ii) Pathologically suggestive: 2 (3.8%) White patients B TAB performed: 146 (71.5%) (i) Pathologically confirmed: 45 (30.8%) (ii) Pathologically suggestive: 10 (6.8%) Positive TAB relative risk (whites vs blacks): 4.61; P = 0.0013; OR = 6.59 Let me end by asking this—how does this study change our clinical thought process about GCA? A very wise man, who will remain unnamed (for those reading, it’s not Mark), said to me that any patient despite their race, with signs and symptoms of GCA, will be given equal consideration of the disease. —M. Tariq Bhatti, MD REFERENCES 1. Yoon MK, Rizzo JF III. Giant cell arteritis in black patients: do we know how rare it is? JAMA Ophthalmol. 2019. doi: 10.1001/ jamaophthalmol.2019.2933 (epub ahead of print). 2. Available at: https://rochesterproject.org/. 3. El-Dairi MA, Chang L, Proia AD, Cummings TJ, Stinnett SS, Bhatti MT. Diagnostic algorithm for patients with suspected giant cell arteritis. J Neuroophthalmol. 2015;35:246–253. I share the concerns you’ve raised, Tariq. In addition, this article really does not go along with my clinical experience. I’ve practiced in Philadelphia for 35 years and for 25 of those years, my practice was in parts of the city that were at least 80% African-American. Despite my practice of using the same 133 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! criteria for obtaining laboratory results or biopsies for a patient of any race (e.g., age .55, systemic symptoms, visual loss, diplopia etc.), I have seen very few African-Americans with GCA. In fact, my last case was an 84-year-old woman who presented elsewhere with simultaneous bilateral anterior ischemic optic neuropathy, and GCA was not considered because of her race. She was from South Carolina and did self-identify as African-American (the criterion used in this study). A year after we diagnosed her with biopsy-proven GCA, I inquired about her family history—her mom was African-American and her dad was Caucasian from Scandinavia. I totally agree with you that the same criteria need to be used to evaluate for GCA, regardless of racial background, but I question the frequency of GCA in African-Americans suggested in this article. —Mark L. Moster, MD Ferro JM, Coutinho JM, Dentali F, Kobayashi A, Alasheev A, Canhão P, Karpov D, Nagel S, Posthuma L, Roriz JM, Caria J, Frässdorf M, Huisman H, Reilly P, Diener HC; RE-SPECT CVT Study Group. Safety and efficacy of dabigatran etexilate vs doseadjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurol. [published ahead of print September 3, 2019] doi: 10.1001/jamaneurol.2019.2764. Importance: Patients with cerebral venous thrombosis (CVT) are at risk of recurrent venous thrombotic events (VTEs). Non-vitamin K oral anticoagulants have not been evaluated in randomized controlled trials in CVT. Objective: To compare the efficacy and safety of dabigatran etexilate with those of dose-adjusted warfarin in preventing recurrent VTEs in patients who have experienced a CVT. Design, Setting, and Participants: RE-SPECT CVT is an exploratory, prospective, randomized (1:1), parallel-group, open-label, multicenter clinical trial with blinded endpoint adjudication (PROBE design). It was performed from December 21, 2016, to June 22, 2018, with a follow-up of 25 weeks, at 51 tertiary sites in 9 countries (France, Germany, India, Italy, the Netherlands, Poland, Portugal, Russia, and Spain). Adult consecutive patients with acute CVT, who were stable after 5–15 days of treatment with parenteral heparin, were screened for eligibility. Patients with CVT associated with central nervous system infection or major trauma were excluded, but those with intracranial hemorrhage from index CVT were allowed to participate. After exclusions, 120 patients were randomized. Data were analyzed following the intention-to-treat approach. Interventions: Dabigatran, 150 mg twice daily, or doseadjusted warfarin for a treatment period of 24 weeks. Main Outcomes and Measures: Primary outcome was a composite of patients with a new VTE (recurrent CVT, deep vein thrombosis of any limb, pulmonary embolism, and splanchnic vein thrombosis) or major bleeding during the study period. Secondary outcomes were cerebral venous recanalization and clinically relevant nonmajor bleeding events. 134 Results: In total, 120 patients with CVT were randomized to the 2 treatment groups (60 to dabigatran and 60 to doseadjusted warfarin). Of the randomized patients, the mean (SD) age was 45.2 (13.8) years, and 66 (55.0%) were women. The mean (SD) duration of exposure was 22.3 (6.16) weeks for the dabigatran group and 23.0 (5.20) weeks for the warfarin group. No recurrent VTEs were observed. One (1.7%; 95% CI, 0.0–8.9) major bleeding event (intestinal) was recorded in the dabigatran group, and 2 (3.3%; 95% CI, 0.4– 11.5) (intracranial) in the warfarin group. One additional patient (1.7; 95% CI, 0.0–8.9) in the warfarin group experienced a clinically relevant nonmajor bleeding event. Recanalization occurred in 33 patients in the dabigatran group (60.0%; 95% CI, 45.9–73.0) and in 35 patients in the warfarin group (67.3%; 95% CI, 52.9–79.7). Conclusions and Relevance: This trial found that patients who had CVT anticoagulated with either dabigatran or warfarin had low risk of recurrent VTEs, and the risk of bleeding was similar with both medications, suggesting that both dabigatran and warfarin may be safe and effective for preventing recurrent VTEs in patients with CVT. COMMENTS This was a prospective, randomized, open-label trial that compared dabigatran (Pradaxa; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) to warfarin in patients with cerebral venous thrombosis (CVT). The primary outcome was composite number of patients with major bleeding or venous thrombotic events (VTEs). Two hundred patients were enrolled from 9 international tertiary care centers. The patients were evenly divided (60) between the 2 groups. Patients were treated for 24 weeks followed by a 7-day follow-up period. Seven (1.7%) patients in the dabigatran group and 4 (6.7%) patients in the warfarin group discontinued the medication before the 24 weeks. In terms of the primary outcome, no VTEs occurred in either group. Three major bleeding events occurred: 1 with dabigatran (gastrointestinal) and 2 with warfarin (subdural). Twenty percent of patients in both groups had any type of bleeding. It is worth noting that in this cohort of patients with CST, the outcomes were very good, which is encouraging for a disease that can be quite devastating. I want to point out that the study was funded by Boehringer Ingelheim Pharmaceuticals, Inc, the makers of Pradaxa. The authors considered this as an exploratory trial because if they were to have conducted a noninferiority trial with the assumption of a preservation of 50% of the benefit with warfarin and 3% rate of VTE, approximately 2000 patients would have been needed to be enrolled, which for such an uncommon disease would be very difficult if not impossible to accomplish. Do you think these are enough data for you to consider dabigatran Mark? —M. Tariq Bhatti, MD Although I’m involved in treatment for the visual aspects of CVT, I defer to the stroke specialists for decisions about Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 130-137 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! anticoagulation. However, as in other conditions requiring anticoagulation, it seems that the oral agents are an acceptable alternative to warfarin. This article lends some support to that. —Mark L. Moster, MD Meer E, Shindler KS, Yu Y, VanderBeek BL. Adherence to clinical trial supported evaluation of optic neuritis. Ophthalmic Epidemiol. 2019;5:321–328. Purpose: The Optic Neuritis (ON) Treatment Trial showed that an MRI of the brain is a powerful predictor of developing multiple sclerosis (MS). However, surveys of practitioners suggest that the recommended use of imaging is not consistently followed in practice. With this study, we aim to assess the rate at which newly diagnosed ON patients receive brain MRIs. Methods: This is a retrospective cohort study using administrative medical claims data from a large, national US insurer. All incident cases from 2000 to 2016 of ON in patients without MS were assessed. The primary outcome was a comparison of patterns of MRI scanning usage after diagnosis of ON. Secondary outcomes evaluated steroid treatment and progression to MS. Results: Of 2,865 qualified ON patients, 1755 (61.3%) received a brain MRI. At 1-year follow-up, 629 (30.3%) patients had progressed to MS, a rate that increased slightly to 34.3% (366 patients) within a 3-year period of their initial ON diagnosis. A total of 520 (18.2%) patients received intravenous steroids, and 383 (13.4%) received oral steroids within 30 days of the ON diagnosis. Conclusion: Across the United States, a surprisingly low number of individuals obtain a brain MRI after onset of ON, suggesting that physicians may not be fully assessing the risk of MS. 13.4% oral steroids speaks to the possibility that the medical insurance coding for ON may have been a “convenience” code rather than a truly believed diagnosis. A high rate of diagnosis of multiple sclerosis (MS) was found (30.3% at 1 year and 34.3% at 3 years). The rate of progression was 65.6% for those with IV steroids, 38.8% with oral steroids, and 26% without steroids. The authors explain that the higher rate may be related to the evolving diagnostic criteria that include MRI features. However, I wonder whether some of the noted diagnoses of MS were to justify immunomodulating therapy in patients with clinically isolated syndrome. —Mark L. Moster, MD I am not a fan of “big data” studies because (just to name one thing) it is very difficult to determine whether the disease you are studying has been truly captured in the data set. Having said that, if what this study found is true, it is disappointing to think that after all these years of highquality evidence and more importantly clinical experience, ON is still not being properly managed. Over a decade ago, an international survey showed that “many neurologists and ophthalmologists do not evaluate and treat acute ON patients according to the best evidence from clinical research.” (1) When will we learn from history and carry it forward? —M. Tariq Bhatti, MD 1. Biousse V, Calvetti O, Drews-Botsch CD, Atkins EJ, Sathornsumetee B, Newman NJ. Optic Neuritis Survey Group. Management of optic neuritis and impact of clinical trials: an international survey. J Neurol Sci. 2009;276:69–74. COMMENTS Park KA, Min JH, Oh SY, Kim BJ. Idiopathic Third and Sixth Cranial Nerve Neuritis. Jpn J Ophthalmol. 2019;63:337–343 This study has made some conclusions related to the diagnosis and treatment of optic neuritis (ON) based on administrative claims data from a national insurer. The authors admittedly note a series of limitations of the study. First, they claim that only 61.3% of patients received a brain MRI. However another 5.9% had an orbital MRI. In my institution, all of our orbital MRIs have T2 fluid-attenuated inversion recovery images of the brain included; so, some of these may have actually also been brain MRIs. Although the authors used criteria to increase the accuracy of the ON diagnosis, I would assume that many patients called ON did not truly have that. I am saying this from my own experience where patients are referred by neurologists, optometrists, and ophthalmologists with an ON diagnosis and end up with a diagnosis of nonarteritic anterior ischemic optic neuropathy (NAION), papilledema, optic nerve sheath meningioma, retinopathy, dry eye syndrome, or refractive error. Another finding that only 18.2% received intravenous (IV) steroids and Purpose: To present cases with idiopathic third and sixth cranial nerve neuritis. Study design: Retrospective observational study. Methods: The results of high-resolution pre- and post-cranial nerve MRI with three-dimensional sequences for visualizing cranial nerves in patients with third, fourth, and sixth cranial nerve palsies who were treated at the Neuro-ophthalmology Department of Samsung Medical Center were reviewed. Patients with cranial nerve enhancement confirmed by experienced radiologists were identified. The medical records of these patients were reviewed, and their demographics, clinical presentations, laboratory results, and clinical outcomes were analyzed. Results: Of 265 patients with third, fourth, and sixth cranial nerve palsy, 60 were identified by high-resolution MRI as having enhancement of the corresponding cranial nerve. Among these, 17 patients with infiltrative, granulomatous, or tumorous lesions were excluded. In addition, 28 patients with identifiable causes of cranial nerve palsy, such as Miller–Fisher syndrome, virus infection, or radiation-induced neuropathy, as well as patients with vasculopathic risk factors, were also excluded. Ultimately, a total of 15 patients with idiopathic third and sixth Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 130-137 135 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! cranial nerve neuritis were included in this study. The mean age of these patients was 43 ± 15 years. Eight patients had sixth cranial nerve palsy, 6 had third cranial nerve palsy (2 partial and 4 complete), and one patient had complete third and sixth cranial nerve palsy. Nine patients received steroid treatment. Eleven patients recovered fully within a period ranging from a few days to one year. Two patients were much improved up to 1 month after initial presentation, but were then ultimately lost to follow-up. Another patient was lost to follow-up after the initial workup. The other patient lost to follow-up had partially recovered during the first 6 months. Conclusions: We present patients with idiopathic third and sixth cranial nerve neuritis. They tended to respond well to steroid treatment and to have good prognoses. To better understand the long-term prognosis of cranial nerve neuritis and possible association with other neurologic disorders, a larger-scale and longer-term study is needed. COMMENTS This article describes 15 patients with an ocular motor palsy with enhancement of the nerve on high-resolution MRI. This is something we haven’t seen clinically except in the erroneous diagnosis of “ophthalmoplegic migraine.” The patients followed the course of a vasculopathic cranial neuropathy, improving with our without steroid treatments; so, perhaps if we studied classic cranial neuropathy patients with these high-resolution MRIs, we’d find them to have enhancement as well. I looked at some of the images in the article. The findings are subtle. In addition, the radiologists were not masked to the diagnosis, which may bias the results. —Mark L. Moster, MD I am not sure what to make of this retrospective case series, except to say that enhancement of any of the ocular motor cranial nerves is always abnormal and deserves a thorough evaluation. If that evaluation is negative, then we can say it is “idiopathic” but that doesn’t exclude that the possibility of an unidentified infectious agent (i.e., virus), microvascular ischemia, or recurrent painful ophthalmoplegic cranial neuropathy (previously known as ophthalmoplegic migraine). —M. Tariq Bhatti, MD Waters P, Fadda G, Woodhall M, et al. Serial anti– myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes. JAMA Neurol. [published ahead of print September 23, 2019] doi: 10.1001/jamaneurol.2019.2940 Importance: Identifying the course of demyelinating disease associated with myelin oligodendrocyte glycoprotein (MOG) autoantibodies is critical to guide appropriate treatment choices. 136 Objective: To characterize serial anti-MOG antibody serologies and clinical and imaging features at presentation and during follow-up in an inception cohort of prospectively monitored children with acquired demyelination. Design, setting, and participants: In this prospective cohort study, study participants were recruited from July 2004 to February 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study. Inclusion criteria included (1) incident central nervous system demyelination, (2) at least 1 serum sample obtained within 45 days from onset, and (3) complete clinical information. Of 430 participants with acquired demyelinating syndrome recruited, 274 were included in analyses. Of 156 excluded participants, 154 were excluded owing to missing baseline samples and 2 owing to incomplete clinical information. Data were analyzed from May to October 2018. Main outcomes and measures: Presence of anti-MOG antibodies was blindly assessed in serial samples collected over a median of 4 years. Clinical, MRI, and cerebrospinal fluid features were characterized at presentation, and subsequent disease course was assessed by development of new brain MRI lesions, total lesion volume at last evaluation, annualized relapse rates, Expanded Disability Status Scale score and visual functional score at 4 years, and any disease-modifying treatment exposure. Results: Of the 274 included participants, 140 (51.1%) were female, and the median (interquartile range) age of all participants was 10.8 (6.2–13.9) years. One-third of children were positive for anti-MOG antibodies at the time of incident demyelination. Clinical presentations included a combination of ON, transverse myelitis, and acute disseminated encephalomyelitis for 81 of 84 anti-MOG antibody–positive children (96%). Brain lesions were present in 51 of 76 anti-MOG antibody–positive participants (67%), but MRI characteristics differed with age at presentation. Complete resolution of baseline lesions was observed in 26 of 49 anti-MOG antibody–positive participants (53%). On serial serum analysis, 38 of 67 participants (57%) who were seropositive at onset became seronegative (median time to conversion, 1 year). Among all participants who were positive for anti-MOG antibodies at presentation, clinical relapses occurred in 9 of 24 children (38%) who remained persistently seropositive and in 5 of 38 children (13%) who converted to seronegative status. Conclusions and relevance: Myelin oligodendrocyte glycoprotein antibodies are common in children with acquired demyelinating syndrome and are transient in approximately half of the cases. Even when persistently positive, most antiMOG antibody–positive children experience a monophasic disease. The presence of anti-MOG antibodies at the time of incident demyelination should not immediately prompt the initiation of long-term immunomodulatory therapy. COMMENTS This prospective cohort study looked at anti-myelin oligodendrocyte glycoprotein (MOG) status at the first clinical presentation in children and followed the patients’ clinical, MRI, and MOG status over time. Approximately 31% of patients with a demyelinating event had MOG antibodies. Younger patients tended to present with acute Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 130-137 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary: Double Feature - Take Two! disseminated encephalomyelitis (ADEM) and/or a large number of ill-defined MRI lesions. Older children presented with ON with no or few brain lesions. The age cutoff between these 2 presentations was approximately 11 years. A negative MOG at onset almost entirely excluded subsequent positive results later. A monophasic illness was seen in patients with MOG-negative presentations with ON or transverse myelitis and normal brain MRI or with ADEM. MOG-negative patients who met McDonald MS criteria followed a typical MS course. MOG-positive patients who met McDonald MS criteria did not follow a typical MS course. Most MOG-positive patients became seronegative and followed a monophasic course. Those who were positive initially and relapsed either remained seropositive or returned to seropositivity. However, 72% of persistently seropositive patients remained relapse free. The strongest association with recurrence was an older age at presentation. Eighty percent of the seropositive patients had monophasic courses, low Expanded Disability Status Scale (EDSS), and low or no residual MRI activity. The authors recommend MOG testing for all children with an acute demyelinating syndrome. Moster and Bhatti: J Neuro-Ophthalmol 2020; 40: 130-137 Although seropositivity is associated with an increased risk of relapse, the authors suggest not instituting immunomodulatory long-term therapy unless relapse occurs. This excellent study continues to develop the evolving picture for use of the anti-MOG syndrome. It is from the Canadian Pediatric Demyelinating Disease Network and has similar findings and recommendations as those coming out of the Mayo group. The bottom line for me is that I would check MOG antibodies in any child with demyelination and in the many adults who are atypical in presentation (bilateral, severe, associated with more than mild optic disc edema) or a negative brain MRI. —Mark L. Moster, MD This must be a bromance, because I completely agree with your bottom line Mark. I have been at Mayo Clinic in Rochester, MN, for approximately 1.5 years, and it is a privilege to be working with John J. Chen, MD PhD, Sean Pittock MD, Eoin Flanagan MD et al, as they advance our understanding of myelin oligodendrocyte glycoproteinIgG-associated disease (MOGAD). —M. Tariq Bhatti, MD 137 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.