Literature Commentary

Literature Commentary Section Editors: Mark L. Moster, MD Marc J. Dinkin, MD Deborah I. Friedman, MD, MPH Literature Commentary In this issue of JNO Drs. Mark L. Moster, Marc Dinkin, and Deborah I. Friedman discuss the following 6 articles: 1. Thaller M, Homer V, Mollan SP, Sinclair AJ. Disease course and long-term outcomes in pregnant women with idiopathic intracranial hypertension: the IIH Prospective Maternal Health Study. Neurology. 2023. doi: 10. 1212/WNL.0000000000206854. Epub ahead of print. PMID: 36750388. 2. Chen JJ, Flanagan EP, Pittock SJ, Stern NC, Tisavipat N, Bhatti MT, Chodnicki KD, Tajfirouz DA, Jamali S, Kunchok A, Eggenberger ER, Nome MAD, Sotirchos ES, Vasileiou ES, Henderson AD, Arnold AC, Bonelli L, Moss HE, Navarro SEV, Padungkiatsagul T, Stiebel-Kalish H, Lotan I, Wilf-Yarkoni A, Danesh-Meyer H, Ivanov S, Huda S, Forcadela M, Hodge D, Poullin P, Rode J, Papeix C, Saheb S, Boudot de la Motte M, Vignal C, Hacohen Y, Pique J, Maillart E, Deschamps R, Audoin B, Marignier R. Visual outcomes following plasma exchange for optic neuritis: an international multicenter retrospective analysis of 395 optic neuritis attacks. Am J Ophthalmol. 2023:S0002-9394(23)00066-1. doi: 10.1016/j.ajo.2023.02.013. Epub ahead of print. PMID: 36822570. 3. daSilva Morgan K, Schumacher J, Collerton D, Colloby S, Elder GJ, Olsen K, Ffytche DH, Taylor JP. Transcranial direct current stimulation in the treatment of visual hallucinations in Charles Bonnet syndrome: a randomized placebo-controlled crossover trial. Ophthalmology. 2022;129:1368–1379. doi: 10.1016/j.ophtha.2022. 06.041. Epub 2022 Jul 9. PMID: 35817197. 4. Friedberg A, Pasquini L, Diggs R, Glaubitz EA, Lopez L, Illán-Gala I, Iaccarino L, La Joie R, Mundada N, Knudtson M, Neylan K, Brown J, Allen IE, Rankin KP, Bonham LW, Yokoyama JS, Ramos EM, Geschwind DH, Spina S, Grinberg LT, Miller ZA, Kramer JH, Rosen H, Gorno-Tempini ML, Rabinovici G, Seeley WW, Miller BL. Prevalence, timing, and network localization of emergent visual creativity in frontotemporal dementia. JAMA Neurol. 2023:e230001. doi: 10.1001/jamaneurol.2023.0001. Epub ahead of print. PMID: 36848111; PMCID: PMC9972248. 5. Reilly MA, Katz SE, Roberts CJ. Orbital fat swelling: a biomechanical theory and supporting model for spaceflightassociated neuro-ocular syndrome (SANS) Front Bioeng Biotechnol. 2023;11:1095948. doi: 10.3389/fbioe.2023. 1095948. eCollection 2023. 6. Carta S, Cobo Calvo Á, Armangué T, Saiz A, Lechner C, Rostásy K, Breu M, Baumann M, Höftberger R, Ayzenberg I, Schwake C, Sepulveda M, Martínez-Hernández E, Olivé-Cirera G, Arrambide G, Tintoré M, Bernard-Valnet R, Du Pasquier RA, Brilot F, Ramanathan S, Schanda K, Gajofatto A, Ferrari S, Sechi E, Flanagan EP, Pittock SJ, Redenbaugh V, Reindl M, Marignier R, Mariotto S. Significance of myelin oligodendrocyte glycoprotein antibodies in CSF: a retrospective multicenter study. Neurology. 2022. doi: 10.1212/WNL. 0000000000201662. Epub ahead of print. PMID: 36526426. Thaller M, Homer V, Mollan SP, Sinclair AJ. Disease course and long-term outcomes in pregnant women with idiopathic intracranial hypertension: the IIH Prospective Maternal Health Study. Neurology. 2023. doi: 10.1212/WNL.0000000000206854. Epub ahead of print. PMID: 36750388. Background: Idiopathic intracranial hypertension (IIH) most typically occurs in women of childbearing age with increased weight as a key risk factor for development or exacerbation of the disease. Pregnancy is common in this group of patients. The longer-term impact of pregnancy on IIH has not been established and was the aim of this study. Methods: A prospective cohort study (IIH Life) recruited consecutive patients with IIH between 2012 and 2021 and evaluated outcomes including vision (logMAR visual acuity, automated visual field perimetric mean deviation [PMD], and optical coherence tomography [OCT] imaging) 440 and headache. Four cohorts were evaluated: those with IIH diagnosed for the first time while pregnant, those with established IIH who became pregnant, those with a pregnancy before their diagnosis of IIH, and those with IIH who never became pregnant. Results: Three hundred seventy-seven people with IIH agreed to participate in the IIH Life maternal health study. The mean follow-up was 17.5 months (SD 20.5). IIH diagnosed in pregnancy was rare. Patients diagnosed with IIH while pregnant had greater papilledema (mean OCT total retinal thickness +11.59 mm/month [95% CI: 1.25, 21.93]), although they had comparable visual field and acuity measures to those with established IIH who became pregnant during their disease course (21.2 mm/month [95% CI: 22.6, 0.21]). In those with established IIH, pregnancy did not adversely affect visual or headache outcomes over time and the trajectory was akin to those with IIH who never had a pregnancy. Headache outcomes showed variability reflecting the IIH cohort as a whole. Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Pregnancy and IIH: Sorting Out Myth From Fact With the IIH Prospective Maternal Health Study papilledema was similar in all the groups, but surgery was never required during pregnancy. In fact, ICP-lowering medications were not used in any pregnant patients in this study. Visual outcomes in pregnant patients with IIH were not different from nonpregnant patients with IIH, although the speed of improvement of the total retinal thickness (TRT) and retinal nerve fiber layer (RNFL) was slower in the pregnant patients. However, patients who were diagnosed with IIH during pregnancy demonstrated a deterioration of visual fields’ mean deviation and an increase in TRT and RNFL. The prognosis for headache outcomes did not different between groups. “Doctor, when can I start planning my family?” is a question we neuro-ophthalmologists hear not too infrequently from our patients with idiopathic intracranial hypertension (IIH). After hearing that the disease is provoked by weight gain or high body mass index, they are understandably concerned about embarking on a pregnancy which will invariably lead to an increase in their weight. And many have learned about the endocrinological contributions to IIH pathophysiology and are concerned that changes in sex hormones associated with pregnancy might provoke a relapse that would be difficult to treat without endangering the fetus. Fortunately, we have at our disposal the excellent study by Digre et al1 from 1984, in which the rate of being pregnant at time of onset of IIH was no higher than expected for women of childbearing age at that time, suggesting that pregnancy was not a predisposing factor but simply a marker of the patient demographics. They also found that the rates of spontaneous miscarriage and obstetric complications were no higher in the patients with IIH than those without and that the risk of vision loss was no greater in their pregnant IIH cohort than that seen in previous studies of IIH. Finally, the risk of recurrence of IIH did not seem to be higher than that of nonpregnant patients with IIH. Although this study offered reassurances, conclusions were tempered by its retrospective nature and that comparative data were typically from previous literature or demographic data. In a recent article in Neurology, Thaller et al2 reported on the results of the IIH Prospective Maternal Health Study, in which the authors followed 311 patients with IIH from 2012 to 2021 with a mean follow-up of 17.5 months and compared clinical outcomes between cohorts defined by pregnancy status. Specifically, they identified a cohort of patients in whom IIH was diagnosed during pregnancy (Group 1, n = 6), those with IIH who became pregnant during their course (Group 2, n = 46), those who had completed a pregnancy before their IIH diagnosis (Group 3, n = 181), and those who were never pregnant (Group 4, n = 144). Only 1 miscarriage occurred, in a patient in Group 2, yielding a rate of 1 of 46, which is less than the expected rate of miscarriage in general. The rate of requiring surgical intervention for sight-threatening Commentary The most important finding of this prospective study was that patients with IIH who became pregnant were not more likely to have a poor visual outcome than those who did not become pregnant. With this in mind, we can inform our patients that they can proceed with plans for pregnancy without fearing severe recurrences. Yet it should be noted that in the patients with IIH in this study who became pregnant, papilledema had been controlled in the year before, so these results cannot be used to suggest that it is safe for patients with active IIH with sight-threatening papilledema to become pregnant. As the authors recommend, we continue to recommend to our patents that IIH be optimally controlled before conception. Those patients who were diagnosed with IIH during pregnancy showed more significant deterioration than those who became pregnant during their IIH course, which comports with my own experience with several patients who first developed the disease while pregnant. However, whether this reflects some effect of the hormonal milieu or weight profile of pregnancy or is simply a reflection of a worsened course after the first course of papilledema in IIH than in patients with chronic papilledema remains unclear. Furthermore, because none of the pregnant patients received any treatment during their pregnancy, it is likely that similar patients who received acetazolamide, which seems to be relative safe during pregnancy,3 would demonstrate a better course. The study is limited by the fact that the number of patients who developed IIH while pregnant was small. Furthermore, these patients happened to have relatively mild IIH, with an average initial mean deviation of 22.00 dB, an initial RNFL of 123 mm, and an average opening pressure on lumbar puncture of only 22 cm H2O. I have certainly seen pregnant women diagnosed with IIH who presented with much more severe papilledema and visual loss at initial diagnosis. It is possible that patients with IIH with more severe underlying disease would fare worse if they presented with pregnancy than the cohort here. With these new results in mind, I will continue to counsel my patients with IIH that they can pursue pregnancy once their disease is well controlled, preferably Discussion: A diagnosis of IIH while pregnant was rare but associated with more severe papilledema. Long-term visual outcomes in IIH were analogous irrespective of the timing of the pregnancy. These data are reassuring; however, close vigilance of IIH clinical features during pregnancy is recommended. COMMENTS Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 441 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary in a state where they are off acetazolamide and without active papilledema. I will continue to monitor them carefully while pregnant, as an added precaution, despite the reassuring observation that their outcome should not be significantly affected. —Marc Dinkin, MD REFERENCES 1. Digre KB, Varner MW, Corbett JJ. Pseudotumor cerebri and pregnancy. Neurology. 1984;34:721–729. 2. Thaller M, Homer V, Mollan SP, Sinclair AJ. Disease course and long-term outcomes in pregnant women with idiopathic intracranial hypertension: the IIH prospective maternal health study. Neurology. 2023. doi: 10.1212/WNL.0000000000206854. Epub ahead of print. PMID: 36750388. 3. Falardeau J, Lobb BM, Golden S, Maxfield SD, Tanne E. The use of acetazolamide during pregnancy in intracranial hypertension patients. J Neuroophthalmol. 2013;33:9–12. Throughout my career, female patients with IIH from all over the world have contacted me regarding getting pregnant. Some were advised by their physicians to never have children because of IIH. Others were counseled to have an abortion if they became pregnant. My standard response was (1) they could get pregnant as long as their IIH was controlled/stable; (2) we have several alternatives for treating IIH during pregnancy, if needed; (3) their neuro-ophthalmic status should be closely monitored during pregnancy; and (4) IIH should not factor into their obstetrician’s choice of delivery method. This study, part of a prospective data collection (LIFE-IIH) project, is the largest study of women with IIH analyzed by pregnancy status. It verified many of our recommendations which we base on clinical experience. The study also, disconcertingly, indicates that IIH still negatively influences women’s family planning in various ways. IIH developing during pregnancy is rare, occurring only 2% in this cohort, and none of those 6 patients required surgical intervention or had a miscarriage. My experience is similar to Marc’s, having treated several women who developed IIH during pregnancy with more severe disease. One of those patients had progressive visual loss and underwent elective pregnancy termination with improvement. Despite the good overall visual prognosis, 17% of the cohort that became pregnant after being diagnosed with IIH required surgery. Although we counsel our patients to avoid excessive weight gain during pregnancy (i.e., more than their obstetrician recommends), change in BMI during pregnancy did not affect the visual prognosis. I found it interesting that the patients were not treated medically during pregnancy. Although topiramate and zonisamide are contraindicated during pregnancy, most neuroophthalmologists in the United States prescribe acetazolamide or other diuretics if needed, after consultation with 442 the obstetrician. Intermittent lumbar punctures are often helpful as a temporizing measure during pregnancy; it was not mentioned whether this modality was needed or offered to pregnant patients in this cohort. Perhaps this is relevant to the gradual worsening of papilledema over the ensuing 12 months in the patients developing IIH during pregnancy. —Deborah I. Friedman, MD, MPH This study from our UK colleagues provides further reassurance that patients with IIH are likely to do well during pregnancy. I agree with your concerns that some pregnant patients have more severe disease and I have also rarely needed to send a patient for surgery. The stated criteria for diagnosis of IIH in this study included an opening pressure of .25 cm H2O. With that in mind, how could the mean opening pressure in this group be 22? —Mark L. Moster, MD Chen JJ, Flanagan EP, Pittock SJ, Stern NC, Tisavipat N, Bhatti MT, Chodnicki KD, Tajfirouz DA, Jamali S, Kunchok A, Eggenberger ER, Nome MAD, Sotirchos ES, Vasileiou ES, Henderson AD, Arnold AC, Bonelli L, Moss HE, Navarro SEV, Padungkiatsagul T, Stiebel-Kalish H, Lotan I, WilfYarkoni A, Danesh-Meyer H, Ivanov S, Huda S, Forcadela M, Hodge D, Poullin P, Rode J, Papeix C, Saheb S, Boudot de la Motte M, Vignal C, Hacohen Y, Pique J, Maillart E, Deschamps R, Audoin B, Marignier R. Visual outcomes after plasma exchange for optic neuritis: an international multicenter retrospective analysis of 395 optic neuritis attacks. Am J Ophthalmol. 2023:S0002-9394(23)00066-1. doi: 10.1016/j. ajo.2023.02.013. Epub ahead of print. PMID: 36822570. Purpose: To evaluate the effectiveness of plasma exchange (PLEX) for optic neuritis (ON). Methods: We conducted an international multicenter retrospective study evaluating the outcomes of ON after PLEX. Outcomes were compared with raw data from the Optic Neuritis Treatment Trial (ONTT) using a matched subset. Results: A total of 395 ON attacks treated with PLEX from 317 patients were evaluated. The median age was 37 years (range 9–75) and 71% were women. Causes of ON included multiple sclerosis (108), myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) (92), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (75), seronegative NMOSD (34), idiopathic (83), and other (3). Median time from onset of vision loss to PLEX was 2.6 weeks (IQR, 1.4–4.0). Median visual acuity (VA) at time of PLEX was count fingers (IQR, 20/200 hand motion) and median final VA was 20/25 (IQR, 20/20– 20/60) with no differences among etiologies except Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary MOGAD-ON which had better outcomes. In 81 ON attacks (20.5%), the final VA was 20/200 or worse. Patients with poor outcomes were older (P = 0.002), had worse VA at time of PLEX (P , 0.001), and longer delay to PLEX (P , 0.001). In comparison with the ONTT subset with severe corticosteroid-unresponsive ON, a final VA of worse than 20/40 occurred in 6 of 50 PLEX-treated ON (12%) vs 6 of 18 (33%) from the ONTT treated with intravenous methylprednisolone without PLEX (P = 0.04). Conclusion: Most ON attacks improved with PLEX, and outcomes were better than attacks with similar severity in the ONTT. The presence of severe vision loss at nadir, older age, and longer delay to PLEX predicted a worse outcome while MOGAD-ON had a more favorable prognosis. COMMENTS Should we routinely treat optic neuritis with plasma exchange (PLEX)? Although the older literature suggests that the answer may be “yes,” many of the studies were small and predated our knowledge of non–MS-related optic neuritis (i.e., neuromyelitis optica spectrum disorder [NMOSD] aquaporin-4-IgG-positive NMOSD [APQ4 + NMOSD] and myelin glycoprotein antibody–associated disease [MOGAD]). To that end, an international team from 11 centers in 6 countries (United States, France, Israel, New Zealand, United Kingdom, and Thailand) performed a retrospective study of patients with optic neuritis who were treated with PLEX and had recorded visual acuity at the time of PLEX and at least 3 months later (unless they recovered to 20/20 in less than 3 months). They excluded patients with recurrent optic neuritis. The cohort was divided by etiologies, including the abovementioned disorders, idiopathic, and other. The final visual acuity was the time point closest to 6–12 month visit posttreatment. Outcomes were compared with those in the Optic Neuritis Treatment Trial (ONTT) at the 6-month visit. Better outcomes were associated with MOGAD optic neuritis (only 1 of 92 attacks had an outcome of 20/200 or worse) and early PLEX treatment. Worse acuity at the time of PLEX, older age, and a longer delay to PLEX treatment were associated with poorer outcomes. Optic neuritis of etiologies other than MOGAD did not enjoy the same degrees of improvement with no significant differences by etiology. PLEX treatment of NMOSD optic neuritis and MS/idiopathic optic neuritis had similar outcomes. Overall, there was no difference in the outcomes of patients with severe visual loss (counting fingers or worse) receiving PLEX within the first 4–11 days compared with the ONTT group. By contrast, patients with a pretreatment visual acuity of 20/200 or worse treated with PLEX were more likely to recover to 20/40 or better with PLEX treatment compared with the ONTT group randomized to IV methylprednisolone. Eyes with previous episodes of optic neuritis had worse outcomes after PLEX compared with PLEX-treated eyes Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 with first attacks. However, eyes with a good recovery (20/25 or better) after the initial attack had identical outcomes to those without a previous attack of optic neuritis, suggesting that the history of improvement, or lack thereof, may help inform us of good candidates for PLEX. The authors acknowledge the selection bias involved in their study and proposed a randomized clinical trial, perhaps starting with a cohort of severe corticosteroidresistant optic neuritis or an early trial of PLEX in patients with visual acuity of counting fingers or worse. Overall, this large study provides more encouraging data regarding PLEX for the treatment of optic neuritis of various etiologies, particularly for patients with MOGAD, younger patients, and those with initial acuities of 20/200 or better. A prospective trial to avoid some of the pitfalls of retrospective studies would be very helpful to assist us in identifying optimal candidates for PLEX. —Deborah I. Friedman, MD, MPH In 2012, Merle et al1 demonstrated a much better visual acuity in patients with NMO with severe optic neuritis treated with IV methylprednisolone followed by PLEX (final VA 20/50) than those treated with IV steroids alone (final VA of 20/200). The patient population was selected based on the 2006 Wingerchuk criteria so AQP4-IgG was not required if there were no MRI lesions and there was a longitudinal transverse myelitis; this cohort may have therefore included some patients with MOGAD. Since its publication, I have treated all patients with significant VA loss from NMO optic neuritis with PLEX and based on the retrospective study of patients with NMO-SD by Bonnan et al2, I have pushed for it to be conducted early. In their study, the chance of recovery to pre-ON visual acuity sharply dropped from 45% to 50% in the groups treated within the first 5 days to approximately 30% in those treated between Day 6 and 10. In practice although, I have not limited the use of PLEX to those patients with ON with a definite diagnosis of NMO-SD because there is a delay before the AQP antibody returns, and waiting for those results could lessen the impact of PLEX on the outcome. Instead, we have considered PLEX for anyone with severe VA loss at presentation with the notion that they might end up being NMO-SD, and even if they did not, PLEX might be helpful for patients with non-NMO-SD ON with severe visual loss. With the benefit of this large multicenter retrospective study, we can now treat all of our patients with severe ON with PLEX regardless of the underlying disease process, assuming that they do not respond to IV steroids in the first 3 days. The data confirm that “time is optic nerve” regarding PLEX treatment for these patients, with a reduction in rates of complete or “good” recovery as the delay increases. The results in the study add to the growing recognition that the humoral immune system plays a significant role in MS-associated demyelination that can be 443 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary targeted.3 Like Deb, I am looking forward to seeing the prospective study proposed by the authors. —Marc Dinkin, MD It is surprising that a full 24% of patients with MS and 23% of patients with idiopathic optic neuritis ended up 20/200 or worse, not much fewer than the 31% with NMOSD. As other recent reports have found, earlier PLEX treatment was associated with better recovery. With this study, I have further support for early PLEX treatment in all cases of optic neuritis that do not improve within the 3– 5 days of IVMP, regardless of underlying etiology. support and education for CBS may have therapeutic benefits. Participants who demonstrated greater occipital excitability on electroencephalography assessment at the start of treatment were more likely to report a positive treatment response. Stimulation was found to be tolerable in all participants, with no significant adverse effects reported, including no deterioration in pre-existing visual impairment. Conclusions: Findings indicate that inhibitory tDCS of visual cortex may reduce the frequency of visual hallucinations in people with CBS, particularly individuals who demonstrate greater occipital excitability before stimulation. tDCS may offer a feasible intervention option for CBS with no significant side effects, warranting larger-scale clinical trials to further characterize its efficacy. —Mark L. Moster, MD REFERENCES 1. Merle H, Olindo S, Jeannin S, et al. Treatment of optic neuritis by plasma exchange (add-on) in neuromyelitis optica. Arch Ophthalmol. 2012;130:858–862. 2. Bonnan M, Valentino R, Debeugny S, et al. Short delay to initiate plasma exchange is the strongest predictor of outcome in severe attacks of NMO spectrum disorders. J Neurol Neurosurg Psychiatry. 2018;89:346–351. 3. Yu X, Graner M, Kennedy PGE, Liu Y. The role of antibodies in the pathogenesis of multiple sclerosis. Front Neurol. 2020;11:533388. daSilva Morgan K, Schumacher J, Collerton D, Colloby S, Elder GJ, Olsen K, Ffytche DH, Taylor JP. Transcranial direct current stimulation in the treatment of visual hallucinations in Charles Bonnet syndrome: a randomized placebo-controlled crossover trial. Ophthalmology. 2022;129:1368– 1379. doi: 10.1016/j.ophtha.2022.06.041. Epub 2022 Jul 9. PMID: 35817197. Objective: To investigate the potential therapeutic benefits and tolerability of inhibitory transcranial direct current stimulation (tDCS) on the remediation of visual hallucinations in Charles Bonnet syndrome (CBS). Design: Randomized, double-masked, placebo-controlled crossover trial. Participants: Sixteen individuals diagnosed with CBS secondary to visual impairment caused by eye disease experiencing recurrent visual hallucinations. Intervention: All participants received 4 consecutive days of active and placebo cathodal stimulation (current density: 0.29 mA/cm2) to the visual cortex (Oz) over 2 defined treatment weeks, separated by a 4-week washout period. Main Outcome Measures: Ratings of visual hallucination frequency and duration after active and placebo stimulation, accounting for treatment order, using a 2 · 2 repeatedmeasures model. Secondary outcomes included impact ratings of visual hallucinations and electrophysiological measures. Results: When compared with placebo treatment, active inhibitory stimulation of visual cortex resulted in a significant reduction in the frequency of visual hallucinations measured by the North East Visual Hallucinations Interview, with a moderate-tolarge effect size. Impact measures of visual hallucinations improved in both placebo and active conditions, suggesting 444 COMMENTS CBS is one of the frustrating conditions we deal with in neuro-ophthalmology. It is quite easy to diagnose, but treatment has been suboptimal. We sometimes try medications that often have adverse effects and limited benefit but most often we just reassure the patient that it is not a disease and it will not cause worsening of their already poor vision. Based on previous benefits of tDCS in patients with visual hallucination (VH) from schizophrenia, the authors studied this in patients with CBS. Patients underwent 4 days of a series of treatments or placebo and were reassessed on day 5. The treatment showed a decrease in frequency of VH but not duration. Both placebo and treatment yielded a decrease in the subjective distress of the hallucinations. This is a very small study with results only 1 day after completion of treatment, but if borne out on further study, may finally offer us a real treatment to benefit those with CBS. —Mark L. Moster, MD It is fascinating to hear patients with CBS syndrome describe their symptoms but the downer comes at the end of the visit. Patients and accompanying individuals are happy to know that the symptoms have a name and the hallucinations are not a manifestation of psychiatric disease but, alas, we have no good treatment. Kudos to the researchers from Newcastle University in the psychology and psychiatry departments for undertaking this clinical trial, the first of its kind for CBS and to the Macular Society for funding it. Although age-related macular degeneration is the most common cause of CBS, it seems that people with the disorder still end up being evaluated by mental health providers. The sample size was small and the authors provided details as to the character of hallucinations experienced. I was pleased that they incorporated the MMSE because similar hallucinations may occur in the early stages of dementia. The diagnosis of CBS requires the presence of at least 1 complex hallucination such as people, animals, buildings, or landscapes, which most but not all of the cohort experienced. tDCS was safe and well tolerated other than tingling and transient headaches, which is a definite advantage over pharmacologic agents. The frequency of Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary VH reduced with active stimulation (on North East Visual Hallucinations Interview but not hallucination section of the neuropsychiatric inventory [NPIhall]) with no effect on duration. Distress and irritation improved with both verum and sham stimulation, suggesting that the mechanism of improvement was not directly related to tDCS. This is an interesting proof-of-concept study and I hope that it is explored further in the future. —Deborah I. Friedman, MD, MPH The idea that the visual hallucinations of CBS are not distressing is a myth, as confirmed by this study in which the emotional impact was high in 3 of 16 patients and moderate in a further 8. Like Deb, I have often ended a consult for CBS with reassurances that the hallucinations were a “natural” consequence of their visual loss but offering no proven treatments other than medications whose side effects would likely outweigh their benefits. This study offers the first glimpse of an effective therapy, despite its small numbers and lack of frequency improvement using one of the assessments (the NPIhall). I would be interested to see the inclusion of more patients with nonretinal etiologies (15/16 of the patients had retinal disease in this study). Inclusion of fMRI as a marker of the effect of tDCS on functional changes that have been previously described in some patients with CBS1 could help support its use and help us understand the treatment mechanism better. —Marc Dinkin, MD Deb, “verum”? Truly? —Mark L. Moster, MD REFERENCE 1. Martial C, Larroque SK, Cavaliere C, et al. Resting-state functional connectivity and cortical thickness characterization of a patient with Charles Bonnet syndrome. PLoS One. 2019;14:e0219656. occur early in frontotemporal dementia (FTD), and multimodal neuroimaging is used to generate a novel mechanistic hypothesis involving dorsomedial occipital cortex enhancement. These findings may illuminate a novel mechanism underlying human visual creativity. Objective: To determine the anatomical and physiological underpinnings of VAC in FTD. Design, Setting, and Participants: This case–control study analyzed records of 689 patients who met research criteria for an FTD spectrum disorder between 2002 and 2019. Individuals with FTD and emergence of visual artistic creativity (VAC-FTD) were matched to 2 control groups based on demographic and clinical parameters: (1) not visually artistic FTD (NVA-FTD) and (2) healthy controls (HCs). Analysis took place between September 2019 and December 2021. Main outcomes and Measures: Clinical, neuropsychological, genetic, and neuroimaging data were analyzed to characterize VAC-FTD and compare VAC-FTD with control groups. Results: Of 689 patients with FTD, 17 (2.5%) met VAC-FTD inclusion criteria (mean [SD] age, 65 [9.7] years; 10 [58.8%] female). NVA-FTD (n = 51; mean [SD] age, 64.8 [7] years; 25 [49.0%] female) and HC (n = 51; mean [SD] age, 64.5 [7.2] years; 25 [49%] female) groups were well matched to VACFTD demographically. Emergence of VAC occurred around the time of onset of symptoms and was disproportionately seen in patients with temporal lobe predominant degeneration (8 of 17 [47.1%]). Atrophy network mapping identified a dorsomedial occipital region whose activity inversely correlated, in healthy brains, with activity in regions found within the patient-specific atrophy patterns in VAC-FTD (17 of 17) and NVA-FTD (45 of 51 [88.2%]). Structural covariance analysis revealed that the volume of this dorsal occipital region was strongly correlated in VAC-FTD, but not in NVA-FTD or HCs, with a volume in the primary motor cortex corresponding to the right-hand representation. Conclusions and Relevance: This study generated a novel hypothesis about the mechanisms underlying the emergence of VAC in FTD. These findings suggest that early lesion-induced activation of dorsal visual association areas may predispose some patients to the emergence of VAC under certain environmental or genetic conditions. This work sets the stage for further exploration of enhanced capacities arising early in the course of neurodegeneration. COMMENTS Friedberg A, Pasquini L, Diggs R, Glaubitz EA, Lopez L, Illán-Gala I, Iaccarino L, La Joie R, Mundada N, Knudtson M, Neylan K, Brown J, Allen IE, Rankin KP, Bonham LW, Yokoyama JS, Ramos EM, Geschwind DH, Spina S, Grinberg LT, Miller ZA, Kramer JH, Rosen H, Gorno-Tempini ML, Rabinovici G, Seeley WW, Miller BL. Prevalence, timing, and network localization of emergent visual creativity in frontotemporal dementia. JAMA Neurol. 2023:e230001. doi: 10.1001/jamaneurol.2023. 0001. Epub ahead of print. PMID: 36848111; PMCID: PMC9972248. Importance: The neurological substrates of visual artistic creativity (VAC) are unknown. VAC is demonstrated here to Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 Losing Language, Becoming an Artist: Functional and Structural Correlates to Visual Artistic Creativity (VAC) in Frontotemporal Dementia Frontotemporal dementia (FTD) refers to a group of degenerative neurological diseases in which the primary areas affected include the frontal, temporal, and insular cortices, resulting in prominent deficits in language and behavior. A syndrome in which novel visual artistic skills and interest emerge, referred to as “visual artistic creativity” (VAC), has been described in both patients with FTD and those with stroke or trauma to frontotemporal regions. Miller et al,1 describing this entity in 5 of 69 patients with 445 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary FTD in 1998, noted its occurrence in patients with predominant atrophy of the anterior temporal lobe with relative sparing of the dorsolateral frontal lobe and attributed the phenomenon to a facilitation of visually mediated artistic skills. Seeley et al2 later described a scientist who developed a strong interest in painting several years before her FTD diagnosis and whose MRIs revealed increased gray matter in right superior parietal and lateral occipital regions involved in visuoconstructive ability, whereas perfusion imaging revealed increased prefusion in the right superior parietal area as well. In their recent JAMA Neurology article, Friedberg et al3 set out to describe the timing and prevalence of VAC and to illuminate its neuroanatomical changes. Of 738 patients with FTD, the authors identified 17 patients with VAC, defined as demonstrating the emergence of novel visual artistic skills, accompanied by a significant increase in output of artistic work or a change in the artistic style not attributable to loss of language skills. Underlying diagnoses included the semantic variant of primary progressive aphasia (svPPA), nonfluent primary progressive aphasia (nfPPA), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), behavioral variant FTD (bvFTD), and corticobasal degeneration (CBD), but the condition with the greatest percentage of patients with VAC was ssPPA (6.7%). Interestingly, the authors found that VAC emerged at the time of or within 5 years after FTD diagnosis, although in 35.3%, VAC began years before the diagnosis. The authors commented on the rare inclusion of human faces in the works of their cohort and the lack of natural emotions conveyed in those faces that were produced, qualities that had been previously described in VAC. Next, the authors used MRI and fMRI to compare structure and function between patients with FTD with VAC (VAC-FTD), patients with FTD who were not visually artistic (NVA-FTD), and healthy controls (HCs). Although MRI showed atrophy primarily in anterior temporal lobes in those with FTD, there was no difference in the degree or location between patients with VAC-FTD and NVA-FTD. Atrophy network mapping, which identifies networks that are functionally correlated in healthy humans to regions of interest (in this case to the areas of atrophy in the patients with FTD), revealed that the dorsomedial occipital cortex inversely correlated with the atrophied regions in all 17 patients with VAC-FTD and 45 of 51 (88.2%) of those with NVA-FTD, with a more extensive correlating occipital region observed in the patients with VAC-FTD. Using structural covariance analysis, which looks for regions that correlate for gray matter volume with a region of interest, the authors found that the left motor cortex, adjacent to the right-hand homunculus, and the superior temporal gyrus, correlated with the dorsomedial occipital cortex in patients with VAC-FTD but not in patients with NVA-FTD. Finally, in 1 case study, the authors compared FDG-PET results in 1 patient with VAC-FTD before and after she 446 began having expressive language issues and started painting, and found that in addition to an expected marked decrease in metabolism in anterior temporal and frontal regions, there was a significant increase in metabolism in multiple occipital regions, including dorsomedial occipital areas. Commentary It has previously been difficult to understand VAC as a condition emerging from the structural and functional changes inherent in FTD, as opposed to simply an observation of a subset of patients with language deterioration who turn to visual artistic expression as a means of compensation. In this illuminating study, the finding that VAC emerged many years before the diagnosis of FTD in over a third of patients suggests that its development may not result from a decision to pursue the visual arts once severe language deficits preclude more semantic activities. Most notably, the finding of an inverse functional correlation in the dorsomedial occipital cortices, using atrophy network mapping, suggests that disinhibition of dorsal stream networks found in the visual association areas of dorsal V2 and V3 (which are involved not only in visuospatial localization but also in visual imagery and perception4) might foment a strong predilection toward the visual arts in some patients with FTD with a latent inclination or in the presence of some other unknown environmental factors. The increase in PET-FDG signal in the dorsomedial region in 1 patient concordant with the emergence of VAC-FTD implies that increased dorsomedial activity in patients with VAC-FTD emerges as the disease progresses rather than simply being a pre-existing trait that predisposes certain patients with FTD to develop VAC. The results are fascinating because they highlight the structural and functional basis of a condition in which the degeneration of brain regions important for language and behavior are accompanied by a simultaneous optimization of visual association areas pivotal to artistic endeavors. Still, the cause-and-effect relationship in FTD-VACs remains murky. For example, is the increased structural covariance between the dorsomedial occipital cortex and dominant hand motor region a result of increased dorsomedial activity in patients with VAC-FTD or does it emerge because these patients then spend hours a day engaged in visual arts that enhances the structural correlation associated with “hand–eye” coordination inherent in creating art? Or finally, does a pre-existing increased structural covariance predispose certain patients to develop VACs? Even the increased FDG-PET signal in the patient case study, while arguing against a pre-existing hypermetabolic dorsomedial occipital cortex in patients with VACs, does not preclude the notion that such changes might occur in any healthy person who suddenly began engaging heavily in the visual arts. Despite these limitations, this study paints a fairly clear image of the neuroanatomical changes accompanying VAC-FTD and in turn our appreciation of the complex interplay between regions involved in various modalities. Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary —Marc Dinkin, MD REFERENCES 1. Miller BL, Cummings J, Mishkin F, et al. Emergence of artistic talent in frontotemporal dementia. Neurology. 1998;51:978– 982. 2. Seeley WW, Matthews BR, Crawford RK, et al. Unravelling Boléro: progressive aphasia, transmodal creativity and the right posterior neocortex. Brain. 2008;131:39–49. 3. Friedberg A, Pasquini L, Diggs R, et al. Prevalence, timing, and network localization of emergent visual creativity in frontotemporal dementia. JAMA Neurol. 2023:e230001. 4. Ishai A, Sagi D. Common mechanisms of visual imagery and perception. Science. 1995;268:1772–1774. I found this article very interesting as my mother is an artist and I am interested in visual art (although with rudimentary knowledge and I am not an artist myself). I also live in a community of mostly “older” people, many of whom are retired and have pursued new artistic endeavors later in life. In fact, I am aware of quite a few NANOS members who learned to play musical instruments and started other artistic endeavors later in their careers. Moreover, it is not unusual for established artists to change their medium or style over time. Consider the many famous painters who transitioned from realism to cubism, impressionism, surrealism, modernism, and other styles. Painters become sculptors and vice versa. Are these phenomena really more unusual in patients with FTD than in the general population? Moreover, studies show that artistic endeavors in older age are associated with improved cognitive benefits and emotional well-being.1 Is the finding of higher MMSE scores in the VAC-FTD group the cause or effect or artistic expression? I was unable to find epidemiologic data regarding emergent voluntary participation in art in older individuals. However, a notable percentage of older Americans engage in making art. A US survey of patterns of arts participation by the National Endowment for the Arts in 2017 included 92 million people ages 55 and older.2 During that year, 27%–34% of those respondents made visual art and 49%–55% made any art. In the study by Friedberg et al, 17 of 689 patients with VACFTD (2.5%) experienced visual artistic creativity. Using their 2.5% prevalence rate, the healthy control group was likely too small to allow for detection of similar functional imaging changes as in the VAC-FTD group. Chacur et al3 reviewed the existing literature on older adults’ (older than 50) participation in artistic activities, including music, visual arts, crafts, literature, and dance. They report that factors promoting participation include the need for selfexpression, family influence (i.e., a family member was an artist), and support, a pre-existing interest and socialization (e.g., group lessons or art clubs). Other factors include economic status, the ability to perform the activity at home, the type of artistic activity, and intrinsic motivation. Illness facilitating artistic participation can have a positive effect on the theme and technique. For example, Maurice Ravel’s best-known work “Bolero” is a love–hate Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 piece—those who hate it cannot stand its droning repetitiveness. Ravel composed it in 1930 at age 55. Known for his perfectionism and obsessive traits, his meticulous handwriting became irregular, he lost his bags and tickets on a concert tour, and skipped an entire section while conducting one of his own works. He became aphasic in his later years and could no longer write music. Although he never had an autopsy, FTD was a proposed cause.4 Others write that creativity is “reawakened” during the second half of life. The biological and genomic associations between art and the brain are an incipient field. In the current study, an interaction model showing changes in the covariance mapping found changes in the left primary motor cortex in the region of the right hand and superior temporal gyrus in the VAC-FTD group compared with the 2 control groups. The 1 patient who had an FDG-PET scan before and after the emergence of artistic activity (painting) showed a decline in frontal and temporal regions and an increase in dorsal visual association areas. It is not clear that the investigators inquired about VAC in the non-FTD control group, which is a limitation. Their findings are fascinating and I look forward to future studies. —Deborah I. Friedman, MD, MPH Thanks Marc and Deb for this fascinating discussion. I do have 1 additional major criticism of this study. In the healthy control group, there does not seem to be any inquiry of whether each person had VAC. Is it possible that it occurs in healthy older adults as well? —Mark L. Moster, MD REFERENCES 1. Christensen JF, Gomila A. Introduction: art and the brain: from pleasure to well-being. Prog Brain Res. 2018;237:xxvii–xlvi. 2. Available at: https://www.arts.gov/sites/default/files/US_ Patterns_of_Arts_ParticipationRevised.pdf. Accessed 3/7/ 2022. 3. Chacur K, Serrat R, Villar F. Older adults’ participation in artistic activities: a scoping view. Eur J Aging 2022;19:931–944. 4. Cavallera GM, Giudici S, Tommasi L. Shadows and darkness in the brain of a genius: aspects of the neuropsychological literature about the final illness of Maurice Ravel (1875-1937). Med Sci Monit. 2012;18:MH1–MH8. Reilly MA, Katz SE, Roberts CJ. Orbital fat swelling: a biomechanical theory and supporting model for spaceflight-associated neuro-ocular syndrome (SANS). Front Bioeng Biotechnol. 2023;11:1095948. doi: 10.3389/fbioe.2023. 1095948. eCollection 2023. Spaceflight-associated neuro-ocular syndrome (SANS) is a descriptor of several ocular and visual signs and symptoms which commonly afflicts those exposed to microgravity. We propose a new theory for the driving force leading to the development of spaceflight-associated neuro-ocular syndrome which is described via a finite element model of 447 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary the eye and orbit. Our simulations suggest that the anteriorly directed force produced by orbital fat swelling is a unifying explanatory mechanism for spaceflight-associated neuro-ocular syndrome, as well as producing a larger effect than that generated by elevation in intracranial pressure. Hallmarks of this new theory include broad flattening of the posterior globe, loss of tension in the peripapillary choroid, and decreased axial length, consistent with findings in astronauts. A geometric sensitivity study suggests several anatomical dimensions may be protective against spaceflight-associated neuro-ocular syndrome. COMMENTS The geek is back. First described in 2011 after 7 crewmembers had visual and ophthalmoscopic changes after low-duration spaceflight on the International Space Station, the origin of spaceflight-associated neuro-ocular syndrome (SANS) remains uncertain. As it is associated with optic disc edema, choroidal folds, cotton wool spots, acquired hyperopia, and globe flattening, theories of pathogenesis include intracranial hypertension, cerebral edema, choroidal expansion, venous stasis, inflammation, oxidative stress/cytotoxic edema, upward brain and chiasm displacement, decreased ocular glymphatic flow, and axoplasmic stasis.1,2 I was involved in early discussions with NASA when a pseudotumor cerebri-like syndrome was posited. As there was no other compelling evidence for intracranial hypertension, I wondered whether the syndrome was related to fluid shifts, similar to the process of orthostatic edema.3 A recent study evaluating optic disc edema (ODE) using fundus photography in crewmembers before and after long-duration spaceflight found that the ODE was milder than typically found in idiopathic intracranial hypertension and often subtle.4 Reilly et al proposed a biomechanical theory that unifies the ophthalmic findings of SANS (schematically described in Figure 10 of their article). Yes, it is in an engineering journal and includes a lot of formulas, but here is the basic gist: Without the influence of hydrostatic pressure from the Earth’s gravity, there is a cephalad fluid shift in the microgravity environment of spaceflight. This increases the volume of the orbital contents with an additional load on the globe which depends on the water content within the orbit. As the orbital bones are rigid compared with the globe and other orbital contents, the increased force from the higher water content deforms the eye and the soft, deformable structures within the orbit (blood vessels, extraocular muscles, and adipose tissue). The authors tested a series of 4 models to simulate vitreous swelling and fat swelling before and after adding extraocular muscle tension to determine the effect on the eye and optic nerve in terrestrial and microgravity conditions. 448 As orbital fat water content increased, the model predicted minimal proptosis (which has not been observed in astronauts and may be either negligible or resolve on return to Earth), shortening of axial length with globe flattening, explaining the hyperopic shift. The globe flattening decreases peripapillary arc length, partially accounting for the choroidal folds. Increased pressure from the edematous orbital fat produces optic nerve and vascular compression leading to increased outflow resistance and consequent cotton wool spots, ODE, and choroidal folds. The model suggests that increased intracranial pressure, which historically was considered a possible contributing factor, has a minimal—if any—effect. The physiologic variability of axial length in individuals may explain why only some crewmembers experience SANS. Many of the factors they modeled are similar to those seen in thyroid eye disease. I think they are on to something. —Deborah I. Friedman, MD, MPH REFERENCES 1. Galdamez LA, Brunstetter TJ, Lee AG, Tarver WJ. Original of cerebral edema: implications for spaceflight-associated neuro-ocular syndrome. J Neuroophthalmol. 2020;40:84– 91. 2. Ong J, Tarver W, Brunstetter T, et al. Spaceflight associated neuro-ocular syndrome; proposed pathogenesis, terrestrial analogues, and emerging countermeasures. Br J Ophthalmol. 2023:bjo-2022–322892 doi: 10.1136/bjo-2022-322892. Online ahead of print. 3. Friedman DI, Streeten DHP. Idiopathic intracranial hypertension and orthostatic edema may share a common pathogenesis. Neurology. 1998;50;1099–1104. 4. Valencia WE, Mason SS, Bronstetter TJ, et al. Evaluation of optic disc edema in long-duration spaceflight crewmembers using retinal photography. J Neuroophthalmol. 2023. doi: 10.1097/WNO.0000000000001787. PMID 26728631. Online ahead of print. Although initially believed to be due to elevated ICP, it has become clear that ICP alone does not explain all the findings in SANS. At our recent NANOS meeting, Patrick Sibony, MD, presented further evidence that SANS is different from findings in IIH. They found much more thickening of the RNFL in IIH, and a different pattern of changes at the level of the Bruch membrane layer and Bruch membrane opening (BMO). They proposed a slightly different mechanism such as an interplay between a mild indentation load at the BMO and a broadly distributed load across the posterior pole caused by fluid shifts and venous congestion of the orbit and choroid.1 As you said, I think they are all on to something. —Mark L. Moster, MD REFERENCE 1. Sibony P, Laurie S, Connor R et al. Ocular deformities in spaceflight-associated neuro-ocular syndrome and idiopathic intracranial hypertension. Presented at NANOS 49th Annual Meeting; 2023; Orlando, FL. Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary This compelling model of SANS has the benefit of explaining all the features observed in astronauts with SANS. This includes choroidal folds, which were not accounted for by an increase in ICP but can result from a decrease in the inner scleral arc length due to anterior forces on the posterior globe. Future refinements of the model might take age into account when estimating EOM tension, based on the recognition of a loosening of the ring of bands that support the EOMS with age, as seen in sagging eye syndrome. The model has the benefit that many of its predictions can be tested in future astronauts with long-term exposure to microgravity. For example, it will be interesting to see whether astronauts in space demonstrate proptosis as measured by the Hertel exophthalmometry, as predicted by the model (I am skeptical that this feature has been present in astronauts and not yet recognized as a part of SANS because even my patients with thyroid with 2 mm of proptosis seem to notice the change, but we will see). Furthermore, anatomical features such as scleral stiffness, axial length, equatorial diameter, and greater orbital depth can be measured before spaceflight and should predict the severity of SANS if the model is correct. I volunteer the entire literature commentary group for these vital experiments! —Marc Dinkin, MD Marc, our heads are already in the clouds, so we are on our way! —Mark L. Moster, MD Carta S, Cobo Calvo Á, Armangué T, Saiz A, Lechner C, Rostásy K, Breu M, Baumann M, Höftberger R, Ayzenberg I, Schwake C, Sepulveda M, MartínezHernández E, Olivé-Cirera G, Arrambide G, Tintoré M, Bernard-Valnet R, Du Pasquier RA, Brilot F, Ramanathan S, Schanda K, Gajofatto A, Ferrari S, Sechi E, Flanagan EP, Pittock SJ, Redenbaugh V, Reindl M, Marignier R, Mariotto S. Significance of myelin oligodendrocyte glycoprotein antibodies in CSF: a retrospective multicenter study. Neurology. 2022. doi: 10.1212/WNL.0000000000201662. Epub ahead of print. PMID: 36526426. Background and Objectives: Although the diagnosis of myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is based on positivity of serum MOG antibodies (MOG-Abs), patients with coexisting or restricted MOG-Abs in the CSF have been reported. The aim of this study is to characterize the relevance of positivity of CSF MOG-Abs in clinical practice. Methods: Eleven medical centers retrospectively collected clinical and laboratory data of adult and pediatric patients with suspected inflammatory CNS disease and MOG-Abs positivity in serum and/or CSF, using live cell-based assays. Comparisons were performed using parametric or nonparametric tests, as appropriate. Potential factors of unfavorMoster et al: J Neuro-Ophthalmol 2023; 43: 440-450 able outcomes were explored by Cox proportional hazard models and logistic regression. Results: The cohort included 255 patients: 139 (55%) women and 132 (52%) children (i.e., ,18-year-old). Among them, 145 patients (56.8%) had MOG-Abs in both serum and CSF (MOG-Abs seropositive and CSF positive), 79 (31%) only in serum (MOG-Abs seropositive and CSF negative), and 31 (12%) only in CSF (MOG-Abs seronegative and CSF positive). MOG-Abs seronegative and CSF positive predominated in adults (22% vs 3% of children), presented more commonly with motor (n = 14, 45%) and sensory symptoms (n = 13, 42%), and all but 4 (2 MS, 1 polyradiculoneuritis, and 1 Susac syndrome) had a final diagnosis compatible with MOGAD. When comparing seropositive patients according to MOG-Abs CSF status, MOG-Abs-seropositive and CSFpositive patients had a higher EDSS at nadir during the index event (median 4.5, IQR 3.0–7.5 vs 3.0, IQR 2.0–6.8, P = 0.007) and presented more commonly with sensory (45.5% vs 24%, P = 0.002), motor (33.6% vs 19%, P = 0.021) and sphincter symptoms (26.9% vs 7.8%, P = 0.001) than MOGAbs seropositive and CSF negative. At the last follow-up, MOG-Abs-seropositive and CSF-positive cases had more often persistent sphincter dysfunction (17.3% vs 4.3%, P = 0.008). Compared with seropositive patients, those MOGAbs seronegative and CSF positive had higher disability at the last follow-up (P # 0.001) and MOG-Abs-seronegative and CSF-positive status was independently associated with an EDSS $3.0. Conclusion: Paired serum and CSF MOG-Abs positivity is common in MOGAD and is associated with a more severe clinical presentation. CSF only MOG-Abs positivity can occur in patients with a phenotype suggestive of MOGAD and is associated with a worse outcome. Taken together, these data suggest a clinical interest in assessing CSF MOGAbs in patients with a phenotype suggestive of MOGAD, regardless of the MOG-Abs serostatus. COMMENTS Most commonly we evaluate patients with optic neuritis with serum tests for MOG-Abs but not CSF. This article demonstrates that there may be value in measuring both serum and CSF MOG-Abs. Those with positive serum and CSF antibodies had a worse EDSS, and more sensory, motor, and sphincter involvement. Interestingly, only 20% of the entire group had optic neuritis (13% isolated and 7% with myelitis). In addition, 12% had negative serum but positive CSF antibodies and also had a worse outcome than those with isolated serum positivity. The authors postulate that in some patients there is intrathecal production of antibodies and therefore a worse outcome. Patients with MOG-Abs in CSF also more frequently had coexisting oligoclonal bands. Limitations include the fact that it was 11 clinical centers and no standardization of assay methods for MOG-Abs. I do not think it is yet time to recommend CSF examinations on all suspected patients with MOGAD. However, in some difficult to diagnose optic neuritis cases, 449 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary we obtain CSF to assess WBCs, protein, and oligoclonal bands to help diagnose demyelinating disease, NMO, or MOGAD. At least in those patients from now on, I will order MOG-Abs in CSF. —Mark L. Moster, MD I am struck by several interesting findings in this retrospective multicenter study. First, that 22% of the adult patients with MOGAD were seronegative but positive in the CSF for MOG-IgG. This observation alone argues for CSF testing in patients with suspected MOGAD who are seronegative because the outcome might affect the type of disease-modifying agent to use in the future. Second, the presence of CSF antibodies among seropositive patients was associated with a more severe clinical presentation, a finding that is not surprising, given the proximity of the immune response to the central nervous system. Third, that patients with “CSF-restricted” immunity (i.e., seronegative but CSF positive) had a greater risk of disability than seropositive patients with either positive or negative CSF. This final observation adds further evidence for the clinical importance of the intrathecal immune response. Not all patients with MOGAD are treated with long-term immunosuppression, with some previous studies demonstrating that persistent MOG-IgG positivity and high remission titers are associated with a higher risk of relapse.1 Many patients with low remission titers will end up having a monophasic course, but not all. With the inclusion of CSF IgG testing, perhaps we could increase our sensitivity for those patients who will benefit from long-term disease-modifying therapy. Finally, it is notable that 1 patient with +CSF MOG antibodies displayed a Susac disease phenotype. It raises the question of a role for MOG-IgG in some cases of that rare disease, a hypothesis that could be tested in the future. other used immunofluorescence assays; the authors acknowledge the lack of standardization as a limitation. Centers without the capability to obtain the required testing sent the samples to a central laboratory, and all MOGseronegative and CSF-positive samples were retested in an independent, expert laboratory. However, the positive predictive value of MOG Ab testing is titer-dependent ($1:1,000 is 100%) and the variations in assay techniques precluded comparisons based on titers in this study. The cutoff values for positivity in the serum varied between laboratories and was lower than 1:1,000. Moreover, Dr. Eggenberger indicated that the antibody titer decreases over time in most patients. The samples were collected within 3 months in this cohort, although most patients received treatment before testing. These types of limitation are common in human research and there is still valuable information to be gained. Most MOG-ABS-seropositive patients were also CSF positive; adults with this pattern were more likely to have encephalopathy and myelitis and less likely to have visual symptoms. These patients were more likely to have severe disease, which seems to reflect the specific manifestations of illness. The ultimate question is whether testing the CSF adds value. Based on this study, MOG-Abs-seronegative patients with positive CSF had a higher risk of reaching an EDSS score of $3.0 (mild to moderate disability of defined functional systems but fully ambulatory) at the last follow-up with no difference in time to first relapse. Thus, the prognostic information may add value. A high clinical suspicion of MOGAD with negative serum titers warrants a CSF examination, particularly in adults. Whether all patients require CSF testing is more of a gray zone, although the authors recommend testing. —Deborah I. Friedman, MD, MPH —Marc Dinkin, MD Mark, I agree with your points. Dr. Eric Eggenberger gave an excellent presentation about MOG and optic neuritis at NANOS, indicating that the live cell-based assay was the most reliable. The current study used this method but some centers in this study used flow cytometry and 450 REFERENCE 1. López-Chiriboga AS, Majed M, Fryer J, et al. Association of MOGIgG serostatus with relapse after acute disseminated encephalomyelitis and proposed diagnostic criteria for MOGIgGassociated disorders. JAMA Neurol. 2018;75:1355–1363. Moster et al: J Neuro-Ophthalmol 2023; 43: 440-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.