Literature Commentary

Literature Commentary Section Editors: Mark L. Moster, MD Marc J. Dinkin, MD Deborah I. Friedman, MD, MPH Literature Commentary Welcome to a new era in “Lit Commentary!” I want to thank Tariq Bhatti for the past years of partnering with me in this endeavor. It has been a pleasure to collaborate with him. We now welcome 2 new colleagues to Lit Commentary, Deborah I. Friedman and Marc J. Dinkin, who will work along with me. This is our first “Rodeo” together and you can see we all have different approaches to our reviews. We look forward to finding our groove and get in to some appropriate banter as we ride along! —Mark L. Moster, MD In this issue of JNO Drs. Marc J. Dinkin, Deborah I. Friedman and Mark L. Moster discuss the following 6 articles: 1. Tu TM, Yi SJ, Koh JS, Saffari SE, Hoe RHM, Chen GJ, Chiew HJ, Tham CH, Seet CYH, Yong MH, Yong KP, Hui AC, Fan BE, Tan BY, Quek AML, Seet RCS, Yeo LLL, Tan K, Thirugnanam UN. Incidence of cerebral venous thrombosis following SARS-CoV-2 infection vs mRNA SARS-CoV-2 vaccination in Singapore. JAMA Netw Open. 2022;5:e222940. 2. Douglas RS, Dailey R, Subramanian PS, Barbesino G, Ugradar S, Batten R, Qadeer RA, Cameron C. Proptosis and diplopia response with teprotumumab and placebo vs the recommended treatment regimen with intravenous methylprednisolone in moderate-to-severe thyroid eye disease: a meta-analysis and matching-adjusted indirect comparison. JAMA Ophthalmol. 2022;140:328–335. 3. Mikolajczyk B, Ritter A, Larson C, Connett J, Olson J, McClelland C, Lee MS. Red desaturation prevalence and severity in healthy patients. Neurol Clin Pract. 2022;12:1–5. 4. Landau Prat D, Liu GT, Avery RA, Ying GS, Chen Y, Tomlinson LA, Revere KE, Katowitz JA, Katowitz WR. Recovery of vision after optic nerve sheath fenestration in children and adolescents with elevated intracranial pressure. Am J Ophthalmol. 2021;237:173–182. 5. Hummert MW, Schoppe LM, Bellmann-Strobl J, Siebert N, Paul F, Duchow A, Pellkofer H, Kümpfel T, Havla J, Jarius S, Wildemann B, Berthele A, Bergh FT, Pawlitzki M, Klotz L, Kleiter I, Stangel M, Gingele S, Weber MS, Faiss JH, Pul R, Walter A, Zettl UK, Senel M, Stellmann J-P, Häußler V, Hellwig K, Ayzenberg I, Aktas O, Ringelstein M, Schreiber-Katz O, Trebst C; on behalf of the Neuromyelitis Optica Study Group (NEMOS). Costs and health-related quality of life in patients with NMO spectrum disorders and MOG-antibody-associated disease: CHANCENMO study. Neurology. 2022;98:e1184–e1196. 6. Pineles SL, Henderson RJ, Repka MX, Heidary G, Liu GT, Waldman AT, Borchert MS, Khanna S, Graves JS, Collinge JE, Conley JA, Davis PL, Kraker RT, Cotter SA, Holmes JM; Pediatric Eye Disease Investigator Group. The pediatric optic neuritis prospective outcomes study—two-year results. Ophthalmology. 2022:S0161-6420(22) 00234-2. doi: 10.1016/j.ophtha.2022.03.021. Epub ahead of print. PMID: 35364222. Tu TM, Yi SJ, Koh JS, Saffari SE, Hoe RHM, Chen GJ, Chiew HJ, Tham CH, Seet CYH, Yong MH, Yong KP, Hui AC, Fan BE, Tan BY, Quek AML, Seet RCS, Yeo LLL, Tan K, Thirugnanam UN. Incidence of cerebral venous thrombosis following SARS-CoV-2 infection vs mRNA SARS-CoV-2 vaccination in Singapore. JAMA Netw Open. 2022;5:e222940 Importance: Reports of cerebral venous thrombosis (CVT) after messenger RNA (mRNA)-based SARS-CoV-2 vaccination has caused safety concerns, but CVT is also known to occur after SARS-CoV-2 infection. Comparing the relative incidence of CVT after infection vs vaccination may provide a better perspective of this complication. Moster et al: J Neuro-Ophthalmol 2022; 42: 409-418 Objective: To compare the incidence rates and clinical characteristics of CVT following SARS-CoV-2 infection or mRNAbased SARS-CoV-2 vaccines. Design, Setting, and Participants: Between January 23, 2020, and August 3, 2021, this observational cohort study was conducted at all public acute hospitals in Singapore, where patients hospitalized with CVT within 6 weeks of SARS-CoV-2 infection or after mRNA-based SARS-CoV-2 vaccination (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) were identified. Diagnosis of SARS-CoV-2 infection was based on quantitative reverse transcription-polymerase chain reaction or positive serology. National SARS-CoV-2 infection data were obtained from the National Centre for Infectious Disease, Singapore, and vaccination data were obtained from the National Immunizaation Registry, Singapore. 409 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Exposures: SARS-CoV-2 infection or mRNA-based SARSCoV-2 vaccines. Main outcomes and Measures: Clinical characteristics, crude incidence rate (IR), and incidence rate ratio (IRR) of CVT after SARS-CoV-2 infection and after mRNA SARS-CoV-2 vaccination. Results: Among 62,447 individuals diagnosed with SARSCoV-2 infections included in this study, 58,989 (94.5%) were men; the median (range) age was 34 (0–102) years; 6 CVT cases were identified (all were men; median [range] age was 33.5 [27–40] years). Among 3,006,662 individuals who received at least 1 dose of mRNA-based SARS-CoV-2 vaccine, 1,626,623 (54.1%) were male; the median (range) age was 50 (12–121) years; 9 CVT cases were identified (7 male individuals [77.8%]; median [range] age: 60 [46–76] years). The crude IR of CVT after SARS-CoV-2 infections was 83.3 per 100,000 person-years (95% CI, 30.6–181.2 per 100,000 person-years) and 2.59 per 100,000 person-years (95% CI, 1.19–4.92 per 100,000 person-years) after mRNA-based SARS-CoV-2 vaccination. Six (66.7%) received BNT162b2 (Pfizer-BioNTech) vaccine and 3 (33.3%) received mRNA1273 (Moderna) vaccine. The crude IRR of CVT hospitalizations with SARS-CoV-2 infection compared with those who received mRNA SARS-CoV-2 vaccination was 32.1 (95% CI, 9.40–101; P , 0.001). Conclusions and Relevance: The incidence rate of CVT after SARS-CoV-2 infection was significantly higher compared with after mRNA-based SARS-CoV-2 vaccination. CVT remained rare after mRNA-based SARS-CoV-2 vaccines, reinforcing its safety. COMMENTS Cerebral venous thrombosis (CVT) has been reported, mainly after adenovirus vector-based vaccines (J & J, AstraZeneca) for Covid-19. This study from Singapore aimed to provide more information on the risk of CVT after messenger RNA (mRNA)-based vaccines (Pfizer and Moderna). The authors compared the incidence of CVT following mRNA-based vaccines with the incidence of CVT following Covid-19 infection. The study was performed at the public hospitals that care for 80% of the Singaporean population. The study found that the crude IR of CVT in those receiving 2 vaccine doses was 2.93 per 100,000 person-years (95% CI, 1.18–6.04 per 100,000 person-years). In contrast, the crude IR of CVT in the population with COVID-19 infection was 83 per 100,000 person years, 28 times higher. The crude IR in vaccinated patients is not much different than for prior reports of 1.3–2.00 per 100,000 person years in the general US population. The results confirm the risk of CVT following COVID-19 infection is increased and suggest that the risk of CVT following vaccination may not be increased. However, there was no comparator group in the study. Other limitations, many of which were pointed out by the authors include that CVT patients were identified in hospital and could miss milder cases, private hospitals were not included. In addition, numerous patients had no respiratory symptoms so that COVID-19 infection may be underdiagnosed in this population. Also the infected population was much younger than the vaccinated 410 population and the variants of the virus were not identified. Nonetheless, these data are reassuring that the vaccines are safe from the standpoint of CVT. —Mark L. Moster, MD Interpreting the literature related to side effects of COVID-19 vaccines has been challenging for clinicians ever since the vaccines were launched in 2020. Rumor, speculation, unsubstantiated news reports, and social media of various medical conditions attributed to the vaccines abounded. Some people refused to receive them, which led to some unnecessary deaths and severe long-term health problems after being infected. CVT is a serious concern for people infected with SARS-CoV-2. However, knowing that the risk of CVT after receiving mRNA vaccines was similar to the general population helps guide our management to search for a different underlying cause of thrombophilia. —Deborah I. Friedman, MD, MPH In light of the high rate of COVID-19 infection and of vaccination, confirming causation of any condition by the disease or the vaccine remains challenging. Using a 6-week latency as a marker for presumed causation may lead to inclusion of some cases of CVT unrelated to infection or inoculation. However, the finding that CVT occurred at a rate 32 times higher during that 6-week period after COVID-19 compared with vaccination confirms that the relationship between the disease and CVT is real. Given an estimated background incidence of CVT of 2–5 per 100,000 personyears,1 the incidence after vaccination suggests little-to-no causal relationship with the mRNA-based vaccines. This study reminds us that any concern over vaccination complications cannot be considered without comparison to the rate of the same complication following infection. —Marc J. Dinkin, MD Or, Marc, with comparison to the general population! —Mark L. Moster, MD 1. Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke. 2012;43:3375–3377. Douglas RS, Dailey R, Subramanian PS, Barbesino G, Ugradar S, Batten R, Qadeer RA, Cameron C. Proptosis and diplopia response with teprotumumab and placebo vs the recommended treatment regimen with intravenous methylprednisolone in moderate to severe thyroid eye disease: a metaanalysis and matching-adjusted indirect comparison. JAMA Ophthalmol. 2022;140:328–335 Importance: Thyroid eye disease can be a debilitating autoimmune disorder characterized by progressive proptosis or Moster et al: J Neuro-Ophthalmol 2022; 42: 409-418 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary diplopia. Teprotumumab has been compared with placebo in randomized clinical trials, but not with intravenous methylprednisolone (IVMP), which sometimes is used in clinical practice for this condition. Objective: To conduct a matching-adjusted indirect comparison of teprotumumab vs IVMP vs placebo. Data sources: Deidentified patient-level data from teprotumumab trials and aggregate-level data from literature on the most recommended regimen of IVMP. Study Selection: PubMed and Embase were searched for randomized/observational studies using key terms and controlled vocabulary. Full texts of eligible articles were reviewed and cataloged. Data Extraction and Synthesis: Conducted by 1 reviewer (R.A.Q.) and 1 verifier (R.B.), including study characteristics, eligibility criteria, baseline characteristics, and outcomes. Main Outcomes and Measures: Changes in proptosis by millimeter and diplopia response (percentage with $1 grade reduction) from baseline to week 12 in patients receiving IVMP and placebo, and to week 24 in patients receiving teprotumumab. Results: The search identified 1,019 records, and 6 through manual searches, alerts, and secondary references. After excluding duplicates and screening full-text records, 12 IVMP studies were included in the matching-adjusted indirect comparison (11 for proptosis change [n = 419], 4 for diplopia response [n = 125], and 2 teprotumumab [n = 79] and placebo [n = 83] comparator studies). Treatment with IVMP resulted in a proptosis difference of 20.16 mm (95% CI, 21.55 to 1.22 mm) from baseline to week 12 vs placebo. The proptosis treatment difference between IVMP and teprotumumab of 22.31 mm (95% CI, 23.45 to 21.17 mm) favored teprotumumab. Treatment with IVMP (odds ratio, 2.69; 95% CI, 0.94–7.70) was not favored over placebo in odds of diplopia response; however, teprotumumab was favored over IVMP (odds ratio, 2.32; 95% CI, 1.07–5.03). Conclusions and Relevance: This meta-analysis suggests that use of IVMP is associated with a small, typically not clinically relevant, change from baseline in proptosis vs placebo, with modest changes in diplopia. Although this nonrandomized comparison suggests that use of teprotumumab, compared with IVMP, is associated with greater improvements in proptosis and may be twice as likely to have a 1 grade or higher reduction in diplopia, randomized trials comparing these 2 treatments would be warranted to determine whether 1 treatment is superior to the other to a clinically relevant degree. results of teprotumumab with IVMP on improvement in proptosis and diplopia in TED patients. Findings were that IVMP showed an improvement in proptosis of 0.16 mm compared with placebo and teprotumumab 2.80 mm. Diplopia OR for a response was 2.69 for IVMP and 5.41 for teprotumumab. There are of course limitations to this type of analysis that compares data from different studies and a head-tohead trial is important to verify these results. Nonetheless, there is evidence here that teprotumumab is much better than IVMP for proptosis and diplopia. In clinical practice, one of the hurdles to insurance approval of teprotumumab is an often required failure to benefit with steroids. Steroids are associated with toxicity and in my opinion it is wrong to have to treat patients with steroids before teprotumumab because of the risks involved and universal experience of clinicians and this study which demonstrate the minor benefits steroids provide. —Mark L. Moster, MD Mark, I agree that despite the limitations of comparing studies with different methodologies, this study makes a compelling argument for the superiority of teprotumumab over IV steroids for treating diplopia and proptosis. The difference between outcomes at 12 weeks in the corticosteroid trials vs 24 weeks in the teprotumumab trials is one significant limitation. These results should not necessarily be generalized to the treatment of compressive optic neuropathy (CON) with thyroid orbitopathy, where not only the degree of response, but the speed of that response may be crucial in preventing permanent vision loss. The efficacy of teprotumumab for CON is suggested by multiple case series1,2 but a prospective study comparing its efficacy for CON with that of IV steroids would be beneficial. —Marc J. Dinkin, MD COMMENTS 1. Sears CM, Wang Y, Bailey LA, Turbin R, Subramanian PS, Douglas R, Cockerham K, Kossler AL. Early efficacy of teprotumumab for the treatment of dysthyroid optic neuropathy: a multicenter study. Am J Ophthalmol Case Rep. 2021;23:101111. 2. Slentz DH, Smith TJ, Kim DS, Joseph SS. Teprotumumab for optic neuropathy in thyroid eye disease. JAMA Ophthalmol. 2021;139:244–247. Teprotumumab has been established in phase III clinical trials as beneficial in TED in decreasing proptosis, improving diplopia, and many other secondary outcomes. In smaller studies postapproval, it has been proven beneficial in the chronic phase of TED and in optic neuropathy. Steroids have been a mainstay of treatment for TED for many years despite the lack of clear evidence for their benefit in double-blind RCTs. This study used a statistical method of matchingadjusted indirect comparison (MAIC) to compare the Mark, you are so correct that indirect comparisons such as these are suboptimal, although sometimes, all we have is to base therapeutic decisions on. The teprotumumab studies were all placebo-controlled, double-masked, multicenter trials. None of the IVMP studies were placebo-controlled although 7 of 16 were RCTs. The samples sizes in this study were relatively small for active therapies and placebo. A head-to-head (or orbit-to-orbit) study would ideally provide a definitive answer, if for no other reason than to satisfy insurance companies and get the most effective (and Moster et al: J Neuro-Ophthalmol 2022; 42: 409-418 411 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary safest) treatment for our patients with the least amount of hassle. —Deborah I. Friedman, MD, MPH Mikolajczyk B, Ritter A, Larson C, Connett J, Olson J, McClelland C, Lee MS. Red desaturation prevalence and severity in healthy patients. Neurol Clin Pract. 2022;12:1–5 Background and Objectives: To determine the percentage of the healthy population that responds asymmetrically to the red desaturation test and to approximate the degree of red desaturation in those individuals. We also sought to elucidate any correlation between demographic variables and red desaturation prevalence and severity. Methods: Adults aged 18 years and older with a normal eye examination, including confrontation fields and bestcorrected visual acuity of $20/25 in both eyes, were eligible for this prevalence study. Those with objective or subjective afferent visual dysfunction were excluded. A total of 101 eligible participants (68.3% women and 31.7% men; racial/ethnic breakdown of 77.2% White, 11.9% Black, 8.9% Asian, 2.0% N/A; mean [SD] age: 41.5 [15.3] years) were queried whether the monocular perception of redness of a standardized tropicamide bottle cap was the same and to estimate the interocular percentage difference, with 1 eye perceiving the bottle cap at “100% redness.” Results: Twenty-four participants (23.8%) experienced some degree of red desaturation. For these individuals with red desaturation, the average interocular difference was 9.0% (range 2%–25%, 95% confidence interval 6.0%– 12.0%). There was no statistical evidence for a relationship between red desaturation and race, sex, or age. Discussion: This study shows that nearly a quarter of healthy patients without apparent optic nerve or macular dysfunction may recognize red desaturation. This deserves consideration when interpreting red desaturation testing in patients suspected to have unilateral optic neuropathy. Further research with larger sample sizes may identify predictors of red desaturation in healthy patients, establish the red desaturation threshold separating pathologic from physiologic phenomena, and assess the repeatability of red desaturation over time in affected individuals. COMMENTS Asking patients to compare red perception between the 2 eyes often provides useful information is the setting of a suspected unilateral optic neuropathy, such as optic neuritis. I find it useful for detecting subtle differences in color perception that may not be apparent using color plates. (Parenthetically, as the last of the dying breed of tangent screen users, the red targets work also well for identifying subtle central scotomas). Patients with optic neuropathies often described the color looking washed out or darker in the affected eye. The most common way of doing the test in 412 the eye clinic involves the low tech but effective method using the red top of the bottle of tropicamide as the target. I admit that I never gave much thought to interocular differences in red perception in patients with normal vision until I read this study. This may be because (1) there was never a need for me to test it and (2) my own color vision seems symmetric. This study used the red bottle cap test to study the prevalence of interocular asymmetry in 101 participants seen for a routine eye examination, with visual acuities of 20/25 or better in both eyes and normal confrontation visual field testing. They excluded patients with known color blindness or eye disease. Each participant indicated the percentage decrease in the intensity of the red target in their “affected” eye. Twenty-four participants had some degree of red desaturation with an average difference of 9%. Twelve participants experienced a difference between 1% and 5%, 7 described a 6%–10% difference, 4 had a 16%–20% difference, and 1 noted a 21%–25% difference. The null hypothesis that red desaturation was 5% was rejected (P = 0.011), but a null hypothesis that red desaturation was equal to 10% could not be rejected (P = 0.49). There were no differences regarding sex, age, or race, and lens pathology did not account for the asymmetry in red perception. Overall, the authors found no explanation for asymmetric red color perception. —Deborah I. Friedman, MD Deborah, I am so glad you picked this article. I always appreciate a study that challenges our long-held traditions as this one does. Most of us do take for granted that checking for red desaturation is helpful in picking up some optic neuropathies or maculopathies, and assume a measure of accuracy. However, we have all observed cases where the patient reports a significant interocular difference, and yet the reminder of the examination and work up rule out optic nerve disease. Reasons for these discrepancies may include a failure to screen for precise perceptions of desaturation. It is important, for example, to make sure one is truly checking for desaturation, which implies a loss of color content, that is, a red cap may look more orange in the affected eye, and not for blurring (as observed with optical problems) or pure darkening. The precise language used in this study, however, likely avoided that type of error. Certainly, some degree of functional overlay may play a role for some patients eager to convince the examiner of the seriousness of their visual loss, even when the etiology is not neurogenic. This article suggests, however, that some degree of intrinsic difference exists in the normal population, even in the absence of pathology. The authors do note some lens pathology, which can alter the perception of colors, but I agree that the degree was not likely to be sufficient to cause the high prevalence of perceived desaturation. To confirm the veracity of the findings, I would like to observe a second examination of the same patients and check for intertest Moster et al: J Neuro-Ophthalmol 2022; 42: 409-418 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary variability. Frequent variability in the side affected would of course argue against true discrepancy in optic nerve function between the eyes. Finally, I would love to see optical coherence testing of these patients to observe whether there is any asymmetry of the retinal nerve fiber layer of the maculopapillary bundle serving the majority of cones and color vision or ganglion cell layer that aligns with the asymmetry of color saturation. Perhaps the discrepancy reflects a degree of interocular structural asymmetry. For now, however, these findings should not prevent us from using red desaturation in our everyday clinical assessment, especially because in many of our optic nerve patients, the degree of red desaturation is higher than reported in most patients in the study. However, as with any subjective test based exclusively on patient reporting, we should continue to view and interpret red desaturation within the greater clinical context. —Marc J. Dinkin, MD Deb, this is a very interesting study that has bearing on clinical practice this coming Monday. What I learned is not to take an isolated red desaturation as a necessary sign of optic neuropathy or any pathology. I have a couple of issues with this study. First, is that we do not know whether these patients had any difficulty with the color plates. I would have wanted to know that those with red desaturation performed normally on A-O or Ishihara plates. Second, my own bias is that it is difficult to assess a percentage of desaturation of color compared with light. So, my routine question for light saturation is “if the right eye sees a dollar’s worth of light, how much is the left eye?” For color, I ask whether it is a different color or shade, as in a lipstick display. —Mark L. Moster, MD Landau Prat D, Liu GT, Avery RA, Ying GS, Chen Y, Tomlinson LA, Revere KE, Katowitz JA, Katowitz WR. Recovery of vision after optic nerve sheath fenestration in children and adolescents with elevated intracranial pressure. Am J Ophthalmol. 2021;237:173–182 Purpose: To evaluate the effect of optic nerve sheath fenestration (ONSF) on the recovery of visual function in pediatric patients with optic disc swelling owing to increased intracranial pressure. Design: Retrospective case series. Methods: Medical chart review of all pediatric patients who underwent ONSF between 2009 and 2020 at the Children’s Hospital of Philadelphia. Visual function was assessed at preoperative and postoperative visits. The main outcome measures were visual acuity, color vision, extraocular motility, visual field mean deviation, and retinal nerve fiber layer thickness measured by optical coherence tomography. Moster et al: J Neuro-Ophthalmol 2022; 42: 409-418 Results: Fourteen pediatric patients (10 females; mean ± SD age of 14 ± 2.6 years; range, 8.5–17.5 years) were included. Five patients underwent bilateral surgeries. Ten patients were diagnosed with idiopathic intracranial hypertension. Of the 10 idiopathic intracranial hypertension patients, 3 had a previous history of weight gain and 2 of systemic steroid treatment; these can be referred to as pseudotumor cerebri. The mean ± SD follow-up length was 16.4 ± 12.3 months. VA improved from 20/138 to 20/68 in the operated eye (P = 0.0003) and from 20/78 to 20/32 in the nonoperated eye (P = 0.02). Color vision improved in the operated eye (P = 0.04), and extraocular motility improved in the operated and nonoperated eye (P = 0.002 and P = 0.04 respectively). Visual field mean deviation improved in the operated (223.4 dB to 211.5 dB, P , 0.0001) and nonoperated eye (219.8 dB to 26.8 dB, P = 0.02). Retinal nerve fiber layer thickness improved in the operated eye (349.1–66.2 mm; P , 0.0001). The postoperative improvement was observed as early as the postoperative day 1. Conclusions: ONSF produces a rapid and persistent vision improvement in the operated eye and nonoperated eye. In children and young adults with papilledema and elevated intracranial pressure causing vision loss that is severe at presentation or refractory to standard medical management, ONSF should be considered. COMMENTS Summary In this retrospective analysis of outcomes in children ,18 years following optic nerve sheath fenestration (ONSF), the authors included 10 patients with idiopathic intracranial hypertension (IIH), and an additional 4 with secondarily elevated intracranial pressure from tumor, stroke, or infection. Five of the children underwent bilateral ONSF, and one had previously undergone placement of a ventriculoperitoneal shunt. The results confirm the efficacy of ONSF in children, demonstrating a resolution or near resolution of headaches in 71% by 1 week. In the operated eye, mean visual acuity improved from 20/168 to 20/68 by the last follow-up, the visual field mean deviation (MD) from 223.4 dB to 211.5 dB and the retinal nerve fiber layer (RNFL) thickening improved from 349.1 m to 66.2 m. The percentage of operated eyes with abnormal extraocular motility (EOM) reduced from 77.2% to 15.8% and the percentage of operated eyes with dyschromatopsia (defined as missing $2 color plates) reduced from 57.9% to 25%. In the nonoperated eye, the visual acuity improved from 20/78 to 20/32 by the final visit, the average MD from 219.8 dB to 26.8 dB and the RNFL from 269.3 m to 87.5 m. The percentage of nonoperated eyes with abnormal EOM reduced from 44.4% to 0% and dyschromatopsia from 22.2% to 0%. There were no postoperative complications. 413 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Commentary In an era where much discussion has revolved around the use of venous stenting for IIH, and in which some surgeons are less enthusiastic about performing ONSF, it is encouraging to see a study that demonstrates the benefits of ONSF for children with papilledema affecting visual function, from IIH and secondary causes of high ICP. The lack of complications is reassuring, given the fears of strabismus, anisocoria, or worsening vision loss resulting from the procedure, but given the relatively small size of this study, patients should still be warned of these possible complications given their prevalence in prior studies. In a review by Kalyvas in 2017 for example, there were complications in 77/278 (27.7%) patients: diplopia occurred in 26%, anisocoria in 9.7%, orbital hematoma in 7.2%, and more severe complications including orbital hematoma or traumatic optic in 0.4%. The effect on headaches by ONSF is encouraging in this study, retorting the oft heard dogma that “ONSF is good for vision loss but shunts are better for headaches.” Only one patient needed a follow-up surgery in this study, but only for ongoing headache. The high efficacy in this study may reflect the relatively small cohort. The need for post-ONFSH diversion procedure has been higher in multiple prior studies: 21% in Fonseca et al (2014) and 28.5% in Obi et al (2015) for example. Prat et al’s study demonstrates a relatively fast improvement in visual parameters and papilledema, which is important for any procedure that aims to reduce and mitigate the degree of visual loss. Interestingly, the visual acuity in the treated eye was observed to worsen in the first day, presumably because of postoperative edema, although the nonoperated eye immediately begins to improve. It is also notable that the visual acuity in both eyes showed some worsening, suggesting that the efficacy of the ONFS may decline after a few weeks. As the authors point out, it is difficult to tease out the effect of ONFS from that of concomitant acetazolamide or corticosteroids in a retrospective study such as this. A graph of VA in the weeks before ONSF demonstrating little improvement, for example, would add to the reader’s confidence that the procedure made the difference in the course. It should also be noted that in several cases of severe VA loss, there was little improvement following ONSF—specifically, in 6 eyes with 20/500 or worse, there was no improvement or a worsening of VA. Furthermore, in 13/14 cases, optic atrophy was present in both eyes at the final visit. The lack of improvement in some of the severe cases of vision loss and the presence of atrophy in almost all patients at final visit presumably reflect irreversible damage, but alternative surgical treatments may theoretically have been more effective. Finally, I was surprised at the inclusion of 3 patients with visual acuities of $20/25 in both eyes—I would have trouble convincing surgeons to operate on eyes with such excellent VA—but one can presume that there were significant visual field defects in these patients. 414 Despite a few limitations, this study provides strong evidence for the use of ONSF in children with papilledema from various causes. Head-to-head prospective studies comparing ONSF to shunt or stent would offer stronger evidence in the future. 1. Kalyvas AV, Hughes M, Koutsarnakis C, Moris D, Liakos F, Sakas DE, Stranjalis G, Fouyas I. Efficacy, complications and cost of surgical interventions for idiopathic intracranial hypertension: a systematic review of the literature. Acta Neurochir (Wien). 2017;159:33–49. 2. Fonseca PL, Rigamonti D, Miller NR, Subramanian PS. Visual outcomes of surgical intervention for pseudotumour cerebri: optic nerve sheath fenestration versus cerebrospinal fluid diversion. Br J Ophthalmol. 2014;98:1360–1363. 3. Obi EE, Lakhani BK, Burns J, Sampath R. Optic nerve sheath fenestration for idiopathic intracranial hypertension: a seven year review of visual outcomes in a tertiary centre. Clin Neurol Neurosurg. 2015;137:94–101. —Marc J. Dinkin, MD Albeit a small study, the experience of these authors—who are recognized authorities in pediatric IIH—is a welcome addition to the literature. Their study included children with IIH and other causes of increased CSF pressure. Although the patients with IIH had papilledema if they met the diagnostic criteria, the study does not specify whether all patients had papilledema, which is typically a requirement to perform ONSF. The mean RNFL thickness preoperatively suggests they did but it would be nice to see a detailed table of the various parameters from each patient. Marc, I also wondered about 2 patients with 20/20 vision in both eyes preoperatively and presume that they were operated on for visual field loss. It was particularly heartwarming to see that the patient with NLP vision regained some vision and 2 eyes with HM vision improved, although not all eyes with poor vision enjoyed the same response. Ocular motility improved in all patients, perimetric mean deviation improved substantially, and headaches improved in most patients. The procedure was well tolerated. I would be thrilled to get rid of the adage that one should shunt for headaches and fenestrate for vision loss. Shunting is not a good headache treatment as most patients experience return of their headaches over time.1 Many of them become shunt-dependent and need additional operations. The most striking part of the Kalyvas meta-analysis, which I often quote, is that the number of patients reported in the literature with analyzable data is ridiculously small for shunts and suboptimal regarding data on visual function. The ONSF data are better for visual outcomes, as expected, but many did not study headache. Improvement in headache is typically judged by patient report in those studies rather than a standardized outcome measure. Sadly, the SIGHT trial comparing shunting to ONSD and medical therapy was terminated because of inadequate enrollment. It would be great to have high-quality comparative studies on our treatment modalities. Moster et al: J Neuro-Ophthalmol 2022; 42: 409-418 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary 1. McGirt MJ, Woodworth G, Thomas G, Miller N, Williams M, Rigamonti D. Cerebrospinal fluid shunt placement for pseudotumor cerebri-associated intractable headache: predictors of treatment response and an analysis of long-term outcomes. J Neurosurg. 2004;101:627–632. 2. Kalyvas AV, Hughes M, Koutsarnakis C, Moris D, Liakos F, Sakas DE, Stranjalis G, Fouyas I. Efficacy, complications and cost of surgical interventions for idiopathic intracranial hypertension: a systematic review of the literature. Acta Neurochir (Wien). 2017;159:33–49. —Deborah I. Friedman, MD, MPH With all the limitations that you both point out, this is quite encouraging data on visual improvement with ONSF in the pediatric population. The outcomes are better than I have had in my adults with IIH with ONSF. I would welcome a study of shunt vs ONSF vs stent for all the visual parameters and symptoms of elevated ICP. It seems that most clinicians (aka me) default to what is most available at their own institution. An interesting finding is the spectrum of motility deficits observed in these patients, including 10 with abduction deficits and 4 with bilateral supraduction, 1 with bilateral infraduction, and 1 with bilateral adduction deficits. These latter findings are not observed in adults and would prompt an evaluation for something other than elevated ICP. What we do not know is whether these rarer motility deficits were observed in the 10 patients with IIH or the 4 with other causes of elevated ICP. —Mark L. Moster, MD Hummert MW, Schoppe LM, Bellmann-Strobl J, Siebert N, Paul F, Duchow A, Pellkofer H, Kümpfel T,Havla J, Jarius S, Wildemann B, Berthele A, Bergh FT, Pawlitzki M, Klotz L, Kleiter I, Stangel M, Gingele S, Weber MS, Faiss JH, Pul R, Walter A, Zettl UK, Senel M, Stellmann J-P, Häußler V, Hellwig K, Ayzenberg I, Aktas O, Ringelstein M, Schreiber-Katz O, Trebst C; on behalf of the Neuromyelitis Optica Study Group (NEMOS). Costs and health-related quality of life in patients with NMO spectrum disorders and MOG-antibody-associated disease: CHANCENMO study. Neurology. 2022;98:e1184– e1196. Background and Objectives: To evaluate costs and healthrelated quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD). Methods: In this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical Moster et al: J Neuro-Ophthalmol 2022; 42: 409-418 data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database. Results: Two hundred twelve patients (80% women, median age 50 [19–83] years, median disease duration 7 [0–43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0–8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225–68,293 or US dollars [USD] 70,297, 95% CI 60,445–80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65–0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (r = 0.56, 95% CI 0.45–0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946–160,336 or USD 153,031, 95% CI 120,296– 189,196). The HRQoL revealed a negative correlation to disease severity (r = 20.69, 95% CI 20.76 to 20.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13–0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL. Discussion: These German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life. COMMENTS Neuro-ophthalmologists are all too familiar with the devastating visual loss and myelopathy associated with NMO spectrum disorder (NMOSD) and MOGantibody-associated disease (MOGAD), that often lead to rapid and impactful neurologic impairment. Affected individuals, previously healthy, productive, and independent in their daily activities, may become disabled and dependent on others. The authors of this study prospectively recruited a German cohort affected by NMOSD and MOGAD and calculated the costs associated with the diagnoses. The cost calculation included direct medical costs, direct nonmedical costs, and indirect costs (i.e., travel expenses, home investments for access and function, loss or work related to patient and caregiver productivity, informal assistance by relatives and friends). They also surveyed health-related quality of life (HRQOL) in this cohort. The average duration of disease in this multicenter study was 7 years, ranging from 0 to 43 years. Two-thirds of participants (n = 141) had APQ-4 NMOSD, whereas 25 had double seronegative NMOSD. The other 46 patients had MOGAD. 80% were women. The average age was 50 years (range 19–83) and mean EDSS was 3.5 (range 0–8.5). The mean medical direct costs per patient year for the entire cohort was €25,600 ($30,208 USD), largely driven by immunotherapy, plasmapheresis, hospitalization, and 415 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary formal care. Direct nonmedical costs were €720 or $850 per patient year, with informal care being the greatest contributor. Not surprisingly, disease severity (EDSS) was the largest contributing factor. Caregivers took an average of 1.8 hours weekly off work for the mildly affected group and 4.4 hours weekly in the severely affected group. Mean indirect costs per patient-year were €13,872 or $16,369 with loss of salary related to sick leave and unemployment being the main drivers. About a quarter of patients took a mean duration of 32.4 days of sick leave in the preceding 3 months, accounting for half of their working assuming a typical US 5-day work week. Sixty percent of the cohort was unemployed. Overall, the total annual cost per patient was approximately €59,574 ($75.8 M) annually. The AQP-4 antibody-positive NMOSD group had significantly higher direct medical costs that then MOGAD group, related to diagnostic tests. This group also had the highest indirect costs. Indirect costs were highest in patients with MOGAD fulfilling the IPND criteria and medication costs were highest in the MOGAD patients not fulfilling the IPND criteria. More than 2/3 of the total cohort indicated impaired HRQOL in pain and discomfort (795), usual activities (69%), mobility (67%), anxiety/depression (62%), and selfcare (35%); these responses correlated with the EDSS, but serological status and disease duration had no impact. Independent predictors of HRQOL were EDSS, need for care, attacks, unemployment, disease duration, care satisfaction, age at diagnosis, and investments in the home. 40% were mostly satisfied with their care but many wanted more information about the disease, its therapy and research. 24% requested more psychological support and 23% expressed the desire for consistent care by one physician. The study included a large number of patients despite the relative rarity of the disease. Although the German health care system differs from the U.S. system, their findings seem largely translatable to other countries and provide a sobering reminder of the impact of these disorders on QOL for patients and their caregivers. The study also points out the need for social workers, to which many neuro-ophthalmologists and others treating patients with NMOSD and MOGAD lack access. —Deborah I. Friedman, MD, MPH This study was performed in 2016, with the main medication for NMOSD and MOGAD being rituximab. With 3 FDA-approved medications now available and the annual cost for one being 750 K, this would raise the cost from 70 K to over 800 K in US dollars. —Mark L. Moster, MD Deborah, I was impressed by the large size of this study and the inclusion of quality of life and cost analyses. I found it interesting that MOGAD and NMOSD resulted in a higher cost of illness (COI) and worse quality of life (QOL) 416 when compared with a corresponding German MS cohort, findings that may reflect a higher expense of therapeutics in MOGAD and NMOSD and the profound effect of vision loss on QOL respectively. I was surprised to see no significant difference in COI or QOL between the MOGAD and NMOSD groups, given the increased risk of severe, permanent vision loss in NMOSD patients vs MOGAD,1 a condition that one would expect to reduce QOL and increase COI. One limitation in this study was the use of questionnaires to collect the patient-reported retrospective consumption of medical and nonmedical care, and the use of estimations of cost and assumptions of stable resource consumption over time to calculate costs. A direct tally of costs measured prospectively would help mitigate the effect of patient recall and cost estimations. Nevertheless, this study clearly demonstrates the immense cost and effect on quality of life of NMOSD and MOGAD and underlines the importance of early treatment to ameliorate the greatest driver of costs—the indirect costs related to the support patients with disability require from family and friends. 1. Akaishi T, Himori N, Takeshita T, Misu T, Takahashi T, Takai Y, Nishiyama S, Fujimori J, Ishii T, Aoki M, Fujihara K, Nakazawa T, Nakashima I. Five-year visual outcomes after optic neuritis in anti-MOG antibody-associated disease. Mult Scler Relat Disord. 2021;56:103222. —Marc J. Dinkin, MD Pineles SL, Henderson RJ, Repka MX, Heidary G, Liu GT, Waldman AT, Borchert MS, Khanna S, Graves JS, Collinge JE, Conley JA, Davis PL, Kraker RT, Cotter SA, Holmes JM; Pediatric Eye Disease Investigator Group. The pediatric optic neuritis prospective outcomes study—two-year results. Ophthalmology. 2022:S0161-6420(22)00234-2. doi: 10.1016/j.ophtha.2022.03.021. Epub ahead of print. PMID: 35364222 Purpose: Pediatric optic neuritis (ON) is a rare disease that has not been well characterized. The Pediatric ON Prospective Outcomes Study (PON1) was the first prospective study to our knowledge aiming to evaluate visual acuity (VA) outcomes, including VA, recurrence risk, and final diagnosis 2 years after enrollment. Design: Nonrandomized observational study at 23 pediatric ophthalmology or neuro-ophthalmology clinics in the United States and Canada. Participants: A total of 28 (64%) of 44 children initially enrolled in PON1 (age 3–,16 years) who completed their 2-year study visit. Methods: Participants were treated at the investigator’s discretion. Main Outcomes Measures: Age-normal monocular highcontrast VA (HCVA). Secondary outcomes included lowMoster et al: J Neuro-Ophthalmol 2022; 42: 409-418 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary contrast VA (LCVA), neuroimaging findings, and final diagnoses. Results: A total of 28 participants completed the 2-year outcome with a median enrollment age of 10.3 years (range, 5–15); 46% were female, and 68% had unilateral ON at presentation. Final 2-year diagnoses included isolated ON (n = 11, 39%), myelin oligodendrocyte glycoprotein-associated demyelination (n = 8, 29%), multiple sclerosis (MS) (n = 4.14%), neuromyelitis optica spectrum disease (NMOSD) (n = 3, 11%), and acute disseminated encephalomyelitis (n = 2, 7%). Two participants (7%; 95% confidence interval [CI], 1–24) had subsequent recurrent ON (plus 1 participant who did not complete the 2-year visit); all had MS. Two other participants (7%) had a new episode in their unaffected eye. Mean presenting HCVA was 0.81 logarithm of the minimum angle of resolution (logMAR) (w20/125), improving to 0.14 logMAR (w20/25 2 2) at 6 months, 0.12 logMAR (w20/25 2 2) at 1 year, and 0.11 logMAR (20/25 2 1) at 2 years (95% CI, 20.08 to 0.3 [20/20 + 1–20/40 2 1]). Twenty-four participants (79%) had age-normal VA at 2 years (95% CI, 60–90); 21 participants (66%) had 20/20 vision or better. The 6 participants without age-normal VA had 2-year diagnoses of NMOSD (n = 2 participants, 3 eyes), MS (n = 2 participants, 2 eyes), and isolated ON (n = 2 participants, 3 eyes). Mean presenting LCVA was 1.45 logMAR (w20/500-2), improving to 0.78 logMAR (w20/125 + 2) at 6 months, 0.69 logMAR (w20/100 + 1) at 1 year, and 0.68 logMAR (w20/100 + 2) at 2 years (95% CI, 0.48– 0.88 [20/50 + 1–20/150 2 1]). Conclusions: Despite poor VA at presentation, most children had marked improvement in VA by 6 months that was maintained over 2 years. Associated neurologic autoimmune diagnoses were common. Additional episodes of ON occurred in 5 (18%) of the participants (3 relapses and 2 new episodes). COMMENTS In contrast to adult optic neuritis, which has been studied in the landmark optic neuritis treatment trial, pediatric optic neuritis has remained a less-understood entity, in part owing to its rare incidence. The Pediatric Optic Neuritis Prospective Outcomes Study (PON1) aimed to rectify this by collecting data on children with optic neuritis from 23 centers in North America. Initial data looking at the first 6 months published in 2020 demonstrated generally good prognosis for recovery of visual acuity and revealed relative rates of demyelinating disease favoring myelin oligodendrocyte glycoprotein associated disease (MOGAD) (diagnosed in 18%), acute disseminated encephalomyelitis (ADEM) in 16%, multiple sclerosis (MS) in 11% and neuromyelitis optica spectrum disorder (NMO-SD) in 7%. This year, Pineless and colleagues published the 2-year data in 28 patients who were followed out to 2 years, offering insights into the long-term visual outcomes, final diagnoses and rates of recurrence. Of the 28 subjects, whose mean age was 10.3 years, 61% had one or more demyelinating lesions outside the optic nerve at presentation and all were treated with corticosteMoster et al: J Neuro-Ophthalmol 2022; 42: 409-418 roids within a month of presentation. The final diagnosis at 2 years was isolated optic neuritis in 39%, MOGAD in 29%, MS in 14%, NMO-SD in 11%, and ADEM in 7%. Concordance with the diagnosis at enrollment occurred in just more than half (57%). Within the 28 subjects, there were 32 study eyes that had optic neuritis. At presentation, the mean high contrast visual acuity (HCVA) was 0.81 logMAR (w20/125), with 24/32 demonstrating some reduction in HCVA. There was a 7.09 line improvement by 2 years, yielding mean HCVA of 0.11 logMAR (w20/25) with only 8/32 eyes demonstrating HCVA that was not age normal. Two eyes were worse than 20/200 at 2 years. There were 2 eyes that worsened (1 from 20/100 to 20/400 and another from 20/500 to worse than 20/800). The low-contrast visual acuity (LCVA) improved 7.24 lines, from an adjusted mean distance of 1.45 logMAR (w20/640) to 0.68 logMAR (w20/100). DISCUSSION There are many take home points one can glean from the longterm PON1 study. First, when faced with a case of new pediatric optic neuritis, one can predict a 61% chance of the patient going on to develop a systemic neurologic condition. After subtracting the 7% with ADEM, which is typically monophasic, 54% went on to develop a disease putting them at risk of neurologic relapses. Interestingly, the chance of developing MOGAD was much higher than that of MS or NMO-SD. However, most of the MOGAD patients were mislabelled as ADEM or NMO-SD at presentation, a fact that may simply reflect the growing recognition of MOGAD as an important entity in children over the time period of the study. Importantly, one patient eventually found to have NMO-SD was mis-labelled as ADEM initially, a diagnostic error that can have serious repercussions for a patient’s visual and neurologic outcomes, given the data in adults in support of treating severe acute optic neuritis in NMO-SD patients with plasmapheresis and corticosteroids, and the discrepancies in maintenance therapy between NMO-SD and the alternative diagnoses. In parallel to the optic neuritis treatment trial (ONTT), the PON1 results suggest that MRI findings at presentation can have an important prognostic value. Of 12 subjects that were diagnosed with isolated optic neuritis (9 unilateral, 3 bilateral) at presentation, only 2 went on to be diagnosed with a systemic neurologic condition (one with MS and the other with MOG). It should be noted however that since the group of 12 isolated optic neuritis subjects was not precisely the same as the group that were felt to be MRI-negative at onset (13 were MRI negative based on site assessment and 11 based on independent masked assessment), the predictive value is not solely based on MRI findings. Rates of significant improvement and final outcomes in high-contrast visual acuity were excellent, with 85% having 417 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary VA better than 20/50 at 2 years, but this is notably worse than the outcome of the ONTT in which visual acuity at 1 year was 20/40 or better in 95% of the placebo group. Not surprisingly, the chance of having an HCVA of ,20/50 was greatest in the NMO-SD patients (2/3). The chance of such a poor outcome was 0% in the MOGAD patients, a reassuring outcome that is consistent with observations in adults that although MOG optic neuritis can be severe at onset, it typically demonstrates robust improvement. Overall, the 2-year results of the PON1 allow a significant step forward in our understanding of the natural history and prognosis for visual acuity outcomes and systemic neurologic disease diagnosis among children with optic neuritis. Limitations included a relatively small size, which was compounded by recruitment and retention problems. Furthermore, those who completed the 2-year follow had a higher rate of systemic neurologic disease than noncompleters and had better initial visual acuities than those that did not, raising the possibility of overestimating both. Finally, these results do not include data on visual fields, in those patients in which it was possible, nor of optic nerve atrophy, as could be assessed by optical coherence tomography, but hopefully more will be forthcoming from this group in the future. —Marc J. Dinkin, MD ***Note that John Chen wrote a commentary about this study https://www.aao.org/editors-choice/outcome-ofpatients-with-pediatric-optic-neuritis. 418 Marc, I agree that this prospective study definitely enhances our knowledge base of pediatric optic neuritis. This observational study was very well designed with solid inclusion and exclusion criteria and outcome measures. The group was racially/ethnically and diagnostically diverse although it is unfortunate that a greater percentage of the initial cohort (44 children) did not complete the 2 year visit. The noncompleters had worse visual acuity at study entry but their long-term outcomes are unknown. The experience of the authors regarding recruitment and retention is an important aspect of this study as further trials are designed. The misdiagnosis of MOG-positive disease as ADEM and NMOSD was also interesting, highlighting the need for neuro-ophthalmic consultation and repeated testing as our knowledge of autoimmune optic neuropathies continues to expand. —Deborah I. Friedman, MD, MPH Well reviewed, Marc and Deb. With studies such as this, we now know so much more than what we used to and the story continues to evolve. When I began my career we knew that children with optic neuritis often had bilateral disease, often had disc edema and less frequently progressed to MS. Now, with diagnoses of NMOSD and MOGAD, we are beginning to understand why. —Mark L. Moster, MD Moster et al: J Neuro-Ophthalmol 2022; 42: 409-418 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.