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 J. Dinkin, and Deborah I. Friedman discuss the following 6 articles: 1. Piehl F, Eriksson-Dufva A, Budzianowska A, Feresiadou A, Hansson W, Hietala MA, Håkansson I, Johansson R, Jons D, Kmezic I, Lindberg C, Lindh J, Lundin F, Nygren I, Punga AR, Press R, Samuelsson K, Sundström P, Wickberg O, Brauner S, Frisell T. Efficacy and safety of rituximab for new-onset generalized myasthenia gravis: the RINOMAX randomized clinical trial. JAMA Neurol. 2022;79:1105–1112. 2. Cortese R, Carrasco FP, Tur C, Bianchi A, Brownlee W, De Angelis F, De La Paz I, Grussu F, Haider L, Jacob A, Kanber B, Magnollay L, Nicholas RS, Trip A, Yiannakas M, Toosy AT, Hacohen Y, Barkhof F, Ciccarelli O. Differentiating multiple sclerosis from AQP4-neuromyelitis optica spectrum disorder and MOG-antibody disease with imaging. Neurology. 2022. doi: 10.1212/WNL.0000000000201465. 3. Carelli V, Newman NJ, Yu-Wai-Man P, Biousse V, Moster ML, Subramanian PS, Vignal-Clermont C, Wang AG, Donahue SP, Leroy BP, Sergott RC, Klopstock T, Sadun AA, Rebolleda Fernández G, Chwalisz BK, Banik R, Girmens JF, La Morgia C, DeBusk AA, Jurkute N, Priglinger C, Karanjia R, Josse C, Salzmann J, Montestruc F, Roux M, Taiel M, Sahel JA; the LHON Study Group. Indirect comparison of Lenadogene Nolparvovec gene therapy versus natural history in patients with leber hereditary optic neuropathy carrying the m.11778G.A MTND4 mutation. Ophthalmol Ther. 2022. doi: 10.1007/s40123-022-00611-x. 4. Noll C, Hiltensperger M, Aly L, Wicklein R, Afzali AM, Mardin C, Gasperi C, Berthele A, Hemmer B, Korn T, Knier B. Association of the retinal vasculature, intrathecal immunity, and disability in multiple sclerosis. Front Immunol. 2022;13:997043. 5. Mitchell JL, Buckham R, Lyons H, Walker JK, Yiangou A, Sassani M, Thaller M, Grech O, Alimajstorovic Z, Julher M, Tsermoulas G, Brock K, Mollan SP, Sinclair AJ. Evaluation of diurnal and postural intracranial pressure employing telemetric monitoring in idiopathic intracranial hypertension. Fluids Barriers CNS. 2022;19:85. 6. Pan Y, Chen YX, Zhang J, Lin ML, Liu GM, Xu XL, Fan XQ, Zhong Y, Li Q, Ai SM, Xu W, Tan J, Zhou HF, Xu DD, Zhang HY, Xu B, Wang S, Ma JJ, Zhang S, Gan LY, Cui JT, Li L, Xie YY, Guo X, Pan-Doh N, Zhu ZT, Lu Y, Shi YX, Xia YW, Li ZY, Liang D. Doxycycline vs placebo at 12 weeks in patients with mild thyroidassociated ophthalmopathy: a randomized clinical trial. JAMA Ophthalmol. 2022;140:1076–1083. Piehl F, Eriksson-Dufva A, Budzianowska A, Feresiadou A, Hansson W, Hietala MA, Håkansson I, Johansson R, Jons D, Kmezic I, Lindberg C, Lindh J, Lundin F, Nygren I, Punga AR, Press R, Samuelsson K, Sundström P, Wickberg O, Brauner S, Frisell T. Efficacy and safety of rituximab for new-onset generalized myasthenia gravis: the RINOMAX randomized clinical trial. JAMA Neurol. 2022;79:1105–1112. Importance: Rituximab is a third-line option for refractorygeneralized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown. Objective: To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a quantitative myasthenia gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key e26 exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids. Interventions: Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo. Main Outcomes and Measures: Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment. Results: Of 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = 0.007; probability ratio, 2.48 [95% CI, 1.20–5.11]). Secondary end points, comparing changes in myasthenia gravis activities of daily living and myasthenia gravis quality of life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial Moster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary infarction with cardiac arrest, and 1 patient in the active arm experienced a fatal cardiac event. Conclusions and Relevance: A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced the need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment. COMMENTS This paper reports a double-blind placebo-controlled study of one 500 mg rituximab infusion early on in the treatment of generalized MG to determine if it will increase the probability of minimal MG manifestations and decrease the need for other medications at 4 months. The bottom line is that it did. The authors claim that based on empirical experience and consensus agreements, oral prednisolone (European study) is the first-line therapy with steroid-sparing immunosuppressants added to taper the steroids. They note that these agents have adverse effects and delayed efficacy. In my experience, this is an accurate summary of current practice. The authors theorized that rituximab started early after disease onset might impede the buildup of a diseaseassociated plasma cell pool. Also, based on preliminary evidence from an observational study of improved effectiveness of rituximab compared with standard of care, they undertook the rituximab in patients with new-onset generalized myasthenia gravis (RINOMAX) trial. Patients had to have a (MGFA) classification of II–IV. This means that there could be ptosis, EOM involvement, and mildto-severe bulbar or limb weakness, short of requiring intubation. The MG diagnosis had to be confirmed by at least 2 of the following: a positive acetylcholine receptor (AChR) antibody, an abnormal repetitive nerve stimulation and/or single fiber electromyography, or a clinically significant response to an oral or intravenous acetylcholinesterase inhibitor (AChEI) test. The primary outcome of minimal manifestations implied a QMG score of 4 or less and a daily dose of prednisolone of 10 mg/day or less at Week 16, with no need for rescue treatment during study Weeks 9–16. Rescue treatments were considered higher doses of prednisolone and all other immunomodulatory treatments, including rituximab, intravenous immunoglobulins, and plasma exchange. In this trial of 47 patients, the percent of individuals with minimal disease manifestations with only low doses of corticosteroids and no need for rescue treatment at 4 months was 71% with rituximab and 29% with placebo (P = 0.007). There are some limitations to this study, mostly acknowledged by the authors. There was an imbalance in numerous baseline characteristics including age, AChR antibody titers, number of patients on prednisolone, and number of patients with MGFA class III disease. This study showed encouraging results at 16 weeks with one 500 mg dose of rituximab. At the very least it may be Moster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 helpful as a “bridge” from onset of disease for some of the immunosuppressants with a long latency to benefit (e.g., azathioprine). We do not yet know if this regimen will be an effective long-term treatment for patients with MG. —Mark L. Moster, MD The RINOMAX trial studied a single dose of IV rituximab 500 mg compared with placebo in patients with early (symptoms for a year or less) MG. 71% of the rituximab group and 29% of the placebo group met the primary outcome measure, but as Mark noted, the rituximab group was older, more likely to have late-onset MG, had much lower AChR antibody titers, and had somewhat milder disease at baseline compared with the placebo group. Nonetheless, low-dose rituximab resulted in a higher number of participants with minimal disease manifestations, and no participant in the rituximab group required hospitalization for MG, plasmapheresis, IVIG, or other biologic treatment within the 24-week follow-up period. A single dose of rituximab 500 mg is a promising addition to current therapy for MG when given during the first year of symptoms. —Deborah I. Friedman, MD, MPH Strong data in support of early use of rituximab in mild to moderate myasthenia gravis are encouraging. The difference in need for rescue treatment was substantial, but I agree that the discrepancies in baseline characteristics may have had an effect on the outcome, especially the proportion of patients with MGFA Level III (moderate weakness) in the placebo group (64.7% vs 47.1% in the rituximab group). The cardiovascular death in one of only 25 patients in the rituximab group at 4 weeks is concerning, although it may not have been caused by the drug. Overall, this study offers compelling evidence that rituximab can affect the outcome in mild-to-moderate generalized myasthenia and potentially reduce disease-related hospitalizations. —Marc Dinkin, MD Cortese R, Carrasco FP, Tur C, Bianchi A, Brownlee W, De Angelis F, De La Paz I, Grussu F, Haider L, Jacob A, Kanber B, Magnollay L, Nicholas RS, Trip A, Yiannakas M, Toosy AT, Hacohen Y, Barkhof F, Ciccarelli O. Differentiating multiple sclerosis from AQP4-neuromyelitis optica spectrum disorder and MOG-antibody disease with imaging. Neurology. 2022. doi: 10.1212/WNL.0000000000201465. Background and Objectives: Relapsing remitting multiple sclerosis (RRMS), aquaporin4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have overlapping clinical features. There is an unmet need for imaging markers that differentiate between them when serologic testing is unavailable or e27 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary ambiguous. We assessed whether imaging characteristics typical of MS discriminate RRMS from AQP4-NMOSD and MOGAD, alone and in combination. Methods: Adult, nonacute patients with RRMS, APQ4NMOSD, MOGAD, and healthy controls were prospectively recruited at the National Hospital for Neurology and Neurosurgery (London, United Kingdom) and the Walton Centre (Liverpool, United Kingdom) between 2014 and 2019. They underwent conventional and advanced brain, cord, and optic nerve MRI and optical coherence tomography. Results: A total of 91 consecutive patients (31 RRMS, 30 APQ4-NMOSD, and 30 MOGAD) and 34 healthy controls were recruited. The most accurate measures differentiating RRMS from AQP4-NMOSD were the proportion of lesions with the central vein sign (CVS) (84% vs 33%, accuracy/specificity/sensitivity: 91/88/93%, P , 0.001), followed by cortical lesions (median: 2 [range: 1–14] vs 1 [0–1], accuracy/specificity/sensitivity: 84/90/77%, P = 0.002) and white matter lesions (mean: 39.07 [±25.8] vs 9.5 [±14], accuracy/specificity/sensitivity: 78/84/73%, P = 0.001). The combination of higher proportion of CVS, cortical lesions, and optic nerve magnetization transfer ratio reached the highest accuracy in distinguishing RRMS from AQP4-NMOSD (accuracy/specificity/sensitivity: 95/92/97%, P , 0.001).The most accurate measures favoring RRMS over MOGAD were as follows: white matter lesions (39.07 [±25.8] vs 1 [±2.3], accuracy/specificity/sensitivity: 94/94/93%, P = 0.006), followed by cortical lesions (2 [1–14] vs 1 [0–1], accuracy/specificity/sensitivity: 84/97/71%, P = 0.004) and retinal nerve fiber layer thickness (RNFL) (mean: 87.54 [±13.83] vs 75.54 [±20.33], accuracy/specificity/sensitivity: 80/79/81%, P = 0.009). Higher cortical lesion number combined with higher RNFL thickness best differentiated RRMS from MOGAD (accuracy/specificity/sensitivity: 84/92/77%, P , 0.001). Discussion: Cortical lesions, CVS, and optic nerve markers achieve a high accuracy in distinguishing RRMS from APQ4NMOSD and MOGAD. This information may be useful in clinical practice, especially outside the acute phase and when serologic testing is ambiguous or not promptly available. Classification of Evidence: This study provides Class II evidence that selected conventional and advanced brain, cord, and optic nerve MRI and OCT markers distinguish adult patients with RRMS from APQ4-NMOSD and MOGAD. COMMENTS Treating optic neuritis used to be straightforward for me, based on the ONTT results. If there were no white matter lesions in the brain—follow clinically. If there were white matter lesions in the brain, treat with pulsed methylprednisolone followed by an oral prednisone taper. Over the past 2 decades, with increasing knowledge about NMO-SD and MOGAD, the appropriate treatment of acute optic neuritis is more challenging, with the risk of permanent visual loss and the potential to restore visual function both much greater. The aim of the current study was to identify brain, cord, and optic nerve MRI and OCT markers to distinguish adult patients with RRMS from APQ4-NMOSD and MOGAD. They studied whether MRI characteristics typical for MS e28 discriminate between RRMS and the 2 antibody-mediated diseases alone and in combination and whether including optic nerve imaging measures may enhance the accuracy of the discrimination. As there are a lot of data, I chose to review only some of it. When serologic testing is clearly diagnostic or MRI features are very characteristic of a particular disease and they fit the clinical image, diagnosis, and treatment are clear. However, if the MRI and/or laboratory results are ambiguous or falsely negative, it would be great to have some imaging features that aid in diagnosis. Ninety-one patients (31 RRMS, 30 AQP4-NMOSD, and 30 MOGAD) and 34 healthy controls were included in the study. A relapsing disease course was reported in 100% of RRMS patients, 87% patients with AQP4-NMOSD, and 67% patients with MOGAD. The most common clinical presentations at onset in the 2 antibody-mediated diseases were optic neuritis and transverse myelitis. Brain white matter lesions were detected in 100% of RRMS, 83% of AQP4NMOSD, and 27% of MOGAD patients. The mean number and volume of lesions were higher in RRMS than AQP4-NMOSD (P , 0.001) and MOGAD (P , 0.001, P = 0.007). No difference in brain lesion number or volume between AQP4-NMOSD and MOGAD was identified. Cervical cord lesions were more common in RRMS (55%) than AQP4-NMOSD (40%) and MOGAD (4%) (P , 0.001). Cortical lesions were detected on phase sensitive inversion recovery (PSIR) images in 73% of MS patients, 4% of AQP4-NMOSD patients, and 3% of MOGAD patients. The central vein sign within white matter lesions on susceptibility-weighted imaging (SWI) was observed in 100% of RRMS, 70% of AQP4-NMOSD, and 17% of MOGAD patients. This sign is the appearance of a vein in the middle of a demyelinating brain lesion. The proportion of lesions with the CVS was higher in RRMS (84%) than AQP4-NMOSD (33%) but did not differ between AQP4NMOSD and MOGAD. All patient groups showed lower RNFL thickness than healthy controls, with the 2 antibody-mediated diseases also showing lower GCIPL than healthy controls (all P , 0.01). When compared with RRMS, GCIPL thickness was lower in AQP4-NMOSD (P = 0.007), whereas RNFL thickness was lower in MOGAD (P = 0.009). The proportion of lesions with the CVS was the most accurate measure that distinguished RRMS from AQP4NMOSD (OR: 1.09, 95% CI: 1.05–1.14, accuracy: 91%, specificity: 88%, sensitivity: 93%, AUC: 0.93, P , 0.001). The presence of at least one cervical cord lesion was the only MRI measure which predicted AQP4-NMOSD than MOGAD (OR: 30.36, 95% CI: 2.15–427.88, accuracy: 71%, specificity: 65%, sensitivity: 76%, AUC: 0.68, P , 0.001). How does this help me in clinic or the ER this coming week? I do have to take a lot of the information with “a grain of salt.” First, my patients are likely to present with isolated optic neuritis. In this study, only 19% of the Moster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary RRMS patients had optic neuritis, compared with 53% of NMO and 64% of MOG patients. In addition, although the OCT results seem similar to our clinical experience, there was no stratification of OCT data based on whether the patient had optic neuritis or not. I also was very surprised that there is no mention of type of lesion on orbital MRI (e.g., anterior, posterior, and perineural). So back to the clinic, I will speak with neuroradiology colleagues about the best images to look for cortical lesions and the central vein sign and will count the white matter lesions in acute optic neuritis patients. However, I will wait in anticipation for the NMO and MOG laboratory results on each patient —Mark L. Moster, MD Mark, I was taught not to treat optic neuritis with intravenous steroids, based on the lack of statistical difference in visual acuity, visual fields, color vision, or contrast vision at one year in the Optic Neuritis Treatment Trial (ONTT) (1). But my practice eventually evolved so that I do treat most patients with ON, since color vision, contrast, and visual fields were somewhat better at 6 months in the ONTT (2) and my patients all seem to value getting better faster. More importantly, I want to cover for the possibility that the patient might have AQP4-NMOSD, a disease in which acute treatment will likely make a difference in the final visual outcome. The results of the blood tests for these causes of neuromyelitis spectrum disorder will not come back until my window for early treatment has passed. However, if I knew the patient had AQP4-NMO up front, it might persuade me to add plasma exchange if the vision loss is significant, based on studies showing better outcomes with its use (3). As such, any features that help me discern one from the other while I am waiting for serology are clinical quite useful. I was surprised to see that RNFL thinning was not more helpful in distinguishing AQP4-NMO from RRMS patients, given prior studies that showed much thinned RNFL in AQP4NMO optic neuritis than after RRMS ON (4). In any case, in patients with a first time acute optic neuritis, at which time differentiating the 2 diseases is most important, the RNFL is not likely to be thinned as it would be in the chronic patients in this study and in fact may be thickened. Furthermore, as with many practitioners, I do not have access to OCT in the ER. The MRI findings, on the other hand, are potentially quite useful, even in the setting of acute ON. A combined analysis of proportion of lesions with the central veins sign (CVS), number of cortical lesions, and average magnetization transfer ratio (MTR) of the optic nerve resulted in a sensitivity of 97% and a specificity of 92%. I am particularly interested in using the MTR of the optic nerve. This technique looks at the exchange of magnetization between protons, which in the white matter is driven by myelin integrity. With demyelination, less protons are restricted and the MTR is reduced (5). When applied to the optic nerve, MTR can serve as a nice compliment to Moster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 OCT; since unlike RNFL and GCL thinning, it can recover with remyelination. Moreover, it may show a reduction even before gadolinium enhancement sets in, allowing us to detect demyelination (such as occurs with ON) earlier. Although this parameter has joined others in serving as an outcomes measure for some clinical trials (6), we might now use it as a means to distinguish AQP4-NMO from MS. —Marc Dinkin, MD 1. Beck RW, Cleary PA. Optic neuritis treatment trial. One-year follow-up results. Arch Ophthalmol. 1993;111:773–775. 2. Beck RW, Cleary PA, Anderson MM Jr, Keltner JL, Shults WT, Kaufman DI, Buckley EG, Corbett JJ, Kupersmith MJ, Miller NR, Savino PJ, Guy JR, Trobe JD, McCrary JA, Smith CH, Chrousos GA, Thompson HS, Katz BJ, Brodsky MC, Goodwin JA, Atwell CW. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992;326:581–588. 3. Merle H, Olindo S, Jeannin S, Valentino R, Mehdaoui H, Cabot F, Donnio A, Hage R, Richer R, Smadja D, Cabre P. Treatment of optic neuritis by plasma exchange (add-on) in neuromyelitis optica. Arch Ophthalmol. 2012;130:858–862. 4. Ratchford JN, Quigg ME, Conger A, Frohman T, Frohman E, Balcer LJ, Calabresi PA, Kerr DA. Optical coherence tomography helps differentiate neuromyelitis optica and MS optic neuropathies. Neurology. 2009;73:302–308. 5. van den Elskamp IJ, Knol DL, Vrenken H, Karas G, Meijerman A, Filippi M, Kappos L, Fazekas F, Wagner K, Pohl C, Sandbrink R, Polman CH, Uitdehaag BM, Barkhof F. Lesional magnetization transfer ratio: a feasible outcome for remyelinating treatment trials in multiple sclerosis. Mult Scler. 2010;16:660–669. 6. Kita M, Goodkin DE, Bacchetti P, Waubant E, Nelson SJ, Majumdar S. Magnetization transfer ratio in new MS lesions before and during therapy with IFNbeta-1a. Neurology. 2000;54:1741–1745. It can be difficult sometimes to determine the underlying cause of optic neuritis, particularly when the serology is unrevealing. The authors incorporated brain, spine, and optic nerve MRI findings and OCT in 91 consecutive patients with RRMS, APQ4-NMOSD, and MOGAD (equally divided) and 34 unaffected controls to determine the accuracy, specificity, and sensitivity of imaging tests for discriminating between the 3 diseases. Of course, all of the patients included in the study had positive antibody testing to ensure that they were accurately diagnosed. As Mark points out, we generally see patients early in their course with optic neuritis—but distinguishing between these 3 etiologies at presentation would be great for us and the patient. Applying their findings incorporating various imaging signs (central vein sign, cortical and white matter lesions, optic nerve magnetic transfer, and RNFL thickness) is useful for us in clinical practice to help reduce the uncertainty in diagnosis. —Deborah I. Friedman, MD, MPH Carelli V, Newman NJ, Yu-Wai-Man P, Biousse V, Moster ML, Subramanian PS, Vignal-Clermont C, Wang AG, Donahue SP, Leroy BP, Sergott RC, e29 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Klopstock T, Sadun AA, Rebolleda Fernández G, Chwalisz BK, Banik R, Girmens JF, La Morgia C, DeBusk AA, Jurkute N, Priglinger C, Karanjia R, Josse C, Salzmann J, Montestruc F, Roux M, Taiel M, Sahel JA; the LHON Study Group. Indirect comparison of Lenadogene Nolparvovec gene therapy versus natural history in patients with leber hereditary optic neuropathy carrying the m.11778G.A MT-ND4 mutation. Ophthalmol Ther. 2022. doi: 10.1007/s40123-022-00611-x. Introduction: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778 GA ND4 mutation (MTND4). A previous pooled analysis of Phase 3 studies showed an improvement in the visual acuity of patients injected with lenadogene nolparvovec compared with natural history. Here, we report updated results by incorporating data from the latest Phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. Methods: The visual acuity of 174 MT-ND4–carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from 4 pooled Phase 3 studies (REVERSE, RESCUE, and their long-term extension trial RESTORE and REFLECT trial) was compared with the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. Results: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared with the natural history. Mean improvement vs natural history was -0.30 logMAR (+15 ETDRS letters equivalent) at last observation (P , 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared with less than half of natural history eyes at 48 months after vision loss (89.6% vs 48.1%; P , 0.01) and at last observation (76.1% vs 44.4%; P , 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was -0.43 logMAR (+21.5 ETDRS letters equivalent) vs natural history at last observation (P , 0.0001). Treatment effect was consistent across all Phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared with unilateral injection. Conclusion: The efficacy of lenadogene nolparvovec in improving the visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared with the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. Trial Registration Numbers: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT032. COMMENTS The investigators continue to build on earlier successes from the REVERSE, RESCUE, and REFLECT Phase 3 clinical trials of lenadogene nolparvovec (rAAV2/2-ND4), a modified adeno-associated virus gene therapy designed to complement the defective ND4 gene for treatment of Leber hereditary optic neuropathy (LHON). This paper adds the e30 data from 98 treated patients to their previous reports, more than doubling the active treatment cohort. To recap, participants in the REVERSE and RESCUE trials, aged 15 and older with the ND4m11778G.A mutation, received a single intravitreal injection of lenadogene nolparvovec in one eye and a sham injection in the fellow eye. In the first unexpected turn of events, the visual acuity in the shamtreated eyes improved to almost the same extent as eyes injected with the active treatment, possibly attributed to chiasmal biodistribution of the viral vector DNA. The improvement was sustained at 3 years. Those participants continue to be followed in the RESTORE study. Based on the results of those studies, the REFLECT study randomized participants to either unilateral intravitreal treatment in the first affected eye (with the fellow eye receiving a placebo injection) or bilateral injections of active treatment. The onset of vision loss occurred within a year of inclusion (median 8.3 months). A pure sham treatment arm was deemed unethical, so the control group comprised patients in the REALITY registry and from 10 natural history published reports. Visual acuity loss in LHON is gradual and progressive. Considering visual acuity data starting 12 months after visual loss, the control group (208 patients, 408 eyes) had visual acuity values plateauing to 1.6 logMAR (the cut-off for on-chart values on the ETDRS scale) up to 36 months after the initial visual loss followed by a slow decline to offchart values from 36 months onward. The pooled treated patients (174 patients, 348 eyes) did not experience the delayed visual decline; rather, their vision gradually improved between 12 and 52 months. A sensitivity analysis taking into account the covariates of ethnicity (Asian vs non-Asian), age at onset, and duration of follow-up showed a difference of 20.43 logMAR (CI 0.53, 20.33; P , 0.0001) in favor of treated eyes. Participants in REFLECT receiving bilateral injections enjoyed a larger response compared with those who received unilateral injections (79.2% responder eyes for bilateral injections, 67.0% for unilateral injections, and 44.4% for natural history controls, P , 0.001). Younger age at onset, Asian ethnicity, and—another unexpected finding—longer duration from visual loss to treatment were all associated with a better response to treatment. This is an exciting news for patients having the most common variant of LHON, with outcomes superior to results with idebenone (although there has been no headto-head comparison). I too was surprised that a longer duration of visual loss before treatment was associated with a better outcome, essentially 1 letter for each month of delayed treatment. Although it seems counterintuitive, this was also observed in the RESCUE and REVERSE trials. The explanation for this is uncertain but may be related to impeded delivery of the viral vector to retinal ganglion cells in the setting of acute nerve fiber edema. Moster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Being able to prevent visual deterioration after the initial attack of LHON and restoring visual acuity so that is “on the chart” is a major advancement in this previously untreatable and devastating disorder. Congratulations to the investigators! this group to offer hope to our patients who suffer from this challenging disease. —Marc Dinkin, MD —Deborah I. Friedman, MD, MPH For full disclosure, I was an investigator in all of these clinical trials. The results are encouraging with an average improvement of 4 lines of visual acuity with lenadogene nolparvovec. However, we need to do better. The current studies use a technique called allotopic expression. The wild-type DNA and associated viral vector enters the nucleus, and the DNA is transcribed there. It is then carried to the mitochondrial membrane where the RNA is translated into the necessary protein. This technique is used because it is not yet possible for DNA to enter the mitochondria. When this is accomplished, results will hopefully be even better. My own experience in these patients is varied. On average, there is a 4-line improvement, but I have some patients with no improvement and others with dramatic improvement, with 2 patients now able to drive. It will be important to determine features that distinguish the responders from nonresponders. One of the other issues is why there would be bilateral improvement with a unilateral injection. Theories have included systemic effect, central reorganization, or placebo effect. However, a study in cynomolgus monkeys has shown bilateral optic nerve viral vector and mitochondrial DNA from a unilateral injection, suggesting transfer by the optic chiasm. —Mark L. Moster, MD I am delighted to see convincing data in support of allotopic gene therapy for MT-ND-4, which until recently had no treatment. The fact that patients receiving gene therapy did not simply experience less worsening of visual acuity but actually improved speaks to the presence of neurons in MT-ND4 that are metabolically dysfunctional but still alive. Although the comparison was limited by some differences in baseline characteristics, accounting for these only improved the estimated mean improvement in visual acuity to 21 more letters in the treatment group vs the natural history cohort. The improved outcome in patients who were treated later may reflect reduced viral vector transfer in the setting of edema as surmised but could also result from a reduced effect of genetic rescue at an earlier stage of metabolic dysfunction. The question of course arises—how long should we wait before treating patients with lenadogene nolparvovec? One would expect an eventual reversal of time-based benefits to a decline in effect with very long delays, based on the effects of increasing atrophy, but when such an inflection point would occur remains unclear. In any case, these promising results build on prior studies from Moster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 Noll C, Hiltensperger M, Aly L, Wicklein R, Afzali AM, Mardin C, Gasperi C, Berthele A, Hemmer B, Korn T, Knier B. Association of the retinal vasculature, intrathecal immunity, and disability in multiple sclerosis. Front Immunol. 2022;13:997043. Background: Optical coherence tomography angiography (OCT-A) is a novel technique allowing noninvasive assessment of the retinal vasculature. During relapsing remitting multiple sclerosis (RRMS), retinal vessel loss occurs in eyes suffering from acute optic neuritis and recent data suggest that retinal vessel loss might also be evident in nonaffected eyes. We investigated whether alterations of the retinal vasculature are linked to the intrathecal immunity and whether they allow prognostication of the future disease course. Material and Methods: This study includes 2 different patient cohorts recruited at a tertiary German academic multiple sclerosis center between 2018 and 2020 and a cohort of 40 healthy controls. A total of 90 patients with RRMS undergoing lumbar puncture and OCT-A analysis were enrolled into a crosssectional cohort study to search for associations between the retinal vasculature and the intrathecal immune compartment. We recruited another 86 RRMS patients into a prospective observational cohort study who underwent clinical examination, OCT-A, and cerebral MRI at baseline and during annual follow-up visits to clarify whether alterations of the retinal vessels are linked to the RRMS disease activity. Eyes with a history of optic neuritis were excluded from the analysis. Results: Rarefication of the superficial vascular complex occurred during RRMS and was linked to higher frequencies of activated B cells and higher levels of the proinflammatory cytokines interferon-g, tumor necrosis factor a, and interleukin-17 in the cerebrospinal fluid. During a median follow-up of 23 (interquartile range 14–25) months, vessel loss within the superficial (hazard ratio [HR] 1.6 for a 1%point decrease in vessel density, P = 0.01) and deep vascular complex (HR 1.6 for a 1%-point decrease, P = 0.05) was associated with future disability worsening. Discussion: Optic neuritis independent rarefication of the retinal vasculature might be linked to neuroinflammatory processes during RRMS and might predict a worse disease course. Thus, OCT-A might be a novel biomarker to monitor disease activity and predict future disability. COMMENTS The empty vessel makes the loudest sound: retinal vasculature as a biomarker in multiple sclerosis. As technological advances offer us novel ways to assess retinal structure, evidence for correlations between neurological disease processes and retinal biomarkers has steadily accumulated. Expected thinning of the retinal nerve fiber layer (pRNFL) and ganglion cell inner plexus (GCIP) e31 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary following optic neuritis (ON) has been shown to be associated with retinal vessel loss within the superficial vascular complex (SVC) as measured by OCT angiography (OCT-A) (1), a finding that may simply reflect secondary vascular loss due to diminished metabolic need of atrophic tissue. However, such rarefication of the SVC has also been shown to occur in eyes without a history of ON in patients with relapsing remitting multiple sclerosis (RRMS) (2). Although these alterations might also be secondary to background attrition of inner retinal layers brought about by chronic RRMS, primary vascular damage by inflammatory mediators may also play a role. In a recent article in Frontiers Immunology, Noll and colleagues used OCT-A to study the relationship of RRMS-associated retinal vessel loss with markers of humoral and cellular immunity in the cerebrospinal fluid (CSF) and further examined the ability of such changes to predict clinical outcomes such as disability (3). To address the first question, 90 RRMS patients who underwent OCT and OCT-A and lumbar puncture were enrolled, resulting in 120 eyes, after those with ON or poorquality studies were excluded. Using standard OCT, the authors found that GCIP thicknesses were inversely correlated with levels of CD27+CD38high-activated B cells. Furthermore, using OCT-A, they demonstrated an inverse relationship between both the SVC vessel density with intrathecal levels of activated B cells. This relationship was observed with the deep vascular complex (DVC) as well, arguing against the notion that vessel rarefication is only secondary to inner layer atrophy. They also found a positive correlation between the size of the foveal avascular zone (FAZ) size and levels of activated B cells. By contrast, levels of T cells did not correlate with SVC or DVC vessel density. On the humoral side, they found that the loss of SVC and DVC vessel density correlated with levels of IFN-g, TNF-a, and IL-22, all proinflammatory cytokines. IL-13, which is a mediator of responses to allergic inflammation, also correlated. A clinical cohort was studied, which included 118 eyes of 86 patients, and excluded any eyes with a history of ON. Among these patients, 20% suffered from relapses, 49% displayed disease activity on MRI, and 10% progressed for disability over a median follow-up of 23 months. After correcting for age, sex, disease duration, and use of immunotherapy, the authors found a correlation between loss of SVC and DVC vessel density and future disability, even after correcting for GCIP thickness. Those with SVC densities ,24.2% were 6.3 times more likely to experience progressive disability, whereas those with DVC densities ,25% were 7 times as likely as those with higher densities. Although prior studies have demonstrated correlations between SVC rarefication in the absence of ON with higher disability scores (4), the current study showed that vessel density loss could be used as a prognostic factor to predict future disability. The utility of OCT in early RRMS patients, therefore, to risk-stratify patients and help determine the importance of aggressive immunomodulatory therapy might e32 now extend to OCT-A. Moreover, the apparent independence of correlation of SVC with most disability factors in this study suggests an independent effect of RRMS on retinal vasculature, independent of neuronal atrophy–associated reduced demand. Although RRMS rarely induces obvious retinal inflammation, including retinal phlebitis and pars planitis, these results suggest that a direct inflammatory effect on retinal vasculature is more common than clinical observations would suggest. This is in line with pathological studies that have shown perivascular infiltrates in 29% of RRMS patients (5). Finally, the correlation of retinal vascular loss with intrathecal immunity suggests that OCT-A could be used to predict CNS inflammation in patients with RRMS. All of these findings must be taken with caution because the number of patients who actually experienced progressive disability over the relatively short follow-up interval was small. Furthermore, OCT-A results are prone to artifacts and may be dependent on the experience of the practitioner analyzing them. As the authors point out, OCT-A results do not delineate loss of vessels from constriction nor venous from arterial loss accurately. Nevertheless, for many of us, OCT-A has been a tool searching for clinical applications, and any research that takes us one step closer to identifying practical use for OCT-A in our daily practice is welcome. —Marc Dinkin, MD 1. Aly L, Noll C, Wicklein R, Wolf E, Romahn EF, Wauschkuhn J, Hosari S, Mardin C, Berthele A, Hemmer B, Korn T, Knier B. Dynamics of retinal vessel loss after acute optic neuritis in patients with relapsing multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022;9:e1159. 2. Feucht N, Maier M, Lepennetier G, Pettenkofer M, Wetzlmair C, Daltrozzo T, Scherm P, Zimmer C, Hoshi M-M, Hemmer B, Korn T, Knier B. Optical coherence tomography angiography indicates associations of the retinal vascular network and disease activity in multiple sclerosis. Mult Scler. 2019;25:224–234. 3. Noll C, Hiltensperger M, Aly L, Wicklein R, Afzali AM, Mardin C, Gasperi C, Berthele A, Hemmer B, Korn T, Knier B. Association of the retinal vasculature, intrathecal immunity, and disability in multiple sclerosis. Front Immunol. 2022;13:997043. 4. Murphy OC, Kwakyi O, Iftikhar M, Zafar S, Lambe J, Pellegrini N, Sotirchos ES, Gonzalez-Caldito N, Ogbuokiri E, Filippatou A, Risher H, Cowley N, Feldman S, Fioravante N, Frohman EM, Frohman TC, Balcer LJ, Prince JL, Channa R, Calabresi PA, Saidha S. Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures. Mult Scler. 2020;26:815–828. 5. Green AJ, McQuaid S, Hauser SL, Allen IV, Lyness R. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. Brain. 2010;133:1591–1601. I agree, Marc, that this moves us forward, but results must be taken with caution. As with RNFL and GCL studies, OCT-A can be affected by so many processes that they must be interpreted by those with expertise in all ophthalmologic causes of OCT-A changes. I do think they will be most useful in the near future for clinical trials, looking at baselines and subsequent changes. —Mark L. Moster, MD Moster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Marc, I think that your final sentence says it all! In addition to findings from OCT, OCT-A may also be useful as a prognostic factor, although we know that there is much individual variability in patients with RRMS, and sometimes patients surprise us when they are clinically much better than their brain or retinal/optic nerve imaging appears. Nonetheless, it will be interesting to see whether these findings stand up to the test of time. And a bonus—I am always happy to learn new words, and there were 2 in this article: rarefication (I learned it as “rarefaction”; to make less dense or thin) and anamnesis (now I feel so pedestrian just saying that I took the medical history). —Deborah I. Friedman, MD, MPH Mitchell JL, Buckham R, Lyons H, Walker JK, Yiangou A, Sassani M, Thaller M, Grech O, Alimajstorovic Z, Julher M, Tsermoulas G, Brock K, Mollan SP, Sinclair AJ. Evaluation of diurnal and postural intracranial pressure employing telemetric monitoring in idiopathic intracranial hypertension. Fluids Barriers CNS. 2022;19:85. Objectives: Intracranial pressure (ICP) has been believed to vary diurnally. This study evaluates diurnal ICP measurements and quantifies changes in ICP occurring with changes in body posture in active idiopathic intracranial hypertension (IIH). Methods: This prospective observational study used telemetric ICP monitoring in people with active IIH. Participants had the Raumedic p-Tel ICP intraparenchymal device (Raumedic, Hembrechts, Germany) surgically inserted. Changes in ICP in the supine position were evaluated. Then, the ICP was measured in the standing, sitting, supine, left lateral decubitus positions, and with coughing and bending. Ultimately, changes in ICP over the course of 24 hours were recorded. ISRCTN registration number 12678718. Results: Fifteen women were included, mean (SD) age 29.5 (9.5) years, body mass index 38.1 (6.2) kg/m2, and baseline mean ICP of 21.2 (4.8) mm Hg (equivalent to 28.8 [6.5] cm CSF). Mean ICP rose with the duration in the supine position 1.2 (3.3) mm Hg over 5 minutes (P = 0.175), 3.5 (2.8) mm Hg over 30 minutes (P = 0.0002), and by a further 2.1 (2.2) mm Hg over 3 hours (P = 0.042). Mean ICP decreased by 51% when moving from the supine position to standing (21.2 [4.8] mm Hg to 10.3 (3.7) mm Hg respectively, P = 0.0001). Mean ICP increased by 13% moving from supine to the left lateral decubitus position (21.2 [4.8] mm Hg to 24.0 (3.8) mm Hg, P = 0.028). There was no significant difference in ICP measurements at any point during the daytime or between 5-minute standing or supine recordings and prolonged ambulatory daytime and end of night supine recordings, respectively. ICP, following an initial drop, increased progressively in conjunction with lying supine position from 23:00 hour to 07:00 hour by 34% (5.2 [1.9] mm Hg, P = 0.026). Conclusion: This analysis demonstrated that ICP does not appear to have a diurnal variation in IIH but varies by position and duration in the supine position. ICP rose at night while the patient was continuously supine. Furthermore, brief standing and supine ICP measures in the day predicted daytime prolonged ambulatory measures and end of night peak ICP, respecMoster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 tively. This knowledge gives reassurance that ICP can be accurately measured and compared at any time of day in an ambulant IIH patient. These are useful findings to inform clinical measurements and in the interpretation of ICP analyses in IIH. COMMENTS A long-standing frustration in the care of patients with idiopathic intracranial hypertension (IIH) is the lack of a noninvasive assessment of intracranial pressure (ICP). By and large, we rely on lumbar puncture (LP) to assess ICP for confirming the diagnosis if IIH and monitoring patients to assess therapeutic efficacy or suspected worsening. Even under the most ideal circumstances, a LP opening pressure measurement provides only a snapshot in time and is potentially misleading regarding a patient’s status. Continuous ICP monitoring traditionally required a subarachnoid bolt or a lumbar catheter attached to an external transducer. While a bolt is not a particularly risky procedure, it requires a burr hole and hospitalization. Lumbar drains can dislodge from the subarachnoid space, and the dural puncture sometimes results in a CSF leak and low-pressure syndrome. The Raumedic Transdermal Telemetric System (Raumedic, Helmbrechts, Germany) measures CSF pressure in the brain parenchyma rather than the ventricles (1). It was designed as an alternative for monitoring ICP in patients who would otherwise need hospitalization for this purpose. The authors incorporated the Neurovent-P 30 mm polyurethane catheter with a piezoresistant pressure transducer containing several electric resistors on a flexible membrane. The membrane stretches with an increase in ICP, changing the length of the resistors and the elastic resistance of the system. The changes are registered by a microchip in a round ceramic housing that sits on the skull surface, converting the electrical changes to ICP values and transmitting the data to a monitor using an electromagnetic field. The catheter is inserted through a burr hole in a 10–20 minute procedure under general or local anesthesia and may remain implanted for up to 90 days. Complications, such as wound infection and intracranial hemorrhage, are uncommon (2). From a purely clinical standpoint, intracranial space– occupying lesions with elevated ICP often cause headaches during sleep due to the rise in ICP during the night. Although patients with IIH do not consistently report a postural component to their headaches, some report that they are worse in the morning. In this paper, Mitchell et al report a prospective observational study of 15 women with active IIH using the Raumedic telemetric ICP monitor to determine whether they had a diurnal variation or a postural component to their ICP. “Active” was defined as elevated ICP and the presence of papilledema. Participants stayed in the research facility for 2 days and had their ICP measurements recorded continuously while supine, in the lateral decubitus position, standing, sitting, bending, coughing, flexing from the hips, and reaching toward the floor. Readings at various times of the day and night were e33 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary recorded in the supine position. Participants were allowed to record at home during normal activity and while sleeping. ICP was highest in the lateral decubitus position (24, SD 3.8 mm Hg), followed by the supine position (21.2, SD 4.8 mm Hg) and followed by the sitting (10.1, SD 5.1 mm Hg) and standing (10.3, SD 3.7 mm Hg) positions. Arising from supine to standing produced the largest positional change in ICP (251%, 210.9, SD 4.2 mm Hg, P = 0.0001). The highest peak pressure occurred in the supine position (27.5, SD 6.7 mm Hg), and lowest trough in ICP occurred while standing (8.2, DF 3.0 mm Hg), both P , 0.0001. Ambulatory pressures did not differ much from those obtained while standing for over 5 minutes. In general, the greatest increase in the amplitude of ICP measurements when standing was highest in participants with the highest baseline ICP. Cough had a marked effect (from 14.9, SD 4.8 to 66.7, SD 28, 334% change, P , 0.0001), returning to baseline in 3.7 (1.5) seconds. Bending increased ICP to 63.5 (SD 12.4 mm HG, 323.2% change P = 0.0001) returning to baseline in 4.2 (2.4) seconds. Twenty-four-hour monitoring revealed the highest “wake time” ICP when the patients first retired for the night then rose 34% when the patient slept in their usual position. What did we learn from this study? CSF pressure when measured in the lumbar spine in the supine position is equal to the pressure at the Foramen of Monro. It is well established that ICP is highest in recumbence and increases when the body is tilted upright (or in the sitting position) due to displacement of the hydrostatic indifferent point (HIP) (3). The level along the spinal axis where the CSF pressure is equal to atmospheric pressure while the patient is sitting is called the ZPS and is normally located in the upper cervical spine. The hydrostatic indifferent point is the location where the CSF pressure is equal in the supine and sitting positions. In the upright posture, the ICP is normally negative, ranging from 20.5 to 7 cm CSF (4). Compliance (or elasticity) also affects changes in ICP in various positions. For example, in the presence of a shunt of CSF leak, dural compliance in the lumbar spine increases, lowering the HIP and producing orthostatic headache. The opposite occurs with elevated CSF pressure, raising the HIP into the cranium and producing headaches that do not improve significantly while standing. A prior study evaluating ICP telemetrically using a similar device in patients with normal ICP, IIH, normal pressure hydrocephalus, and other types of hydrocephalus found similar results which could not be distinguished by the patient group (5). A rise in ICP and intraocular pressure with Valsalva maneuvers is also well known (6,7). Importantly, previous studies using MRI data showed that CSF measurements in any posture other than supine require correction for the HIP (4). Neither the current study nor the one by Andresen et al indicate that a corrective factor was incorporated (I contacted the company to see whether their device required a correction factor but did not receive a reply in time for our submission timeline). This study was performed when the device was relatively new on the European market and had never been used to e34 study IIH in particular. Another group published a study of 20 patients with headaches and suspected IIH, a few of whom had shunts, studied with the same monitoring system from 2014 to 2020, confirming the diagnosis in 18 patients which changed their management (8). Although their patients recorded various activities, postural measurements were not specifically obtained. The system is a good alternative for patients who need continuous ICP monitoring to direct their therapy but do not otherwise need hospitalization. However, I am puzzled as to the need for this study, given that it was invasive (requiring a burr hole and intraparenchymal catheter), potentially risky, and these parameters were studied in the past. There is no indication that the results changed the participants’ management. The device has an 8% complication rate, including wound infection, seizures, intraparenchymal hemorrhage, and subdural hematoma. Fortunately, none of the participants in the study had complications. The study was approved by their Ethics Committee, but, all things considered, I am not confident that an institutional review board in the United States would have performed the same. —Deborah I. Friedman, MD, MPH 1. Antes S, Tschan CA, Heckelmann M, Breuskin D, Oertel J. Telemetric intracranial pressure monitoring with the Raumedic Neurovent P-tel. World Neurosurg. 2016;91:133–148. 2. Noranger NH, Lilja-Cryon A, Hansen TS, Juhler M. Deciding on appropriate telemetric intracranial pressure monitoring system. World Neurosurg. 2019;126:564–569. 3. Magnes B. Body position and cerebrospinal fluid pressure. Part 2: clinical studies on orthostatic pressure and the hydrostatic indifferent point. J Neurosurg. 1976;44:698–705. 4. Alperin N, Lee HL, Bagci AM. MRI measurements of intracranial pressure in the upright posture: the effect of the hydrostatic gradient. J Magn Reson Imaging. 2015;42:1158–1163. 5. Andresen M, Hadi A, Peterson LG, Juhler M. Effect of postural changes on ICP in healthy and ill subjects. Act Neurochir. 2015;157:109–113. 6. Zhang Z, Wang X, Jonas JB, Wang H. Valsalva manouver, intraocular pressure, cerebrospinal fluid pressure, optic disc topography: Beijing intracranial and intra-ocular pressure study. Acta Ophthalmol. 2014;92:e475–e480. 7. Neville L, Egan RA. Frequency and amplitude of elevation of cerebrospinal fluid resting pressure by the Valsalva maneuver. Can J Ophthalmol. 2005;40:775–777. 8. Velazquez Sanchez VF, Al Dayri G, Tschan CA. Long-term telemetric intracranial pressure monitoring for diagnosis and therapy optimisation of idiopathic intracranial hypertension. BMC Neurol. 2021;21:343. The information gleaned from this study is helpful. What we do not know is what is a normal pressure on this system. I contacted the company that manufactures the device to get information on ICP measurements in a normal population, but the response seems to be arriving by snail mail, rather than telemetrically (? Sp). I agree with you, Deb, that implanting a device in the frontal lobe in patients where the findings will not change treatment would be a tough sell to most IRBs. —Mark L. Moster, MD Moster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Although the study was relatively small and only applicable to patients with IIH, it offers several insights. The quick return to baseline ICP after coughing or bending could be reassuring to patients that they need not worry after a cough or 2, but the effects of repeated coughing (as often occurs during a respiratory illness) or repeated bending (which might occur in some activities such as gardening) might be more long lasting. I found the confirmation of an increase in amplitude (consistent with a decrease in compliance) with higher ICP noteworthy. Mark, I agree that it would have been nice to have data from lumbar punctures for a subset of patients in this study to understand the relationship between values using the Raumedic Transdermal Telemetric System and the pressures we are measuring in practice. In the end, I am not sure how helpful continued measurement would be for medical decision-making in most patients with IIH. For the most part, once the diagnosis of IIH has been confirmed with an initial ICP measurement, I will base my treatment plan on the degree of papilledema, vision loss, and symptom severity, regardless of the exact pressure measurement. —Marc Dinkin, MD Pan Y, Chen YX, Zhang J, Lin ML, Liu GM, Xu XL, Fan XQ, Zhong Y, Li Q, Ai SM, Xu W, Tan J, Zhou HF, Xu DD, Zhang HY, Xu B, Wang S, Ma JJ, Zhang S, Gan LY, Cui JT, Li L, Xie YY, Guo X, Pan-Doh N, Zhu ZT, Lu Y, Shi YX, Xia YW, Li ZY, Liang D. Doxycycline vs placebo at 12 weeks in patients with mild thyroidassociated ophthalmopathy: a randomized clinical trial. JAMA Ophthalmol. 2022;140:1076–1083. Importance: Mild thyroid-associated ophthalmopathy (TAO) negatively affects quality of life, yet no clinical guidelines for its treatment are available. Existing evidence supports the use of doxycycline in treating mild TAO. Objective: To evaluate the short-term (12 weeks) efficacy of doxycycline in treating mild TAO. Design, Setting, and Participants: In this placebocontrolled multicenter randomized double-masked trial, 148 patients were assessed for eligibility. After exclusions (patients who were pregnant or lactating, had an allergy to tetracyclines, or had uncontrolled systematic diseases), 100 patients with mild TAO (orbital soft tissue affected mildly) at 5 centers in China were enrolled from July 2013 to December 2019 and monitored for 12 weeks. Interventions: Participants were randomly assigned 1:1 to receive doxycycline (50 mg) or placebo once daily for 12 weeks. Main Outcomes and Measures: The primary outcome was the rate of improvement at 12 weeks compared with baseline assessed by a composite indicator of eyelid aperture (reduction $2 mm), proptosis (reduction $2 mm), ocular motility (increase $8°), and Graves Ophthalmopathy– Specific Quality-Of-Life (GO-QOL) Scale score (increase $6 points). Adverse events were recorded. Moster et al: J Neuro-Ophthalmol 2023; 43: e26-e36 Results: A total of 50 participants were assigned to doxycycline and 50 to placebo. The mean (SD) age was 36.7 (9.1) years; 75 participants (75.0%) were female, and 100 (100.0%) were Asian. Medication compliance was checked during participant interviews and by counting excess tablets. At week 12, the improvement rate was 38.0% (19 of 50) in the doxycycline group and 16.0% (8 of 50) in the placebo group (difference, 22.0%; 95% CI, 5.0–39.0; P = 0.01) in the intention-to-treat population. The per-protocol sensitivity analysis showed similar results (39.6% [19 of 48] vs 16.0% [8 of 50]; difference, 23.6%; 95% CI, 6.4–40.8; P = 0.009). No adverse events other than 1 case of mild gastric acid regurgitation were recorded in either group. Conclusions and Relevance: The results of this study indicate that oral doxycycline, 50 mg daily, resulted in greater improvement of TAO-related symptoms at 12 weeks compared with placebo in patients with mild TAO. These findings support the consideration of doxycycline for mild TAO but should be tempered by recognizing the relatively short follow-up and the size of the cohort. Trial Registration: ClinicalTrials.gov Identifier: NCT02203682. COMMENTS Doxycycline for mild thyroid eye disease—A new addition to the toolbox? While strong evidence has supported the use of the IGF-1 receptor ligand teprotumumab for moderate-to-severe thyroidassociated ophthalmopathy (TAO), its cost and risk profile are such that it is not recommended for patients with mild disease (1). In fact, therapy for mild TAO is mostly conservative, including artificial tears, botulinum toxin for lid retraction, and prismatic therapy for diplopia. The antioxidant supplement selenium has been shown to reduce the clinical activity score (CAS) by 2.2 vs 1.0 in patients taking placebo over the first year (2). However, some studies evaluating the effects of selenium supplementation on populations who already have sufficient dietary intake have shown little clinical response (3). Since patients with mild TAO still can experience cosmetic deterioration, photophobia, blurriness, discomfort, and eventual deterioration towards more severe disease, expanding our options for disease-modifying therapy remains important. In this month’s issue of JAMA Ophthalmology, Pan et al (4) explored the efficacy of 50 mg of doxycycline daily in patients with mild TAO in a 5-center randomized, double masked, placebo-controlled trial. Of 100 patients with mild TAO, 50 were randomized to 50 mg of doxycycline a day and 50 to placebo with assessments at 4 and 12 weeks. A composite indicator (CI) was devised based on lid aperture (LA), proptosis, ocular motility, and Graves ophthalmopathy– specific Quality Of Life (GO-QOL). Patients were said to have improved if any one of the following criteria was achieved in the study (worse) eye, without a deterioration in the fellow eye: improvement in LA by $2 mm, a reduction in proptosis by $2 mm, an improvement in ductions by $6o, or an improvement in the GO-QOL by $6 points. At e35 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary 12 weeks, the authors found that in the intention-to-treat population, 38% of the doxycycline-treated patients demonstrated improvement in the CI as opposed to only 16% of the placebo population. Only one complication (reflux requiring omeprazole) was reported in the treatment group. The effect of doxycycline in this study did not match that seen in the selenium trial (61%); the placebo arm in that trial also improved more frequently (36%). Thus, the 2 studies are not comparable, owing perhaps to the later entry point in the Rundle curve (7 months vs 4 months) so that spontaneous improvement was more likely. The mechanism of action of doxycycline in TAO may rest on its role as an inhibitor of lymphocyte proliferation and downregulator of proinflammatory cytokines such as IL-8, TNF-a, and IL-6 (5). The encouraging results of this study, indicating a potential use of a relatively safe and cost-efficient drug for use in mild TAO, must be tempered by several limitations. First, none of the differences in the individual features used in the composite were statistically significant between the treatment and placebo group. Second, the safety and efficacy of doxycycline beyond 12 weeks remains unclear (an improvement of mild TAO would be outweighed by the development of iatrogenic pseudotumor cerebri for example). Finally, the utility of doxycycline for patients with the more severe ocular motility limitations producing diplopia that we would typically see in neuro-ophthalmology remains unclear. Effects on future clinical progression are similarly nebulous. Still, it is exciting to see a prospective, placebo trial adding to the previous literature on doxycycline and mild TAO, and I for one am eager to treat these patients with more than artificial tears and prisms. —Marc Dinkin, MD An effective, well-tolerated, inexpensive, and easily administered treatment for mild TAO would certainly enhance our current limited options. Doxycycline has anti-inflammatory as well as antimicrobial properties, and the current study showed benefit in 38% of participants receiving doxycycline 50 mg daily compared with 16% of placebo-treated patients in this doublemasked, randomized trial. The primary outcome was a composite score incorporating measures of ptosis, proptosis, ocular motility, and quality of life. Interestingly, no individual measure in the composite score was anywhere close to showing statistical superiority at either 4 or 12 weeks, with marked e36 overlap of the confidence intervals. The 6.5-year overall trial duration was also striking.until I realized that the study (apparently) did not receive any external funding or grant support (it was not mentioned either in the article or on ClinicalTrials.gov). Given the cost of doing clinical research, the investigators’ ability to conducting the trial to completion without financial support is remarkable; the funding agency/sponsor would have terminated the study much sooner for inadequate enrollment had it been performed in the United States. In summary, although the results are modest, there are few contraindications to taking doxycycline, and it is certainly worth a try in patients with mild TAO. Hopefully, no one will develop pseudotumor cerebri. —Deborah I. Friedman, MD, MPH It is a bit surprising that none of the individual parameters reached statistical significance, but it required a composite indicator to get positive results. However, it is a relatively well-tolerated drug and likely worth a try in mild cases of TED. —Mark L. Moster, MD 1. Douglas RS, Kossler AL, Abrams J, Briceño CA, Gay D, Harrison A, Lee M, Nguyen J, Joseph SS, Schlachter D, Tan J, Lynch J, Oliver L, Perry R, Ugradar S. Expert consensus on the use of teprotumumab for the management of thyroid eye disease using a modified-Delphi approach. J Neuroophthalmol. 2022;42:334–339. 2. Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, Altea MA, Nardi M, Pitz S, Boboridis K, Sivelli P, von Arx G, Mourits MP, Baldeschi L, Bencivelli W, Wiersinga W; European Group on Graves’ Orbitopathy. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med. 2011;364:1920–1931. 3. Leo M, Bartalena L, Rotondo Dottore G, Piantanida E, Premoli P, Ionni I, Di Cera M, Masiello E, Sassi L, Tanda ML, Latrofa F, Vitti P, Marcocci C, Marinò M. Effects of selenium on short-term control of hyperthyroidism due to Graves’ disease treated with methimazole: results of a randomized clinical trial. J Endocrinol Invest. 2017;40:281–287. 4. Pan Y, Chen Y, Zhang J, et al. Doxycycline vs placebo at 12 weeks in patients with mild thyroid-associated ophthalmopathy: a randomized clinical trial. 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