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Yosbelkys Martin Paez,1,2 Lucy I Mudie,1 Prem S Subramanian1– 3 1Sue Anschutz-Rodgers/UCHealth Eye Center and Departments of Ophthalmology, Aurora, CO, 80045, USA; 2Neurology, University of Colorado School of Medicine, Aurora, CO 80045, USA; 3Neurosurgery, University of Colorado School of Medicine, Aurora, CO 80045, USACorrespondence: Prem S SubramanianUniversity of Colorado School of Medicine, 1675 Aurora Court, Mail Stop F731, Aurora, CO 80045, USATel +1 720 848 2500Fax +1 720 848 5014Email prem.subramanian@cuanschutz.eduPurpose: To present a systematic review of the current body of literature surrounding spaceflight associated neuro-ocular syndrome (SANS) and highlight priorities for future research.Methods: Three major biomedical databases were searched with the following terms: ((neuro ocular) OR ((brain) AND (eye))) AND ((spaceflight) OR (astronaut) OR (microgravity)) AND (ENGLISH[Language]). Once duplicates were removed, 283 papers were left. Articles were excluded if they were not written in English or conference abstracts only. We avoided including review papers which did not provide any new information; however, two reviews on the pathophysiology of SANS were included for completeness. No limitations on date of publication were used. All included entries were then summarized for their contribution to knowledge about SANS.Results: Four main themes among the publications emerged: papers defining the clinical entity of SANS, its pathophysiology, technology used to study SANS, and publications on possible prevention of SANS. The key clinical features of SANS include optic nerve head elevation, hyperopic shifts, globe flattening, choroidal folds, and increased cerebrospinal fluid (CSF) volume in optic nerve sheaths. Two main hypotheses are proposed for the pathophysiology of SANS. The first being elevated intracranial pressure and the second compartmentalization of CSF to the globe. These hypotheses are not mutually exclusive, and our understanding of the pathophysiology of SANS is still evolving. The use of optical coherence tomography (OCT) has greatly furthered our knowledge about SANS, and with the deployment of OCT to the International Space Station, we now have ability to collect intraflight data. No effective prevention for SANS has been found, although fortunately, even with persistent anatomic and physiologic neuro-ocular changes, any functional impact has been correctable with spectacles.Conclusion: This is the first systematic review of SANS. Despite the limitations of studying a syndrome that can only occur in a small, discrete population, we present a thorough overview of the literature surrounding SANS and several key areas important for future research are identified.Keywords: subarachnoid space, cerebrospinal fluid, idiopathic intracranial hypertension, space flight, optic nerve

Dianna Liu, Franz Marie Cruz, Prem S SubramanianWilmer Eye Institute, The Johns Hopkins School of Medicine, Baltimore, Maryland, USAAbstract: A 57-year-old otherwise healthy woman presented with painless binocular vision loss 1 week after direct application of radiofrequency energy to her orbits. She had no light perception bilaterally. Pupils were dilated and not reactive to light. Fundoscopic exam initially showed optic disc swelling in the right eye and a normal-appearing disc in the left eye. Magnetic resonance imaging of the brain and orbits showed gadolinium enhancement of both intraorbital optic nerves. She underwent a course of high-dose steroid treatment without recovery of vision. Optic discs were pale 11 weeks after injury. With exclusion of other possible causes, this represents a unique case of irreversible binocular optic nerve damage and blindness secondary to radiofrequency exposure.Keywords: optic neuropathy, blindness, radiofrequency, vision loss

Traumatic strabismus may result from orbital or head injury (closed or open). Patients may have other complex injuries that delay diagnosis and treatment. Twelve consecutive adult patients with persistent (> 3 month) strabismus after combat-related head, orbital, or eye trauma underwent strabismus surgery on one or both eyes. The main outcome measures were ocular alignment and diplopia resolution at least 6 months postoperatively. Seven of 12 patients (58%) had traumatic vision loss (< 20/200) in one eye in addition to the traumatic strabismus. Strabismus procedures were complicated intraoperatively by previous ocular and orbital surgery in the majority of patients. One patient required an additional procedure to obtain a satisfactory result, and all patients achieved resolution of diplopia and/or cosmetic improvement 6 months postoperatively. Acceptable outcomes at 6 months may be obtained by using customary amounts of muscle recession and resection both horizontally and vertically. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of laser refractive surgery on night weapons firing.Methods: Firing range performance was measured at baseline and postoperatively following photorefractive keratectomy and laser in situ keratomileusis. Subjects fired the M-16A2 rifle with night vision goggles (NVG) at starlight, and with iron sight (simulated dusk). Scores, before and after surgery, were compared for both conditions.Results: No subject was able to acquire the target using iron sight without correction before surgery. After surgery, the scores without correction (95.9 +/- 4.7) matched the preoperative scores with correction (94.3 +/- 4.0; p = 0.324). Uncorrected NVG scores after surgery (96.4 +/- 3.1) exceeded the corrected scores before surgery (91.4 +/- 10.2), but this trend was not statistically significant (p = 0.063).Conclusion: Night weapon firing with both the iron sight and the NVG sight improved after surgery. This study supports the operational benefits of refractive surgery in the military. [ABSTRACT FROM AUTHOR]

Despite significant progress in the catalytic hydrogenation of nitriles, the persistent challenge of requiring additives to prevent condensation byproducts and achieve selectivity toward primary amines demands urgent attention. In this work, we present an integrated approach utilizing a ligand-bridged Ni-Ti bimetallic complex as a precursor to tune Ni 0 -NiO-NiO(OH) heterojunctions and phases of black titania (bTiO 2 ) by controlling pyrolytic conditions. This tailored phase distribution and charge dynamics across heterojunctions create an effective balance of acidic and basic sites, enabling the direct hydrogenation of nitriles to primary amines without the need for additives. However, at elevated pyrolysis temperatures, this balanced composition begins to shift, with the loss of critical phases that alter the catalyst's structural and chemical properties. This shift reduces amphoteric behavior, resulting in decreased selectivity for primary amines and favoring the formation of condensation byproducts. The catalyst's structure, amphoteric nature, crystallinity, surface area, and active sites are comprehensively characterized using high-resolution transmission electron microscopy (HR-TEM), X-ray photoelectron spectroscopy (XPS), powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR), temperature programmed desorption of ammonia (NH 3 -TPD), temperature programmed desorption of carbon dioxide (CO 2 -TPD), and CO 2 adsorption techniques. The magnetically retrievable catalyst exhibited excellent functional group tolerance, high selectivity, multiple reusability, broad substrate scope, and high activity for nitrile hydrogenation to primary amines, with the potential for advanced catalytic hydrogenation of other functional groups.

Metal-metal oxide interface catalysts are in high demand for advanced catalytic applications due to their multi-component active sites, which facilitate synergistic cooperation where a single component alone cannot effectively promote the desired reaction. Demonstrated herein graphene oxide-supported nanoscale Mn 3 O 4 -CoO-Co as highly efficient catalysts for hydrogenation of nitro styrenes/nitro arenes to amino styrenes/arenes under mild reaction conditions (0.5 MPa and 100 °C in 1 : 1 THF/water). Charge relocalization at the Co-CoO-Mn 3 O 4 heterojunction interfaces, primarily driven by Mn 3 O 4 , significantly improves reaction selectivity. Replacing Mn 3 O 4 with MnO or using other supported bimetallic CoMnO x catalysts decreases selectivity, leading to the formation of a mixture of products. The catalyst demonstrated remarkable selectivity in converting nitro groups to amines, even in the presence of highly reactive functional groups such as C=C, O-C=O, C=O, C≡N, chalcones, and halides. It also exhibited high yields, multiple reusability, and a broad substrate scope. This study demonstrates how Mn 3 O 4 , in synergy with CoO-Co, fine-tunes selectivity, paving the way for the development of advanced metal-metal oxide interface catalysts to enhance both selectivity and efficiency in organic transformations., (© 2024 Wiley-VCH GmbH.)

Competing Interests: The authors report no conflicts of interest.

Purpose of Review: Idiopathic intracranial hypertension (IIH) typically affects women of childbearing age, is associated with recent weight gain, and can result in debilitating headache as well as papilledema that can cause vision loss. There have been advances in the medical and surgical treatment of affected patients with IIH that can improve outcomes and tolerability of therapy., Recent Findings: Medical treatment with agents that lower intracranial pressure through pathways other than carbonic anhydrase inhibition are being developed, and medically-directed weight loss as well as bariatric surgery now may be considered as primary therapy. New surgical options including venous sinus stenting have shown efficacy even with cases of severe vision loss. Our treatment options for IIH patients are becoming more diverse, and individualized treatment decisions are now possible to address specific components of the patient's disease manifestations and to lead to IIH remission., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The use of neuroimaging allows the ophthalmologist to identify structural lesions in the orbit or along the neuroaxis that allow for more accurate diagnosis and treatment of patients with neuro-ophthalmic diseases. The primary imaging tools include computed tomography (CT) and magnetic resonance imaging (MRI), both of which can be used to evaluate the brain, spinal cord and canal, and orbits. Neurovascular structures, both arterial and venous, also can be imaged in high resolution with modern CT and MR angiography and CT and MR venography. In many cases, invasive procedures such as catheter angiography can be avoided with these studies, and angiography is often reserved for confirmation of vascular lesions combined with endovascular treatment. In this article, we illustrate how the evaluation of patients presenting with neuro-ophthalmic diseases involving the afferent and efferent visual pathways can be optimized with the use of appropriate diagnostic imaging studies. The complementary value of ophthalmic imaging is also demonstrated, and the advantages and disadvantages of both CT and MRI as well as their use in longitudinal patient follow up is demonstrated., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

The novel synthetic amino acid-like zwitterion containing imine bond ionic compound 2-[( E )-(2-carboxy benzylidene) amino] ethan ammonium salt, C 10 H 12 N 2 O 2, was synthesized. Computational functional characterization is now being used to predict novel compounds. Here, we report on a titled combination that has been crystallizing in orthorhombic space group Pcc2 with Z  = 4. The zwitterions form centrosymmetric dimers to polymeric supramolecular network via intermolecular N-H … O hydrogen bonds between the carboxylate groups and ammonium ion. The components are linked by ionic (N + -H-O - ) and hydrogen bonds (N + -H-O), forming a complex three-dimensional supramolecular network. Further, molecular computational docking characterization study was performed with compound against multi-disease drug target biomolecule of anticancer target molecule of HDAC8 (PDB ID 1T69) receptor and antiviral molecular target protease (PDB ID 6LU7) to evaluate the interaction stability, conformational changes and to get insights into the natural dynamics on different timescales in solution. HighlightsThe novel zwitter ionic amino acid compound 2-[( E )-(2-carboxybenzylidene) amino] ethan ammonium salt, C 10 H 12 N 2 O 2. The crystal structure determined for this compound illustrates the presence of intermolecular ionic N + -H-O - and N + -H-O hydrogen bonds between the carboxylate groups and ammonium ion, which influence the formation of a complex three-dimensional supramolecular polymeric network.Molecular docking studies helps to understand the conformational stability and interaction stabilityThe novel molecule can be considered for anticancer treatment.

Multicentric Osteolysis Nodulosis and Arthropathy (MONA) is a rare skeletal disorder driven by mutations in the MMP2 gene, leading to bone and joint degradation. This case series presents three unique MONA cases, highlighting clinical, radiological, and genetic aspects. These insights shed light on the complexities of MONA, aiding early diagnosis and multidisciplinary management. Case 1 is a 13-year-old male, born to consanguineous parents, presented with a 5-year history of progressive joint deformities, pain, and difficulty walking. Initially diagnosed as juvenile idiopathic arthritis (JIA), despite treatment, his symptoms persisted. Examination revealed multiple clinical findings, including joint contractures and nodules. Genetic analysis identified a pathogenic variant in the MMP2 gene, confirming MONA. Case 2 and Case 3 were two siblings, aged 12 and 17 years respectively, who presented progressive joint contractures in their hands and feet since early childhood. Clinical examinations revealed contractures and subcutaneous nodules. Genetic analysis confirmed MONA with a shared homozygous pathogenic MMP2 variant, emphasising the genetic basis of this rare disorder., Competing Interests: The authors declare no conflict of interest., (© 2024 The Mediterranean Journal of Rheumatology (MJR).)

Neuropsychiatric systemic lupus erythematosus (NPSLE) presents a significant diagnostic and therapeutic challenge due to its varied clinical manifestations. The prevalence of NPSLE ranges widely, reported between 37% and 95% in different case series, reflecting this condition's complex and heterogeneous nature. Here we report three cases of juvenile systemic lupus erythematosus (SLE) presenting with catatonia as a rare neuropsychiatric manifestation. Case 1 is a 15-year-old male with fever, and pancytopenia, diagnosed with SLE and subsequent development of catatonia. Case 2 is a 14-year-old female with a history of SLE presenting with altered sensorium, restlessness, and catatonia. Case 3 is a 15-year-old male with SLE exhibiting abnormal behaviour and catatonia. Treatment strategies for these cases include high-dose steroids, immunosuppression, and benzodiazepines. This case series emphasises the importance of a multidisciplinary approach, prompt diagnosis, aggressive treatment, and vigilant follow-up to optimise outcomes in these vulnerable paediatric patients. In conclusion, this case series contributes to the literature on catatonia in paediatric SLE, emphasising the need for expanded awareness, early recognition, and comprehensive management strategies. Further research is warranted to refine predictive factors and establish optimal maintenance protocols for this complex neuropsychiatric manifestation., Competing Interests: The author team has no conflict of interest to declare., (© 2024 The Mediterranean Journal of Rheumatology (MJR).)

Introduction: Thyroid eye disease (TED) is an autoimmune process characterized by extraocular muscle and orbital fat remodeling/expansion resulting in swelling, pain, redness, proptosis, and diplopia. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, demonstrated improvements in TED signs and symptoms in three adequately powered clinical trials of 24 weeks duration. Here we analyze the long-term maintenance of responses with teprotumumab from these trials. Methods: A total of 112 patients who received 7 or 8 infusions of teprotumumab in the Phase 2, Phase 3 (OPTIC study), and OPTIC Extension (OPTIC-X) studies were included in this analysis. Responses, including clinical activity score (CAS ≥2-point improvement), the European Group of Graves' Orbitopathy ophthalmic composite outcome, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), Overall (improvement in proptosis + CAS), and disease inactivation (CAS ≤1), were assessed and pooled from study baseline to week 24 (formal study) and up to week 72 (formal follow-up). Graves' Ophthalmopathy quality-of-life (GO-QoL) scores were also assessed. Outcomes included the percentages of observed patient responses from the study baseline. Additional alternative treatments for TED were assessed as a surrogate of persistent benefit from week 24 through week 120 (extended follow-up). Studies differed in the timing of follow-up visits, and data from some visits were unavailable. Results: At week 72, 52/57 (91.2%), 51/57 (89.5%), 35/48 (72.9%), 38/56 (67.9%), and 37/56 (66.1%) of patients were responders for CAS, composite outcome, diplopia, proptosis, and Overall response, respectively. The mean reduction in proptosis was 2.68 mm (SD 1.92, n = 56), mean GO-QoL improvement was 15.22 (SE 2.82, n = 56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Over 99 weeks following teprotumumab therapy, 19/106 (17.9%) patients reported additional TED therapy during formal and extended follow-up. Conclusion: The long-term response to teprotumumab as observed 51 weeks after therapy was similar to week 24 results in the controlled clinical trials. Inflammatory and ophthalmic composite outcome improvements were seen in 90% of patients with nearly 70% reporting improvement in diplopia and proptosis. Further, 82% of patients in this analysis did not report additional TED treatment (including surgery) over 99 weeks following the final teprotumumab dose.

Transition-metal-doped black titania, primarily in the anatase phase, shows promise for redox reactions, water splitting, hydrogen generation, and organic pollutant removal, but exploring other titania phases for broader catalytic applications is underexplored. This study introduces a synthetic approach using a Co-Ti bimetallic complex bridged by a 1,10-phenanthroline-5,6-dione ligand as a precursor for the synthesis of cobalt-doped black titania [Co@L2N@b-TiO 2 ]. The synthesis involves precise control of pyrolysis conditions, yielding a distinct structure dominated by the rutile phase over anatase, with active cobalt encapsulated within a nitrogen-doped graphitic layer, primarily as Co 0 rather than Co II and Co III . The synthesized material is employed for the selective hydrogenation of cinnamaldehyde (CAL) to cinnamyl alcohol (COL) under industrially viable conditions. The efficiency and selectivity of Co@L2N@b-TiO 2 was compared with other catalysts, including cobalt-doped rutile TiO 2 (Co@r-TiO 2 ), anatase TiO 2 (Co@a-TiO 2 ), and black titania (Co@b-TiO 2 ) as well as materials pyrolyzed under different atmospheres and temperatures, materials with phenanthroline ligands, and materials lacking any ligands. The superior performance of Co@L 2 N@b-TiO 2 is attributed to its high surface area, stable Co 0 within the nitrogen-doped graphitic layer, and composition of rutile and anatase phases of TiO 2 and Ti 2 O 3 (referred to as RAT), along with the synergistic interaction between RAT and Co 0 . These factors significantly influence the efficiency and selectivity of COL over hydrocinnamaldehyde (HCAL) and hydrocinnamyl alcohol (HCOL), indicating potential for broader applications beyond catalysis, particularly in designing of black titania-based materials.

Introduction: Given the traffic safety and occupational injury prevention implications associated with cannabis impairment, there is a need for objective and validated measures of recent cannabis use. Pupillary light response may offer an approach for detection., Method: Eighty-four participants (mean age: 32, 42% female) with daily, occasional, and no-use cannabis use histories participated in pupillary light response tests before and after smoking cannabis ad libitum or relaxing for 15 min (no use). The impact of recent cannabis consumption on trajectories of the pupillary light response was modeled using functional data analysis tools. Logistic regression models for detecting recent cannabis use were compared, and average pupil trajectories across cannabis use groups and times since light test administration were estimated., Results: Models revealed small, significant differences in pupil response to light after cannabis use comparing the occasional use group to the no-use control group, and similar statistically significant differences in pupil response patterns comparing the daily use group to the no-use comparison group. Trajectories of pupillary light response estimated using functional data analysis found that acute cannabis smoking was associated with less initial and sustained pupil constriction compared to no cannabis smoking., Conclusion: These analyses show the promise of pairing pupillary light response and functional data analysis methods to assess recent cannabis use., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON., Competing Interests: Declaration of interests P.Y.-W.-M., V.C., N.J.N., B.P., L.C., and T.K. received research support and/or personal compensation from Santhera Pharmaceuticals, Chiesi, and GenSight Biologics. P.Y.-W.-M. is also a consultant for Neurophth and Stoke Therapeutics. N.J.N. is also a consultant for Santhera Pharmaceutical, Chiesi, GenSight Biologics, Stoke Therapeutics, Avidity Biosciences, and Neurophoenix SAS, and has been a speaker and contributing writer for educational activities under the auspices of WebMD and First Class. P.S.S. is a consultant to GenSight Biologics and received research support from GenSight Biologics and Santhera Pharmaceuticals. M.H.L. received personal compensation from Santhera Pharmaceuticals. C.L.M. has acted as a consultant for Chiesi Farmaceutici, Regulatory PharmaNet, and Thenewway srl, and has also received speaker honoraria and/or financial support for meetings from these companies, as well as from First Class srl and Biologix. C.L.M. has also acted as a principal or study investigator for clinical trials sponsored by GenSight Biologics, Santhera Pharmaceuticals, Stoke Therapeutics, and Reneo Pharmaceuticals. C.P. received personal compensation from Novartis and has acted as an investigator in clinical trials for Santhera Pharmaceuticals, GenSight Biologics, and Iveric Bio. X.L. and L.T. are employees of Chiesi Farmaceutici S.p.A., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Background: To evaluate the classification performance of machine learning based on the 4 vessel density features of peripapillary optical coherence tomography angiography (OCT-A) for classifying healthy, nonarteritic anterior ischemic optic neuropathy (NAION), and optic neuritis (ON) eyes., Methods: Forty-five eyes of 45 NAION patients, 32 eyes of 32 ON patients, and 76 eyes of 76 healthy individuals with optic nerve head OCT-A were included. Four vessel density features of OCT-A images were developed using a threshold-based segmentation method and were integrated in 3 models of machine learning classifiers. Classification performances of support vector machine (SVM), random forest, and Gaussian Naive Bayes (GNB) models were evaluated with the area under the receiver-operating-characteristic curve (AUC) and accuracy., Results: We divided 121 images into a 70% training set and 30% test set. For ON-NAION classification, best results were achieved with 50% threshold, in which 3 classifiers (SVM, RF, and GNB) discriminated ON from NAION with an AUC of 1 and accuracy of 1. For ON-Normal classification, with 100% threshold, SVM and RF classifiers were able to discriminate normal from ON with AUCs of 1 and accuracies of 1. For NAION-normal classification, with 50% threshold, the SVM and RF classified the NAION from normal with AUC and accuracy of 1., Conclusions: ML based on the combined peripapillary vessel density features of total vessels and capillaries in the whole image and ring image could provide excellent performance for NAION and ON distinction., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

Context: Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials., Objective: We present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED., Methods: This randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed., Results: A total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (-2.41 [0.228]) than with placebo (-0.92 [0.323]), difference -1.48 (95% CI -2.28, -0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths., Conclusion: Teprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Competing Interests: The authors report no conflicts of interest.

Competing Interests: The authors report no conflicts of interest.

Competing Interests: The authors report no conflicts of interest.

Purpose of Review: Spaceflight-associated neuro-ocular syndrome (SANS) remains a phenomenological term, and advances in ophthalmic imaging as well as new insights from ground-based experiments have given support to new theories of how SANS develops and what may be done to counter it., Recent Findings: SANS has been postulated to arise from elevated intracranial pressure (ICP) during long-duration spaceflight (LDSF). However, recent work has shown that acute microgravity exposure does not increase ICP, and the effect of cephalad fluid shifts on ICP in microgravity remain unknown. In addition, structural imaging of the retina and optic nerve show changes after LDSF that are distinct from findings in terrestrial patients with elevated ICP. Since astronauts have not reported symptoms that would be expected with chronic ICP elevation, new theories that orbital and/or intracranial venous pressure may be the primary contributors to the development of SANS., Summary: Research has been filling knowledge gaps that exist regarding the cause(s) of SANS, and these advances are crucial steps in the effort to design countermeasures that will be required before human deep space exploration missions can be undertaken., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Teprotumumab, an inhibitor of the insulin-like growth factor 1 receptor (IGF-1R), was approved by the US Food and Drug Administration in January 2020 for the treatment of thyroid eye disease (TED). The clinical trials leading to its approval enrolled patients with recent disease onset and significant inflammatory symptoms and signs. Subsequent real-world teprotumumab use in patients with longer duration of disease also may be effective, and there have been several publications reporting on experience in these patient groups., Recent Findings: TED results in disfiguring changes such as ocular proptosis and affects visual function by altering extraocular muscle function, leading to diplopia. Compressive optic neuropathy also may occur, and disease manifestations may persist for years. Teprotumumab treatment in cases of TED in which prior interventions (medical or surgical) had failed, or in treatment-naïve patients whose disease had been stable for years, has been reported to improve both clinical signs and symptoms (proptosis, diplopia) and to reduce the pathologic orbital changes as assessed by orbital imaging., Summary: Teprotumumab may be an appropriate treatment for TED regardless of disease duration and irrespective of the presence or absence of markers of active inflammation within the orbit., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Purpose: A deep learning framework to differentiate glaucomatous optic disc changes due to glaucomatous optic neuropathy (GON) from non-glaucomatous optic disc changes due to non-glaucomatous optic neuropathies (NGONs)., Design: Cross-sectional study., Method: A deep-learning system was trained, validated, and externally tested to classify optic discs as normal, GON, or NGON, using 2183 digital color fundus photographs. A Single-Center data set of 1822 images (660 images of NGON, 676 images of GON, and 486 images of normal optic discs) was used for training and validation, whereas 361 photographs from 4 different data sets were used for external testing. Our algorithm removed the redundant information from the images using an optic disc segmentation (OD-SEG) network, after which we performed transfer learning with various pre-trained networks. Finally, we calculated sensitivity, specificity, F1-score, and precision to show the performance of the discrimination network in the validation and independent external data set., Results: For classification, the algorithm with the best performance for the Single-Center data set was DenseNet121, with a sensitivity of 95.36%, precision of 95.35%, specificity of 92.19%, and F1 score of 95.40%. For the external validation data, the sensitivity and specificity of our network for differentiating GON from NGON were 85.53% and 89.02%, respectively. The glaucoma specialist who diagnosed those cases in masked fashion had a sensitivity of 71.05% and a specificity of 82.21%., Conclusions: The proposed algorithm for the differentiation of GON from NGON yields results that have a higher sensitivity than those of a glaucoma specialist, and its application for unseen data thus is extremely promising., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Severe burn patients require high-volume fluid resuscitation, which increases risk for orbital compartment syndrome (OCS). We aimed to understand surgeons' practice patterns and to examine risk factors for OCS, timing of lateral canthotomy and cantholysis (LCC), and complications of intervention., Methods: A survey of American Society of Ophthalmic Plastic and Reconstructive Surgery and North American Society of Academic Orbital Surgeons' practice patterns in burn patients was undertaken. In addition, a retrospective analysis was conducted of 107 patients with burns greater than 20% total body surface area at 1 institution from January 1, 2009, to June 1, 2018. Patients with Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis, frostbite, or no ophthalmologic consultation were excluded. Risk factors for OCS, timing of LCC, and complications of the intervention were examined., Results: In the survey, 37 of 54 respondents had treated burn patients, of which 29 followed no protocol. Threshold intraocular pressure for intervention varied widely, and nearly all reported having seen complications from LCC in burn patients. For the retrospective analysis, 107 patients met criteria, of which 22 (20.6%) required LCC. Renal failure, inhalation injury, eyelid burns, higher total body surface area, elevated lactate, increased number of escharotomies, and greater total fluid required were significantly associated with the clinical decision that the patient was at risk for OCS requiring LCC. Fluid resuscitation in excess of the Ivy Index (250 ml/kg) increased odds of LCC 8.6 times. Average time of LCC was 15.8 hours after burn. LCC patients experienced higher rates of complications including eyelid retraction, exposure keratopathy, and corneal ulceration., Conclusions: Severe burn patients should be monitored closely by an ophthalmologist during the first 48 hours for signs of OCS. Further studies should aim to recommend protocols guiding evaluation and intervention., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2022 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Herein, we disclose a selective, versatile, accessible, cost-effective and highly efficient cation-exchange industrial grade INDION 130 resin as a reusable catalyst for the synthesis of 3-substituted isoindolinones from various γ-hydroxy lactams and a variety of C, N, O, and S nucleophiles involving N-acyliminium ion intermediates under mild reaction conditions. Mechanistic studies suggested the generation of a different kind of kinetically and thermodynamically controlled intermediates/eliminated products, which further converted to their corresponding products depending upon the nucleophile, reaction parameter and nitrogen substitution (benzyl vs. aryl) of the substrate (succinamidals vs. phthalimidals). The easy synthesis, efficient reactivity and selectivity, broad substrate scope with verities of C, N, O, and S nucleophiles, and efficient recycling make the catalyst and the protocol economical and sustainable., (© 2023 Wiley-VCH GmbH.)

Competing Interests: The authors report no conflicts of interest.

Purpose: To evaluate the safety profile of lenadogene nolparvovec (Lumevoq) in patients with Leber hereditary optic neuropathy., Design: Pooled analysis of safety data from 5 clinical studies., Methods: A total of 189 patients received single unilateral or bilateral intravitreal injections of a recombinant adeno-associated virus 2 (rAAV2/2) vector encoding the human wild-type ND4 gene. Adverse events (AEs) were collected throughout the studies, up to 5 years. Intraocular inflammation and increased intraocular pressure (IOP) were ocular AEs of special interest. Other assessments included ocular examinations, vector bio-dissemination, and systemic immune responses against rAAV2/2., Results: Almost all patients (95.2%) received 9 × 10 10 viral genomes and 87.8% had at least 2 years of follow-up. Most patients (75.1%) experienced at least one systemic AE, but systemic treatment-related AEs occurred in 3 patients; none were serious. Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all intraocular inflammations occurred in the anterior chamber (58.8%) or in the vitreous (40.3%), and were of mild (90.3%) or moderate (8.8%) intensity; most resolved with topical corticosteroids alone. All IOP increases were mild to moderate in intensity. No AE led to study discontinuation. Bio-dissemination of lenadogene nolparvovec and systemic immune response were limited. The safety profile was comparable for patients treated bilaterally and unilaterally., Conclusions: Lenadogene nolparvovec had a good overall safety profile with excellent systemic tolerability, consistent with limited bio-dissemination. The product was well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A significant role of the neuro-ophthalmologist is to counsel patients on appropriate management and anticipated visual prognosis for conditions affecting the afferent and efferent visual systems, including those requiring neurosurgical treatment. However, the literature regarding anticipated neuro- ophthalmologic prognosis after neurosurgical intervention for cerebral aneurysms, sellar lesions, optic pathway tumors, and elevated intracranial pressure is limited with many key questions unanswered. For example, if a cerebral aneurysm is equally amenable to clipping or endovascular coiling, is there a preferred approach in terms of visual prognosis based on aneurysm location? Is dural venous sinus stenting (VSS) for idiopathic intracranial hypertension (IIH) superior, equivalent or inferior to shunting in terms of visual recovery and safety profile? Landmark studies on pituitary tumors using pre-operative optical coherence tomography (OCT) imaging of the optic nerve head to predict visual recovery after surgical decompression of the optic chiasm have changed neuro-ophthalmologic practice and enabled patients to be better informed regarding expected visual outcomes. 1,2 In order to optimize an interdisciplinary team approach to patient care, further studies of visual outcomes for neuro- ophthalmologic conditions requiring neurosurgical intervention are needed., Competing Interests: AL: National Football League consultant, NASA consultant, US Department of Justice consultant, Horizon speakers bureau and advisory board, AstraZeneca consultant, Bristol Meyers Squibb consultant PS: Invex Therapeutics consultant and researcher, hold patent for intranasal prostaglandin analogues to lower intracranial pressure SM: Invex Therapeutics consultant, Velux Foundation consultant, Gensight advisory board, Invex Therapeutics advisory board, Heidelberg engineering speaker fees, Chugai-Roche Ltd. speaker fees, Saten speaker fees, Chiesi speaker fees The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Williams, Lee, Fraser, Falardeau, Subramanian, Chen, Al Othman, Dinkin, Mollan, Al-Zubidi and Vates.)

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids ( days-to-Rx ). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON., Trial Registration: ClinicalTrials.gov, identifier: NCT05605951., Competing Interests: SA has received speaker honoraria from Alexion, Bayer, and Roche. JB reports payment for consultation from Horizon Therapeutics, Alexion, Antigenomycs, BeiGene, Chugai, Clene Nanomedicine, Genentech, Reistone Bio, Roche, Imcyse, and TG; grants from Alexion, Novartis, and the National Institutes of Health. In addition, JB has a patent on Compositions and methods for the treatment of neuromyelitis optica. YB has received speaker honoraria from Novartis, Roche, Genzyme-Sanofi, Merck, and Biogen. EC has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen Argentina, Genzyme Argentina, Merck Argentina and LATAM, Roche Argentina and LATAM, Raffo, Novartis Argentina, LACTRIMS, and The Guthy-Jackson Charitable Foundation. JC has served on advisory boards for Horizon, Roche, and UCB. CC has received honoraria for speaking from Bayer and research funding from Novartis. JD has received royalties from Wolters Kluwer, Neurology—UpToDate and from Medlink Neurology as contributing author, from Athena Diagnostics for the use of Ma2 as an autoantibody test, and from Euroimmun for the use of NMDA-receptor, GABA(B)-receptor, GABA(A)-receptor, DPPX, and IgLON5 as autoantibody tests and has received research support from Advance Medical (allosteric modulation of NMDAR) SAGE Therapeutics, Instituto Carlos III/FEDER (FIS PI20/00197, CIBERER CB15/00010, Proyectos Integrados de Excelencia, PIE 16/00014 and AC18/00009), Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR), CERCA Programme Generalitat de Catalunya, ERA-NET NEURON, La Caixa Foundation Health Research Award, Pablove Foundation Childhood Cancer Grant, Safra Foundation, Sage therapeutics, Cellex Foundation, and La Caixa Health Foundation. EF has served on advisory boards for Alexion, Genentech, Horizon Therapeutics, and UCB. He has received speaker honoraria from Pharmacy Times. He received royalties from up-to-date. EF was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. EF has received funding from the NIH (R01NS113828). EF is a member of the medical advisory board of the MOG project. EF is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity. CF participates in a regional medical board advisory of Alexion. CG-A has received grants from Biogen Colombia. JH reports grants for OCT research from the Friedrich-Baur-Stiftung and Merck, personal fees, and non-financial support from Celgene, Janssen, Bayer, Merck, Alexion, Horizon, Novartis, Roche, Biogen, and non-financial support of the Guthy-Jackson Charitable Foundation, all outside the submitted work. JH was partially funded by the German Federal Ministry of Education and Research [(DIFUTURE), Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H]]. HK has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, Aprilbio, Altos Biologics, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, Handok, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, MDimune, Mitsubishi Tanabe Pharma, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva-Handok, and UCB; and is a coeditor for the Multiple Sclerosis Journal and an associated editor for the Journal of Clinical Neurology. CLM reports consultancy fees for Chiesi Farmaceutici, Regulatory PharmaNet, and Thenewway Srl and received speaker honoraria and/or travel support for meetings from Santhera Pharmaceuticals, Chiesi Farmaceutici, Regulatory Pharma Net, Thenewway Srl, First Class Srl, and Biologix. ML-P has received funding for travel and speaker honoraria from Novartis, Biogen, and Roche. MLei was funded by NHS (Myasthenia and Related Disorders Service and National Specialized Commissioning Group for Neuromyelitis Optica, UK) and by the University of Oxford, UK. She has been awarded research grants from the UK association for patients with myasthenia—Myaware and the University of Oxford. She has received speaker honoraria or travel grants from Biogen Idec, Novartis, Argenx, UCB, and the Guthy–Jackson Charitable Foundation. MLei serves on scientific or educational advisory boards for UCB Pharma, Argenx, and Viela/Horizon. SL has received consulting fees and speaker honoraria from Biogen, Novartis, TEVA, Genzyme, Sanofy, and Merck. PL has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen Argentina and LATAM, Genzyme Argentina, Merck Argentina, Roche Argentina, Novartis Argentina, and LACTRIMS. AL has served as a Biogen, Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi/Genzyme, and Teva Advisory Board Member, has received congress and travel/accommodation expense compensations, or speaker honoraria from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva, and Fondazione Italiana Sclerosi Multipla (FISM), her institutions received research grants from Novartis and Sanofi/Genzyme. SMo reports consultancy fees (Invex Therapeutics); advisory board fees (Invex therapeutics, Gensight); and speaker fees (Heidelberg engineering, Chugai-Roche Ltd., Allergan, Santen, Chiesi, and Santhera), all outside the submitted work. RM serves on scientific advisory boards for Alexion, Horizon Therapeutics, Roche, and UCB has received speaker honoraria from Alexion, Biogen, Horizon Therapeutics, Novartis, Roche, and Sanofi Genzyme, has received support for attending scientific meetings by Merck and Euroimmun, has received speaker honoraria from Biogen and Novartis. SMa received speaker honoraria for presenting at scientific meetings by Novartis and Biogen. SMo reports consultancy fees (Invex Therapeutics); advisory board fees (Invex therapeutics, Gensight); and speaker fees (Heidelberg engineering, Chugai-Roche Ltd., Allergan, Santen, Chiesi, and Santhera). All outside the submitted work. FC receives ongoing research support from the National Multiple Sclerosis Society (NMSS), the American Academy of Neurology (AAN), and Deutsche Gesellschaft für Neurologie (DGN). JPa has received support for scientific meetings and honorariums for advisory work from Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen, and Sanofi. Grants from Alexion, Roche, Medimmune, UCB, and Amplo biotechnology. Patent ref P37347WO and license agreement Numares multimarker MS diagnostics Shares in AstraZeneca. Acknowledges Partial funding by Highly specialized services NHS England. SP is a named inventor on filed patents that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker, was consulted for Alexion and MedImmune, has received research support from Grifols, MedImmune, and Alexion, all compensation for consulting activities is paid directly to Mayo Clinic. SR has received research funding from the National Health and Medical Research Council (Australia), the Petre Foundation, the Brain Foundation (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She was supported by an NHMRC Investigator Grant (GNT2008339). She serves as a consultant on an advisory board for UCB and Limbic Neurology and has been an invited speaker for Biogen, Excemed, and Limbic Neurology. AS received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck-Serono, Sanofi, Biogen, Roche, Novartis, Alexion, Janssen, and Horizon Therapeutics. DS received a grant from the National Multiple Sclerosis Society and serves on several advisory committees for the Multiple Sclerosis International Federation in unpaid roles. MS received speaker honoraria from Teva Pharmaceuticals and has received funding from the German Research Foundation, Federal Ministry of Education and Research and Federal Ministry for Economic Affairs and Energy, Volkswagen Stiftung, and Berlin Institute of Health. He is holding patents for the 3D printing of computed tomography models and is a shareholder of PhantomX and MSC3D. All unrelated to this work. PSu has served on advisory boards for Horizon Therapeutics, Viridian Therapeutics, Invex Therapeutics, Kriya Therapeutics, and GenSight Biologics. He receives research support from the NIH, DOD, Horizon, Invex, and Viridian. AM has received a grant for Biopas Laboratories and reports speaking fees from Chiesi. HZ received research grants from Novartis and speaking fees from Bayer Healthcare, unrelated to this project. FP served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS. HS-K received speaker honoraria from Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Asseyer, Asgari, Bennett, Bialer, Blanco, Bosello, Camos-Carreras, Carnero Contentti, Carta, Chen, Chien, Chomba, Dale, Dalmau, Feldmann, Flanagan, Froment Tilikete, Garcia-Alfonso, Havla, Hellmann, Kim, Klyscz, Konietschke, La Morgia, Lana-Peixoto, Leite, Levin, Levy, Llufriu, Lopez, Lotan, Lugaresi, Marignier, Mariotto, Mollan, Ocampo, Cosima Oertel, Olszewska, Palace, Pandit, Peralta Uribe, Pittock, Ramanathan, Rattanathamsakul, Saiz, Samadzadeh, Sanchez-Dalmau, Saylor, Scheel, Schmitz-Hübsch, Shifa, Siritho, Sperber, Subramanian, Tiosano, Vaknin-Dembinsky, Mejia Vergara, Wilf-Yarkoni, Zarco, Zimmermann, Paul and Stiebel-Kalish.)

Introduction: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to 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 four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to 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 to natural history. Mean improvement versus 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 to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 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) versus 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 to unilateral injection., Conclusion: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to 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); NCT03293524 (REFLECT); NCT03295071 (REALITY)., (© 2022. The Author(s).)

Optometric visual rehabilitation therapy has been used for a variety of visual disorders. Descriptively named entities such as posttrauma visual syndrome, visual midline shift syndrome, and vertical heterophoria syndrome are frequently diagnosed by neuro-optometrists and/or behavioral optometrists in patients after stroke or head injury or in the setting of dizziness and/or headache. The scientific underpinnings of these diagnoses and treatments are weak, and published clinical studies comprise case reports and case series without comparison to control populations. Neuro-ophthalmologists are frequently questioned by patients about the utility of such treatment strategies. Many ophthalmologists and neurologists also are involved in the care of patients who carry these diagnoses and undergo these visual therapies. Involved physicians may benefit from guidance about the rationale, evidence, and level of evidence for the efficacy of these therapeutic approaches., (© 2022 American Academy of Neurology.)

This work aims at determining the ability of a deep learning (DL) algorithm to measure retinal nerve fiber layer (RNFL) thickness from optical coherence tomography (OCT) scans in anterior ischemic optic neuropathy (NAION) and demyelinating optic neuritis (ON). The training/validation dataset included 750 RNFL OCT B-scans. Performance of our algorithm was evaluated on 194 OCT B-scans from 70 healthy eyes, 82 scans from 28 NAION eyes, and 84 scans of 29 ON eyes. Results were compared to manual segmentation as a ground-truth and to RNFL calculations from the built-in instrument software. The Dice coefficient for the test images was 0.87. The mean average RNFL thickness using our U-Net was not different from the manually segmented best estimate and OCT machine data in control and ON eyes. In NAION eyes, while the mean average RNFL thickness using our U-Net algorithm was not different from the manual segmented value, the OCT machine data were different from the manual segmented values. In NAION eyes, the MAE of the average RNFL thickness was 1.18 ± 0.69 μm and 6.65 ± 5.37 μm in the U-Net algorithm segmentation and the conventional OCT machine data, respectively (P = 0.0001)., (© 2022. The Author(s).)

Background: Unrecognized neurodegenerative diseases (NDD) in age-related eye disease research studies have the potential to confound vision-specific quality of life and retinal optical coherence tomography (OCT) outcome measures. The aim of this exploratory study was to investigate relationships between NDD screening tools and visual outcome measures in a small cohort of controls from the Colorado Age-Related Macular Degeneration Registry (CO-AMD), to consider the utility of future studies., Methods: Twenty-nine controls from the CO-AMD were screened using the Montreal Cognitive Assessment (MoCA), a Colorado Parkinsonian Checklist, and the Lewy Body Composite Risk Score. Univariate and multivariable linear regression modeling was used to assess associations between screening tools and the National Eye Institute Visual Function Questionnaire-25 (VFQ-25) and macular OCT outcome measures, and t tests were used to evaluate outcome measure differences between those with normal vs abnormal MoCA scores., Results: One patient withdrew. The average age was 72.8 years, and 68% were female patients. Ten participants (36%) had abnormal MoCA scores, and their VFQ-25 scores were only 1 point less and not statistically different than those with normal MoCA scores. Macular OCT volumes and thicknesses for retinal nerve fiber layer (RNFL) and retinal ganglion cell layer were consistently and moderately lower for those with abnormal MoCA scores, and a positive association between MoCA and macular RNFL volume was observed, although differences and regression were not significant. Parkinson screening tests were abnormal for only 4 participants and were not associated with OCT or VFQ-25 measures by regression modeling., Conclusions: Given the degree and direction of observed differences, further investigation is warranted regarding the relationship between cognitive screening tools and macular OCT measures in age-related eye disease research, but future investigations regarding the relationship between NDD screening tools and VFQ-25 seem unwarranted., (Copyright © 2022 by North American Neuro-Ophthalmology Society.)