Pearls & Oy-sters: A Challenging Optic Neuropathy-What Not to Miss in Optic Nerve Sheath Enhancement.

Optic neuropathies include a wide range of disorders from ischemic, toxic, demyelinating, or inflammatory processes with acute/subacute onset to more gradual compressive or genetic etiologies. Accurate clinical history and multimodality optic nerve imaging including MRI and optical coherence tomography have greatly improved the diagnosis of patients with optic neuropathies. We report a case of a woman with severe monocular visual acuity deficit. Optic nerve sheath enhancement seen on MRI led to a broad differential diagnosis including demyelinating causes, optic nerve sheath meningioma (ONSM), tuberculosis, and sarcoid optic neuropathy. Lack of response to treatment with steroids or plasmapheresis led to biopsy, which confirmed the diagnosis of ONSM.

[INTERVENTIONAL GLAUCOMA - A SHIFT IN THE TREATMENT PARADIGM].

INTRODUCTION: Glaucoma is a progressive optic neuropathy and is the leading cause of preventable irreversible blindness worldwide. Glaucoma causes progressive visual field loss and can have significant implications on the patient's quality of life. Lowering intraocular pressure (IOP) is the only treatment proven to prevent vision loss from glaucoma. It is achieved using medication, laser treatment and surgery. The treatment paradigm of glaucoma has been one whereby surgical intervention has been left for advanced cases due to a variety of reasons, mainly concerning safety and long term success. The past two decades have seen a paradigm shift towards earlier IOP lowering interventions using a wide array of different technologies in the laser and surgical spaces. This review aims to understand the background to this paradigm shift, its necessity, and its potential impact on the vision and life of glaucoma patients.

Racial Differences in Diagnostic Accuracy of Retinal Nerve Fiber Layer Thickness in Primary Open-Angle Glaucoma.

Purpose: To evaluate the diagnostic accuracy of retinal nerve fiber layer thickness (RNFLT) by spectral-domain optical coherence tomography (OCT) in primary open-angle glaucoma (POAG) in eyes of African (AD) and European descent (ED). Design: Comparative diagnostic accuracy analysis by race. Participants: 379 healthy eyes (125 AD and 254 ED) and 442 glaucomatous eyes (226 AD and 216 ED) from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. Methods: Spectralis (Heidelberg Engineering GmbH) and Cirrus (Carl Zeiss Meditec) OCT scans were taken within one year from each other. Main Outcome Measures: Diagnostic accuracy of RNFLT measurements. Results: Diagnostic accuracy for Spectralis-RNFLT was significantly lower in eyes of AD compared to those of ED (area under the receiver operating curve [AUROC]: 0.85 and 0.91, respectively, P=0.04). Results for Cirrus-RNFLT were similar but did not reach statistical significance (AUROC: 0.86 and 0.90 in AD and ED, respectively, P =0.33). Adjustments for age, central corneal thickness, axial length, disc area, visual field mean deviation, and intraocular pressure yielded similar results. Conclusions: OCT-RNFLT has lower diagnostic accuracy in eyes of AD compared to those of ED. This finding was generally robust across two OCT instruments and remained after adjustment for many potential confounders. Further studies are needed to explore the potential sources of this difference.

Tocilizumab use for optic nerve compression in thyroid eye disease: a prospective longitudinal cohort.

PURPOSE: To assess the effectiveness of tocilizumab in reverting the signs and symptoms of dysthyroid optic neuropathy (DON) in thyroid eye disease and the need for emergency orbital decompression. The secondary outcomes are to identify the optimal number of tocilizumab cycles to achieve the primary outcome, to analyze the association between thyroid stimulating immunoglobulin (TSI), clinical activity score (CAS) and proptosis in response to the treatment and the need for rehabilitative orbital decompression. METHODS: Prospective longitudinal cohort study that included 13 patients who had unilateral or bilateral dysthyroid optic neuropathy (DON) due to severe and progressive sight-threatening thyroid eye disease based on the CAS system. Patients were seen in this facility starting from July 2017, and all had received intravenous tocilizumab. RESULTS: Initial visual acuity mean was 0.52 ± 0.38 and the final were 0.93 ± 0.11 with a mean difference of 0.41 and P < 0.00245. The mean CAS prior to the initiation of the treatment was 7.92 ± 0.66 and the final was 2.85 ± 1.03 with mean difference of 5.07 and P < 0.00001. Initial mean proptosis was 24.85 ± 2.31 and the final was 21.78 ± 2.18 with a mean difference of 3.07 and P < 0.000497. No emergency orbital decompression was performed. TSI was high initially in all cases with a wide range of 2.4 to 40 IU/L and with a mean of 10.70 ± 13.40. The final TSI mean was 2.90 ± 3.90 with a mean difference of 7.81 and significant P value (P < 0.0272). CONCLUSION: Tocilizumab use in optic nerve compression showed promising results as it can be the primary or an alternative treatment option.

TGFß Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage.

Purpose: Mutations in the genes encoding type IV collagen alpha 1 (COL4A1) and alpha 2 (COL4A2) cause a multisystem disorder that includes ocular anterior segment dysgenesis (ASD) and glaucoma. We previously showed that transforming growth factor beta (TGFß) signaling was elevated in developing anterior segments from Col4a1 mutant mice and that reducing TGFß signaling ameliorated ASD, supporting a role for the TGFß pathway in disease pathogenesis. Here, we tested whether altered TGFß signaling also contributes to glaucoma-related phenotypes in Col4a1 mutant mice. Methods: To test the role of TGFß signaling in glaucoma-relevant phenotypes, we genetically reduced TGFß signaling using mice with mutated Tgfbr2, which encodes the common receptor for all TGFß ligands in Col4a1+/G1344D mice. We performed slit-lamp biomicroscopy and optical coherence tomography for qualitative and quantitative analyses of anterior and posterior ocular segments, histological analyses of ocular tissues and optic nerves, and intraocular pressure assessments using rebound tonometry. Results: Col4a1+/G1344D mice showed defects of the ocular drainage structures, including iridocorneal adhesions, and phenotypes consistent with glaucomatous neurodegeneration, including thinning of the nerve fiber layer, retinal ganglion cell loss, optic nerve head excavation, and optic nerve degeneration. We found that reducing TGFß receptor 2 (TGFBR2) was protective for ASD, ameliorated ocular drainage structure defects, and protected against glaucomatous neurodegeneration in Col4a1+/G1344D mice. Conclusions: Our results suggest that elevated TGFß signaling contributes to glaucomatous neurodegeneration in Col4a1 mutant mice.

Afectación iatrogénica de la motilidad ocular por fármacos antitumorales inhibidores de los puntos de control / Iatrogenic impairment of ocular motility by immune checkpoint inhibitors

Se encontraron 4 revisiones sistemáticas que incluían este tipo de iatrogenia ocular, así como numerosos reportes de casos aislados. Los efectos adversos reportados comprenden: paresias oculomotoras, neuropatía óptica, atrofia óptica, síndromes miasteniformes, pseudo-orbitopatía tiroidea, síndrome del ápex orbitario e hipofisitis. La mayoría se manejaron sin interrupción o con interrupción parcial del tratamiento oncológico. Se requirieron tratamientos sistémicos agresivos para el manejo adecuado de la iatrogenia ocular.Es imprescindible que el oftalmólogo se familiarice con los nuevos tratamientos oncológicos ICI, capaces de provocar iatrogenia sobre la motilidad ocular grave e incapacitante para el paciente. La comunicación de efectos adversos con los tratamientos empleados puede ayudar al manejo más adecuado de estos pacientes. La investigación debe ir orientada al diagnóstico diferencial complejo y a optimizar las decisiones sobre los tratamientos oncológicos. (AU)

Cancer therapy relies on new antitumoral drugs called immune checkpoint inhibitors (ICI), which produce long-lasting anti-tumor responses and lengthen survival, but cause autoimmune-type toxicity. The clinical characteristics induced by ICI are not well characterized to date and careful collection of clinical data is required to accurately define its safety profile.We conducted a literature search in the main clinical search engines to identify pharmacological ocular iatrogenic events of ICIs related to ocular motility. Four systematic reviews were found that included this type of ocular iatrogenesis as well as numerous isolated case reports. Reported adverse effects include: oculomotor paresis, optic neuropathy, optic atrophy, myastheniform syndromes, thyroid pseudo-orbitopathy, orbital apex syndrome, and hypophysitis. Most were managed without interruption or with partial interruption of cancer treatment. Aggressive systemic treatments were required for adequate management of ocular iatrogenic events.It is essential that the ophthalmologist become familiar with the new ICI oncological treatments, capable of causing severe and disabling motilidad ocular iatrogenesis for the patient. The communication of adverse effects and the report of the treatments used can help the most appropriate management of these patients. Research should be oriented towards complex differential diagnosis and to optimize decisions on cancer treatments. (AU)

Longitudinal changes in optic disc cupping from the baseline in chiasmal lesion optic neuropathy and glaucoma.

We aimed to investigate the changes in cupping in chiasmal lesion optic neuropathy (chON) compared to baseline optic disc and glaucoma. We used a novel study design to enroll patients who had fundus photographs incidentally taken during routine health check-ups prior to the onset of optic neuropathy. In 31 eyes (21 patients) with chON and 33 eyes (30 patients) with glaucoma, we investigated the change in cup-to-disc (C/D) area from the baseline to overt cupping using flicker analysis. Compared to the baseline, 23 eyes (74.2%) had increased cup size and 3 (9.7%) had vascular configuration changes in the chONgroup; in contrast, all glaucoma eyes exhibited changes in cup size and vascular configuration. The increase in C/D area ratio was significantly smaller in chON (0.04 ± 0.04) compared to glaucoma (0.10 ± 0.04, P < 0.001); the minimum residual neuroretinal rim width showed a more pronounced difference (29.7 ± 8.2% vs 7.1 ± 3.9%, P < 0.001). The changes distributed predominantly towards the nasal direction in chON, contrasting the changes to the arcuate fibers in glaucoma. In conclusion, our results provide the first longitudinal evidence of true pathological cupping in chONcompared to photographically disease-free baseline. The marked difference in the residual minimum rim width reaffirms the importance of rim obliteration in the differential diagnosis between the two diseases.

[Paying attention to neuropathic changes in high myopia].

The incidence of myopia is high in China. The proportion of high myopia is also high in the myopic population. High myopia is associated with multiple fundus changes, among which the neuropathic damage is usually ignored, and thus there has been limited clinical research on the pathogenesis, standard follow-up and effective treatment of optic neuropathy in high myopia. This article focuses on the types of high myopia-associated neuropathic changes, the quantitive imaging of neuropathic damage, and the need of relevant cohort studies and pathogenesis research, aiming to attract more attention to optic neuropathic changes in high myopia.

Is Glaucoma a Two-Pressure-Related Optic Neuropathy? A Systematic Review and Meta-Analysis.

Objectives: To review the current literature related to the correlation between translaminar pressure difference (TLPD) and glaucoma. Materials and Methods: In this article, we conducted a literature review using MEDLINE via PubMed, Cochrane Eyes and Vision, and Google Scholar from 01/01/2010 to 31/12/2022. Search terms included "glaucoma", "intraocular pressure", "translaminar cribrosa pressure gradient/difference", "intracranial pressure", and "cerebrospinal fluid pressure". Of 471 results, 8 articles were selected for the meta-analysis. Results: Our meta-analysis demonstrated significantly higher intraocular pressure, lower cerebrospinal fluid pressure (CSFp), and greater TLPD in high-tension and normal-tension glaucoma groups compared to healthy groups. Conclusion: The differences in CSFp and TLPD between glaucoma and healthy people detected in current studies suggests a potential relationship between TLPD and glaucoma.

Comparison of Brn3a and RBPMS Labeling to Assess Retinal Ganglion Cell Loss During Aging and in a Model of Optic Neuropathy.

Purpose: Retinal ganglion cell (RGC) loss provides the basis for diagnosis and stage determination of many optic neuropathies, and quantification of RGC survival is a critical outcome measure in models of optic neuropathy. This study examines the accuracy of manual RGC counting using two selective markers, Brn3a and RBPMS. Methods: Retinal flat mounts from 1- to 18-month-old C57BL/6 mice, and from mice after microbead (MB)-induced intraocular pressure (IOP) elevation, are immunostained with Brn3a and/or RBPMS antibodies. Four individuals masked to the experimental conditions manually counted labeled RGCs in three copies of five images, and inter- and intra-person reliability was evaluated by the intraclass correlation coefficient (ICC). Results: A larger population (approximately 10% higher) of RGCs are labeled with RBPMS than Brn3a antibody up to 6 months of age, but differences decrease to approximately 1% at older ages. Both RGC-labeled populations significantly decrease with age. MB-induced IOP elevation is associated with a significant decrease of both Brn3a- and RBPMS-positive RGCs. Notably, RGC labeling with Brn3a provides more consistent cell counts than RBPMS in interpersonal (ICC = 0.87 to 0.11, respectively) and intra-personal reliability (ICC = 0.97 to 0.66, respectively). Conclusions: Brn3a and RBPMS markers are independently capable of detecting significant decreases of RGC number with age and in response to IOP elevation despite RPBMS detecting a larger number of RGCs up to 6 months of age. Brn3a labeling is less prone to manual cell counting variability than RBPMS labeling. Overall, either marker can be used as a single marker to detect significant changes in RGC survival, each offering distinct advantages.

Trends in the Prevalence of Common Retinal and Optic Nerve Diseases in China: An Artificial Intelligence Based National Screening.

Purpose: Retinal and optic nerve diseases have become the primary cause of irreversible vision loss and blindness. However, there is still a lack of thorough evaluation regarding their prevalence in China. Methods: This artificial intelligence-based national screening study applied a previously developed deep learning algorithm, named the Retinal Artificial Intelligence Diagnosis System (RAIDS). De-identified personal medical records from January 2019 to December 2021 were extracted from 65 examination centers in 19 provinces of China. Crude prevalence and age-sex-adjusted prevalence were calculated by mapping to the standard population in the seventh national census. Results: In 2021, adjusted referral possible glaucoma (63.29, 95% confidence interval [CI] = 57.12-68.90 cases per 1000), epiretinal macular membrane (21.84, 95% CI = 15.64-29.22), age-related macular degeneration (13.93, 95% CI = 11.09-17.17), and diabetic retinopathy (11.33, 95% CI = 8.89-13.77) ranked the highest among 10 diseases. Female participants had significantly higher adjusted prevalence of pathologic myopia, yet a lower adjusted prevalence of diabetic retinopathy, referral possible glaucoma, and hypertensive retinopathy than male participants. From 2019 to 2021, the adjusted prevalence of retinal vein occlusion (0.99, 95% CI = 0.73-1.26 to 1.88, 95% CI = 1.42-2.44), macular hole (0.59, 95% CI = 0.41-0.82 to 1.12, 95% CI = 0.76-1.51), and hypertensive retinopathy (0.53, 95% CI = 0.40-0.67 to 0.77, 95% CI = 0.60-0.95) significantly increased. The prevalence of diabetic retinopathy in participants under 50 years old significant increased. Conclusions: Retinal and optic nerve diseases are an important public health concern in China. Further well-conceived epidemiological studies are required to validate the observed increased prevalence of diabetic retinopathy, hypertensive retinopathy, retinal vein occlusion, and macular hole nationwide. Translational Relevance: This artificial intelligence system can be a potential tool to monitor the prevalence of major retinal and optic nerve diseases over a wide geographic area.

A challenging differential diagnosis - Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON) is the most common maternally inherited disease linked to mitochondrial DNA (mtDNA). The patients present with subacute asymmetric bilateral vision loss. Approximately 95% of the LHON cases are caused by m.3460G>A (MTND1), m.11778G>A (MTND4), and m.14484T>C (MTND6) mutations. The hallmark of hereditary optic neuropathies determined by mitochondrial dysfunction is the vulnerability and degeneration of retinal ganglion cells (RGC). We present the case of a 28-year-old man who came to our clinic complaining of a subacute decrease in visual acuity of his left eye. From his medical history, we found out that one month before he had the same symptoms in the right eye. From the family history, we noted that an uncle has had vision problems since childhood. We carried out complete blood tests, including specific antibodies for autoimmune and infectious diseases. Laboratory tests and MRI were within normal limits. A blood test of the mtDNA showed the presence of 11778 G>A mutation on the mtND6 gene. The medical history, the fundus appearance, the OCT, and the paraclinical investigations, made us diagnose our patient with Leber's hereditary optic neuropathy. As soon as possible, we began the treatment with systemic idebenone, 900 mg/day. We examined the patient 2, 6, and 10 weeks after initiating the treatment. Abbreviations: LHON = Leber's Hereditary Optic Neuropathy, mtDNA = mitochondrial DNA, VA = visual acuity, RE = right eye, LE = left eye, OCT = Optical coherence tomography, pRNFL = peripapillary retinal nerve fiber layer, GCL = retinal ganglion cells layer, MRI = magnetic resonance imaging, VEP = visual evoked potentials, VEP IT = VEP implicit time, VEP A = VEP amplitude.

Optic nerve involvement in patients with Lyme neuroborreliosis: an electrophysiological study.

PURPOSE: The aim of this neurophysiological study was to retrospectively analyze visual evoked potentials (VEPs) acquired during an examination for diagnosing optic nerve involvement in patients with Lyme neuroborreliosis (LNB). Attention was focused on LNB patients with peripheral facial palsy (PFP) and optic nerve involvement. METHODS: A total of 241 Czech patients were classified as having probable/definite LNB (193/48); of these, 57 were younger than 40 years, with a median age of 26.3 years, and 184 were older than 40 years, with a median age of 58.8 years. All patients underwent pattern-reversal (PVEP) and motion-onset (MVEP) VEP examinations. RESULTS: Abnormal VEP results were observed in 150/241 patients and were noted more often in patients over 40 years (p = 0.008). Muscle/joint problems and paresthesia were observed to be significantly more common in patients older than 40 years (p = 0.002, p = 0.030), in contrast to headache and decreased visual acuity, which were seen more often in patients younger than 40 years (p = 0.001, p = 0.033). Peripheral facial palsy was diagnosed in 26/241 LNB patients. Among patients with PFP, VEP peak times above the laboratory limit was observed in 22 (84.6%) individuals. Monitoring of patients with PFP and pathological VEP showed that the adjustment of visual system function occurred in half of the patients in one to more years, in contrast to faster recovery from peripheral facial palsy within months in most patients. CONCLUSION: In LNB patients, VEP helps to increase sensitivity of an early diagnostic process.

Posterior segment manifestations of Takayasu arteritis: A narrative review.

Ocular symptoms can be the presenting manifestation of Takayasu arteritis (TA) or could be indicative of disease reactivation. A review of published literature related to posterior segment manifestations of TA by using the keywords "Takayasu arteritis," "ophthalmic manifestations," "retina," "retinopathy," "ocular," "optic nerve," and "optic neuropathy" was performed. In total, 62 case reports and 12 case series were included. The majority of the articles were from Asia (n = 47, 64%). Females outnumbered males in the ratio of 7:1. The mean age of patients was 33 years (range: 8-78 years, SD: 13.5 years). In 58% (n = 41 out of 71) cases, ocular symptoms were the presenting manifestation of the underlying disease. Hypotensive retinopathy was found in 70% of eyes, and hypertensive retinopathy was found in 27%. The mean presenting visual acuity (VA) was +1.03 logMAR (range: -0.12 to 3, SD: 1.07), and at the final follow-up was +1.02 logMAR (range: -0.12 to 3, SD 1.17). VA improved in 34% (n = 29/86), remained stable in 45% (39/86), and worsened in 21% (18/86). The mean follow-up was 9 months (range: 0.5-204, SD: 16 months).

[Sleep apnea and ocular diseases].

Sleep apnea presents as recurrent respiratory arrests or shallow breathing during sleep, resulting in decreased oxygen saturation and sleep disruption. Among its various types, obstructive sleep apnea is the most common. Over the past few decades, the prevalence of sleep apnea has been on the rise, drawing increasing attention, particularly with the growing obesity and aging population. Prolonged exposure to a hypoxic environment due to sleep apnea not only damages multiple systems throughout the body but may also pose a threat to vision. Examining the relationship between sleep apnea and ocular diseases, along with exploring its pathogenesis, has become a prominent research topic in recent years. This article provides a comprehensive review of the existing literature concerning the correlation between sleep apnea and ocular diseases such as glaucoma, optic nerve diseases, retinal and choroidal diseases, and anterior eye segment diseases. In clinical practice, prioritizing early screening and treatment for sleep apnea is crucial to prevent the worsening of associated ophthalmic conditions.

[Toward the complete understanding of the pathogenic mechanism of clioquinol-induced subacute myelo-optic neuropathy (SMON)].

Clioquinol was extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). SMON is characterized by the subacute onset of sensory and motor disturbances in the lower extremities with occasional visual impairments, which are preceded by abdominal symptoms. Although pathological studies demonstrated axonopathy of the spinal cord and optic nerves, the underlying mechanisms of clioquinol toxicity have not been elucidated in detail. We previously performed a global analysis of human neuroblastoma cells using DNA chips and demonstrated that clioquinol induced 1) DNA double-strand breaks and subsequent activation of ATM/p53 signaling; 2) the expression of VGF, the precursor of neuropeptides involved in pain reactions, by inducing c-Fos; 3) the expression of interleukin-8, which is reported to be involved in intestinal inflammation, optic neuropathy, and neuropathic pain, by down-regulating GATA-2 and GATA-3. We also demonstrated that clioquinol induced zinc influx and oxidation of the copper chaperone ATOX1, leading to the impairment of the functional maturation of a copper-dependent enzyme dopamine-ß-hydroxylase and the inhibition of noradrenaline biosynthesis. Thus, clioquinol-induced neurotoxicity in SMON seems to be mediated by multiple pathways.