Loss Of Color Vision Research Articles

Update on Clinical Trial Endpoints in Gene Therapy Trials for Inherited Retinal Diseases.

Inherited retinal diseases (IRDs) encompass a wide spectrum of rare conditions characterized by diverse phenotypes associated with hundreds of genetic variations, often leading to progressive visual impairment and profound vision loss. Multiple natural history studies and clinical trials exploring gene therapy for various IRDs are ongoing. Outcomes for ophthalmic trials measure visual changes in three main categories-structural, functional, and patient-focused outcomes. Since IRDs may range from congenital with poor central vision from birth to affecting the peripheral retina initially and progressing insidiously with visual acuity affected late in the disease course, typical outcome measures such as central visual acuity and ocular coherence tomography (OCT) imaging of the macula may not provide adequate representation of therapeutic outcomes including alterations in disease course. Thus, alternative unique outcome measures are necessary to assess loss of peripheral vision, color vision, night vision, and contrast sensitivity in IRDs. These differences have complicated the assessment of clinical outcomes for IRD therapies, and the clinical trials for IRDs have had to design novel specialized endpoints to demonstrate treatment efficacy. As genetic engineering and gene therapy techniques continue to advance with growing investment from industry and accelerated approval tracks for orphan conditions, the clinical trials must continue to improve their assessments to demonstrate safety and efficacy of new gene therapies that aim to come to market. Here, we will provide an overview of the current gene therapy approaches, review various endpoints for measuring visual function, highlight those that are utilized in recent gene therapy trials, and provide an overview of stage 2 and 3 IRD trials through the second quarter of 2024.

Gene Therapy for Achromatopsia.

Achromatopsia is the most common cone dysfunction syndrome, affecting 1 in 30,000 people. It is an autosomal recessive disorder with a heterogeneous genetic background with variants reported in CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6. Up to 90% of achromatopsia patients harbour mutations in CNGA3 or CNB3, which encode for the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel in cone-specific phototransduction. The condition presents at birth or early infancy with poor visual acuity, nystagmus, photophobia, and colour vision loss in all axes. Multimodal retinal imaging has provided insightful information to characterise achromatopsia patients based on their genotype. There is no FDA-approved treatment for achromatopsia; however, studies have reported several preclinical gene therapies with anatomical and functional improvements reported in vivo. There are currently five gene therapy clinical trials registered for human patients at the phase I/II stage and for CNGA3 or CNGB3 causing achromatopsia. This review aims to discuss the genetics of achromatopsia, genotypic and phenotypic correlations in multimodal retinal imaging, and the developments and challenges in gene therapy clinical trials.

Molecular Mechanisms Governing Sight Loss in Inherited Cone Disorders.

Inherited cone disorders (ICDs) are a heterogeneous sub-group of inherited retinal disorders (IRDs), the leading cause of sight loss in children and working-age adults. ICDs result from the dysfunction of the cone photoreceptors in the macula and manifest as the loss of colour vision and reduced visual acuity. Currently, 37 genes are associated with varying forms of ICD; however, almost half of all patients receive no molecular diagnosis. This review will discuss the known ICD genes, their molecular function, and the diseases they cause, with a focus on the most common forms of ICDs, including achromatopsia, progressive cone dystrophies (CODs), and cone-rod dystrophies (CORDs). It will discuss the gene-specific therapies that have emerged in recent years in order to treat patients with some of the more common ICDs.

A Rare Case Report of Bardet–Biedl Syndrome: A Syndrome of Pentad Symptoms

Bardet–Biedl syndrome (BBS) is a clinically and genetically heterogeneous disorder that manifests as a result of primary cilia impairment, characterized by retinitis pigmentosa, obesity, mental retardation, hypogonadism, and polydactyly. The five findings together are called “the pentad” and are found in most of the cases. This is the case of a 14-year-old boy, 2nd issue of consanguineous marriage of his parents, having a positive family history, who presented with progressive dimness of vision, learning disability, increased hunger, and weight since childhood. Initially, there were impaired night vision and peripheral vision problems, and later loss of color vision. He had no hearing problem, anosmia, cold intolerance, or steroid-taking history. His intranatal and postnatal history was uneventful except slightly delayed developmental milestone. His body mass index was 32.7 kg/m2, waist–hip ratio was 1.08, height was in the 50th centile on the growth chart. He had polydactyly, high-arched palate, acanthosis nigricans, and buried penis; testicular volume was prepubertal. Laboratory findings revealed high triglyceride, impaired glucose tolerance, hypogonadotropic hypogonadism, and grade-III fatty liver. He had bony spicule-like pigmentation in the periphery of both eyes suggestive of retinitis pigmentosa. Based on these data, BBS was diagnosed. In conclusion, BBS is a rare clinical syndrome that may go unnoticed by many clinicians. Renal failure is the leading cause of morbidity and mortality in patients with BBS. Therefore, early detection of BBS is vital to halt the progression of renal impairment.

VISIBL-MS: A bilingual educational framework to increase awareness of early multiple sclerosis

Background: Despite advancements in treatments of multiple sclerosis (MS), there is a lack of awareness of early MS symptoms, especially in students and the public, contributing to delays in diagnosis and treatment. This review aims to identify gaps in tools to increase awareness and to provide a bilingual framework to facilitate recognition of early MS symptoms. Methods: We performed a literature review to determine the use of English and Spanish mnemonics in MS education for medical students and patients. Results: There is no educational tool to help remember the early signs of MS at present. Here we present a framework for early awareness encompassed in the bilingual mnemonics VISIBLY (English) and VISIBLE (Spanish). VISIBLY stands for (1) Vision changes: Painful vision loss, loss of color vision or double vision; (2) Belly or Back numbness and Balance issues; (3) Limb weakness or Numbness; (4), Young people. Spanish version is included in the manuscript. Conclusion: We posit that VISIBL-MS provides a framework for MS awareness that addresses the interconnection between language, culture, health literacy, and health outcomes and can be a useful educational tool to tackle the effects of health literacy on diverse communities.

Hereditary Retinal Dystrophies: Current Scientific Knowledge

Hereditary retinal dystrophies are a heterogeneous group of inherited diseases characterized by involvement of different layers of the retina, most often the complex retinal pigment epithelium (RPE) – photoreceptors and cause severe visual impairment – loss of night vision, visual field, colour vision and visual acuity in the initial stages and lead to progressive and severe loss of visual function by altering the anatomy and function of the retina.
 The development of medical science and technology has led to the introduction of new, increasingly sophisticated methods for early diagnosis of these diseases – the electrophysiological studies have become more complex and informative. Together with computer automated perimetry, optical coherence tomography (OCT), angio-OCT, fluorescein angiography (FA), fundus autofluorescence (FAF) and adaptive optics, they allow very accurate topographical localization of the defect. And along with the advances in genetics, optogenetics, molecular biology, retinal biochemistry and regenerative medicine, they provide a better understanding of the mechanism of these diseases and increase the therapeutic opportunities.
 The treatment of many of these diseases is still problematic, but because most of them are severely disabling the individual, the scientists' efforts are focused on finding an appropriate therapy. For many of these diseases, there are clinical trials worldwide, the results of some of them are quite encouraging, and many effective therapies for these currently incurable diseases are expected to be introduced in the near future.
 The purpose of this study is to analyze the scientific knowledge, as well as the therapeutic opportunities that are being experimented to date.

Maculopathies Referred to Neuro-Ophthalmology Clinic as Optic Neuropathies: A Case Series.

The clinical features of maculopathies and optic neuropathies often overlap: Both present with decreased visual acuity and variable loss of color vision; thus, maculopathy can be misdiagnosed as optic neuropathy, leading to patient harm. We aimed to determine what findings and/or tests were most helpful in differentiating between optic neuropathy and maculopathy. A retrospective chart review of consecutive patients over 4.5 years who were referred to neuro-ophthalmology clinics with the diagnosis of optic neuropathy but whose final diagnosis was maculopathy. Patient demographics, mode of presentation, clinical profile, complete ophthalmological examination, results of all ancillary testing, and final diagnosis were recorded. A total of 47 patients (27 women) were included. The median age was 55 years (range, 18-85). Most referrals were by ophthalmologists (72.3%) and optometrists (12.8%). The diagnosis of maculopathy was made in 51.1% of patients at the time of first neuro-ophthalmic consultation. Only 6.4% patients (3) had relative afferent pupillary defect. Benign disc anomalies (tilted, myopic, small, or anomalous discs) were present in 34.0%, and 21.3% had pathologic disc changes unrelated or secondary to maculopathy. Macular ocular coherence tomography (OCT) was abnormal in 84.4% (with outer retinal pathology in 42.2% and inner retina pathology in 17.8%). Retinal nerve fiber layer (RNFL) thickness was normal in 82.6% of patients. Macular OCT is a high-yield test in differentiating between optic neuropathy and maculopathy and should be obtained in patients with suspected optic neuropathies who have normal RNFL thickness. Macular dystrophies, particularly cone dystrophies, unspecified retinal disorders, and macular degeneration were the most common mimics of optic neuropathy. The diagnosis was often present on OCT of the macula. The presence of coexistent benign and pathological disc anomalies may lead to maculopathy being misdiagnosed as optic neuropathy.

MOG Antibody-Associated Bilateral Optic Neuritis Associated with Johnson and Johnson COVID-19 Vaccination (P12-3.009)

<h3>Objective:</h3> To describe a case of bilateral optic neuritis associated with MOG Antibodies following vaccination with Johnson and Johnson (J&amp;J) COVID-19 vaccine. <h3>Background:</h3> Cases of MOG Antibody Disease (MOGAD) following infection or vaccination have been reported, including in association with both COVID-19 infection and vaccination. However, no cases have been reported in Africa, associated with the J&amp;J vaccine or presenting with bilateral optic neuritis. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 37-year-old Zambian woman presented two weeks after vaccination with the J &amp; J COVID-19 vaccine with progressive vision loss and headache associated with eye movement. Loss of color vision developed a week later and progressed over four days to complete blindness. On examination, she had no light perception in both eyes, dilated pupils with sluggish light reflex, and bilateral papilledema. The remainder of her examination was normal. Baseline investigations were unremarkable, and MRI and MRV of the brain were normal. Orbital MRI was not available in our setting. OCT showed bilateral thickening of the retinal nerve fiber layer with nasal depression of the macular ganglion cell inner plexiform layer. Serum aquaporin-4 antibodies were negative, and serum MOG antibodies were positive. The patient received a 5-day course of pulse-dose steroids followed by 1mg/kg oral prednisolone tapered over 8 weeks. She experienced full recovery of her visual acuity within 10 days of pulse-dose steroids and remained relapse free for six months. <h3>Conclusions:</h3> This case of MOG-antibody associated bilateral optic neuritis triggered by J&amp;J COVID-19 vaccine in a Zambian woman is unique in that the diagnosis was made in a resource limited setting, necessitating a high index of suspicion, reliance on clinical skills and highly targeted testing. This case further highlights the need for surveillance for similar cases and it adds literature of cases of MOGAD associated with various COVID-19 vaccines. <b>Disclosure:</b> Dr. Mutete has nothing to disclose. NALUCA MWENDAWELI has nothing to disclose. Dr. Asukile has nothing to disclose. Dr. Serenje has received research support from Orbis International. Willard Mumbi has nothing to disclose. The institution of Dr. Saylor has received research support from National Institutes of Health. The institution of Dr. Saylor has received research support from National Multiple Sclerosis Society. The institution of Dr. Saylor has received research support from American Academy of Neurology. The institution of Dr. Saylor has received research support from United States Department of State. Dr. Saylor has a non-compensated relationship as a Member of multiple committees and task forces focused on improving access to MS medications to people across the world with Multiple Sclerosis International Federation that is relevant to AAN interests or activities. Dr. Saylor has a non-compensated relationship as a Member of the Neurology and COVID19 committee with World Health Organization that is relevant to AAN interests or activities. Dr. Saylor has a non-compensated relationship as a Member of the International Outreach Committee, Junior and Early Career Membership Committee, and Educational Innovation Commitees with American Neurological Association that is relevant to AAN interests or activities.

Visual Characteristics of Adults with Long-Standing History of Dietary Exposure to Mercury in Grassy Narrows First Nation, Canada.

Since the 1960s, Grassy Narrows First Nation (Ontario, Canada) has been exposed to methyl mercury (Hg) through fish consumption, resulting from industrial pollution of their territorial waters. This cross-sectional study describes the visual characteristics of adults with documented Hg exposure between 1970 and 1997. Oculo-visual examinations of 80 community members included visual acuity, automated visual fields, optical coherence tomography [OCT], color vision and contrast sensitivity. Median age was 57 years (IQR 51-63) and 55% of participants were women. Median visual acuity was 0.1 logMAR (Snellen 6/6.4; IQR 0-0.2). A total of 26% of participants presented a Visual Field Index inferior to 62%, and qualitative losses assessment showed concentric constriction (18%), end-stage concentric loss (18%), and complex defects (24%). On OCT, retinal nerve fiber layer scans showed 74% of participants within normal/green range. For color testing with the Hardy, Rand, and Rittler test, 40% presented at least one type of color defect, and with the Lanthony D-15 test, median color confusion index was 1.59 (IQR 1.33-1.96). Contrast sensitivity showed moderate loss for 83% of participants. These findings demonstrate important loss of visual field, color vision, and contrast sensitivity in older adults in a context of long-term exposure to Hg in Grassy Narrows First Nation.

Elaborate Evaluation of Farnsworth Dichotomous D-15 Panel Test Can Help Differentiate between Best Vitelliform Macular Dystrophy and Autosomal Recessive Bestrophinopathy

Introduction: The colour vision in bestrophinopathies has not been assessed in detail so far. The aim of this study was to explore the extent to which distinct types of bestrophinopathies differ in regard to colour vision deficiencies using Farnsworth Dichotomous D-15 and Lanthony Desaturated D-15 panel tests. Methods: Both D-15 tests were performed in 52 eyes of 26 patients with Best vitelliform macular dystrophy (BVMD) and 10 eyes of 5 patients with autosomal recessive bestrophinopathy (ARB). Two methods were used for a quantitative assessment of the colour vision deficiencies: moment of inertia method and Bowman method. The following parameters were calculated: confusion angle, confusion index (C-index), selectivity index (S-index), total error score (TES), and colour confusion index (CCI). Results: The median value of confusion angle for all stages of BVMD fell into a narrow range around 62, indicating normal results. The median confusion angle value was 57 in ARB patients within a very wide range down to −82, indicating non-specific deficits. These differences were statistically significant. Significantly abnormal C-index and CCI values were found only in ARB patients, being 2.0 and 1.49, respectively. The majority of parameters of D-15 tests were independent of the visual acuity in both bestrophinopathies. Conclusions: Elaborate evaluation of the D-15 panel tests might help establish a differential diagnosis between different bestrophinopathies, as the pattern of the colour vision loss is different between BVMD and ARB. The quantitative parameters of colour vision tests in bestrophinopathies are independent of the visual acuity.

Loss of colour vision in patients at risk of developing diabetes

AbstractRecent studies carried out in diabetic patients with no more than moderate maculopathy revealed that over 70% had significant losses of both Yellow/Blue (YB) and Red/Green (RG) colour vision (https://doi.org/10.1111/j.1755-3768.2012.F073.x). The purpose of this study was to investigate whether clinically ‘normal’ subjects, identified as being at ‘risk’ of developing diabetes show significant changes in rod‐ and cone‐mediated rapid flicker sensitivity as well as RG and YB colour vision.Three groups of subjects were recruited; a normal subject group (n = 40), a ‘high‐risk’ group (n = 150) and subjects diagnosed with diabetes (n = 23). The inclusion criteria for ‘high‐risk’ group required 3 or more recognized risk factors for diabetes (e.g., age &gt; 45, HbA1C &gt;5.7, high blood pressure, smoking history, high BMI, family history of diabetes, FPG levels &gt;100 mg/dL). All subjects had full ophthalmic assessment and their RG and YB colour vision, Functional Contrast Sensitivity (FCS), Visual Acuity (VA) and Rod‐ and Cone‐mediated flicker sensitivity were measured using AVOT tests (https://researchcentres.city.ac.uk/applied-vision/avot).Consistent with previous findings, the diabetic group show significant loss of both RG and YB colour vision. Our findings show that these subjects also exhibit higher thresholds for rod and cone mediated vision. In addition, the ‘high‐risk’ group who are clinically classified as ‘normal’, also show significant loss of colour vision and rod and cone sensitivity. The latter group, do not, however, show significant differences in either VA or FCS. These findings suggest that accurate assessment of colour vision and rod‐ and cone‐ mediated rapid flicker sensitivity qualify as important risk factors in prediabetic screening.

Cerebral achromatopsia

AbstractChromatic sensitivity was assessed in patients with pregeniculate and postgeniculate lesions. We examine changes in central vision along at foveal fixation and in each of the four paracentral quadrants of the visual field using the Colour Assessment and Diagnosis (CAD) test, a dynamic luminance contrast masking technique that isolates the use of Red / Green (RG) and Yellow / Blue (YB) colour signals. Because the extraction of colour signals in early visual processing involves opponent mechanisms, subjects with congenital RG loss of sensitivity exhibit symmetric increase in thresholds towards the long wavelength (“red”) and middle wavelength (“green”) regions of the spectrum locus. This is also frequently the case with acquired loss of chromatic sensitivity as a result of retinal or optic nerve disease. The findings from this study represent an exception to this rule. The patients investigated showed a marked asymmetry in colour thresholds. The study reveals how discrete, localized damage to visual pathways can cause selective loss of visual function and how the latter varies with retinal topography.The 36 pregeniculate patients investigated exhibited impairment in both RG and YB. Loss of colour vision was symmetrical for both RG and YB discrimination. Some pregeniculate patients exhibited substantial loss of colour vision in areas where perimetric loss was largely absent. All quadrants revealed similar symmetric loss of colour sensitivity.In 23 patients with postgeniculate lesions, patients with pre‐striate damage exhibited symmetric loss of chromatic sensitivity which affected either one or both chromatic mechanisms. Striate or extra‐striate lesions tended to exhibit general loss of colour vision within the area identified by visual field testing. More specific chromatic loss was associated with less impaired areas that were often normal on perimetric testing. Some patients with striate or extra‐striate lesions presented with asymmetric chromatic loss for one or more colour categories. When striate or extra‐striate lesions were also accompanied by underlying pre‐striate damage, chromatic sensitivity loss was always symmetric.The findings from this study show that the loss of chromatic sensitivity in cerebral achromatopsia depends strongly on the exact location and extent of the lesion with significant variation over the visual field. The same subject can exhibit loss of chromatic sensitivity that is either RG or YB specific, but also, spatially localized, non‐opponent loss of sensitivity for primary colours.

Colour‐related, binocular interactions in patients with dyschromatopsia

AbstractWe report findings of monocular and binocular assessments of colour vision and thresholds for rod‐ and cone‐mediated sensitivity in two young patients (P1 and P2) diagnosed with monocular dyschromatopsia. Altered, monocular, colour perception with no clear diagnosis was reported in each patient based on results from a number of clinical visual assessment tests carried out over several years. Electrodiagnostic tests also revealed reduced Yellow / Blue (YB) chromatic sensitivity in P1. Both patients exhibited unexpected binocular interactions of colour signals. This abstract focuses mostly on the results obtained in P1, but similar results using the same visual assessment tests will also be presented for P2.P1 experienced visual discomfort, often manifested as differences between monocular and binocular viewing, noise‐like appearance of uniform fields and colours over the field, when viewed monocularly with either eye. As a result of these reports, we re‐examined P1's visual deficits using the Colour Assessment and Diagnosis (CAD) and the Flicker‐Plus (FP) tests (http://www.city-occupational.co.uk/). The FP test measures rod‐ and cone‐mediated rapid flicker sensitivity centrally (along the direction of gaze) and at 6 deg eccentricity in each of the four quadrants.Colour Vision. P1 shows significant loss of YB colour vision when tested monocularly in the right eye, but normal red‐green (RG) and YB colour vision in the left eye. When tested binocularly, P1 continues to show the same loss of YB colour vision observed when using only the right eye. These results were unexpected since P1 shows ‘normal’ binocular summation for both colour and flicker sensitivity, even when the thresholds are above the normal range.Rod‐ / Cone‐sensitivity. The patient's cone‐mediated, flicker sensitivity at all five locations investigated (under binocular viewing) was normal (with flicker detection thresholds, often under 2%), but only for the cone‐enhanced condition. When tested with rod‐enhanced stimuli, P1 shows much reduced sensitivity with larger thresholds in the periphery, but only in binocular viewing. Such responses have not been observed previously.In conclusion, P1 shows loss of YB colour vision in the right eye and also significant loss of rod‐mediated sensitivity at each of the five locations investigated. The patient's cone mediated thresholds, at every location tested, were consistently below the mean expected for normal trichromats, both binocularly and with each eye. The YB colour vision measured binocularly remained severely abnormal with thresholds similar to the right eye, in spite of normal colour vision in the left eye. Preliminary observations also suggest that the patient's colour and rapid flicker sensitivity can be affected by fatigue and other factors.Although patient, P2, varied significantly to P1 in monocular thresholds, a similar binocular, inhibitory interaction between the two eyes was observed when processing colour signals. These observations and the unusual interactions between signals derived from the two eyes point towards abnormal central processing of colour signals.

Mitochondrial optic neuropathies (MON)

AbstractWhen we first proposed the term, Mitochondrial Optic Neuropathies (MON) (Sadun AA. Mitochondrial optic neuropathies. J Neurol Neurosurg Psychiatry. 2002 Apr;72(4):423–5.), it may have seemed odd. The paradigm before then was that many things could injure the optic nerves, and genetic, nutritional and many toxic causes made the list alongside tumours, infections, inflammations, etc. Our experiences in Cuba changed this mode of thinking. There, an epidemic of optic neuropathy (CEON) was found to exist among those consuming small amounts of methanol in the presence of folic acid deficiency. This demonstrated the convergence of toxic and nutritional causes that affected the same (oxidative‐phosphorylation) systems. Several publications have demonstrated that certain metabolic optic neuropathies are more likely in the setting of genetic predispositions. In short, asymptomatic carriers of well characterized genetic disorders such as Leber's Hereditary Optic Neuropathy (LHON), may lose vision when additionally stressed by exposures to certain drugs like ethambutol or to nutritional deficiencies. Several studies have revisited the original diagnosis of tobacco‐alcohol amblyopia (their term) and found about 20% harboured LHON mtDNA mutations (Cullom, et al., Arch Ophthalmol. 1993 Nov;111(11):1482–5).We hereby present a framework for seeing many forms of metabolic (hereditary, nutritional and toxic) optic neuropathies as related. One unifier is the stereotypic clinical presentation. These patients have, after a while, very symmetric visual losses. The loss of visual acuity, colour vision, and high spatial frequency contrast sensitivity, reflects a pair of symmetrical central or cecocentral scotomas. These aforementioned functional defects are to be expected by the equally characteristic anatomical loss of the small fibres of the papillo‐macular bundle (PMB) which also explains the temporal optic disc pallor. The other unifier is that the molecular injuries cause impairments of mitochondria, and specifically oxidative phosphorylation (Ox‐Phos). We and others have further demonstrated that this especially entails the accumulation of reactive oxygen species (ROS) more than a problem with bioenergetics. This also explains the particular predilection for injury of the smallest and unmyelinated fibres of the PMB.Several drugs are causes or additional risk factors in MON. Remarkably, most drugs that are best demonstrated to injure the optic nerve are also understood to impair mitochondria and Ox‐Phos. These include ethambutol and linezolid, chloramphenicol, streptomycin, and some antivirals (Wang and Sadun, J Neuroophthalmol. 2013 Jun;33(2):172–8). These drugs can also be regarded, in addition to heavy smoking and binge drinking of alcohol, as exogenous sources of ROS that are likely to bring out Type II LHON (vs Type I LHON which is apt to be genetic/genetic, and occurs at an early age more acutely).In general, MON represent the unique susceptibility of the optic nerve, and most specifically, the small fibres of the PMB, to the ROS that are generated when mitochondrial Ox‐Phos is defective. When the ROS threshold is exceeded, these fibres are the first to decompensate and this leads to a remarkably consistent phenotype.

The value of colour assessment in diagnostic dilemmas

AbstractBackground: When the goal of clinical assessment is to segment, divide, and classify cases into neat discrete boxes it can often be frustrating to encounter cases which do not fit standard diagnosis algorithms. However, such diagnostic dilemmas often provide a valuable insight into the boundaries of current clinical procedures and the potential value psychophysical assessment can provide when used in conjunction with standard diagnosis algorithms. We present such a case involving localized retinal dysfunction that is not fully consistent with signs of either autoimmune retinopathy or occult maculopathy.Methods: Specific visual function loss was investigated in a health 32‐year‐old male with suspected localized retinal dysfunction, affecting the central retina. Blood tests and electro‐diagnostics were carried out after the patient presented with acute onset ‘foggy’ central vision. The working diagnosis from this initial visit was autoimmune retinopathy and oral steroids were prescribed. Following no change in symptoms a year after initially presenting, the patient was referred to City, University of London for bespoke assessments of specific visual functions. These included assessments of central and peripheral red / green (RG) and yellow / blue (YB) colour vision, mesopic visual acuity (VA), functional contrast sensitivity (FCS), rod‐ and cone‐mediated flicker sensitivity, and pupil responses measured using both rod‐ and cone‐enhanced stimuli.Results: The loss of vision affected primarily the central 20° with a mean VA of 6/36 in each eye. Fundus images, fluorescein angiography, and full field electroretinograms (ERGs) were normal, but pattern and focal ERGs were undetectable indicating localized dysfunction in central vision with OCT images showing a disrupted ellipsoid zone in each eye. The patient's mean corpuscular volume was 69 femtoliters, with red cell indices suggestive of thalassemia. Testing at City, University of London confirmed a loss of VA and FCS in the central 10° field, although both VA and FCS depended strongly on light level and were less affected with negative contrast stimuli. A loss of RG and YB colour vision was also measured centrally. Outside the central 10° field EA had almost normal colour and spatial vision. Rod‐ and cone‐mediated, flicker thresholds were elevated, with cone thresholds 10‐fold higher than normal. Pre‐stimulus pupil size, constriction amplitudes and latencies were normal with both centrally presented and peripheral stimuli.Conclusions: Psychophysical measurements in a patient with presumed autoimmune maculopathy showed atypical macular dysfunction that appears to preferentially affect negative contrast stimuli. Despite damage to the retinal mechanisms involved in spatial vision and light adaptation pupil responses remained unaffected. This unusual case highlights the importance of detailed phenotyping in understanding unknown aetiology.

RF35 | PSAT299 Thyroid Eye Disease Activation After mRNA SARS-CoV-2 Vaccination in Patients With Autoimmune Thyroid Disease

Abstract Background Occurrence of Graves’ disease (GD) has been reported following SARS-CoV-2 vaccine administration, but little is known about thyroid eye disease (TED) after SARS-CoV-2 vaccination. Case 1 A 50-year-old non-smoker male was diagnosed with GD in March 2019 and treated with methimazole. In April 2020, he developed TED with bilateral proptosis, pain, erythema and diplopia and clinical activity score (CAS) 6/7. Following poor response to 3-month oral steroids, he underwent total thyroidectomy in November 2020. In six weeks, his TED improved (CAS 4/7) and thyroid stimulated immunoglobulin (TSI) levels normalized from 4.13 IU/l (preoperatively) to 0.70 IU/l (reference&amp;lt; 1.75 IU/l). In January 2021, he received 2 doses of the mRNA BNT162b2-SARS-CoV-2 vaccine (Pfizer-BioNTech). Three weeks after the second dose, TED deteriorated significantly with severe eye pain, lid swelling, conjunctival erythema, and worsening proptosis and diplopia (CAS 6/7). TSI levels rose to 4.45 IU/l, while patient was euthyroid on levothyroxine (TSH 2.3 mIU/l). He received 12 weekly methylprednisolone infusions (cumulative dose of 4.5 g) with limited response. He was then treated with three monthly cycles of intravenous tocilizumab with partial response (CAS 5/7). Case 2 A 71-year-old non-smoker female had a 40-year history of hypothyroidism, controlled on levothyroxine. In March 2021, three days after her second dose of the mRNA-1273 SARS-CoV-2 vaccine (Moderna), she developed bilateral eye swelling and burning. She initially received anti-histamines and steroid eye drops without improvement. By August 2021, her eyes further deteriorated with eye pain, redness, lid edema and erythema, diplopia, and worsening proptosis (CAS 4/7). She also experienced 20 Ib weight loss, palpitations, tremors, and heat intolerance. TSI index was 5.5 (reference ≤1.3), TSH was undetectable, and FT4 1.4 ng/dl (reference 0.93-1.70 ng/dl). Levothyroxine was discontinued. Two weeks later she was admitted to the hospital with loss of color vision and decreased visual acuity in the right eye. She received 2 daily doses of 1 g intravenous methylprednisolone and intravenous teprotumumab on hospital day 3. She responded well to teprotumumab infusions every 3 weeks, with return of color vision and improvement of proptosis and periorbital edema (CAS 1/7). Discussion Activation of TED has so far only been described in four patients following SARS-CoV-2 vaccination. Here we report two more cases: one of TED deterioration in a GD patient with prior TED, and one of de novo TED progressing to dysthyroid optic neuropathy in a patient with a long history of Hashimoto's hypothyroidism. Possible etiologies include a maladaptive autoimmune/inflammatory syndrome from polyclonal B cell stimulation by adjuvants or activation of preexisting autoimmune disease. The possibility of new onset or deterioration of TED after SARS-CoV-2 vaccination in patients with underlying autoimmune thyroid disease and its mechanism should be further studied. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:18 p.m. - 1:23 p.m.

Modeling Reactive Oxygen Species-Induced Axonal Loss in Leber Hereditary Optic Neuropathy.

Leber hereditary optic neuropathy (LHON) is a rare syndrome that results in vision loss. A necessary but not sufficient condition for its onset is the existence of known mitochondrial DNA mutations that affect complex I biomolecular structure. Cybrids with LHON mutations generate higher rates of reactive oxygen species (ROS). This study models how ROS, particularly H2O2, could signal and execute the axonal degeneration process that underlies LHON. We modeled and explored several hypotheses regarding the influence of H2O2 on the dynamics of propagation of axonal degeneration in LHON. Zonal oxidative stress, corresponding to H2O2 gradients, correlated with the morphology of injury exhibited in the LHON pathology. If the axonal membrane is highly permeable to H2O2 and oxidative stress induces larger production of H2O2, small injuries could trigger cascading failures of neighboring axons. The cellular interdependence created by H2O2 diffusion, and the gradients created by tissue variations in H2O2 production and scavenging, result in injury patterns and surviving axonal loss distributions similar to LHON tissue samples. Specifically, axonal degeneration starts in the temporal optic nerve, where larger groups of small diameter fibers are located and propagates from that region. These findings correlate well with clinical observations of central loss of visual field, visual acuity, and color vision in LHON, and may serve as an in silico platform for modeling the mechanism of action for new therapeutics.

The Association Between Acquired Color Deficiency and PET Imaging of Neurodegeneration in Mild Cognitive Impairment and Alzheimer Disease.

PurposeTo evaluate color vision changes and retinal processing of chromatic and luminance pathways in subjects with Alzheimer disease (AD) and mild cognitive impairment (MCI) compared with a matched control group and whether such changes are associated with impaired brain glucose metabolism and β-amyloid deposition in the brain.MethodsWe evaluated 13 patients with AD (72.4 ± 7.7 years), 23 patients with MCI (72.5 ± 5.5 years), and 18 controls of comparable age (P = 0.44) using Cambridge color test and the heterochromatic flicker ERG (HF-ERG). The Cambridge color test was performed using the trivector protocol to estimate the protan, deutan and tritan color confusion axes. HF-ERG responses were measured at a frequency of 12 Hz, which ERGs reflect chromatic activity, and at 36 Hz, reflecting luminance pathway. A study subsample was performed using neuropsychological assessments and positron emission tomography.ResultsPatients with AD presented higher mean values indicating poorer color discrimination for protan (P = 0.04) and deutan (P = 0.001) axes compared with the controls. Along the tritan axis, both patients with AD and patients with MCI showed decreased color vision (P = 0.001 and P = 0.001) compared with controls. The analyses from the HF-ERG protocol revealed no differences between the groups (P = 0.31 and P = 0.41). Diffuse color vision loss was found in individuals with signs of neurodegeneration (protan P = 0.002, deutan P = 0.003 and tritan P = 0.01), but not in individuals with signs of β-amyloid deposition only (protan P = 0.39, deutan P = 0.48, tritan P = 0.63), regardless of their clinical classification.ConclusionsHere, patients with AD and patients with MCI present acquired color vision deficiency that may be linked with impaired brain metabolism.

Retinoic acid signaling mediates peripheral cone photoreceptor survival in a mouse model of retina degeneration.

Retinitis Pigmentosa (RP) is a progressive, debilitating visual disorder caused by mutations in a diverse set of genes. In both humans with RP and mouse models of RP, rod photoreceptor dysfunction leads to loss of night vision, and is followed by secondary cone photoreceptor dysfunction and degeneration, leading to loss of daylight color vision. A strategy to prevent secondary cone death could provide a general RP therapy to preserve daylight color vision regardless of the underlying mutation. In mouse models of RP, cones in the peripheral retina survive long-term, despite complete rod loss. The mechanism for such peripheral cone survival had not been explored. Here, we found that active retinoic acid (RA) signaling in peripheral Muller glia is necessary for the abnormally long survival of these peripheral cones. RA depletion by conditional knockout of RA synthesis enzymes, or overexpression of an RA degradation enzyme, abrogated the extended survival of peripheral cones. Conversely, constitutive activation of RA signaling in the central retina promoted long-term cone survival. These results indicate that RA signaling mediates the prolonged peripheral cone survival in the rd1 mouse model of retinal degeneration, and provide a basis for a generic strategy for cone survival in the many diseases that lead to loss of cone-mediated vision.

Ethambutol-Induced bilateral retrobulbar neuritis with cecocentral scotoma in cervical tuberculous lymphadenitis patient: A case report with estimated plasma level consideration

Ethambutol is considered to be safest first-line antitubercular drug, and patient acceptability is rather good in both intensive and continuation phase of the tuberculosis treatment with daily regimen. The important adverse effect associated with ethambutol is optic neuritis, resulting in loss of visual acuity, color vision, and field defects. The incidence of optic neuritis is generally directly proportional to the dose and duration of ethambutol therapy and rarely reported in a low standard dose. Here, we report a case of a 40-year-old female patient with complaints of progressive diminished vision (especially during day time) with a low daily dose (15 mg/kg/day) of ethambutol. She got diagnosed with cervical tuberculous lymphadenitis and was receiving isoniazid, rifampicin, ethambutol, and levofloxacin. In rare instances, ethambutol ocular toxicity may present with cecocentral scotoma. In rare instances, plasma levels are performed. An estimated plasma level of ethambutol was found to be in higher end (5.6 μg/ml) of the reported therapeutic range (2–6 μg/ml). Bilateral retrobulbar neuritis with cecocentral scotoma adverse effect due to ethambutol can be seen in plasma therapeutic range.