Loss Of Acuity Research Articles

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.

12‐month outcomes of trabecular microbypass iStent inject W implantation combined with cataract surgery in open‐angle glaucoma eyes

AbstractPurpose: To evaluate the effectiveness (lowering medication) of a single trabecular microbypass stent (iStent Inject® W, Glaukos) implantation in combination with phacoemulsification in open‐angle glaucoma eyes over a 12‐month period.Methods: Non‐randomized, single‐centre, retrospective case series of glaucoma eyes undergoing iStent implantation with phacoemulsification. Patients with no prior glaucoma surgery and intolerant or non‐compliant with medications were eligible for inclusion. Primary outcome effectiveness measures include reduction number of glaucoma medications and stabilization of intraocular pressure (IOP).Results: 30 eyes of 24 patients (mean age 74.9 ± 8.4) were included in this study. Mean baseline IOP was 17.7 ± 3.5 mmHg and was reduced to 16.1 ± 2.6 and 15.7 ± 2.5 at 6‐ and 12 months respectively (p = 0.002). Mean number of medications was 2.3 ± 1 at baseline and was significantly reduced to 0.7 ± 0.9 at 12 months (p < 0.001; −68%). No eye was medication free at baseline versus 50% (n = 15) at 12 months. In controlled glaucoma eyes (≤18 mmHG), mean IOP was stable (15.5 ± 2.1 at baseline; 15.3 ± 2.4 at 12‐month) while medications were reduced from 1.9 ± 0.7 at baseline to 0.5 ± 0.6, whereas in uncontrolled glaucoma eyes (>18mmHG at baseline) both IOP and medications were reduced from 20.7 ± 2.5 and 2.7 ± 1.2 at baseline to 16.2 ± 2.6 and 1.1 ± 1.1 at 12‐month respectively. There was no statistically significant change in retinal nerve fibre layer (RNFL) thickness at 12 months (p = 0.32). No eyes have experienced adverse events such as postoperatively IOP spikes or hyphema.Conclusions: iStent Inject W implantation with phacoemulsification results in a significant reduction in mean glaucoma medications in glaucoma eyes. IOP was also reduced and there was no loss of visual acuity or RNFL. In uncontrolled IOP eyes, the stent implantation has brought IOP under control and reduced the number of medications, while in controlled IOP eyes, it has lowered the number of medications.

Brain mechanism of sight recovery

AbstractPatients who were born with total bilateral cataracts and who were treated late in life show permanent deficits in visual acuity and other basic visual functions. Some higher visual functions are more (face identity processing, coherent motion processing) and other higher order visual functions (biological motion processing, visual exploration) are less impaired than expected from the visual acuity loss. Moreover, the integration of the late available visual input with the intact sensory inputs (hearing, touch) seems to be partially altered. The present talk will focus on new behavioural, electrophysiological and both functional and structural brain imaging results aiming to uncover the neural mechanisms of sight recovery in patients who had suffered from an extended period of blindness before they underwent cataract removal surgery.

Effects of refraction on straylight

AbstractThe effect of cataract and other media opacities on functional vision is typically assessed clinically using visual acuity. However, from both clinical and basic research, it has become evident that straylight (the functional result of light scattering in the eye) must be considered also as significant part of quality of vision. The optical basis of acuity and scatter are quite different. Acuity (and contrast sensitivity) depend on the refractile structure of the eye optics (refractive error and aberrations), whereas straylight mostly depends on the presence of light scattering particles of microscopic size. It must be noted that the first aspect is of global nature; the refractile structure concerns all light entering the pupil, whereas light scattering is of local nature, concerning only part of the light entering the pupil. The other part is under the influence of the refractile structure only. The subject of this presentation is the potential link between these two phenomena, and their functional counterparts: is visual acuity in cataract and other media opacities related to straylight? On the other hand, is straylight or its measurement under the influence of refractile errors, more in particular for myopic eyes?Potential interdependence between acuity and straylight was addressed for normal eyes by manipulating refractive correction with plus lenses. No effect on measured straylight values was found. Also statistically, little relation between straylight and acuity exists in the normal population, in concordance with expectation from theoretical modelling. Visual acuity losses with cataract and other media opacities are not due to straylight, but caused by aberrations and micro‐aberrations. Straylight defines disability glare, and causes symptoms of glare, haloes, hazy vision etc. Overall, visual acuity and straylight are rather independent aspects of quality of vision.For myopic eyes, literature has shown a clear interdependence (Rozema et al. IOVS 2010 pp 2795–2799). To understand this finding, straylight values were measured with the C‐Quant (Oculus Optikgeräte, GmbH, Wetzlar, Germany) in (1) near‐emmetropic eyes (n = 30) with various negative powered refractive lenses and in (2) myopic eyes (n = 30) corrected with prescribed eyeglasses and contact lenses. The straylight measurements in each group were compared in the different conditions. In the near‐emmetropic group, a significant effect (p < 0.001) of each added negative diopter was found to increase straylight values with 0.006 log‐units. In the second group, no significant correlation with type of correcting lens was found on straylight values. So, refractive correction with high minus power (contact) lenses result in subtle increase of straylight values. These changes are relatively small though.

Corneal epithelial microcysts as side effect of belantamab mafodotin: Management and evolution

AbstractPurpose: Blenrep® (Belantamab mafodotin) is an antibody‐drug conjugate that targets an overexpressed antigen in myeloma plasma cells. This agent has its indication on adults with triple‐class refractory multiple myeloma (MM). The most frequently reported adverse event is the appearance of microcyst‐like epithelial changes in the cornea (MEC), produced by the apoptosis of epithelial cells. Our purpose is to describe these findings and their evolution.Methods: The evaluation of the MM patients treated with Blenrep® is a coordinated labor between ophthalmology and haematology departments. At the beginning of the treatment, a regulated baseline examination including visual acuity (VA) and slit lamp examination is performed and a cold mask and artificial tears are provided. Subsequently examination is repeated every 3 weeks, prior to the administration of the next cycle. The ophthalmological findings determine if the next dose can be administered or if it has to be postponed due to a VA loss. The evolution of three patients undergoing Blenrep® treatment was analysed, using anterior segment photography and OCT.Results: 31–92% of the patients on Blenrep® develop ocular events. In our case, the three patients studied developed epitheliopathy during the follow up. One of them, after 2 months, presented a VA loss due to MEC affecting visual axis that required next dose administration delay following haematologist's recommendation. After that period, the microcysts disappeared and VA was recovered. The other two patients also developed MEC, but did not need modification of the scheme since VA was not affected.Conclusions: Blenrep® has proved to be effective on the treatment of triple‐class refractory MM. Its principal adverse event is the appearance of MEC, which in some cases may impair the VA. This effect is reversible with the disappearance of the microcysts with the corneal epithelial regeneration cycle by prolonging the interval between the doses.

Eight years follow‐up of two choroideremia patients with a new mutation of the choroideremia gene

AbstractPurpose: Choroideremia (CHM) is an inherited retinal dystrophy with an X‐linked inherited patron. It presents changes in the outer retina and choroid. CHM has a typical fundus appearance with preservation of the central retina, that progresses over the years. Fundus autofluorescence (FAF) shows the changes in the pigment distribution not only in patients but also in carriers. We present an 8‐year follow‐up of two boys affected by the disease.Methods: We studied a family with two cousins referring visual loss and nyctalopia and presented clinical findings of CHM at 11 and 10 years old. Their mothers referred that their deceased father had an important loss of visual acuity (VA) and that he had been diagnosed of Retinitis Pigmentosa. They were diagnosed of CHM with an undescribed mutation in the CHM gene c.1083_1084dupT (p.L362Sfs*56) at the Xp21.2 location. We present the patients and the carriers follow‐up.Results: During 8 years one of the patients had a progressive loss of VA. He presented a high myopic refraction and retinal changes that could be related to both conditions. His macular function decreased during the years with loss of retinal sensitivity evaluated by MAIA microperimetry, with Multifocal ERG showing a marked diminution on the central peak. His cousin has not presented important changes during the follow‐up time, preserving macular sensitivity and central visual field. Both mothers show a different AF pattern, with one geographic pattern and another sparse mottled on periphery. Carriers have not changed during these 8 years, neither in their retinal function nor in the anatomical findings.Conclusions: Evolution in CHM disease could differ in patients affected by the same mutation. Myopic defect may increase the retinal damage, with a more aggressive evolution.

Motion sickness susceptibility and visually induced motion sickness as diagnostic signs in Parkinson's disease.

Postural instability and loss of vestibular and somatosensory acuity can be part of the signs encountered in Parkinson's Disease (PD). Visual dependency is described in PD. These modifications of sensory input hierarchy are predictors of motion sickness (MS). The aim of this study was to assess MS susceptibility and effects of real induced MS in posture. 63 PD patients, whose medication levels (levodopa) reflected the pathology were evaluated, and 27 healthy controls, filled a MS questionnaire; 9 PD patients and 43 healthy controls were assessed by posturography using virtual reality. Drug amount predicted visual MS (p=0.01), but not real induced MS susceptibility. PD patients did not experience postural instability in virtual reality, contrary to healthy controls. Since PD patients do not seem to feel vestibular stimulated MS, they may not rely on vestibular and somatosensory inputs during the stimulation. However, they feel visually induced MS more with increased levodopa drug effect. Levodopa amount can increase visual dependency. The strongest MS predictors must be studied in PD to better understand the effect of visual stimulation and its absence in vestibular stimulation.

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.

Retinal involvement in mitochondrial disease

AbstractRetinal involvement in mitochondrial disease is a variable feature of mitochondrial dysfunction. The retinal pigment epithelium and photoreceptor layers can both be affected. It manifests with signs ranging from asymptomatic peripheral salt‐and‐pepper retinopathy to classic bone‐spicule pigmentary changes. The consequences can be progressive mild or severe visual field constriction and central visual acuity loss. The pathophysiological mechanisms involved in retinal dysfunction in mitochondrial disease are still being elucidated and may include a range of metabolic and bioenergetic defects.Mitochondrial conditions affecting the eye that display prominent outer retinal involvement include.(a) mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) secondary to the m.3243A > G mtDNA mutation in MT‐TL1,(b) neuropathy, ataxia and retinitis pigmentosa (NARP) secondary to the m.8993 T > G mtDNA mutation in MT‐ATP6,(c) chronic progressive external ophthalmoplegia (CPEO), in particular the Kearns‐Sayre syndrome (KSS) secondary to single large‐scale mtDNA deletions, and.(d) some newer entities, such as optic neuropathy and pigmentary retinopathy seen in patients with mutations in the gene SSBP1.The features and diagnostic pathway for these conditions will be illustrated and discussed.

Impact of induced pseudomyopia and refractive fluctuations of accommodative spasm on visual acuity

ABSTRACT Clinical relevance High-contrast visual acuity is disproportionately poor in patients with accommodative spasm subtype of near reflex (SNR-A), relative to uncorrected refractive errors of equivalent magnitude. This exaggerated loss of performance in SNR-A may be explained by the combination of pseudomyopia and its fluctuations, vis-à-vis, each factor considered separately. Background To determine how combinations of pseudomyopic refraction and its temporal variations in SNR-A impact high-contrast visual acuity by inducing these patterns in healthy cyclopleged adults, relative to their baseline acuity. Methods Refractive profiles of 15 patients with SNR-A were obtained from a previous study, averaged, and induced before the right eye of 14 cyclopleged adults (mean ±1 SD age: 22.7 ± 2.6 yrs) by feeding the profile into a coaxially placed, motorised, Badal optometer. LogMAR acuity was measured using the method of constant stimuli: (1) before cycloplegia, (2) after cycloplegia and post-cycloplegia with (3) combination of pseudomyopia and its temporal fluctuations, (4) only pseudomyopia, (5) only temporal fluctuations in refraction about emmetropia, (6) condition 5 with double the amplitude of induced fluctuations and (7) condition 5 with half the amplitude of induced fluctuations. Results The induced refractive fluctuations ranged from −0.80 to −1.75D, around a mean pseudomyopia of −1.20D. Visual acuity deterioration was maximum for the combination of pseudomyopia and temporal fluctuations condition (0.51 ± 0.07logMAR), followed by only pseudomyopia (0.27 ± 0.05logMAR) and only refractive fluctuations conditions (0.17 ± 0.04logMAR), all relative to baseline post-cycloplegia (0.13 ± 0.04logMAR) (p < 0.001). Visual acuity loss increased with doubling of refractive fluctuations (0.20 ± 0.04logMAR), relative to native fluctuations or halving the amplitude (0.15 ± 0.03logMAR) (p < 0.01). Task precision, as adjudged from the slope of psychometric function, followed a similar pattern of loss as visual acuity. Conclusion Combination of induced pseudomyopia and temporal fluctuations in refraction produces an additive loss of visual acuity and task precision, relative to baseline and each factor considered separately.

Keeping an Eye on Belantamab: Characterizing Ocular Toxicities

Background: Belantamab mafodotin is an anti-BCMA monoclonal antibody conjugated to a microtubule inhibitor that is approved for the treatment of relapsed refractory multiple myeloma in patients after 4 prior lines of therapy. It has shown efficacy in these late-relapse patients as a single agent, but has been associated with ocular toxicity, a unique adverse effect not seen with other anti-myeloma therapies. In addition to dry eyes, belantamab associated ocular toxicity can manifest as loss of visual acuity and/or keratopathy. Visual acuity is the eye's ability to distinguish shapes and details at a given distance and keratopathy refers to microcyst-like epithelial changes which may cause patients to experience irritation, tearing, foreign body sensation or blurred vision. Methods: This was a single-center, retrospective, observational study assessing patients who received at least one dose of belantamab from June 2015 to June 2021 at Dana-Farber Cancer Institute (DFCI). We preformed a chart review to determine the incidence and severity of ocular toxicities with belantamab and the resulting management. This includes dose reductions, treatment delays, and therapy discontinuations that resulted from ocular toxicity. Secondary objectives include efficacy of belantamab regimens including response rate, duration of response, progression-free survival, and overall survival. Results: Forty patients received at least one dose of belantamab at DFCI who were included in the analysis. High risk cytogenetics were found in 13 patients (33%) and 10 patients (25%) had extramedullary disease. History of ocular disease was found in 26 patients (65%). Thirty-eight patients (95%) received belantamab as monotherapy while 2 patients (5%) received as a combination regimen. Eight patients (20%) received one dose and the remaining 32 patients (80%) received at least 2 doses. Only 14 patients (35%) received ≥3 doses. Among patients that received at least 2 doses, 21 patients (66%) developed ocular toxicity (Figure 1). The median time to onset of ocular toxicity was 2 cycles (1 - 7) (Table 1). Dose delays occurred in 16 patients (40%) which were all due to ocular toxicity. Any grade keratopathy was found in 41% of patients and loss of visual acuity was found in 35% of patients. In total, 27 patients (67.5%) discontinued therapy, 18 patients (45%) due to progressive disease, 7 (17.5%) due to ocular toxicity, and 2 patients (5%) due to both ocular toxicity and progressive disease. Additionally, 6 patients (15%) died while on treatment. History of ocular disease did not corelate with belantamab related ocular toxicity. Single agent belantamab showed a meaningful response as the overall response rate (ORR) was 34% in this heavily pretreated population but due to frequent cases of ocular toxicity, there were treatment delays, dose reductions and progression of disease while therapy needed to be held. Conclusions: This retrospective study confirms that belantamab mafodotin leads to a clinically meaningful response in a heavily pre-treated patient population. However, ocular toxicity affected two-thirds of patients who received at least 2 doses. This led to frequent treatment delays, dose reductions, and in some cases progression of disease. More long-term research is needed regarding the feasibility of alternative dosing strategies that could mitigate the ocular toxicity, such as prolonged intervals or cycle lengths, as well as combination with other anti-myeloma therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hdp-101, an Anti-BCMA Antibody-Drug Conjugate with a Novel Payload Amanitin in Patients with Relapsed Multiple Myeloma, Initial Findings of the First in Human Study

Several antibody-drug conjugates (ADCs) are currently being evaluated in clinical trials in a variety of malignancies. Vast majority of these ADCs are based on a few toxic compounds, largely limited to microtubule- or DNA-targeting toxins targets proliferating cells and have limited efficacy in diseases with a low proliferative fraction such as multiple myeloma. Thus, new compounds with alternative mode of actions and the ability to actively induce cell death in non-proliferating tumor cells could enhance the therapeutic potential of ADCs. We are currently developing amanitin based ADCs. Amanitin specifically inhibits RNA polymerase II thereby inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell. Subsequently tumor cells enter apoptosis and are eliminated. HDP-101 is a new ADC targeting BCMA (B cell maturation antigen) carrying a synthetic version of amanitin as a payload. In vitro cytotoxic potency of HDP-101 was demonstrated on BCMA-positive myeloma cell lines, as well as on non-proliferating primary CD138+ cells isolated from patients with refractory myeloma. Furthermore, the cytotoxic effects of HDP-101 were seen even in non-proliferating myeloma cells with low BCMA density. Toxicity was observed neither in non-BCMA expressing control cells nor in myeloma cells exposed to an amanitin-loaded non-target control antibody. In murine xenograft models of human myeloma, HDP-101 caused dose-dependent tumor regression including complete remissions after a single dose in subcutaneous and as well as in disseminated models. Safety profiling in Cynomolgus monkeys revealed a good therapeutic index after repeated dosing. Our non-clinical studies concluded that this amanitin-based ADC is a novel promising approach in the therapy of multiple myeloma to overcome drug resistance and improve patient outcome. HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial with HDP-101 in patients with multiple myeloma whose disease has progressed. The aim of the Phase 1 dose escalation part is to determine the Maximum Tolerated Dose and/or establish the Recommended phase 2 Dose. The primary objective of the phase 2 dose expansion phase is to assess the preliminary anti-tumor activity of HDP-101. An adaptive Bayesian logistic regression model with overdose control principle is used to guide the dose escalation steps. An Interim Analysis is planned after each cohort is completed. The design of the study ensures a safe and adaptive dose escalation to reach a potential clinical benefit in a patient who have limited or no therapeutic options. The study started enrollment in February 2022. As of 12th of July 2022 four (1 female and 3 male) patients were dosed in 2 consecutive dose cohorts. The median age of the patients was 63.5 years, ranging between 51 and 80. All 4 patients were heavily pre-treated and multidrug-resistant. The median previous lines of treatment were 11 (5 to 16). Three of 4 patients were evaluable for dose limiting toxicities (DLT). The initial 2 cohorts were well tolerated, without any reports on DLTs. No reports of keratopathy or visual acuity loss were observed. Free payload was not detected in any of the available pharmacokinetic samples. In line with our expectation objective responses also were not reported in these initial cohorts. The initial dose cohorts showed good tolerability in late stage relapsed and/or refractory multiple myeloma patients. The study continues to enroll patient to higher dose cohorts. An updated dataset will be presented at the ASH2022 meeting.

A brief review of Valsalva retinopathy

Background: Valsalva retinopathy is a specific type of retinopathy that appears following an acute rise in intrathoracic or intra-abdominal pressure. This review focuses on current literature and future directions for the diagnosis and management of Valsalva retinopathy.&#x0D; Methods: In this brief review, the literature was searched to provide an extensive general and updated description of Valsalva retinopathy, focusing on its management and prognosis. Selected articles are summarized to present the etiology, general pathology, pathophysiology, symptoms, signs, diagnosis, differential diagnosis, treatment, and prognosis of Valsalva retinopathy.&#x0D; Results: The main symptom of Valsalva retinopathy is loss of visual acuity following exertion. This is caused by the rupture of small superficial vessels in the macula and perimacular areas, leading to extravasation of blood. No link between age, sex, or race has been found, although fundus vessel abnormalities pose some predisposition to the disease. During fundoscopy, Valsalva retinopathy appears most frequently as well-defined preretinal hemorrhages confined to the sub-internal limiting membrane (ILM) or subhyaloid space. If ILM rupture occurs, hyaloid hemorrhage can appear. Diagnosis is based on the patient’s medical history and a standard examination. Usually, only observation of the patient is required, with the hemorrhage resolving within weeks to months. In cases of large premacular hemorrhage or large sub-ILM/subhyaloid hemorrhage, vitrectomy or Nd:YAG krypton laser membranotomy can be performed.&#x0D; Conclusions: Of all the aspects of Valsalva retinopathy that might trouble the physician, the most challenging features are differential diagnosis and the choice of optimal treatment. Therapeutic strategies for Valsalva retinopathy can be either conservative or based on Nd:YAG laser membranotomy and/or vitrectomy. All methods seem to have good outcomes. However, physicians should not be afraid of advancing beyond conservative therapy, especially in the event of persistent premacular hemorrhage, which could lead to permanent retinal damage if valuable time is lost, even after vitrectomy.

Resting-state functional MRI of the visual system for characterization of optic neuropathy.

Optic neuropathy refers to disease of the optic nerve and can result in loss of visual acuity and/or visual field defects. Combining findings from multiple fMRI modalities can offer valuable information for characterizing and managing optic neuropathies. In this article, we review a subset of resting-state functional magnetic resonance imaging (RS-fMRI) studies of optic neuropathies. We consider glaucoma, acute optic neuritis (ON), discuss traumatic optic neuropathy (TON), and explore consistency between findings from RS and visually driven fMRI studies. Consistent with visually driven studies, glaucoma studies at rest also indicated reduced activation in the visual cortex and dorsal visual stream. RS-fMRI further reported varying levels of functional connectivity in the ventral stream depending on disease severity. ON patients show alterations within the visual cortex in both fMRI techniques. Particularly, higher-than-normal RS activity is observed in the acute phase and decreases as the disease progresses. A similar pattern is observed in the visual cortex of TON-like, open globe injury (OGI), patients. Additionally, visually driven and RS-fMRI studies of ON patients show recovery of brain activity in the visual cortex. RS-fMRI suggests recovery of signals in higher-tier visual areas MT and LOC as well. Finally, RS-fMRI has not yet been applied to TON, although reviewing OGI studies suggests that it is feasible. Future RS-fMRI studies of optic neuropathies could prioritize studying the fine scale RS activity of brain areas that visually driven studies have identified. We suggest that a more systematic longitudinal comparison of optic neuropathies with advanced fMRI would provide improved diagnostic and prognostic information.

Biomarkers of Allostatic Load in Patients with Diabetic Retinopathy

Diabetic retinopathy occupies a special place among the causes of the progression of decrease and loss of visual acuity, significantly impairing the quality of life and age-related viability, an integral indicator that is considered allostatic load. However, the allostatic load in patients suffering from diabetic retinopathy, as well as in other ophthalmological diseases, has not been practically studied and biomarkers characterizing the allostatic load of patients with diabetic retinopathy remain unknown.Purpose. To study of allostatic load in patients with diabetic retinopathy and the identification of biomarkers that most determine it.Patients and methods. Allostatic load was studied in 78 elderly patients with diabetic retinopathy and in 62 patients with type 2 diabetes mellitus without diabetic retinopathy. Allostatic load was analyzed according to systolic and diastolic blood pressure, body mass index, glycated hemoglobin, total cholesterol, triglycerides, albumins, C-reactive protein, homocysteine in the blood and glomerular filtration rate.Results. The most pronounced and statistically significant excess in patients with diabetic retinopathy compared with patients with diabetes mellitus without diabetic retinopathy was found to be the content of glycated hemoglobin in the blood up to 10.2 % versus 7.4 % and homocysteine up to 15.5 mmol/l versus 7.9 mmol/l, respectively. The value of the allostatic index was significantly higher in patients with diabetic retinopathy, amounting to 4.6 ± 0.4 points, versus 2.9 ± 0.3 points in patients with diabetes mellitus without ophthalmopathology under consideration (p &lt; 0.001). Factor analysis made it possible to identify biomarkers of allostatic load in patients with diabetic retinopathy — glycated hemoglobin, homocysteine, triglycerides and albumins.Conclusion. These biomarkers are proposed to be used in assessing the age-related viability and effectiveness of rehabilitation measures carried out among patients with diabetic retinopathy.

Retinal Structure and Function in a Knock-in Mouse Model for the FAM161A-p.Arg523∗ Human Nonsense Pathogenic Variant

Pathogenic variants in FAM161A are the most common cause of retinitis pigmentosa in Israel. Two founder pathogenic variants explain the vast majority of cases of Jewish origin, 1 being a nonsense variant (p.Arg523∗). The aim of this study was to generate a knock-in (KI) mouse model harboring the corresponding p.Arg512∗ pathogenic variant and characterize the course of retinal disease. Experimental study of a mouse animal model. A total of 106 Fam161a knock-in mice and 29 wild-type mice with C57BL/6J background particiapted in this study. Homozygous Fam161a p.Arg512∗ KI mice were generated by Cyagen Biosciences. Visual acuity (VA) was evaluated using optomotor tracking response and retinal function was assessed by electroretinography (ERG). Retinal structure was examined invivo using OCT and fundus autofluorescence imaging. Retinal morphometry was evaluated by histologic and immunohistochemical (IHC) analyses. Visual and retinal function assessments, clinical imaging examinations, quantitative histology, and IHC studies of KI as compared with wild-type (WT) mice retinas. The KI model was generated by replacing 3 bp, resulting in p.Arg512∗. Homozygous KI mice that had progressive loss of VA and ERG responses until the age of 18 months, with no detectable response at 21 months. OCT showed complete loss of the outer nuclear layer at 21 months. Fundus autofluorescence imaging revealed progressive narrowing of blood vessels and formation of patchy hyper-autofluorescent and hypo-autofluorescent spots. Histologic analysis showed progressive loss of photoreceptor nuclei. Immunohistochemistry staining showed Fam161a expression mainly in photoreceptors cilia and the outer plexiform layer (OPL) in WT mice retinas, whereas faint expression was evident mainly in the cilia and OPL of KI mice. The Fam161a - p.Arg512∗ KI mouse model is characterized by widespread retinal degeneration with relatively slow progression. Surprisingly, disease onset is delayed and progression is slower compared with the previously reported knock-out model. The common human null mutation in the KI mouse model is potentially amenable for correction by translational read-through-inducing drugs and by gene augmentation therapy and RNA editing, and can serve to test these treatments as a first step toward possible application in patients. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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.

Mental health and visual acuity in patients with age-related macular degeneration

BackgroundVisual acuity (VA) loss has been associated with depression in patients with age-related macular degeneration (AMD). However, previous studies did not incorporate subgroups of AMD when correlating VA and mental health. The goal of this study was to describe the relationship between VA and mental health questions in patients with different classifications of AMD, and to identify associations of mental health subscale scores.MethodsAMD patients classified by multi-modal imaging were recruited into an AMD registry. Habitual VA was obtained by ophthalmic technicians using the Snellen VA at distance. At enrollment, patients completed the NEI-VFQ-25, which includes 25 questions regarding the patient’s visual functionality. Median with interquartile-range (IQR) scores on the mental health subscale of the VFQ were calculated by AMD classification and VA groups. Univariate and multivariable general linear models were used to estimate associations between mental health scores and variables of interest.ResultsEight hundred seventy-five patients were included in the study. Patients with bilateral geographic atrophy (GA) or bilateral GA and neovascular (NV) AMD scored lowest on the mental health subscales with a median (IQR) of 58.2 (38–88) and 59.3 (38–88). When stratified by VA, patients with a habitual VA of 20/200 or worse scored the lowest on mental health subscales scores: median of 43.8 (IQR: 31–62). Patients with a VA of 20/20 scored the highest: 87.5 (IQR: 81–94). Habitual VA of the better- and worse-seeing eye and AMD classification were significantly associated with mental health subscale scores (all p < 0.0001 in both the univariate and multivariable analysis, except the VA of the worse-seeing eye in multivariable model p = 0.027). Patients enrolled during the COVID pandemic had mental health scores that were 2.7 points lower than prior to the pandemic, but this difference was not significant in univariate (p = 0.300) or multivariable analysis (p = 0.202).ConclusionThere is a significant association between mental health questionnaire scores and AMD classification, as well as VA in both the better and worse-seeing eyes in patients with AMD. It is important for clinicians to recognize feelings of worry/ frustration in these patients, so they can be appropriately referred, screened, and treated for mental health problems.

Femtoassisted posterior lamellar keratoplasty in bullous keratopathy of stage IV–V (clinical application experience)

BACKGROUND: Bullous keratopathy is a chronic edema of the cornea, accompanied by a significant visual acuity loss and pain. The cause of bullous keratopathy is a pathological irreversible decrease in the number of endothelial cells, in which the endothelial layer cannot perform its main barrier and pumping functions.&#x0D; AIM: To evaluate the reproducibility and functional results of femto-assisted posterior lamellar keratoplasty using intraoperative OCT at the stage IVV of bullous keratopathy.&#x0D; MATERIALS AND METHODS: The study was conducted on 23 eyes of 23 patients diagnosed with stage IVV of bullous keratopathy. The mean age of patients was 69 12 years, there were 14 male patients and 9 female patients. Before surgery, light perception with correct light projection was recorded in 15 cases, in 5 cases the count of fingers at the face (0.005), in 3 cases visual acuity was 0.01. The central corneal thickness varied from 981 m to 1960 m and averaged 1008 96 m. Femto LDV Z8 femtosecond laser (Ziemer, Switzerland) was used to form an endothelial graft. All surgeries were performed using the Hi-R Neo 900 operating microscope with an integrated third-generation OCT module (Haag-Streit Surgical, Germany).&#x0D; RESULTS: No intraoperative complications were noted. The presence of objective control in the form of intraoperative OCT made it possible in all cases to clearly differentiate stromal and endothelial surfaces of the posterior layered graft located in the anterior chamber of the eye. The postoperative course was standard for posterior lamellar keratoplasty, accompanied by resorption of corneal edema with restoration of its transparency. The normalization of corneal thickness was noted by 1 month after surgery, and the restoration of corneal optical properties was noted by 36 months and was accompanied by gradual increase in visual acuity. Corrected visual acuity by 1 month was 0.05 0.03, by 3, 6, 12 months 0.1 0.05, 0.15 0.05 and 0.15 0.04, respectively. By 12 months after surgery, the central corneal thickness was 596 42 m, the thickness of the ultrathin graft tended to decrease somewhat to 67 8 m, the loss of endothelial cells was 59.3%. Endothelial graft survival was achieved in 82.6% of cases.&#x0D; CONCLUSIONS: The use of intraoperative OCT allows expanding the indications for posterior lamellar keratoplasty in bullous keratopathy, including the stage IVV of the disease.

Developing decision support tools incorporating personalised predictions of likely visual benefit versus harm for cataract surgery: research programme

Developing decision support tools incorporating personalised predictions of likely visual benefit versus harm for cataract surgery: research programme