Association of dark-adapted visual function with retinal structural changes in patients with Stargardt disease.

PURPOSE: To evaluate dark-adapted retinal sensitivity in patients with Stargardt disease (STGD1) using a modified MP-1 microperimeter and to compare the sensitivity loss with structural changes observed using spectral domain optical coherence tomography and confocal scanning laser ophthalmoscope infrared imaging. METHODS: Twelve STGD1 patients and 10 normally sighted controls participated. Dark-adapted mean sensitivity (MS) was obtained using a MP-1 microperimeter. Additionally, MS percent difference between the patients and the controls was obtained. Sensitivity results were superimposed on confocal scanning laser ophthalmoscope infrared images and compared with corresponding spectral domain optical coherence tomography scans. RESULTS: Dark-adapted MS ± standard deviation was 8.34 ± 1.54 dB for the controls and 3.68 ± 1.74 dB for STGD1 patients (P < 0.001). There was a significant reduction in MS of 24.0% in these patients. Sensitivity reductions were observed in areas that showed changes on confocal scanning laser ophthalmoscope infrared images and on spectral domain optical coherence tomography, including disorganizational loss of the retinal pigment epithelium, and abnormal photoreceptor inner segment ellipsoid and external limiting membrane reflectance bands. CONCLUSION: With topographical accuracy, dark-adapted MS measurements can be made in STGD1 patients and controls using the MP-1 microperimeter. Sensitivity loss is associated with structural changes. This finding can be useful for the determination of optimal areas for potential improvement of retinal function in patients with Stargardt disease.

PolySialic Acid Nanoparticles Actuate Complement-Factor-H-Mediated Inhibition of the Alternative Complement Pathway: A Safer Potential Therapy for Age-Related Macular Degeneration.

The alternative pathway of the complement system is implicated in the etiology of age-related macular degeneration (AMD). Complement depletion with pegcetacoplan and avacincaptad pegol are FDA-approved treatments for geographic atrophy in AMD that, while effective, have clinically observed risks of choroidal neovascular (CNV) conversion, optic neuritis, and retinal vasculitis, leaving room for other equally efficacious but safer therapeutics, including Poly Sialic acid (PSA) nanoparticle (PolySia-NP)-actuated complement factor H (CFH) alternative pathway inhibition. Our previous paper demonstrated that PolySia-NP inhibits pro-inflammatory polarization and cytokine release. Here, we extend these findings by investigating the therapeutic potential of PolySia-NP to attenuate the alternative complement pathway. First, we show that PolySia-NP binds CFH and enhances affinity to C3b. Next, we demonstrate that PolySia-NP treatment of human serum suppresses alternative pathway hemolytic activity and C3b deposition. Further, we show that treating human macrophages with PolySia-NP is non-toxic and reduces markers of complement activity. Finally, we describe PolySia-NP-treatment-induced decreases in neovascularization and inflammatory response in a laser-induced CNV mouse model of neovascular AMD. In conclusion, PolySia-NP suppresses alternative pathway complement activity in human serum, human macrophage, and mouse CNV without increasing neovascularization.

Comprehensive Ocular and Systemic Safety Evaluation of Polysialic Acid-Decorated Immune Modulating Therapeutic Nanoparticles (PolySia-NPs) to Support Entry into First-in-Human Clinical Trials.

An inflammation-resolving polysialic acid-decorated PLGA nanoparticle (PolySia-NP) has been developed to treat geographic atrophy/age-related macular degeneration and other conditions caused by macrophage and complement over-activation. While PolySia-NPs have demonstrated pre-clinical efficacy, this study evaluated its systemic and intraocular safety. PolySia-NPs were evaluated in vitro for mutagenic activity using Salmonella strains and E. coli, with and without metabolic activation; cytotoxicity was evaluated based on its interference with normal mitosis. PolySia-NPs were administered intravenously in CD-1 mice and Sprague Dawley rats and assessed for survival and toxicity. Intravitreal (IVT) administration in Dutch Belted rabbits and non-human primates was assessed for ocular or systemic toxicity. In vitro results indicate that PolySia-NPs did not induce mutagenicity or cytotoxicity. Intravenous administration did not show clastogenic activity, effects on survival, or toxicity. A single intravitreal (IVT) injection and two elevated repeat IVT doses of PolySia-NPs separated by 7 days in rabbits showed no signs of systemic or ocular toxicity. A single IVT inoculation of PolySia-NPs in non-human primates demonstrated no adverse clinical or ophthalmological effects. The demonstration of systemic and ocular safety of PolySia-NPs supports its advancement into human clinical trials as a promising therapeutic approach for systemic and retinal degenerative diseases caused by chronic immune activation.

Characteristics of late negative ERG responses elicited by sawtooth flicker.

BACKGROUND: This study aimed to determine whether the properties of the late negative responses (LNRs) of the electroretinogram (ERG) elicited by sawtooth flicker are consistent with the characteristics of the photopic negative response generated by a light pulse (PhNRpulse). METHODS: ERG recordings were obtained from 10 visually normal individuals and from 6 patients with optic atrophy (OA) in response to 8-Hz rapid-on and rapid-off sawtooth flicker and to brief (4 ms) light pulses. All stimuli were either long wavelength (R), middle wavelength (G), or a combination of equal luminances of long and middle wavelengths (Y) presented on a short-wavelength, rod-saturating adapting field. Amplitudes of LNRs were obtained in response to rapid-on (LNRon) and rapid-off (LNRoff) sawtooth flicker and were also derived from the sum of the ERG waveforms to the two sawtooth phases (LNRadd). RESULTS: For the control subjects, PhNRpulse amplitude varied with stimulus wavelength, being largest in response to a long-wavelength pulse, as expected. However, the amplitudes of LNRon, LNRoff, and LNRadd were not significantly different for R, Y, and G sawtooth flicker. Despite the absence of a chromatic effect, LNRoff and LNRadd amplitudes were significantly smaller in the OA patients than in the controls, similar to the results for the PhNRpulse, implying an inner retinal origin for the LNRoff and LNRadd. However, LNRon amplitudes did not differ significantly between the OA patients and controls, although there was a significant correlation between the LNRon and PhNRpulse for R stimuli. CONCLUSION: We conclude that LNRoff and LNRadd but not LNRon can be useful measures to assess the integrity of the inner retina that can complement the PhNRpulse.

Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD), a leading cause of visual loss and dysfunction worldwide, is a disease initiated by genetic polymorphisms that impair the negative regulation of complement. Proteomic investigation points to altered glycosylation and loss of Siglec-mediated glyco-immune checkpoint parainflammatory and inflammatory homeostasis as the main determinant for the vision impairing complications of macular degeneration. The effect of altered glycosylation on microglial maintained retinal para-inflammatory homeostasis and eventual recruitment and polarization of peripheral blood monocyte-derived macrophages (PBMDMs) into the retina can explain the phenotypic variability seen in this clinically heterogenous disease. Restoring glyco-immune checkpoint control with a sialic acid mimetic agonist targeting microglial/macrophage Siglecs to regain retinal para-inflammatory and inflammatory homeostasis is a promising therapeutic that could halt the progression of and improve visual function in all stages of macular degeneration.

PolySialic acid-nanoparticles inhibit macrophage mediated inflammation through Siglec agonism: a potential treatment for age related macular degeneration.

Age-related macular degeneration (AMD) is a chronic, progressive retinal disease characterized by an inflammatory response mediated by activated macrophages and microglia infiltrating the inner layer of the retina. In this study, we demonstrate that inhibition of macrophages through Siglec binding in the AMD eye can generate therapeutically useful effects. We show that Siglecs-7, -9 and -11 are upregulated in AMD associated M0 and M1 macrophages, and that these can be selectively targeted using polysialic acid (PolySia)-nanoparticles (NPs) to control dampen AMD-associated inflammation. In vitro studies showed that PolySia-NPs bind to macrophages through human Siglecs-7, -9, -11 as well as murine ortholog Siglec-E. Following treatment with PolySia-NPs, we observed that the PolySia-NPs bound and agonized the macrophage Siglecs resulting in a significant decrease in the secretion of IL-6, IL-1ß, TNF-α and VEGF, and an increased secretion of IL-10. In vivo intravitreal (IVT) injection of PolySia-NPs was found to be well-tolerated and safe making it effective in preventing thinning of the retinal outer nuclear layer (ONL), inhibiting macrophage infiltration, and restoring electrophysiological retinal function in a model of bright light-induced retinal degeneration. In a clinically validated, laser-induced choroidal neovascularization (CNV) model of exudative AMD, PolySia-NPs reduced the size of neovascular lesions with associated reduction in macrophages. The PolySia-NPs described herein are therefore a promising therapeutic strategy for repolarizing pro-inflammatory macrophages to a more anti-inflammatory, non-angiogenic phenotype, which play a key role in the pathophysiology of non-exudative AMD.

Health diplomacy in action: The cancer legacy of the Good Friday Agreement.

2023 marks the 25th anniversary of the Good Friday Agreement, which led peace in Northern Ireland. As well as its impact on peace and reconciliation, the Good Friday Agreement has also had a lasting positive impact on cancer research and cancer care across the island of Ireland. Pursuant to the Good Friday Agreement, a Memorandum of Understanding (MOU) was signed between the respective Departments of Health in Ireland, Northern Ireland and the US National Cancer Institute (NCI), giving rise to the Ireland - Northern Ireland - National Cancer Institute Cancer Consortium, an unparalleled tripartite agreement designed to nurture and develop linkages between cancer researchers, physicians and allied healthcare professionals across Ireland, Northern Ireland and the US, delivering world class research and better care for cancer patients on the island of Ireland and driving research and innovation in the US.

Topical dorzolamide for treatment of cystoid macular edema in patients with choroideremia.

PURPOSE: : To determine the value of a topical carbonic anhydrase inhibitor on the macular thickness and function in choroideremia patients with cystoid macular edema. METHODS: : Two choroideremia patients with cystoid macular edema, observed by spectral-domain optical coherence tomography, were treated with a topical form of carbonic anhydrase inhibitor. Examinations performed before and during treatment included best-corrected visual acuity by using the Early Treatment Diabetic Retinopathy Study charts and contrast sensitivity measured with briefly presented grating targets and the Pelli-Robson letter contrast sensitivity chart, microperimetry, and spectral-domain optical coherence tomography. RESULTS: : The 2 choroideremia patients treated with dorzolamide 2% formulation had a noticeable reduction in macular thickness by spectral-domain optical coherence tomography. This reduction was found in both eyes after 2 months of treatment. After an additional 3 months of the same treatment regimen, a more noticeable reduction in macular thickness was observed. The two study patients had improvement of their visual acuity, in at least one eye, on Early Treatment Diabetic Retinopathy Study charts, but no clinically significant changes for the other measures of visual function. CONCLUSION: : The present study shows the potential efficacy of topical dorzolamide for treating choroideremia patients with cystoid macular edema.

Evaluation of retinal nerve fiber layer thickness in patients with retinitis pigmentosa using spectral-domain optical coherence tomography.

PURPOSE: To measure the peripapillary retinal nerve fiber layer (RNFL) thickness using spectral-domain optical coherence tomography in patients with retinitis pigmentosa. METHODS: Fifty eyes of 30 patients with retinitis pigmentosa underwent a complete ocular examination, including best-corrected visual acuity using a Snellen chart, slit-lamp biomicroscopic examination, and Goldmann applanation intraocular pressure measurement. Dilated fundus examination was performed using both direct and indirect ophthalmoscopy. In addition, all patients underwent peripapillary RNFL thickness measurements using an OPKO spectral-domain optical coherence tomography (OPKO Instrumentations, Miami, FL). RESULTS: The mean (± SD) age of the study cohort was 45.8 (± 16.3) years. Of the 50 eyes, 18 (36%) showed a thinning of the peripapillary RNFL in 1 or more quadrants and 21 (42%) showed a thickening of the peripapillary RNFL in 1 or more quadrants. Four eyes (8%) showed both thinning and thickening of the peripapillary RNFL thickness. The overall circumferential RNFL thickness of the 14 eyes that showed only thinning in at least 1 quadrant was 78.78 µm. For the 17 eyes that showed only thickening in at least 1 quadrant, the RNFL thickness was 119.69 µm. The values of the eyes with thinning and the eyes with thickening were significantly different from normal (t = 6.31 and P < 0.01 for thickening; t = 3.62 and P < 0.01 for thinning). CONCLUSION: Using spectral-domain optical coherence tomography testing, we demonstrated in the current study that the peripapillary RNFL thickness in patients with RP can be decreased, increased, or maintained within normal limits. Assessment of the RNFL thickness seems prudent in these patients, particularly for identifying notable degrees of RNFL thinning in those being considered for future therapeutic trials.

Visual acuity loss in recessive retinitis pigmentosa and its correlation with macular lesions.

PURPOSE: To determine the visual acuity loss in patients with autosomal recessive retinitis pigmentosa and its relation to the presence of macular lesions. METHODS: A total of 145 patients were included in the visual acuity analysis, and 139 patients were included in the analysis of their macular status. Patients with a history of parental consanguinity or an affected sister and parents unaffected with retinitis pigmentosa were considered as having an autosomal recessive mode of inheritance. RESULTS: Regardless of age, 68 patients (47%) had visual acuity of 20/40 or better, 109 (75%) had better than 20/200 in at least 1 eye, and 36 (25%) had an acuity of 20/200 or worse in both eyes. An evaluation of the macular status demonstrated that 55 patients (39.6%) had no macular lesion and 77 (55.4%) had an atrophic lesion (either bull's-eye or geographic). Seventy-five percent of patients with no macular lesion had a visual acuity of 20/40 or better and 34 patients (44%) with an atrophic lesion had a visual acuity better than 20/70. CONCLUSION: These data can be useful to counsel patients on the potential visual acuity impairment likely to be observed at different ages and identify the association of visual acuity loss with macular changes.

Infrared scanning laser ophthalmoscope imaging of the macula and its correlation with functional loss and structural changes in patients with stargardt disease.

PURPOSE: To correlate the degree of functional loss with structural changes in patients with Stargardt disease. METHODS: Eighteen eyes of 10 patients with Stargardt disease were studied. Scanning laser ophthalmoscope infrared images were compared with corresponding spectral-domain optical coherence tomography scans. Additionally, scanning laser ophthalmoscope microperimetry was performed, and results were superimposed on scanning laser ophthalmoscope infrared images and in selected cases on fundus autofluorescence images. RESULTS: Seventeen of 18 eyes showed a distinct hyporeflective foveal and/or perifoveal area with distinct borders on scanning laser ophthalmoscope infrared images, which was less evident on funduscopy and incompletely depicted in fundus autofluorescence images. This hyporeflective zone corresponded to areas of significantly elevated psychophysical thresholds on microperimetry testing, in addition to thinning of the retinal pigment epithelium and disorganization or loss of the photoreceptor cell inner segment-outer segment junction and external-limiting membrane on spectral-domain optical coherence tomography. CONCLUSION: Scanning laser ophthalmoscope infrared fundus images are useful for depicting retinal structural changes in patients with Stargardt disease. A spectral-domain optical coherence tomography/scanning laser ophthalmoscope microperimetry device allows for a direct correlation of structural abnormalities with functional defects that will likely be applicable for the determination of retinal areas for potential improvement of retinal function in these patients during future clinical trials and for the monitoring of the diseases' natural history.

Efficacy of topical dorzolamide for treatment of cystic macular lesions in a patient with enhanced S-cone syndrome.

The purpose of this study was to evaluate the efficacy of topical dorzolamide 2% eye drops on macular function and thickness in a case of enhanced S-cone syndrome (ESCS). A 24-year-old Asian man with enhanced S-cone syndrome treated with topical dorzolamide in the left eye participated in the study. Examinations performed before and during treatment were included visual acuity (VA), contrast sensitivity measured with briefly presented grating targets (grating CS) and the Pelli-Robson chart (P-R CS), microperimetry (MP), and spectral-domain optical coherence tomography (SD-OCT). Following 4 months of treatment, the mean thickness of the central 1-mm foveal subfield of the left eye, as measured by SD-OCT, decreased from 551 to 242 µm. Mean MP sensitivity within the central 12 degrees (28 points) increased from 9.4 dB at baseline to 11.2 dB. Although Pelli-Robson contrast sensitivity improved only minimally in the left eye, grating contrast sensitivity improved by more than a factor of two. Mean log MAR VA was 0.22 OD and 1.00 OS (at baseline), which improved to 0.10 OD and 0.66 OS after 4 months of treatment. The results indicate that in our patient with enhanced S-cone syndrome, treatment with topical dorzolamide was effective in improving macular thickness, VA, microperimetry sensitivity, and grating contrast sensitivity. These measures of retinal structure and function are sensitive tools for evaluating the effects of treatment in enhanced S-cone syndrome patients with cystoid macular edema. Further investigation is warranted to assess the relationships among visual performance for daily activities, visual sensitivity, and macular thickness.

Macular vitelliform lesion in desferrioxamine-related retinopathy.

To report a case of a macular vitelliform lesion associated with desferrioxamine treatment. Ocular, electrophysiological, psychophysical, perimetric, fluorescein angiographic, fundus autofluorescence, and spectral-domain OCT examinations were obtained on a 45-year-old Caucasian woman with thalassemia major treated with blood transfusions and desferrioxamine. The patient was observed to have a vitelliform macular lesion in the right eye with a hypopigmented macular lesion and retinal pigment mottling in the left. At the most recent follow-up visit, best-corrected visual acuity was 20/70 in the right eye and 20/25 in left. Full-field electroretinogram (ERG) testing showed normal cone and rod responses. Mild localized elevations of rod psychophysical thresholds were found. A vitelliform macular lesion can develop in patients treated with desferrioxamine. Some such patients may not show diffuse photoreceptor cell functional loss as determined by electrophysiological testing.

Structural and functional characteristics in carriers of X-linked retinitis pigmentosa with a tapetal-like reflex.

PURPOSE: The purpose of this study was to identify the functional and structural characteristics in three female obligate carriers of X-linked retinitis pigmentosa from the same family by using spectral domain optical coherence tomography, fundus autofluorescence, and microperimetry. METHODS: Three female obligate carriers with a tapetal-like reflex, 21, 49, and 57 years of age, from a single family of X-linked retinitis pigmentosa that was seen in the ophthalmology department at the University of Illinois at Chicago, were enrolled in the study. All carriers underwent a complete ophthalmic examination. Spectral domain optical coherence tomography measurements, a macular microperimetry examination, and fundus autofluorescence testing were performed. RESULTS: The spectral domain optical coherence tomography examination in all three carriers showed a normal retinal microstructure and thickness. Microperimeter testing showed subnormal retinal sensitivity in the areas of the tapetal-like reflex. Fundus autofluorescence examination showed the presence of speckled areas of enhanced autofluorescence. CONCLUSION: Our study demonstrates that the carriers of X-linked retinitis pigmentosa with a tapetal-like reflex can show an enhanced reflectance on infrared images, abnormal autofluorescence properties, elevated retinal thresholds, and a normal retinal morphology within the posterior pole on spectral domain optical coherence tomography testing.

Fundus white spots and acquired night blindness due to vitamin A deficiency.

To report a successfully treated case of acquired night blindness associated with fundus white spots secondary to vitamin A deficiency. An ocular examination, electrophysiologic testing, as well as visual field and OCT examinations were obtained on a 61-year-old man with vitamin A deficiency who had previously undergone gastric bypass surgery. The patient had a re-evaluation after treatment with high doses of oral vitamin A. The patient was observed to have numerous white spots in the retina of each eye. Best-corrected visual acuity was initially 20/80 in each eye, which improved to 20/40-1 OU after oral vitamin A therapy for 2 months. Full field electroretinogram (ERG) testing, showed non-detectable rod function and a 34 and 41% reduction for 32-Hz flicker and single flash cone responses, respectively, below the lower limits of normal. Both rod and cone functions markedly improved after initiation of vitamin A therapy. Vitamin A deficiency needs to be considered in a patient with white spots of the retina in the presence of poor night vision.

The prevalence of macular cysts in patients with clinical cone-rod dystrophy determined by spectral-domain optical coherence tomography.

BACKGROUND: To determine the prevalence of macular cysts in patients with clinical cone-rod dystrophy (CORD) using spectral-domain optical coherence tomography (SD-OCT). If macular cysts could be demonstrated in such patients, they might benefit from treatment with a carbonic anhydrase inhibitor that has been shown to be effective for treating macular cysts in various night-blinding disorders. MATERIAL AND METHODS: Thirty-six CORD patients underwent a complete ophthalmic examination and an SD-OCT examination using two different systems. The presence of hypo-reflective lacunae was used to determine the presence of macular cysts. RESULTS: The patients' mean age was 42.9 ± 19.5 years (range 6-71 years). Mean BCVA was 1.09 ± 0.64 logMAR (range no light perception to 20/25 + 2 in the better-seeing eye). All the 72 eyes studied showed a variable degree of retinal thinning, disruption of what has been referred to as the inner segment ellipsoid and outer nuclear layer (ONL) thinning of the macula. None showed evidence of macular cysts on OCT testing. CONCLUSIONS: Although macular cysts are a common feature of various hereditary night-blinding retinal dystrophies, these were not identified in our cohort of CORD patients.

Treatment of cystic macular lesions in hereditary retinal dystrophies.

Cystic macular lesions frequently contribute to impaired visual acuity in hereditary retinal dystrophies. Their pathogenesis varies and is not entirely understood. Carbonic anhydrase inhibitors have proven to be potentially efficacious, although not in all cases. We discuss the various factors and mechanisms implicated in the etiology of cystic macular lesions (anatomical abnormalities, impairment of the blood-retinal barrier, tangential vitreous traction, and mutations in retinoschin, etc.) and the various treatments that have been proposed.

Equivalent intrinsic noise, sampling efficiency, and contrast sensitivity in patients with retinitis pigmentosa.

PURPOSE: To determine the relationships among equivalent intrinsic noise (Neq), sampling efficiency, and contrast sensitivity (CS) in patients with retinitis pigmentosa (RP), where Neq is an estimate of the amount of noise within the visual pathway and sampling efficiency represents the subject's ability to use stimulus information optimally. METHODS: Participants included 10 patients with RP aged 10 to 54 years, who had visual acuities of 20/40 or better, and 10 visually normal control subjects aged 22 to 65 years. CS was measured for 2-cycles-per-degree Gabor patch targets presented in the absence of noise (CS0) and in five levels of noise spectral density. Data were fit with a standard linear amplifier model, which provided estimates of Neq and sampling efficiency. RESULTS: CS0 for the patients ranged from normal to as much as a factor of 3 below the lower limit of normal. All 10 patients had abnormally high Neq, including two patients with normal CS0. In comparison, only two patients had lower-than-normal sampling efficiency, and these two patients also had below-normal CS0. Log CS0 for the patients was correlated significantly with log Neq (r = -0.80, P < 0.05), but not with log efficiency (r = 0.54, P = 0.11). CONCLUSIONS: Low CS was associated with elevated intrinsic noise in this group of RP patients, but even patients with normal CS had elevated noise levels. The results suggest that CS measurement in both the presence and absence of luminance noise can provide important information about visual dysfunction in RP patients.

Visual acuity changes in patients with leber congenital amaurosis and mutations in CEP290.

OBJECTIVE: To evaluate changes in visual acuity (VA) over time in patients with Leber congenital amaurosis (LCA) and mutations in the CEP290 gene. METHODS: Visual acuity was determined at the initial and most recent visits of 43 patients with LCA and CEP290 mutations. The main outcome measures included the best-corrected VA at the initial and most recent visits, as well as the correlation between age and VA. RESULTS: At the initial visit, 14 patients had measurable chart VA in the better-seeing eye, 25 patients had nonmeasurable chart VA, and 4 young patients did not have VA assessed. At the most recent visit, 15 patients had measurable chart VA and 28 had nonmeasurable chart VA. The average interval between the 2 visits was 10.4 years (range, 2-47 years). For patients with measurable chart VA, the median logMAR value at the initial visit (0.75; range, 0.10-2.30) and at the most recent visit (0.70; range, 0.10-2.00) did not differ significantly (P> .05). There was no significant relationship between VA and age. CONCLUSIONS: Patients with LCA and CEP290 mutations had a wide spectrum of VA that was not related to age or length of follow-up. Severe VA loss was observed in most, but not all, patients in the first decade. These data will help clinicians provide counseling on VA changes in patients with CEP290 mutations and could be of value for future treatment trials.