Anti-inflammatory Effects of Siponimod in a Mouse Model of Excitotoxicity-Induced Retinal Injury.

Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. Glutamate excitotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors plays a crucial role in glaucomatous RGC loss. Sphingosine 1-phosphate receptors (S1PRs) are important mediators of neurodegeneration and neuroinflammation in the brain and the retina. Siponimod is an immunomodulatory drug for multiple sclerosis and is a selective modulator of S1PR subtypes 1 and 5 and has been shown to have beneficial effects on the central nervous system (CNS) in degenerative conditions. Our previous study showed that mice administered orally with siponimod protected inner retinal structure and function against acute NMDA excitotoxicity. To elucidate the molecular mechanisms behind these protective effects, we investigated the inflammatory pathways affected by siponimod treatment in NMDA excitotoxicity model. NMDA excitotoxicity resulted in the activation of glial cells coupled with upregulation of the inflammatory NF-kB pathway and increased expression of TNFα, IL1-ß, and IL-6. Siponimod treatment significantly reduced glial activation and suppressed the pro-inflammatory pathways. Furthermore, NMDA-induced activation of NLRP3 inflammasome and upregulation of neurotoxic inducible nitric oxide synthase (iNOS) were significantly diminished with siponimod treatment. Our data demonstrated that siponimod induces anti-inflammatory effects via suppression of glial activation and inflammatory singling pathways that could protect the retina against acute excitotoxicity conditions. These findings provide insights into the anti-inflammatory effects of siponimod in the CNS and suggest a potential therapeutic strategy for neuroinflammatory conditions.

Efficacy and Safety of iStent Inject Implantation in Manual and Femtosecond Laser-assisted Cataract Surgery before Lens Extraction.

Aim: To describe the efficacy and safety of iStent implantation prior to phacoemulsification in manual as well as femtosecond laser-assisted cataract surgery (FLACS), and highlight this approach as a reasonable, if not necessary, step to advance one's ability and confidence in the use of microinvasive glaucoma surgery (MIGS) technology in phakic patients. Methods: A retrospective consecutive case series of patients with open angle glaucoma or ocular hypertension who underwent iStent inject implantation followed by cataract surgery (manual or FLACS). All cases underwent postoperative video review and were assessed and classified for intraoperative lens injury and hyphaema. Postoperative data included intraocular pressure (IOP), medication usage and adverse events. Results: Sixty-three eyes (n = 40 manual, n = 23 FLACS) were analyzed. Preoperatively, the mean IOP was 19.2 ± 4.9 mm Hg on 1.4 ± 0.96 mean medications, with 100% of eyes treated with medication. Intraoperatively, no lens injury was identified, and no significant hyphaema that impeded surgery occurred. At 6 months postoperative, mean IOP was 14.2 ± 1.8 mm Hg (38% reduction: p < 0.001), and >90% of eyes had IOP ≤ 16 mm Hg. The mean number of medications reduced to 0.11 ± 0.3 (92% reduction: p < 0.001), with 89% of eyes medication free. Safety was excellent for both manual and FLACS, with two iStents implanted in all eyes, and no cases of significant hyphaema or lens injury. Conclusion: Early implantation is safe, maximizes corneal clarity and angle visualization, avoids the risk of non-implantation due to surgical complications, and has a high success rate in both manual cataract surgery and the setting of FLACS. Clinical significance: The conventional recommended approach of iStent implantation following cataract extraction has been adopted by many, however, with the advent of stand-alone procedures and concern about potential lens injury, there is an opportunity to gain experience with minimal risk in patients undergoing MIGS procedures combined with cataract surgery by implanting iStents at the start of the procedure. There is currently little emphasis or data published in the literature on an early approach to implantation to guide surgeons. How to cite this article: Manning DK, Haider A, Clement C, et al. Efficacy and Safety of iStent Inject Implantation in Manual and Femtosecond Laser-assisted Cataract Surgery before Lens Extraction. J Curr Glaucoma Pract 2022;16(2):105-110.

PARACENTRAL ACUTE MIDDLE MACULOPATHY IN SUSAC SYNDROME.

PURPOSE: To present the first reported case of paracentral acute middle maculopathy in association with Susac syndrome. METHOD: Case report. RESULTS: A young female patient presented with unilateral sudden loss of vision of her right eye to count fingers. There were numerous cotton wool spots in a multifocal pattern concentrated around the right macula and optic disk. Clinical examination and spectral domain optical coherence tomography imaging were consistent with paracentral acute middle maculopathy, and fluorescein angiography showed features of retinal arteriole vasculitis. Magnetic resonance imaging demonstrated multiple white matter lesions in a pericallosal distribution. High-dose corticosteroid therapy was commenced, and visual acuity gradually improved to 6/6 corrected. The patient reported hearing impairment and was diagnosed with Susac syndrome for which she has responded extremely well to long-term immunosuppressive therapy. CONCLUSION: Paracentral acute middle maculopathy can occur in association with Susac syndrome. Susac syndrome may present only with multifocal retinal ischemia, and such patients with paracentral acute middle maculopathy should be checked for characteristic magnetic resonance imaging lesions and hearing loss.

Corneal Collagen Crosslinking for Post-LASIK Ectasia: An Australian Study.

PURPOSE: Post laser-assisted in situ keratomileusis (LASIK) ectasia is a rare and unpredictable complication after LASIK. Corneal collagen crosslinking (CXL) has emerged as a promising technique to address this complication. Our study evaluates the long-term efficacy of CXL for post-LASIK ectasia in an Australian setting. DESIGN: Retrospective review of post-LASIK ectasia patients referred to and treated at 3 corneal refractive surgery institutions in Sydney, Australia. METHODS: Eleven patients (14 eyes; mean age, 39.7 ± 12.6 years) underwent epithelium-off CXL with follow-up ranging from 12-78 months. Best spectacle-corrected visual acuity (BSCVA), simulated keratometry, corneal topography indices, and higher-order aberrations (HOAs) [mean ± standard error of the mean (SEM)] were measured with a rotating Scheimpflug camera (Pentacam, Oculus). Comparisons between baseline measurements and postoperative outcomes were performed using paired t test analysis. RESULTS: At last follow-up, BSCVA improved significantly by 0.2 ± 0.06 logMAR (P = 0.01), and 12 of 14 eyes showed no keratometric deterioration. Of the corneal topography indices, index of height asymmetry showed a trend toward a significant improvement (P = 0.05). There was no progression of corneal HOAs. Central corneal thickness was not significantly altered (P = 0.6). No major postoperative complications were observed. CONCLUSIONS: In the Australian setting, CXL has proven effective at stabilizing the progression of post-LASIK ectasia, inducing corneal regularity, and improving visual acuity.

Relationship of Structural Characteristics to Biomechanical Profile in Normal, Keratoconic, and Crosslinked Eyes.

PURPOSE: To evaluate the correlation of corneal biomechanical parameters with structural characteristics in normal, keratoconic, and collagen crosslinked eyes. METHODS: A prospective observational study that included 50 normal, 100 keratoconic, and 25 crosslinked eyes. All eyes were imaged using a Scheimpflug camera and an ocular response analyzer. The main outcome measures analyzed were central corneal thickness (CCT), corneal volume (CV), maximal keratometry (Kmax), corneal hysteresis (CH), and corneal resistance factor (CRF). RESULTS: Significant differences were noted among all 3 groups of eyes for CCT, CV, Kmax, CH, and CRF values (P < 0.05 by analysis of variance). CH and CRF correlated negatively (CH, r = -0.40; CRF, r = -0.44; both P < 0.0001) with the Pentacam topographic keratoconus classification. Both CH and CRF correlated positively with CCT and CV for the normal, keratoconic, and crosslinked eyes. In contrast, significant negative correlations were observed between CH, CRF, and Kmax in the keratoconic eyes (CH, r = -0.43; CRF, r = -0.53; both P < 0.0001), whereas no association was noted for the normal and crosslinked eyes. CONCLUSIONS: CH and CRF are influenced by the corneal structure, with higher values noted in corneas with greater thickness and volume. Corneal biomechanical parameters progressively decrease as the severity of keratoconus increases. After collagen crosslinking, the relationship of the corneal curvature to the biomechanical profile is similar to normal eyes.

The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis.

Human SCO1 fulfills essential roles in cytochrome c oxidase (COX) assembly and the regulation of copper (Cu) homeostasis, yet it remains unclear why pathogenic mutations in this gene cause such clinically heterogeneous forms of disease. Here, we establish a Sco1 mouse model of human disease and show that ablation of Sco1 expression in the liver is lethal owing to severe COX and Cu deficiencies. We further demonstrate that the Cu deficiency is explained by a functional connection between SCO1 and CTR1, the high-affinity transporter that imports Cu into the cell. CTR1 is rapidly degraded in the absence of SCO1 protein, and we show that its levels are restored in Sco1-/- mouse embryonic fibroblasts upon inhibition of the proteasome. These data suggest that mitochondrial signaling through SCO1 provides a post-translational mechanism to regulate CTR1-dependent Cu import into the cell, and they further underpin the importance of mitochondria in cellular Cu homeostasis.

Comparative analysis of corneal measurements obtained from a Scheimpflug camera and an integrated Placido-optical coherence tomography device in normal and keratoconic eyes.

PURPOSE: To assess the agreement between a Scheimpflug camera (Pentacam) and a combined Placido-optical coherence tomography device (Visante OMNI) in measuring corneal curvature, thickness and elevation values in normal and keratoconic eyes. METHODS: Corneal measurements of 110 normal eyes (one eye per subject) and 70 keratoconic eyes were obtained from both devices and compared. Agreement was determined using the Bland-Altman analysis 95% limits of agreement (LoA). RESULTS: The Pentacam measured significantly greater keratometry readings in the flattest (K1) and steepest meridians (K2) in normal and keratoconic eyes. The 95% LoA in normal eyes were -0.32 to 0.59 dioptres (D) (K1) and -0.41 to 0.74 D (K2). In keratoconic eyes, the 95% LoA were -1.35 to 1.92 D (K1) and -1.38 to 1.99 D (K2). The Pentacam recorded significantly higher central corneal thickness (CCT) values in both groups of eyes. The 95% LoA were -4.31 to 39.89 microns (µ) and -12.92 to 41.35 µ in normal and keratoconic eyes, respectively. Pentacam anterior and posterior corneal elevations were significantly greater in both groups of eyes. The devices demonstrated excellent repeatability and reproducibility for corneal curvature and thickness but not elevation measurements. CONCLUSIONS: The Pentacam measured significantly greater corneal curvature, thickness and elevation values compared to the Visante OMNI in normal and keratoconic eyes. The devices agree moderately for anterior corneal elevations in normal eyes and do not appear to be interchangeable for corneal measurements in clinical practice.

Outcome of corneal collagen crosslinking for progressive keratoconus in paediatric patients.

PURPOSE: To evaluate the efficacy of corneal collagen crosslinking for progressive keratoconus in paediatric patients. METHODS: This prospective study included 25 eyes of 18 patients (aged 18 years or younger) who underwent collagen crosslinking performed using riboflavin and ultraviolet-A irradiation (370 nm, 3 mW/cm2, 30 min). RESULTS: The mean patient age was 14.3±2.4 years (range 8-17) and mean followup duration was 20.1±14.25 months (range 6-48). Crosslinked eyes demonstrated a significant reduction of keratometry values. The mean baseline simulated keratometry values were 46.34 dioptres (D) in the flattest meridian and 50.06 D in the steepest meridian. At 20 months after crosslinking, the values were 45.67 D (P=0.03) and 49.34 D (P=0.005), respectively. The best spectacle corrected visual acuity (BSCVA) and topometric astigmatism improved after crosslinking. Mean logarithm of the minimum angle of resolution (logMAR) BSCVA decreased from 0.24 to 0.21 (P=0.89) and topometric astigmatism reduced from mean 3.50 D to 3.25 D (P=0.51). CONCLUSIONS: Collagen crosslinking using riboflavin and ultraviolet-A is an effective treatment option for progressive keratoconus in paediatric patients. Crosslinking stabilises the condition and, thus, reduces the need for corneal grafting in these young patients.

Bilateral femtosecond laser-enabled intrastromal astigmatic keratotomy to correct high post-penetrating keratoplasty astigmatism.

A 35-year-old man presented with bilateral high astigmatism following penetrating keratoplasties performed for advanced keratoconus. Femtosecond laser-enabled intrastromal astigmatic keratotomy was performed, resulting in a significant reduction in corneal astigmatism. At 4 months, the corneal astigmatism continued to decrease. The visual acuity, refraction, and serial corneal topographic data are presented.

Relationship of change in central corneal thickness to visual field progression in eyes with glaucoma.

BACKGROUND: To assess the relationship between baseline central corneal thickness (CCT) and/or ongoing CCT change over time with subsequent visual field progression. METHODS: One hundred sixty three eyes of 163 patients with medically treated glaucoma were followed up for 6.8 ± 1.8 years. Exclusion criteria was laser or intraocular surgery. Baseline and follow up CCT, confocal scanning laser tomography and visual fields were performed. CCT and CCT change related to visual field progression using Glaucoma Progress Analysis were assessed. Multivariate logistic regression analysis for predictive factors of glaucoma progression was used to analyze data. RESULTS: Thinner baseline CCT was associated with more advanced damage at presentation, mean deviation (MD) (r=0.17, p=0.02) and neuroretinal rim area (NRR) (r=0.20, p=0.02). Progressing eyes had significantly thinner (p=0.01) baseline CCT compared to non-progressing eyes. The slope of visual field change was significantly greater (p=0.05) for thinner (<540 µm) as compared to thicker eyes. A small but significant CCT reduction (12.78 ± 13.35 µm, p<0.0001) was noted in all eyes; however, there was no significant difference (p=0.95) in the amount of change between progressing and non-progressing eyes. CCT change did not correlate with MD or NRR change. A thinner CCT (Odds ratio=1.80, p=0.02), but not CCT change (Odds ratio=1.07, p=0.69), was a significant risk factor for glaucoma progression. CONCLUSIONS: CCT correlates significantly with the amount of glaucomatous damage at presentation. Thinner corneas may be associated with increased risk of visual field progression. CCT reduced slightly over time in eyes with glaucoma; but the magnitude of this change was not related to visual field progression.

Longitudinal effect of topical antiglaucoma medications on central corneal thickness.

BACKGROUND: To determine the change in central corneal thickness over time and whether the use of long-term topical antiglaucoma medications influences central corneal thickness. DESIGN: Case control study with retrospective and prospective data collection. PARTICIPANTS: One hundred eighty-seven eyes of 187 glaucoma patients (mean follow up 6.92 ± 1.67 years) being treated with topical antiglaucoma medications (at least 3 years) with no history of surgery or laser were included and compared with 100 eyes of 100 age-matched, untreated control subjects (mean follow up 6.58 ± 1.93 years) who were glaucoma suspects with normal intraocular pressure not on any treatment. METHODS: Demographic data, central corneal thickness and intraocular pressure were collected at initial glaucoma diagnosis and at most recent visit, and findings were compared between two groups. MAIN OUTCOME MEASURES: Mean change in central corneal thickness in microns (µm). RESULTS: Central corneal thickness fell significantly (P < 0.0001) in treated eyes but not in control eyes (P = 0.18); mean central corneal thickness reduction was 12.29 ± 13.65 µm in treated eyes and 1.17 ± 8.75 µm in controls. Among treated eyes, central corneal thickness reduction was significant (P < 0.0001) in those treated with either prostaglandins or a combination of prostaglandin and beta-blockers, while no significant reduction occurred in eyes treated with only beta-blockers (P = 0.15) when compared with control eyes. CONCLUSIONS: Prostaglandins appear to be associated with a small but significant central corneal thickness reduction over time. Serial central corneal thickness measurements might be helpful in glaucoma patients, particularly those on prostaglandins.

Prospective longitudinal study of corneal collagen cross-linking in progressive keratoconus.

BACKGROUND: Collagen cross-linking has been reported to be effective in treating progressive keratoconus, and this study aims to evaluate the long-term efficacy of this procedure. DESIGN: Prospective longitudinal interventional study of patients with progressive keratoconus who underwent cross-linking in a tertiary referral hospital. PARTICIPANTS: Thirty-five patients (51 eyes) who underwent cross-linking with a mean follow-up of 14.38 ± 9.36 months (range 6-48) were compared with a control group of 25 fellow eyes that did not undergo the procedure. METHODS: Cross-linking was performed using 0.1% riboflavin (in 20% dextran T500) and ultraviolet A irradiation (370 nm, 3 mW/cm(2) , 30 min). MAIN OUTCOME MEASURES: Maximum keratometry in dioptres, logMAR best spectacle-corrected visual acuity, cylindrical power, manifest refraction spherical equivalent and central corneal thickness. RESULTS: Analysis of the treated group demonstrated a significant flattening of maximum keratometry by 0.96 ± 2.33 dioptres (P = 0.005) and a significant improvement in visual acuity by 0.05 ± 0.13 logMAR (P = 0.04). In the control group, maximum keratometry increased significantly by 0.43 ± 0.85 dioptres (P = 0.05), and visual acuity decreased by mean 0.05 ± 0.14 (P = 0.2). No statistical differences were noted regarding cylindrical power, spherical equivalent or corneal thickness in both groups. CONCLUSIONS: Results indicate that corneal collagen cross-linking using riboflavin and ultraviolet A is effective as a therapeutic option in cases of progressive keratoconus by reducing the corneal curvature and by improving the visual acuity in these patients.

The effect of stimulus expectancy on dishabituation of auditory evoked potentials.

OBJECTIVES: Having foreknowledge of the type and timing of sensory stimulation modulates the electrophysiological response and can result in short-term habituation. Here we explore if dishabituation is similarly affected. METHODS: Seventeen healthy subjects were tested with five different auditory stimuli paradigms to see if knowledge of the stimulus train length and/or deviant stimulus affects the amount of dishabituation of auditory evoked potentials. Furthermore it was determined if the degree of difference between the repeating stimulus and deviant stimulus affected the amount of dishabituation. RESULTS: Stimulus complexity is the main determinant of the degree of dishabituation, followed by lack of knowledge about train length. Not knowing the deviant stimulus has little or no effect on dishabituation. Also, P200 is the most affected by expectancy and P50 not at all. CONCLUSIONS: Foreknowledge of the type and timing of sensory stimulation modulates the degree of dishabituation. SIGNIFICANCE: Previous reports have shown that expectancy does affect (certain) evoked potential components. Here we extend this knowledge to the effect of expectancy on dishabituation.

Wavefront aberrations in eyes with decentered ablations.

PURPOSE: To compare the refractive and functional outcomes and wavefront profiles in eyes with decentered ablations and eyes with well-centered ablations. SETTING: Medical Research Foundation, Chennai, Tamil Nadu, India. METHODS: This retrospective analysis comprised eyes with topographically diagnosed decentered ablations after laser in situ keratomileusis (LASIK). Refraction, contrast sensitivity, and ocular wavefront aberrations were measured preoperatively and 1 month postoperatively. The induced aberrations in these eyes were compared with those in eyes with well-centered ablations. RESULTS: Forty-six eyes (38 patients) had decentered ablations and 60 eyes (32 patients), well-centered ablations. The mean decentration in the study group was 0.86 mm +/- 0.29 (SD) (range 0.35 to 1.61 mm). There was no significant correlation between decentration and attempted refractive correction. There was, however, a statistically significant (P<.05) linear correlation between the distance of decentration and the magnitude of induced tilt (r = -0.31), coma (r = -0.41), and secondary astigmatism (r = 0.36). The induced changes in tilt, oblique astigmatism, vertical coma, and spherical aberration were statistically significantly higher in eyes with decentered ablations than in eyes with well-centered ablations. A statistically significantly higher percentage of eyes (87%) with well-centered ablations than eyes with decentered ablations (70%) had a postoperative uncorrected visual acuity (UCVA) of 20/20 or better. There was no significant difference in contrast sensitivity between groups. CONCLUSION: Eyes with decentered ablations had a significantly higher magnitude of induced aberrations and lower UCVA than eyes with well-centered ablations.

Wavefront-guided versus wavefront-optimized laser in situ keratomileusis: contralateral comparative study.

PURPOSE: To compare the outcomes of wavefront-guided and wavefront-optimized treatment in fellow eyes of patients having laser in situ keratomileusis (LASIK) for myopia. SETTING: Medical and Vision Research Foundation, Tamil Nadu, India. METHODS: This prospective comparative study comprised 27 patients who had wavefront-guided LASIK in 1 eye and wavefront-optimized LASIK in the fellow eye. The Hansatome (Bausch & Lomb) was used to create a superior-hinged flap and the Allegretto laser (WaveLight Laser Technologie AG), for photoablation. The Allegretto wave analyzer was used to measure ocular wavefront aberrations and the Functional Acuity Contrast Test chart, to measure contrast sensitivity before and 1 month after LASIK. The refractive and visual outcomes and the changes in aberrations and contrast sensitivity were compared between the 2 treatment modalities. RESULTS: One month postoperatively, 92% of eyes in the wavefront-guided group and 85% in the wavefront-optimized group had uncorrected visual acuity of 20/20 or better; 93% and 89%, respectively, had a postoperative spherical equivalent refraction of +/-0.50 diopter. The differences between groups were not statistically significant. Wavefront-guided LASIK induced less change in 18 of 22 higher-order Zernike terms than wavefront-optimized LASIK, with the change in positive spherical aberration the only statistically significant one (P= .01). Contrast sensitivity improved at the low and middle spatial frequencies (not statistically significant) and worsened significantly at high spatial frequencies after wavefront-guided LASIK; there was a statistically significant worsening at all spatial frequencies after wavefront-optimized LASIK. CONCLUSION: Although both wavefront-guided and wavefront-optimized LASIK gave excellent refractive correction results, the former induced less higher-order aberrations and was associated with better contrast sensitivity.

Hyperplastic persistent pupillary membranes with congenital corneal anomalies.

We report a case of a 14-year-old girl who presented with impaired vision in the left eye since birth. Examination showed extensive bilateral persistent pupillary membranes associated with microcornea, cornea plana, and central localized posterior keratoconus in both eyes. The uncorrected visual acuity was 0.2 (logMAR) (20/32) in the right eye and 1.9 (logMAR) (20/1300) in the left eye, with no improvement with pinhole. Surgical excision of the membranes was done in both eyes using vitreous microscissors. At 6 months, the best corrected visual acuity was 0.1 (logMAR) (20/25) in the right eye and 1.3 (logMAR) (20/400) in the left eye. No significant intraoperative or postoperative complications were noted.

Novel SLC4A11 mutations in patients with recessive congenital hereditary endothelial dystrophy (CHED2). Mutation in brief #958. Online.

Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) is a severe and rare corneal disorder that presents at birth or shortly thereafter, characterized by corneal opacification and nystagmus. Recently the gene for CHED2 was identified and seven different mutations in the SLC4A11 gene were reported. Here, we report seven novel mutations and two previously identified mutations in families from India and the United Kingdom with recessive CHED. The novel changes include two nonsense (p.Trp240X; p.Gln800X) three missense (p.Glu143Lys; p.Cys386Arg; p.Arg755Trp) and two splice site mutations (c.2240+1G>A; c.2437-1G>A). Interestingly, the c.2398C>T (p.Gln800X) and c.2437-1G>A identified in two affected siblings represent the first compound heterozygous mutations in the SLC4A11 gene.