The Orphan Drug for Acanthamoeba Keratitis (ODAK) Trial: PHMB 0.08% (Polihexanide) and Placebo versus PHMB 0.02% and Propamidine 0.1.

PURPOSE: To compare topical PHMB (polihexanide) 0.02% (0.2 mg/ml)+ propamidine 0.1% (1 mg/ml) with PHMB 0.08% (0.8 mg/ml)+ placebo (PHMB 0.08%) for Acanthamoeba keratitis (AK) treatment. DESIGN: Prospective, randomized, double-masked, active-controlled, multicenter phase 3 study (ClinicalTrials.gov identifier, NCT03274895). PARTICIPANTS: One hundred thirty-five patients treated at 6 European centers. METHODS: Principal inclusion criteria were 12 years of age or older and in vivo confocal microscopy with clinical findings consistent with AK. Also included were participants with concurrent bacterial keratitis who were using topical steroids and antiviral and antifungal drugs before randomization. Principal exclusion criteria were concurrent herpes or fungal keratitis and use of antiamebic therapy (AAT). Patients were randomized 1:1 using a computer-generated block size of 4. This was a superiority trial having a predefined noninferiority margin. The sample size of 130 participants gave approximately 80% power to detect 20-percentage point superiority for PHMB 0.08% for the primary outcome of the medical cure rate (MCR; without surgery or change of AAT) within 12 months, cure defined by clinical criteria 90 days after discontinuing anti-inflammatory agents and AAT. A prespecified multivariable analysis adjusted for baseline imbalances in risk factors affecting outcomes. MAIN OUTCOME MEASURES: The main outcome measure was MCR within 12 months, with secondary outcomes including best-corrected visual acuity and treatment failure rates. Safety outcomes included adverse event rates. RESULTS: One hundred thirty-five participants were randomized, providing 127 in the full-analysis subset (61 receiving PHMB 0.02%+ propamidine and 66 receiving PHMB 0.08%) and 134 in the safety analysis subset. The adjusted MCR within 12 months was 86.6% (unadjusted, 88.5%) for PHMB 0.02%+ propamidine and 86.7% (unadjusted, 84.9%) for PHMB 0.08%; the noninferiority requirement for PHMB 0.08% was met (adjusted difference, 0.1 percentage points; lower one-sided 95% confidence limit, -8.3 percentage points). Secondary outcomes were similar for both treatments and were not analyzed statistically: median best-corrected visual acuity of 20/20 and an overall treatment failure rate of 17 of 127 patients (13.4%), of whom 8 of 127 patients (6.3%) required therapeutic keratoplasty. No serious drug-related adverse events occurred. CONCLUSIONS: PHMB 0.08% monotherapy may be as effective (or at worse only 8 percentage points less effective) as dual therapy with PHMB 0.02%+ propamidine (a widely used therapy) with medical cure rates of more than 86%, when used with the trial treatment delivery protocol in populations with AK with similar disease severity. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Multimodal testing reveals subclinical neurovascular dysfunction in prediabetes, challenging the diagnostic threshold of diabetes.

AIM: To explore if novel non-invasive diagnostic technologies identify early small nerve fibre and retinal neurovascular pathology in prediabetes. METHODS: Participants with normoglycaemia, prediabetes or type 2 diabetes underwent an exploratory cross-sectional analysis with optical coherence tomography angiography (OCT-A), handheld electroretinography (ERG), corneal confocal microscopy (CCM) and evaluation of electrochemical skin conductance (ESC). RESULTS: Seventy-five participants with normoglycaemia (n = 20), prediabetes (n = 29) and type 2 diabetes (n = 26) were studied. Compared with normoglycaemia, mean peak ERG amplitudes of retinal responses at low (16-Td·s: 4.05 µV, 95% confidence interval [95% CI] 0.96-7.13) and high (32-Td·s: 5·20 µV, 95% CI 1.54-8.86) retinal illuminance were lower in prediabetes, as were OCT-A parafoveal vessel densities in superficial (0.051 pixels/mm2 , 95% CI 0.005-0.095) and deep (0.048 pixels/mm2 , 95% CI 0.003-0.093) retinal layers. There were no differences in CCM or ESC measurements between these two groups. Correlations between HbA1c and peak ERG amplitude at 32-Td·s (r = -0.256, p = 0.028), implicit time at 32-Td·s (r = 0.422, p < 0.001) and 16-Td·s (r = 0.327, p = 0.005), OCT parafoveal vessel density in the superficial (r = -0.238, p = 0.049) and deep (r = -0.3, p = 0.017) retinal layers, corneal nerve fibre length (CNFL) (r = -0.293, p = 0.017), and ESC-hands (r = -0.244, p = 0.035) were observed. HOMA-IR was a predictor of CNFD (ß = -0.94, 95% CI -1.66 to -0.21, p = 0.012) and CNBD (ß = -5.02, 95% CI -10.01 to -0.05, p = 0.048). CONCLUSIONS: The glucose threshold for the diagnosis of diabetes is based on emergent retinopathy on fundus examination. We show that both abnormal retinal neurovascular structure (OCT-A) and function (ERG) may precede retinopathy in prediabetes, which require confirmation in larger, adequately powered studies.

XEN-45 collagen implant for the treatment of uveitic glaucoma.

IMPORTANCE: The XEN-45 implant, a hydrophilic collagen implant which drains aqueous to the subconjunctival space, has not been investigated in the context of uveitic glaucoma. BACKGROUND: To determine the safety and efficacy of the XEN-45 collagen implant in eyes with uveitic glaucoma. DESIGN: Exploratory prospective case series. PARTICIPANTS: patients with medically uncontrolled uveitic glaucoma. METHODS: Twenty-four consecutive patients (mean age ± standard deviation [SD] = 45.3 ± 18.1 years) were implanted with the XEN-45 implant. MAIN OUTCOME MEASURES: The primary outcome measure was intraocular pressure (IOP) reduction at 12 months as compared to baseline. Secondary outcome measures included ocular hypotensive medication use at 12 months, the requirement for further glaucoma surgery and failure. Intraoperative and postoperative complications were documented. RESULTS: The baseline mean ± SD IOP was 30.5 ± 9.8 mmHg and the mean ± SD number of glaucoma medications required was 3.3 ± 0.8. In 20 eyes (83.3%) in whom conventional glaucoma surgery was originally perceived to be inevitable, further surgery was not required after XEN-45 implantation. The mean IOP was reduced by 60.2% from baseline to 12.2 ± 3.1 mmHg and mean medication usage was reduced to 0.4 ± 0.9 at 12 months (both P < 0.001). One patient had hypotony persisting beyond 2 months that required surgical revision and one patient developed blebitis. The 12-month cumulative Kaplan-Meier survival probability was 79.2%. CONCLUSIONS AND RELEVANCE: The XEN-45 implant is effective for the treatment of patients with medically uncontrolled uveitic glaucoma. Potentially sight-threatening complications, including bleb-related ocular infection and persistent hypotony, may occur.

Prospective Study of the Diagnostic Accuracy of the In Vivo Laser Scanning Confocal Microscope for Severe Microbial Keratitis.

PURPOSE: To determine the diagnostic accuracy of in vivo confocal microscopy (IVCM) for moderate to severe microbial keratitis (MK). DESIGN: Double-masked prospective cohort study. PARTICIPANTS: Consecutive patients presenting to Aravind Eye Hospital, Madurai, India, between February 2012 and February 2013 with MK (diameter ≥3 mm, excluding descemetocele, perforation, or herpetic keratitis). METHODS: Following examination, the corneal ulcer was scanned by IVCM (HRT3/RCM, Heidelberg Engineering, Heidelberg, Germany). Images were graded for the presence or absence of fungal hyphae or Acanthamoeba cysts by the confocal microscopist who performed the scan (masked to microbial diagnosis) and 4 other experienced confocal graders (masked to clinical features and microbiology). The regrading of the shuffled image set was performed by 3 graders, 3 weeks later. Corneal-scrape samples were collected for microscopy and culture. MAIN OUTCOME MEASURES: The main outcome measures were sensitivity, specificity, and positive and negative predictive values of IVCM compared with those of a reference standard of positive culture or light microscopy. Sensitivities and specificities for multiple graders were pooled and 95% confidence intervals calculated using a bivariate random-effects regression model. RESULTS: The study enrolled 239 patients with MK. Fungal infection was detected in 176 (74%) and Acanthamoeba in 17 (7%) by microbiological methods. IVCM had an overall pooled (5 graders) sensitivity of 85.7% (95% confidence interval [CI]: 82.2%-88.6%) and pooled specificity of 81.4% (95% CI: 76.0%-85.9%) for fungal filament detection. For Acanthamoeba, the pooled sensitivity was 88.2% (95% CI: 76.2%-94.6%) and pooled specificity was 98.2% (95% CI: 94.9%-99.3%). Intergrader agreement was good: κ was 0.88 for definite fungus; κ was 0.72 for definite Acanthamoeba. Intragrader repeatability was high for both definite fungus (κ: 0.88-0.95) and definite Acanthamoeba classification (κ: 0.63-0.90). IVCM images from 11 patients were considered by all 5 graders to have a specific organism present (10 fungus, 1 Acanthamoeba) but had negative results via culture and light microscopy. CONCLUSIONS: Laser scanning IVCM performed with experienced confocal graders has high sensitivity, specificity, and test reproducibility for detecting fungal filaments and Acanthamoeba cysts in moderate to large corneal ulcers in India. This imaging modality was particularly useful for detecting organisms in deep ulcers in which culture and light microscopy results were negative.

Optometrist-delivered selective laser trabeculoplasty in the HES - a training protocol and early service evaluation.

Over the last decade, the delivery of glaucoma care in the UK has changed dramatically, with more non-medical ophthalmic practitioners involved in the care of glaucoma patients. Optometrists and other non-medical professionals are now involved in the delivery of laser treatments in the Hospital Eye Service (HES), but there is currently no standardised national training framework for non-medical clinicians. Moorfields Eye Hospital and UCL's Institute of Ophthalmology have developed and delivered an education and training programme for the delivery of lasers, including Selective Laser Trabeculoplasty (SLT) by non-medical ophthalmic practitioners. The training programme is based on medical education principles, is informed by previous qualitative research into the role of ophthalmic practitioners in the delivery of laser treatments and is expected to have multidisciplinary benefits for ophthalmic healthcare. Clinical audit data indicate that optometrists can deliver safe SLT treatments, adhering to local protocols.

Correlation of ex vivo and in vivo confocal microscopy imaging of Acanthamoeba.

BACKGROUND/AIMS: The aim of this study was to correlate the various forms of Acanthamoeba on ex vivo confocal microscopy (EVCM) with in vivo confocal microscopy (IVCM) and findings from cultured positive cases of Acanthamoeba keratitis. METHODS: Acanthamoeba live, dead and empty cysts, and live trophozoites were prepared in vitro and inoculated into porcine cornea using a sterile 26-gauge needle and examined ex vivo using the Heidelberg Retina Tomograph II/Rostock Corneal Module. IVCM images from 12 cultured positive Acanthamoeba cases, obtained using the same instrument, were compared with EVCM findings. Phase contrast images were also obtained to compare with both EVCM and IVCM findings. The change in cyst morphology with depth was evaluated by imaging the same cysts over a defined cornea depth measurement. RESULTS: EVCM morphologies for live cysts included four main types-hyper-reflective central dot with hyper-reflective outer ring, hyper-reflective central dot with hyporeflective outer region, stellate shaped hyper-reflective centre with hyporeflective outer region and hyper-reflective round/polygonal shaped cyst; one main type for dead cysts-hyper-reflective central dot with hyporeflective outer region; two main types for empty cysts- hyper-reflective central dot with hyper-reflective outer ring/hyporeflective outer region; and one main type for trophozoites-large coarse speckled area of heterogeneous hyper-reflective material. Matching IVCM images show good correlation with EVCM. Cyst morphology altered when imaged at different depths. CONCLUSION: EVCM demonstrated the various forms of Acanthamoeba cyst and trophozoites can be used as a reference to identify similar structures on IVCM.

Quantitative and qualitative assessment of anterior segment optical coherence tomography capture of disease state in childhood anterior uveitis.

BACKGROUND/AIMS: Anterior segment optical coherence tomography (AS-OCT) assessment of anterior chamber inflammation is an emerging tool. We describe the performance of AS-OCT in a paediatric population. METHODS: A mixed-methods prospective study, using routine clinical assessment as reference standard, and AS-OCT, with Tomey CASIA2 or Heidelberg Spectralis HS1, as index test, with data collected on patient perceptions of imaging. Repeatability, diagnostic indices, responsiveness to clinical change and clinical correlations of imaging-based metrics (image cell count, size, density and brightness) were assessed, with construction of receiver operated characteristic curves. Exploratory thematic analysis of responses from families was undertaken. RESULTS: A total of 90 children (180 eyes) underwent imaging. Bland Altman limits of agreement for CASIA2 repeatability ranged from +17 cells (95% CI 13.6 to 21.1) to -19 cells (95% CI -15.6 to -23.2) and HS1 from +1 (95% CI 0.9 to 1.2) to -1.0 (-1.2 to -0.8) cells. CASIA2 imaging had higher sensitivity of 0.92 (95% CI 0.78 to 0.97) vs HS1 imaging 0.17 (95% CI 0.07 to 0.34), with positive correlation between clinical grade and CASIA2 cell count (coefficient 12.8, p=0.02, 95% CI 2.2 to 23.4). Change in clinical grade at follow-up examinations correlated with change in image based 'cell' count (r2=0.79, p<0.001). Patients reported a potential positive impact of seeing their disease activity. CONCLUSION: Our findings suggest that OCT-based imaging holds the promise of deeper understanding of disease, improved patient experience and more granular monitoring of activity with resultant improved outcomes, but further work is needed to refine acquisition and analysis protocols.

Immune defense single nucleotide polymorphisms and recruitment strategies associated with contact lens keratitis.

PURPOSE: To determine the association of single nucleotide polymorphisms (SNPs) of defensin 1B and toll-like receptor 4 with contact lens keratitis susceptibility and severity, and to understand the factors that influence study participation. DESIGN: Retrospective, case-control study. PARTICIPANTS: Ninety cases of keratitis and 185 controls recruited from studies conducted at Moorfields Eye Hospital and throughout Australia from 2003 to 2005 were analyzed for genetic associations. The reasons for participation of a subset of 146 participants from 1 site were also investigated. METHODS: Buccal swab samples were collected on Whatman FTA cards and mailed by post for analysis. DEFB1 (rs1799946, -52, rs1800972, -44, and rs11362, -20) and TLR4 (rs4986790, D299G) SNPs were screened by pyrosequencing and analyzed using a regression model for susceptibility (sterile, microbial keratitis [MK], controls) and severity. Study participation was investigated for age, gender, condition, and phone follow-up also using regression analysis. MAIN OUTCOME MEASURES: Relative risk of developing contact lens-related keratitis and more severe forms of the disease based on genetic profiles. RESULTS: Carriers of risk alleles of DEFB1 -52 and -20 showed a trend toward increased susceptibility to keratitis (-52: odds ratio [OR], 1.45; 95% confidence interval [CI], 0.99-2.11; P = 0.051; -20: OR, 1.37; 95% CI, 0.95-1.98; P = 0.088). A DEFB1 promoter haplotype (G-G-A) had a tendency toward decreased susceptibility of MK (OR, 0.68; 95% CI, 0.45-1.03; P = 0.062) and reduced severity (OR, 0.56; 95% CI, 0.30-1.07; P = 0.066). The TLR4 D299G was not associated with type and severity of keratitis. Older age (OR, 1.07; 95% CI, 1.05-1.08) and follow-up phone call (OR, 2.0; 95% CI, 1.2-3.5) were independent predictors of study participation. CONCLUSIONS: Genetic variation in DEFB1 that may lead to decreased protein expression of hBD-1 exhibits a tendency toward increased susceptibility and severity of contact lens-related keratitis. Investigation of these and other hBD genes that play important roles in animal models in a larger sample size is warranted. The approach of requesting samples from retrospective case series was generally feasible, although significant resources, including repeat phone calls, are required. More targeted strategies to recruit younger individuals to participate in genetic studies may be useful.

Association of single nucleotide polymorphisms of interleukins-1ß, -6, and -12B with contact lens keratitis susceptibility and severity.

PURPOSE: To investigate whether single nucleotide polymorphisms (SNPs) in interleukin (IL)-1ß, IL-6, and IL-12ß are associated with the susceptibility and severity of contact lens-related keratitis. DESIGN: Retrospective, case control study. PARTICIPANTS: One hundred twelve cases of keratitis and 225 controls were recruited from studies conducted at Moorfields Eye Hospital and in Australia during 2003 through 2005. METHODS: Buccal swab samples were collected on Whatman FTA cards and were mailed by post for analysis. IL-1ß (-31), IL-6 (-174, -572, -597), and IL-12B (3'+1158) genotypes were analyzed with pyrosequencing and analyzed using a regression model for susceptibility (sterile, microbial keratitis, controls) and severity. Statistical significance was set at 0.05. MAIN OUTCOME MEASURES: The relative risk of developing contact lens-related keratitis and more severe forms of the disease based on allele, genotype, and haplotype associations. RESULTS: Carriers of IL-6 SNPs were more likely to experience moderate and severe events compared with those with nonmutated genotypes (-174 heterozygous: odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-8.3; homozygous: OR, 6.4; 95% CI, 1.4-28.4; -174/-597: OR, 4.1; 95% CI, 1.6-11.0). More severe keratitis and microbial keratitis were less likely to occur in wearers with the nonmutated IL-6 haplotype (severity OR, 0.4 [95% CI, 0.2-0.7]; microbial OR, 0.6 [95% CI, 0.4-0.9]). Wearers carrying an IL-12B SNP had an increased risk of sterile keratitis (OR, 9.7; 95% CI, 1.2-76.9) compared with controls. CONCLUSIONS: The IL-6 SNPs are known to reduce protein expression of this cytokine and thus ocular immune defense, and carriers of these SNPs were more likely to experience more severe and microbial keratitis, suggesting that IL-6 decreases the severity and susceptibility of contact lens-related keratitis. Carriers of a functional SNP of IL-12B that is known to increase IL-12 expression and stability are more likely to experience sterile keratitis, suggesting that this is associated with the intense inflammatory reaction that occurs in this condition.

Comparison of culture, confocal microscopy and PCR in routine hospital use for microbial keratitis diagnosis.

AIMS: To evaluate the sensitivity and specificity of polymerase chain reaction (PCR), in vivo confocal microscopy (IVCM) and culture for microbial keratitis (MK) diagnosis. METHODS: Retrospective review of PCR, IVCM and culture results for MK diagnosis at Moorfields Eye Hospital between August 2013 and December 2014. RESULTS: PCR results were available for 259 MK patients with concurrent culture for 203/259 and IVCM for 149/259. Sensitivities and specificities with 95% confidence intervals [95% CI] were calculated for Acanthamoeba keratitis (AK) and fungal keratitis (FK), by comparison with culture, for both IVCM and PCR. For AK, FK and bacterial keratitis (BK) sensitivities were calculated, for each diagnostic method, by comparison with a composite reference standard (a positive result for one or more of culture, PCR or IVCM having a specificity of 100% by definition). For the latter, sensitivities with [95% CI] were: for AK, IVCM 77.1% [62.7-88.0%], PCR 63.3% [48.3-76.6%], culture 35.6 [21.9-51.2]; for FK, IVCM 81.8% [48.2-97.7%], PCR 30.8% [9.09-61.4%], culture 41.7% [15.2-72.3%]; for BK, PCR 25.0% [14.7-37.9%], culture 95.6% [87.6-99.1%]. CONCLUSION: IVCM was the most sensitive technique for AK and FK diagnosis but culture remains our gold standard for BK. These findings reflect results to be expected from service providers to UK ophthalmology units and demonstrates the need at our centre for ongoing diagnostic result audit leading to the potential to improve PCR diagnosis. Both FK and AK are now common in the UK; ophthalmology units need to have all these techniques available to optimise their MK management.

The use of in vivo confocal microscopy in fungal keratitis - Progress and challenges.

Fungal keratitis (FK) is a serious and sight-threatening corneal infection with global reach. The need for prompt diagnosis is paramount, as a delay in initiation of treatment could lead to irreversible vision loss. Current "gold standard" diagnostic methods, namely corneal smear and culture, have limitations due to diagnostic insensitivity and their time-consuming nature. PCR is a newer, complementary method used in the diagnosis of fungal keratitis, whose results are also sample-dependent. In vivo confocal microscopy (IVCM) is a promising complementary diagnostic method of increasing importance as it allows non-invasive real-time direct visualization of potential fungal pathogens and manifesting infection directly in the patient's cornea. In numerous articles and case reports, FK diagnosis by IVCM has been evaluated, and different features, approaches, sensitivity/specificity, and limitations have been noted. Here, we provide an up-to-date, comprehensive review of the current literature and present the authors' combined recommendations for fungal identification in IVCM images, while also looking to the future of FK assessment by IVCM using artificial intelligence methods.

Anterior Segment Optical Coherence Tomography Angiography and Optical Coherence Tomography in the Evaluation of Episcleritis and Scleritis.

Purpose: To evaluate the feasibility of using anterior segment optical coherence tomography (AS-OCT) and AS-OCT angiography (AS-OCTA) in assessing patients with episcleritis and scleritis.Methods: Degree of vascularity [vessel density index (VDI)], measured with AS-OCTA, and sclera thickness [conjunctiva epithelium (CE), conjunctiva/episclera complex (CEC), and episclera/sclera complex (ESC)], measured with AS-OCT were compared.Results: A total of 37 eyes (13 episcleritis, 11 scleritis, 13 controls) were analyzed. VDI was lowest for controls for the various tissue depths (p < .001). Episcleritis versus scleritis revealed a significant difference in VDI at ESC (38.1 ± 11.4% vs 46.4 ± 6.4%; p = .03). Mean sclera thickness was lower in controls for CE (p < .001), CEC (p < .001) but not for ESC (p = .54).Conclusions: The degree of vascularity and tissue thickness were different between episcleritis, scleritis and controls. AS-OCTA and AS-OCT may potentially be useful in evaluating patients with scleral inflammation.

Corneal Endothelial Cell Loss after Baerveldt Glaucoma Implant Surgery.

PURPOSE: To evaluate risk factors for corneal endothelial cell density (ECD) loss after Baerveldt glaucoma implant (BGI) insertion. DESIGN: Prospective cohort study. PARTICIPANTS: Seventy-two patients (72 eyes) with glaucoma. METHODS: Before and 1, 2, 3, 4, and 5 years after anterior chamber BGI insertion, we evaluated the central corneal ECD (CCECD) and peripheral corneal ECD (PCECD) in the area of the tube; anterior chamber (AC) flare; tube insertion entry site position relative to Schwalbe's line (SL), defined as all of the entry site behind SL (tube insertion position 1), less than 50% of entry site anterior to SL (tube insertion position 2), more than 50% but less than 100% of entry site anterior to SL (tube insertion position 3 [TIP3]), and all of the entry site in front of SL (tube insertion position 4 [TIP4]); anterior segment (AS) OCT tube parameters, including posterior cornea-to-tube tip distance, tube angle-to-posterior corneal surface distance, tube tip-to-anterior iris distance, tube length (TL), and tube angle-to-anterior iris distance. MAIN OUTCOME MEASURES: Primary outcomes were CCECD and PCECD loss at 5 years. Secondary outcomes included prognostic factors for ECD loss: tube insertion entry site position relative to SL, AS OCT tube parameters, AC flare, and clinical factors including IOP. RESULTS: Sixty-four patients (64 eyes) completed the study. The mean percentage CCECD and PCECD losses at 5 years were 36.8% and 50.1%, respectively. On univariate analysis at 5 years, a lower CCECD was associated with TIP3. Tube angle-to-anterior iris distance, TL, and TIP3 were associated with lower PCECD at 5 years. Multiple regression analysis revealed TIP3 to be associated with both lower CCECD (standardized ß coefficient, -0.27; P = 0.015) and PCECD (standardized ß coefficient, -0.23; P = 0.028). A short TL (standardized ß coefficient, 0.26; P = 0.016) also was associated with lower PCECD. The fastest rate of cell loss was associated with TIP3 for CCECD and TIP4 for PCECD. CONCLUSIONS: Anterior chamber BGI insertion is associated with ECD loss greatest close to the tube. Tube insertion in the vicinity of, or anterior to SL, and short TL were associated with significant ECD loss with time.

Clinical and confocal imaging findings in congenital corneal anaesthesia.

BACKGROUND/AIMS: Congenital corneal anaesthesia (CCA) is an uncommon cause of corneal ulceration in young patients, with a reported poor visual prognosis. We correlated clinical findings in patients with CCA with corneal sub-basal nerve plexus (SBNP) morphology and dendritiform cell density (DCD) on confocal microscopy. METHODS: A prospective, case-control study was conducted at a referral clinic. History includied presenting features in patients with CCA, clinical course and examination findings. Differences in SBNP morphology and DCD on in vivo confocal microscopy (IVCM) were compared in cases and control subjects with healthy corneas. RESULTS: Eight patients with CCA were examined, of which three had a diagnosis of familial dysautonomia. Age at initial diagnosis of corneal disease ranged from infancy to 22 years, the most common presentation being corneal ulceration. All patients with CCA except one with optic neuropathy had corrected visual acuity 6/18 (logMAR 0.35) or better in at least one eye. Measured corneal sensation was minimal in all patients. Major abnormalities were found on confocal microscopy in all patients with CCA, whether or not inherited, including statistically significant reduction in SBNP nerve fibre density, fibre length and branch density. Increased DCD in superficial cornea was found in all patients with CCA. CONCLUSION: Good visual acuity can be maintained in eyes with corneal anaesthesia present from birth. IVCM provides direct evidence of a morphological correlate for measured corneal anaesthesia. Increased DCD may indicate an enhanced role for innate immune cells in superficial cornea in protection of the anaesthetic ocular surface.

Functional and Structural Changes Following Corneal Neurotisation in the Management of Neurotrophic Keratopathy: UK Single Centre Series.

OBJECTIVE: To report the functional and anatomical outcomes including structural changes in corneal nerve density and morphology using in vivo confocal microscopy (IVCM) after corneal neurotisation in patients with neurotrophic keratopathy (NK), using a sural nerve graft. PATIENTS AND METHODS: Prospective study of patients undergoing corneal neurotisation for NK. Functional outcomes were measured through visual acuity, slit-lamp examination of corneal and conjunctival staining, tear production (Schirmer's 1 test), tear film break-up time, tear film meniscus height, quality and osmolarity, central corneal thickness and corneal sensation using Cochet-Bonnet esthesiometry. Structural outcomes were assessed from changes in corneal nerve density and morphology with IVCM. Subjective outcomes were assessed using VFQ-25 and latest telephonic consultation. RESULTS: Between February 2016 and April 2018, 11 corneal neurotisations were performed on 11 patients (3 males, 8 females). Median age was 43 (range 25-62) years. Mean follow-up was 14.5 (range, 4-36) months. Snellen visual acuity improved in 6 patients, corneal and conjunctival staining decreased in 10, tear film breakup time increased in 9, tear meniscus height increased in 7, Schirmers test readings increased in 4, tear film osmolarity reduced in 8 and central corneal thickness increased in 10 patients. Corneal sensation improved in nine patients. Complete IVCM data were available in five cases and demonstrated an improvement of corneal nerve density and length at 12 months. CONCLUSION: This series confirms the fact that the outcomes of this technique are reproducible and that corneal neurotisation surgery helps restore trophic nerve function more consistently than touch-related sensation.

Machine Learning Algorithms to Detect Subclinical Keratoconus: Systematic Review.

BACKGROUND: Keratoconus is a disorder characterized by progressive thinning and distortion of the cornea. If detected at an early stage, corneal collagen cross-linking can prevent disease progression and further visual loss. Although advanced forms are easily detected, reliable identification of subclinical disease can be problematic. Several different machine learning algorithms have been used to improve the detection of subclinical keratoconus based on the analysis of multiple types of clinical measures, such as corneal imaging, aberrometry, or biomechanical measurements. OBJECTIVE: The aim of this study is to survey and critically evaluate the literature on the algorithmic detection of subclinical keratoconus and equivalent definitions. METHODS: For this systematic review, we performed a structured search of the following databases: MEDLINE, Embase, and Web of Science and Cochrane Library from January 1, 2010, to October 31, 2020. We included all full-text studies that have used algorithms for the detection of subclinical keratoconus and excluded studies that did not perform validation. This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations. RESULTS: We compared the measured parameters and the design of the machine learning algorithms reported in 26 papers that met the inclusion criteria. All salient information required for detailed comparison, including diagnostic criteria, demographic data, sample size, acquisition system, validation details, parameter inputs, machine learning algorithm, and key results are reported in this study. CONCLUSIONS: Machine learning has the potential to improve the detection of subclinical keratoconus or early keratoconus in routine ophthalmic practice. Currently, there is no consensus regarding the corneal parameters that should be included for assessment and the optimal design for the machine learning algorithm. We have identified avenues for further research to improve early detection and stratification of patients for early treatment to prevent disease progression.

Quality of life in high myopia before and after implantable Collamer lens implantation.

PURPOSE: To examine changes in vision-related quality of life after implantable Collamer lens (ICL) implantation for the correction of myopia. DESIGN: Prospective, interventional, consecutive case series. PARTICIPANTS: We included 34 consecutive patients (68% female; mean age, 37 years [range, 23-49]) with preoperative myopia (mean ± standard deviation [SD] refraction spherical equivalent, -11.0 ± 3.12). INTERVENTION: Bilateral ICL implantation. MAIN OUTCOME MEASURES: Quality of life Impact of Refractive Correction (QIRC) score. RESULTS: The median postoperative interval before questionnaire administration was 4 months (range, 3-7). The QIRC scores were significantly higher postoperatively (preoperative QIRC score [mean ± SD], 40.45 ± 4.83; postoperative QIRC score 53.79 ± 5.60; P < 0.001), with significant improvements (P<0.01) for 14 of 19 items. Nineteen (58%) patients reported a worsening in night vision symptoms (mostly nonspecific glare and halo or arc effects) after surgery, but overall levels of satisfaction were high; 88% were either satisfied or very satisfied with the results of surgery. No patients reported overall dissatisfaction. In free text responses, 11 patients (32%) described ICL implantation as life changing or wished that they had opted for the surgery sooner. CONCLUSIONS: Implantation of an ICL for myopia is associated with significant improvements in quality of life. Any dissatisfaction with the procedure largely relates to night vision symptoms, which are common in the early postoperative period.

In Vivo Confocal Microscopy Morphologic Features and Cyst Density in Acanthamoeba Keratitis.

PURPOSE: To correlate in vivo confocal microscopy morphologic features (IVCM-MF) and Acanthamoeba cyst density (ACD) with final best-corrected visual acuity (BCVA) in Acanthamoeba keratitis (AK). DESIGN: Retrospective cohort study. METHODS: Patient demographics, treatment outcome, and corresponding IVCM-MF performed at the acute stage of infection were analyzed. Inclusion criteria were microbiological positive AK cases seen at Moorfields Eye Hospital between February 2013 and October 2017. Statistical significance was assessed by multinomial regression and multiple linear regression analysis. Main outcome measure was final BCVA. RESULTS: A total of 157 eyes (157 patients) had AK. Absence of single-file round/ovoid objects was associated with a BCVA of 6/36 to 6/9 (odds ratio [OR] 8.13; 95% confidence interval [CI], 1.55-42.56, P = .013) and ≥6/6 (OR 10.50; 95% CI, 2.12-51.92, P = .004) when compared to no perception of light to 6/60. Absence of rod/spindle objects was associated with a BCVA of ≥6/6 (OR 4.55; 95% CI, 1.01-20.45, P = .048). Deep stromal/ring infiltrate was associated with single-file round/ovoid objects (OR 7.78; 95% CI, 2.69-22.35, P < .001), rod/spindle objects (OR 7.05; 95% CI, 2.11-23.59, P = .002), and binary round/ovoid objects (OR 3.45; 95% CI, 1.17-10.14, P = .024). There was a positive association between ACD and treatment duration (ß = 0.14, P = .049), number of IVCM-MF (ß = 0.34, P = .021), and clusters of round/ovoid objects (ß = 0.29, P = .002). CONCLUSIONS: Specific IVCM-MF correlate with ACD and clinical staging of disease, and are prognostic indicators for a poorer visual outcome.

The Utility of Corneal Nerve Fractal Dimension Analysis in Peripheral Neuropathies of Different Etiology.

Purpose: Quantification of corneal confocal microscopy (CCM) images has shown a significant reduction in corneal nerve fiber length (CNFL) in a range of peripheral neuropathies. We assessed whether corneal nerve fractal dimension (CNFrD) analysis, a novel metric to quantify the topological complexity of corneal subbasal nerves, can differentiate peripheral neuropathies of different etiology. Methods: Ninety patients with peripheral neuropathy, including 29 with diabetic peripheral neuropathy (DPN), 34 with chronic inflammatory demyelinating polyneuropathy (CIDP), 13 with chemotherapy-induced peripheral neuropathy (CIPN), 14 with human immunodeficiency virus-associated sensory neuropathy (HIV-SN), and 20 healthy controls (HCs), underwent CCM for estimation of corneal nerve fiber density (CNFD), CNFL, corneal nerve branch density (CNBD), CNFrD, and CNFrD adjusted for CNFL (ACNFrD). Results: In patients with DPN, CIDP, CIPN, or HIV-SN compared to HCs, CNFD (P = 0.004-0.0001) and CNFL (P = 0.05-0.0001) were significantly lower, with a further significant reduction among subgroups. CNFrD was significantly lower in patients with CIDP compared to HCs and patients with HIV-SN (P = 0.02-0.0009) and in patients with DPN compared to HCs and patients with HIV-SN, CIPN, or CIDP (P = 0.001-0.0001). ACNFrD was lower in patients with CIPN, CIDP, or DPN compared to HCs (P = 0.03-0.0001) and in patients with DPN compared to those with HIV-SN, CIPN, or CIDP (P = 0.01-0.005). Conclusions: CNFrD can detect a distinct pattern of corneal nerve loss in patients with DPN or CIDP compared to those with CIPN or HIV-SN and controls. Translational Relevance: Various peripheral neuropathies are characterized by a comparable degree of corneal nerve loss. Assessment of corneal nerve topology by CNFrD could be useful in differentiating neuropathies based on the pattern of loss.

Corneal complications of glaucoma surgery.

PURPOSE OF REVIEW: Most glaucoma surgery can adversely affect the cornea. This often consists of mild endothelial loss on specular microscopy, but occasionally corneal decompensation may occur. The effect on the cornea also depends on preexisting corneal disease, severity and chronicity of intraocular pressure elevation, prior intraocular procedures and complications. With the exception of aqueous shunts, glaucoma procedures are not known to result in progressive endothelial cell loss. RECENT FINDINGS: Corneal problems are most common after aqueous shunts, especially in children, in which tube-endothelial touch is common. However, other corneal effects of glaucoma surgery have also been reported. Antiproliferative drugs have a toxic effect on endothelium that may be reduced by concurrent use of viscoelastics. Subconjunctival mitomycin C injection may cause limbal stem cell deficiency. In combined phacoemulsification and trabeculectomy, a one-site approach induces less endothelial trauma than two sites. Overhanging blebs may induce corneal dissection, and even decompensation. Descemet's membrane detachment has been reported after nonpenetrating glaucoma surgery, although less endothelial loss is induced than after trabeculectomy. SUMMARY: Corneal complications are commonest in patients with aqueous shunts, and long-term prospective studies of endothelial cell density are required to elucidate the factors that predispose to corneal endothelial cell loss.