PURPOSE: The Retinal Detachment after Open Globe Injury (RD-OGI) Score is a clinical prediction model that was developed at the Massachusetts Eye and Ear Infirmary to predict the risk of retinal detachment (RD) after open globe injury (OGI). This study sought to validate the RD-OGI Score in an independent cohort of patients. DESIGN: Retrospective cohort study. PARTICIPANTS: The predictive value of the RD-OGI Score was evaluated by comparing the original RD-OGI Scores of 893 eyes with OGI that presented between 1999 and 2011 (the derivation cohort) with 184 eyes with OGI that presented from January 1, 2012, to January 31, 2014 (the validation cohort). METHODS: Three risk classes (low, moderate, and high) were created and logistic regression was undertaken to evaluate the optimal predictive value of the RD-OGI Score. A Kaplan-Meier survival analysis evaluated survival experience between the risk classes. MAIN OUTCOME MEASURES: Time to RD. RESULTS: At 1 year after OGI, 255 eyes (29%) in the derivation cohort and 66 eyes (36%) in the validation cohort were diagnosed with an RD. At 1 year, the low risk class (RD-OGI Scores 0-2) had a 3% detachment rate in the derivation cohort and a 0% detachment rate in the validation cohort, the moderate risk class (RD-OGI Scores 2.5-4.5) had a 29% detachment rate in the derivation cohort and a 35% detachment rate in the validation cohort, and the high risk class (RD-OGI scores 5-7.5) had a 73% detachment rate in the derivation cohort and an 86% detachment rate in the validation cohort. Regression modeling revealed the RD-OGI to be highly discriminative, especially 30 days after injury, with an area under the receiver operating characteristic curve of 0.939 in the validation cohort. Survival experience was significantly different depending upon the risk class (P < 0.0001, log-rank chi-square). CONCLUSIONS: The RD-OGI Score can reliably predict the future risk of developing an RD based on clinical variables that are present at the time of the initial evaluation after OGI.
In this article we review the mechanism of ocular surface staining. Water-soluble dyes are excluded from the normal epithelium by tight junctions, the plasma membranes and the surface glycocalyx. Shed cells can take up dye. A proportion of normal corneas show sparse, scattered time-dependent, punctate fluorescein uptake, which, we hypothesise, is due to a graded loss of the glycocalyx barrier, permitting transcellular entry into pre-shed cells. In pathological staining, there is little evidence of 'micropooling' at sites of shedding and the term 'punctate erosion' may be a misnomer. It is more likely that the initial event involves transcellular dye entry and, in addition, diffusion across defective tight junctions. Different dye-staining characteristics probably reflect differences in molecular size and other physical properties of each dye, coupled with differences in visibility under the conditions of illumination used. This is most relevant to the rapid epithelial spread of fluorescein from sites of punctate staining, compared to the apparent confinement of dyes to staining cells with dyes such as lissamine green and rose bengal. We assume that fluorescein, with its lower molecular weight, spreads initially by a paracellular route and then by transcellular diffusion. Solution-Induced Corneal Staining (SICS), related to the use of certain contact lens care solutions, may have a different basis, involving the non-pathological uptake of cationic preservatives, such as biguanides, into epithelial membranes and secondary binding of the fluorescein anion. It is transient and may not imply corneal toxicity. Understanding the mechanism of staining is relevant to the standardisation of grading, to monitoring disease and to the conduct of clinical trials.
Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, Knop E, Markoulli M, Ogawa Y, Perez V, Uchino Y, Yokoi N, Zoukhri D, Sullivan DA. TFOS DEWS II pathophysiology report. Ocul Surf 2017;15(3):438-510.Abstract
The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjögren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.
We determined whether binocular central scotomas above or below the preferred retinal locus affect detection of hazards (pedestrians) approaching from the side. Seven participants with central field loss (CFL), and seven age-and sex-matched controls with normal vision (NV), each completed two sessions of 5 test drives (each approximately 10 minutes long) in a driving simulator. Participants pressed the horn when detecting pedestrians that appeared at one of four eccentricities (-14°, -4°, left, 4°, or 14°, right, relative to car heading). Pedestrians walked or ran towards the travel lane on a collision course with the participant's vehicle, thus remaining in the same area of the visual field, assuming participant's steady forward gaze down the travel lane. Detection rates were nearly 100% for all participants. CFL participant reaction times were longer (median 2.27s, 95% CI 2.13 to 2.47) than NVs (median 1.17s, 95%CI 1.10 to 2.13; difference p<0.01), and CFL participants would have been unable to stop for 21% of pedestrians, compared with 3% for NV, p<0.001. Although the scotomas were not expected to obscure pedestrian hazards, gaze tracking revealed that scotomas did sometimes interfere with detection; late reactions usually occurred when pedestrians were entirely or partially obscured by the scotoma (time obscured correlated with reaction times, r = 0.57, p<0.001). We previously showed that scotomas lateral to the preferred retinal locus delay reaction times to a greater extent; however, taken together, the results of our studies suggest that any binocular CFL might negatively impact timely hazard detection while driving and should be a consideration when evaluating vision for driving.
Photoreceptors are sensory neurons designed to convert light stimuli into neurological responses. This process, called phototransduction, takes place in the outer segments (OS) of rod and cone photoreceptors. OS are specialized sensory cilia, with analogous structures to those present in other nonmotile cilia. Deficient morphogenesis and/or dysfunction of photoreceptor sensory cilia (PSC) caused by mutations in a variety of photoreceptor-specific and common cilia genes can lead to inherited retinal degenerations (IRDs). IRDs can manifest as isolated retinal diseases or syndromic diseases. In this review, we describe the structure and composition of PSC and different forms of ciliopathies with retinal involvement. We review the genetics of the IRDs, which are monogenic disorders but genetically diverse with regard to causality.
Primary cilia are sensory organelles present on most mammalian cells. The assembly and maintenance of primary cilia are facilitated by intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium. Mutations in genes coding for IFT components have been associated with a group of diseases called ciliopathies. These genetic disorders can affect a variety of organs including the retina. Using whole exome sequencing in three families, we identified mutations in Intraflagellar Transport 172 Homolog [IFT172 (Chlamydomonas)] that underlie an isolated retinal degeneration and Bardet-Biedl syndrome. Extensive functional analyses of the identified mutations in cell culture, rat retina and in zebrafish demonstrated their hypomorphic or null nature. It has recently been reported that mutations in IFT172 cause a severe ciliopathy syndrome involving skeletal, renal, hepatic and retinal abnormalities (Jeune and Mainzer-Saldino syndromes). Here, we report for the first time that mutations in this gene can also lead to an isolated form of retinal degeneration. The functional data for the mutations can partially explain milder phenotypes; however, the involvement of modifying alleles in the IFT172-associated phenotypes cannot be excluded. These findings expand the spectrum of disease associated with mutations in IFT172 and suggest that mutations in genes originally reported to be associated with syndromic ciliopathies should also be considered in subjects with non-syndromic retinal dystrophy.
PURPOSE: Patients with Usher syndrome type I (USH1) have retinitis pigmentosa, profound congenital hearing loss, and vestibular ataxia. This syndrome is currently thought to be associated with at least six genes, which are encoded by over 180 exons. Here, we present the use of state-of-the-art techniques in the molecular diagnosis of a cohort of 47 USH1 probands. METHODS: The cohort was studied with selective exon capture and next-generation sequencing of currently known inherited retinal degeneration genes, comparative genomic hybridization, and Sanger sequencing of new USH1 exons identified by human retinal transcriptome analysis. RESULTS: With this approach, we were able to genetically solve 14 of the 47 probands by confirming the biallelic inheritance of mutations. We detected two likely pathogenic variants in an additional 19 patients, for whom family members were not available for cosegregation analysis to confirm biallelic inheritance. Ten patients, in addition to primary disease-causing mutations, carried rare likely pathogenic USH1 alleles or variants in other genes associated with deaf-blindness, which may influence disease phenotype. Twenty-one of the identified mutations were novel among the 33 definite or likely solved patients. Here, we also present a clinical description of the studied cohort at their initial visits. CONCLUSIONS: We found a remarkable genetic heterogeneity in the studied USH1 cohort with multiplicity of mutations, of which many were novel. No obvious influence of genotype on phenotype was found, possibly due to small sample sizes of the genotypes under study.
PURPOSE: Despite substantial progress in sequencing, current strategies can genetically solve only approximately 55-60% of inherited retinal degeneration (IRD) cases. This can be partially attributed to elusive mutations in the known IRD genes, which are not easily identified by the targeted next-generation sequencing (NGS) or Sanger sequencing approaches. We hypothesized that copy-number variations (CNVs) are a major contributor to the elusive genetic causality of IRDs. METHODS: Twenty-eight cases previously unsolved with a targeted NGS were investigated with whole-genome single-nucleotide polymorphism (SNP) and comparative genomic hybridization (CGH) arrays. RESULTS: Deletions in the IRD genes were detected in 5 of 28 families, including a de novo deletion. We suggest that the de novo deletion occurred through nonallelic homologous recombination (NAHR) and we constructed a genomic map of NAHR-prone regions with overlapping IRD genes. In this article, we also report an unusual case of recessive retinitis pigmentosa due to compound heterozygous mutations in SNRNP200, a gene that is typically associated with the dominant form of this disease. CONCLUSIONS: CNV mapping substantially increased the genetic diagnostic rate of IRDs, detecting genetic causality in 18% of previously unsolved cases. Extending the search to other structural variations will probably demonstrate an even higher contribution to genetic causality of IRDs.Genet Med advance online publication 13 October 2016.
Progress in understanding the pathophysiology, and providing novel treatments for glaucoma is dependent on good animal models of the disease. We present here a protocol for elevating intraocular pressure (IOP) in the rat, by injecting magnetic microspheres into the anterior chamber of the eye. The use of magnetic particles allows the user to manipulate the beads into the iridocorneal angle, thus providing a very effective blockade of fluid outflow from the trabecular meshwork. This leads to long-lasting IOP rises, and eventually neuronal death in the ganglion cell layer (GCL) as well as optic nerve pathology, as seen in patients with the disease. This method is simple to perform, as it does not require machinery, specialist surgical skills, or many hours of practice to perfect. Furthermore, the pressure elevations are very robust, and reinjection of the magnetic microspheres is not usually required unlike in some other models using plastic beads. Additionally, we believe this method is suitable for adaptation for the mouse eye.
PURPOSE: To identify determinants of adverse outcomes in acute retinal necrosis (ARN), presenting characteristics and incidence rates of vision loss and ocular complications in a cohort of polymerase chain reaction (PCR)-positive eyes were analyzed. DESIGN: Retrospective observational cohort study. METHODS: Forty-one eyes of 36 patients with clinically diagnosed ARN, PCR-positive for herpes simplex virus or varicella zoster virus and evaluated between January 2002 and June 2013, were included. Main outcome measures included incidence rates of vision loss and retinal detachment (RD). RESULTS: Presenting visual acuity was generally poor (20/50 to >20/200 in 27%; 20/200 or worse in 56%). The incidence rate of ≤20/200 was 0.66/eye-year (EY), (95% confidence interval [CI], 0.32/EY to 1.22/EY); the rate of light perception or no light perception vision was 0.07/EY (95% CI, 0.02/EY to 0.16/EY). During follow-up, 59% of eyes developed at least 1 RD (rate = 0.40/EY, 95% CI, 0.19/EY to 0.58/EY). Eyes with retinitis involving ≥25% of the retina at presentation detached at nearly 12 times the rate, as compared to those with <25% retinal involvement (0.70/EY vs 0.06/EY; P = .001). Development of an RD was the greatest determinant of adverse visual outcomes, with 4% of eyes, that had experienced at least 1 RD, achieving a best-corrected visual acuity of ≥20/40 compared to 53% of eyes that never detached (P = .0003). CONCLUSIONS: Poor outcomes in ARN were common in this cohort. RD confers the greatest risk of incident vision loss, and once 25% or more of the retina is involved the risk of RD and visual loss increases significantly.
PURPOSE: To assess the clinical validity of visual field (VF) archetypal analysis, a previously developed machine learning method for decomposing any Humphrey VF (24-2) into a weighted sum of clinically recognizable VF loss patterns. MATERIALS AND METHODS: For each of 16 previously identified VF loss patterns ("archetypes," denoted AT1 through AT16), we screened 30,995 reliable VFs to select 10-20 representative patients whose VFs had the highest decomposition coefficients for each archetype. VF global indices and patient ocular and demographic features were extracted retrospectively. Based on resemblances between VF archetypes and clinically observed VF patterns, hypotheses were generated for associations between certain VF archetypes and clinical features, such as an association between AT6 (central island, representing severe VF loss) and large cup-to-disk ratio (CDR). Distributions of the selected clinical features were compared between representative eyes of certain archetypes and all other eyes using the two-tailed t-test or Fisher exact test. RESULTS: 243 eyes from 243 patients were included, representative of AT1 through AT16. CDR was more often ≥ 0.7 among eyes representative of AT6 (central island; p = 0.002), AT10 (inferior arcuate defect; p = 0.048), AT14 (superior paracentral defect; p = 0.016), and AT16 (inferior paracentral defect; p = 0.016) than other eyes. CDR was more often < 0.7 among eyes representative of AT1 (no focal defect; p < 0.001) and AT2 (superior defect; p = 0.027), which was also associated with ptosis (p < 0.001). AT12 (temporal hemianopia) was associated with history of stroke (p = 0.022). AT11 (concentric peripheral defect) trended toward association with trial lens correction > 6D (p = 0.069). CONCLUSIONS: Shared clinical features between computationally derived VF archetypes and clinically observed VF patterns support the clinical validity of VF archetypal analysis.
PURPOSE: Inflammatory macular hole is a rare complication of uveitis, and data on surgical outcomes of closure are scarce. The purpose of this study is to evaluate the anatomical and visual outcomes of conventional pars plana vitrectomy for patients with uveitis. METHODS: Noncomparative, interventional, and consecutive case series from 6 vitreoretinal surgical centers from 2007 to 2015. Twenty eyes of 19 patients were included with 4 patients separated as viral retinitis. The primary outcome was change in best-corrected visual acuity at Month 3. Secondary outcomes were closure of the macular hole and postoperative optical coherence tomography characteristics. RESULTS: All eyes underwent conventional three-port pars plana vitrectomy with indocyanine green-assisted internal limiting membrane peeling. Mean Snellen best-corrected visual acuity improved from 20/200 to 20/63 (P = 0.01 for a difference in logarithm of the minimum angle of resolution) at Month 3. Twelve (75%) of patients achieved 2 or more lines of visual acuity improvement by postoperative Month 3. Surgery resulted in decreased epiretinal membrane (P = 0.002), intraretinal fluid (P < 0.001), subretinal fluid (P = 0.029), central subfield thickness (P < 0.001), and central cube volume (P = 0.041). Surgical intervention achieved anatomical success, as measured by macular hole closure, in 13 (81%) of patients at postoperative Month 3. CONCLUSION: Patients with inflammatory macular hole respond well to conventional surgery, with good anatomical and visual acuity outcomes.
A 29-year-old woman with a history of 2 bone marrow transplants for acute myelogenous leukemia developed bilateral sequential dacryocystitis in the context of known ocular graft-versus-host disease. With each infection, the patient underwent uneventful dacryocystorhinostomy. Postoperatively, she developed severe dry eye disease requiring replacement of punctal plugs and use of a prosthetic replacement of the ocular surface ecosystem lens. Histopathologic and immunohistochemical examination of the lacrimal sac showed a dense diffuse nonfollicular lymphocytic subepithelial infiltrate in the lacrimal sac that contained moderately more T-cells than B-cells. This is the first report of acute dacryocystitis associated with graft-versus-host disease. The authors caution that similar patients may develop worsening of ocular surface dryness due to restoration of normal lacrimal outflow.
The authors describe a 20-year-old man who sustained multiple facial fractures in a high-speed motor vehicle crash, including a bone fragment from a skull base fracture that penetrated the orbital soft tissues superomedially. Serial CT scans documented spontaneous resorption over a 6-month period. While it is known that autologous bone grafts used in craniofacial reconstruction exhibit variable amounts of bone resorption, the complete resorption of an intraorbital fracture fragment has not been documented in the literature. His clinical care and the report of his case were undertaken in a fashion in accordance with the principles of the Health Insurance Portability and Accountability Act regulations.
PURPOSE: To describe the outcomes of the use of rituximab in the treatment of refractory noninfectious scleritis. DESIGN: Retrospective case series. METHODS: Review of the medical charts of patients with noninfectious scleritis refractory to conventional immunomodulatory therapy who were seen at the Massachusetts Eye Research and Surgery Institution between 2005 and 2015. The primary outcome measure in this study was steroid-free remission. Secondary outcomes were favorable response (decrease in scleritis activity score) and decrease in steroid dependence. RESULTS: There were 15 patients, with a mean follow-up duration of 34 months. Fourteen patients (93.3%) showed a clinical improvement, with 13 (86.6%) achieving a scleritis activity score of zero at 6 months. To date, 2 patients continue to enjoy durable drug-free remission (28 and 32 months follow-up). There was only 1 adverse effect recorded (infusion hypotension) requiring cessation of rituximab. CONCLUSION: Rituximab can be an effective treatment modality for recalcitrant noninfectious scleritis and, in some, can result in long-term durable drug-free remission.
PURPOSE: This study retrospectively reviews preseptal cellulitis and abscesses involving the eyebrow to elucidate the bacteriology and potential causative factors. METHODS: A retrospective chart review was conducted to identify patients who had been diagnosed with preseptal cellulitis or abscess involving the eyebrow at the Massachusetts Eye and Ear Infirmary between 2008 and 2015. Demographic, clinical, and microbiological data were collected. RESULTS: Eighty patients with eyebrow infections were identified, of whom 49 (61.3%) were female and 31 (38.7%) were male. The median age was 37 years (range 14-67 years). Eyebrow abscess was present in 54 cases (67.5%), while 26 cases (32.5%) were limited to preseptal cellulitis without abscess formation. Methicillin-resistant Staphylococcus aureus was found in 20 abscesses (39.2% of culture results), and methicillin-sensitive S. aureus was found in 12 abscesses (23.5% of culture results). Coagulase-negative staphylococci were present in 7 eyebrow abscesses (13.7% of culture results). Clinical history was remarkable for eyebrow hair removal (tweezing, waxing, threading, or shaving) in 17 cases (21.3%), manipulation of acne lesions ("popping," "picking," or "squeezing") in 6 cases (7.5%), and both brow hair removal and acne manipulation in 1 case (1.3%). CONCLUSIONS: There is a high incidence of methicillin-resistant Staphylococcus aureus in the bacteriology of eyebrow infections. Empirical antibiotic coverage for methicillin-resistant Staphylococcus aureus should be strongly considered in any patient with an eyebrow area abscess or preseptal cellulitis. Individuals who practice cosmetic eyebrow grooming should be encouraged to consider hygiene practices, which could reduce the risk of infection.
Gene therapy is a promising approach in the treatment of inherited and common complex disorders of the retina. Preclinical and clinical studies have validated the use of adeno-associated viral vectors (AAV) as a safe and efficient delivery vehicle for gene transfer. RPE and rods, and to a lesser extent, cone photoreceptors can be efficiently targeted with AAV. Other retinal cell types however are more challenging targets. The aim of this study was to characterize the transduction profile and efficiency of in silico designed, synthetic Anc80 AAVs for retinal gene transfer. Three Anc80 variants were evaluated for retinal targeting in mice and primates following subretinal delivery. In the murine retina Anc80L65 demonstrated high level of RPE and photoreceptor targeting with comparable cone photoreceptor affinity compared to other AAVs. Remarkably, Anc80L65 enhanced transduction kinetics with visible expression as early as day 1 and steady state mRNA levels at day 3. Inner retinal tropism of Anc80 variants demonstrated distinct transduction patterns of Müller glia, retinal ganglion cells and INL neurons. Finally, murine findings with Anc80L65 qualitatively translated to the Rhesus macaque in terms of cell targets, levels and onset of expression. Our findings support the use of Anc80L65 for therapeutic subretinal gene delivery.
Colour vision is only achieved in the presence of healthy and functional cone photoreceptors found in the retina. It is an essential component of human vision and usually the first complaint patients undergoing vision degeneration have is the loss of daylight colour vision. Therefore, an understanding of the biology and basic mechanisms behind cone death under the degenerative state of retinal dystrophies and how the activation of the apoptotic pathway is triggered will provide valuable knowledge. It will also have broader applications for a spectrum of visual disorders and will be critical for future advances in translational research.
The maturity in our understanding of the genetics and the pathogenesis of disease in degenerative retinal disorders has intersected in past years with a novel treatment paradigm in which a genetic intervention may lead to sustained therapeutic benefit, and in some cases even restoration of vision. Here, we review this prospect of retinal gene therapy, discuss the enabling technologies that have led to first-in-human demonstrations of efficacy and safety, and the road that led to this exciting point in time.