PURPOSE: To evaluate construct and face validity of the Eyesi Binocular Indirect Ophthalmoscope Simulator. METHODS: The performance of 25 medical students (Group A) was compared with that of 17 ophthalmology and optometry trainees (Group B) on the Eyesi Binocular Indirect Ophthalmoscope Simulator. During the course of a single session, each participant viewed an orientation module followed by an instruction session and a demonstration case, and performed 6 cases of progressively increasing difficulty (4 levels) and a 10-question face validity questionnaire. Outcomes included total score, total examination time, percent retina examined, and duration of eye exposure to light. RESULTS: Group B achieved significantly better total scores than Group A on all difficulty levels (P = 0.02, P = 0.001, P = 0.001, and P = 0.0001, for Levels 1-4, respectively) and had a significantly faster mean duration of examination (8 minutes 58 seconds vs. 5 minutes 21 seconds, P < 0.0001). Medical students reported higher scores in the face validity questionnaire for the simulator experience being helpful at orienting them to true indirect ophthalmology, and that further training on the simulator would improve their skills in the clinic (P = 0.03 for all). CONCLUSION: The Eyesi Binocular Indirect Ophthalmoscope Simulator has significant construct and face validity and shows promise for medical education.
PURPOSE OF REVIEW: Recent advances in experimental studies of optic nerve regeneration to better understand the pathophysiology of axon regrowth and provide insights into the future treatment of numerous optic neuropathies. RECENT FINDINGS: The optic nerve is part of the central nervous system and cannot regenerate if injured. There are several steps that regenerating axons of retinal ganglion cells (RGCs) must take following optic nerve injury that include: maximizing the intrinsic growth capacity of RGCs, overcoming the extrinsic growth-inhibitory environment of the optic nerve, and optimizing the reinnervation of regenerated axons to their targets in the brain. Recently, some degree of experimental optic nerve regeneration has been achieved by factors associated with inducing intraocular inflammation, providing exogenous neurotrophic factors, reactivating intrinsic growth capacity of mature RGCs, or by modifying the extrinsic growth-inhibitory environment of the optic nerve. In some experiments, regenerating axons have been shown to reinnervate their central targets in the brain. SUMMARY: Further approaches to the combination of aforementioned treatments will be necessary to develop future therapeutic strategy to promote ultimate regeneration of the optic nerve and functional vision recovery after optic nerve injury.
Perioperative vision loss (POVL) may cause devastating visual morbidity. A prompt anatomical and etiologic diagnosis is paramount to guide management and assess prognosis. Where possible, steps should be undertaken to minimize risk of POVL for vulnerable patients undergoing high-risk procedures. We review the specific risk factors, pathophysiology, and management and prevention strategies for various etiologies of POVL.
PURPOSE: To assess the sensitivity of corneal cold receptors to a known transient receptor potential melastatin 8 (TRPM8) agonist, menthol, in dry eye and normals, and to determine whether factors such as disease duration or age affect responses. METHODS: Dry eye disease (DED) (N = 33) and normal (N = 15) subjects were randomly assigned to receive Rohto® Hydra (0.01% menthol) or Systane® Ultra treatments (OU) in a prospective, double-blind, crossover study. DED subjects had documented disease and symptom response scores >2 on a 0- to 5-point scale. Normals had no history of DED and scores <2 on the same scale. Endpoints included mean cooling score (0 = not cool and 10 = very cool) evaluated at 0, 0.5, 1, 2, 3, and 4 min post-instillation, sum cooling scores (5 time points, range 0-60), and ocular signs and symptoms. RESULTS: Mean (±SD) ages were similar, 62.2 ± 8.6-year (DED) versus 53.5 ± 7.6-year (normal). Corneal sensitivity scores were not different between groups. Mean cooling scores at 0.5-4 min post-menthol instillation were significantly higher in DED subjects (P ≤ 0.03). Sum cooling scores were significantly higher (P = 0.04) in DED subjects with a disease duration <10 years (N = 18, 28.3 ± 2.58) versus ≥10 years (N = 15, 20.2 ± 2.76). Age did not affect cooling response in either group. CONCLUSION: DED subjects had greater sensitivity to cold than normal subjects. DED duration, and not age, was critical to cooling sensitivity. The finding that cooling scores were higher in subjects with DED for less than 10 years compared to more than 10 years suggests that corneal cold receptor sensitivity decreases as the duration of DED increases.
Purpose: Eccentric viewing is a common strategy used by people with central vision loss (CVL) to direct the eye such that the image falls onto functioning peripheral retina, known as the preferred retinal locus (PRL). It has been long acknowledged that we do not know whether the PRL used in a fixation test is also used when performing tasks. We present an innovative method to determine whether the same PRL observed during a fixation task was used to watch videos and whether poor resolution affects gaze location. Methods: The gaze of a group of 60 normal vision (NV) observers was used to define a democratic center of interest (COI) of video clips from movies and television. For each CVL participant (N = 20), we computed the gaze offsets from the COI across the video clips. The distribution of gaze offsets of the NV participants was used to define the limits of NV behavior. If the gaze offset was within this 95% degree confidence interval, we presumed that the same PRL was used for fixation and video watching. Another 15 NV participants watched the video clips with various levels of defocus blur. Results: CVL participants had wider gaze-offset distributions than NV participants (P < 0.001). Gaze offsets of 18/20 CVL participants were outside the NV confidence interval. Further, none of the 15 NV participants watching the same videos with spherical defocus blur had a gaze offset that was decentered (outside the NV confidence interval), suggesting that resolution was not the problem. Conclusions: This indicates that many CVL participants were using a PRL to view videos that differed from that found with a fixation task and that it was not caused by poor resolution alone. The relationship between these locations needs further investigation.
PurposeThe purpose of the study was to investigate nailfold microvascular morphology in exfoliation syndrome with or without glaucoma (XFS/XFG) compared with primary open-angle glaucoma (POAG) and control subjects using nailfold capillary videomicroscopy.Patients and methodsWe used a JH-1004 capillaroscope to perform nailfold capillary videomicroscopy on the fourth and fifth digit of the non-dominant hand. We enrolled 56 XFS/XFG patients, 87 POAG patients, and 75 control subjects. Masked observers graded the videos for hemorrhages, avascular zones ≥200 microns (μm), and degree of microvascular tortuosity on a four-point subjective scale. Multivariable odds ratios, 95% confidence intervals and P-for trends for assessing the relation between morphological changes and POAG or XFS/XFG were obtained from logistic regression analyses. We also assessed this relation with XFS/XFG compared with POAG in multivariable models.ResultsAfter adjusting for multiple covariates, nailfold hemorrhages, avascular zones ≥200 μm, and higher degree of vascular tortuosity were more common in XFS/XFG vs controls (P-for trend ≤0.0001) and in POAG vs controls (P-for trend ≤0.01). For each 100 capillaries, the number of hemorrhages was similar (P-for trend=0.91) between XFS/XFG and POAG patients; however, there were more avascular zones per 100 capillaries with borderline significance (P-for trend=0.04) in the XFS/XFG group. XFS/XFG patients had more tortuosity than POAG patients; specifically, having a tortuosity score ≥1.5 was associated with a 4.4-fold increased odds of XFS/XFG (95% confidence interval: 1.5-13.3) relative to a tortuosity score <1.0 (P-for trend=0.005).ConclusionA high degree of nailfold capillary tortuosity is a distinct non-ocular feature associated with XFS/XFG compared with either POAG or controls.
Craig JP, Nelson DJ, Azar DT, Belmonte C, Bron AJ, Chauhan SK, de Paiva CS, Gomes JAP, Hammitt KM, Jones L, Nichols JJ, Nichols KK, Novack GD, Stapleton FJ, Willcox MDP, Wolffsohn JS, Sullivan DA. TFOS DEWS II Report Executive Summary. Ocul Surf 2017;15(4):802-812.Abstract
This article presents an Executive Summary of the conclusions and recommendations of the 10-chapter TFOS DEWS II report. The entire TFOS DEWS II report was published in the July 2017 issue of The Ocular Surface. A downloadable version of the document and additional material, including videos of diagnostic and management techniques, are available on the TFOS website: www.TearFilm.org.
In vivo confocal microscopy (IVCM) is becoming an indispensable tool for studying corneal physiology and disease. Enabling the dissection of corneal architecture at a cellular level, this technique offers fast and noninvasive in vivo imaging of the cornea with images comparable to those of ex vivo histochemical techniques. Corneal nerves bear substantial relevance to clinicians and scientists alike, given their pivotal roles in regulation of corneal sensation, maintenance of epithelial integrity, as well as proliferation and promotion of wound healing. Thus, IVCM offers a unique method to study corneal nerve alterations in a myriad of conditions, such as ocular and systemic diseases and following corneal surgery, without altering the tissue microenvironment. Of particular interest has been the correlation of corneal subbasal nerves to their function, which has been studied in normal eyes, contact lens wearers, and patients with keratoconus, infectious keratitis, corneal dystrophies, and neurotrophic keratopathy. Longitudinal studies have applied IVCM to investigate the effects of corneal surgery on nerves, demonstrating their regenerative capacity. IVCM is increasingly important in the diagnosis and management of systemic conditions such as peripheral diabetic neuropathy and, more recently, in ocular diseases. In this review, we outline the principles and applications of IVCM in the study of corneal nerves in various ocular and systemic diseases.
The roles of transforming growth factor (TGF)-β in extracellular matrix production and vascular remodeling, coupled with increased TGF-β expression and signaling in diabetes, suggest TGF-β as an important contributor to the microangiopathy of diabetic retinopathy and nephropathy. To investigate whether increased TGF-β signaling could be a therapeutic target for preventing retinopathy, we used a pharmacologic approach (SM16, a selective inhibitor of the type 1 TGF-β receptor activin receptor-like kinase 5, orally active) to inhibit the increased, but not the basal, Tgf-β signaling in retinal vessels of diabetic rats. At the level of vascular gene expression, 3.5 months' diabetes induced minimal changes. Diabetes + SM16 for 3 weeks caused widespread changes in gene expression poised to enhance vascular inflammation, thrombosis, leakage, and wall instability; these changes were not observed in control rats given SM16. The synergy of diabetes and SM16 in altering gene expression was not observed in the lung. At the level of vascular network morphology, 7 months' diabetes induced no detectable changes. Diabetes + SM16 for 3 weeks caused instead distorted morphology and decreased density. Thus, in diabetes, retinal vessels become dependent on a small increase in TGF-β signaling via activin receptor-like kinase 5 to maintain early integrity. The increased TGF-β signaling may protect against rapid retinopathy progression and should not be a target of inhibitory interventions.
PURPOSE: V-pattern strabismus observed with syndromic craniosynostosis has been attributed to disparate causes. We compared severity of V pattern with degree of excyclorotation of rectus muscles to appraise significance of this proposed aetiology. METHODS: 43 patients with Apert, Crouzon or Pfeiffer syndrome referred to Boston Children's Hospital Department of Ophthalmology were identified. 28 met inclusion criteria for retrospective cohort study, specifically: (1) sensorimotor measurements in minimum of seven cardinal gazes, (2) quantified fundus torsion and (3) orbital CT imaging sufficient to measure rectus muscle cyclorotation in coronal and quasicoronal planes, posteriorly (near orbital apex) and anteriorly (near pulleys). Patients were placed in one of four V-pattern severity groups. The most severe group demonstrated inability to elevate abducted eye above midline with characteristic 'seesaw' misalignment during horizontal saccades. Rectus muscle cyclorotation was measured by paediatric neuroradiologist blinded to group placement. Primary outcome was correlation of severity of V pattern with degree of excyclorotation. Secondary outcome was correlation of severity with craniosynostosis syndrome. RESULTS: Increasing severity of V pattern correlated with greater excyclorotation in anterior coronal (p=0.009), anterior quasicoronal (p=0.021), posterior coronal (p=0.014) and posterior quasicoronal (p=0.040) planes for moderate-to-severe V pattern. Even greater excyclorotation was associated with seesaw V pattern in anterior quasicoronal (p=0.004) and posterior quasicoronal (p=0.001) views. Highly significant association was found between Apert syndrome and severity of V pattern (p=0.004). CONCLUSIONS: Severity of V pattern is associated with magnitude of excyclorotation. More severe V pattern and seesaw strabismus noted with Apert syndrome may relate to distinctive orbital morphology.
This report demonstrates a unique case of conjunctival melanoma harboring a BRAF V600E mutation responsive to systemic therapy with BRAF and MEK inhibitors. While systemic therapy would not be appropriate in patients with local disease alone, it may act therapeutically in cases of higher stage ocular surface and eyelid melanoma.
PURPOSE: To describe the risk and risk factors for ocular hypertension (OHT) in adults with noninfectious uveitis. DESIGN: Retrospective, multicenter, cohort study. PARTICIPANTS: Patients aged ≥18 years with noninfectious uveitis seen between 1979 and 2007 at 5 tertiary uveitis clinics. METHODS: Demographic, ocular, and treatment data were extracted from medical records of uveitis cases. MAIN OUTCOME MEASURES: Prevalent and incident OHT with intraocular pressures (IOPs) of ≥21 mmHg, ≥30 mmHg, and increase of ≥10 mmHg from documented IOP recordings (or use of treatment for OHT). RESULTS: Among 5270 uveitic eyes of 3308 patients followed for OHT, the mean annual incidence rates for OHT ≥21 mmHg and OHT ≥30 mmHg are 14.4% (95% confidence interval [CI], 13.4-15.5) and 5.1% (95% CI, 4.7-5.6) per year, respectively. Statistically significant risk factors for incident OHT ≥30 mmHg included systemic hypertension (adjusted hazard ratio [aHR], 1.29); worse presenting visual acuity (≤20/200 vs. ≥20/40, aHR, 1.47); pars plana vitrectomy (aHR, 1.87); history of OHT in the other eye: IOP ≥21 mmHg (aHR, 2.68), ≥30 mmHg (aHR, 4.86) and prior/current use of IOP-lowering drops or surgery in the other eye (aHR, 4.17); anterior chamber cells: 1+ (aHR, 1.43) and ≥2+ (aHR, 1.59) vs. none; epiretinal membrane (aHR, 1.25); peripheral anterior synechiae (aHR, 1.81); current use of prednisone >7.5 mg/day (aHR, 1.86); periocular corticosteroids in the last 3 months (aHR, 2.23); current topical corticosteroid use [≥8×/day vs. none] (aHR, 2.58); and prior use of fluocinolone acetonide implants (aHR, 9.75). Bilateral uveitis (aHR, 0.69) and previous hypotony (aHR, 0.43) were associated with statistically significantly lower risk of OHT. CONCLUSIONS: Ocular hypertension is sufficiently common in eyes treated for uveitis that surveillance for OHT is essential at all visits for all cases. Patients with 1 or more of the several risk factors identified are at particularly high risk and must be carefully managed. Modifiable risk factors, such as use of corticosteroids, suggest opportunities to reduce OHT risk within the constraints of the overriding need to control the primary ocular inflammatory disease.
INTRODUCTION: Understanding the evolution of complications after scleral-fixated lens placement demonstrates advantageous surgical techniques and suitable candidates. MATERIALS/METHODS: A literature search in PubMed for several terms, including "scleral intraocular lens complication," yielded 17 relevant articles. RESULTS: Reviewing complication trends over time, lens tilt and suture erosion have decreased, cystoid macular edema has increased, and retinal detachment has remained the same after scleral-fixated lens placement. The successful reduction in complications are attributed to several alterations in technique, including positioning sclerotomy sites 180 degrees apart and using scleral flaps or pockets to bury sutures. Possible reduction in retinal risks have been proposed by performing an anterior vitrectomy prior to lens placement in certain settings. DISCUSSION: Complications after scleral-fixated lens placement should assist patient selection. Elderly patients with a history of hypertension should be counseled regarding risk of suprachoroidal hemorrhage, while young patients and postocular trauma patients should be considered for concurrent anterior vitrectomy.
PURPOSE: To evaluate clinical and ancillary testing, including adaptive optics, outcomes in autoimmune retinopathy (AIR) patients treated with rituximab. DESIGN: Retrospective, interventional case series. METHODS: patients: Sixteen AIR patients treated with rituximab. OBSERVATION PROCEDURES: All patients were treated with a loading and maintenance dose schedule of intravenous rituximab. Visual acuity (VA), electroretinography (ERG), and spectral-domain optical coherence tomography (SDOCT) and visual field (VF) results were recorded. A subset of patients was also imaged using adaptive optics scanning laser ophthalmoscopy (AO-SLO). MAIN OUTCOME MEASURES: Rates of VA change before vs after rituximab initiation were compared with mixed-model linear regression. RESULTS: The rate of visual decline was significantly less after rituximab initiation compared with the rate of visual decline prior to rituximab initiation (P = .005). Seventy-seven percent of eyes had stable or improved VA 6 months after rituximab initiation. Amplitudes and implicit times on ERG, mean deviation on VF, central subfield mean thickness, and total macular volume did not decrease to a significant degree over the rituximab treatment period. Six eyes had serial AO-SLO imaging. Cone densities did not change significantly over the treatment period. CONCLUSION: VA was stable or improved in a majority of AIR patients while they were being treated with rituximab. OCT and ERG parameters, as well as AO-SLO cone densities, were stable during treatment. Studies with additional patients and longer follow-up periods are needed to further explore the utility of rituximab in the management of AIR.
Staphylococcus aureus is a leading cause of both nosocomial and community-acquired infection. Biofilm formation at the site of infection reduces antimicrobial susceptibility and can lead to chronic infection. During biofilm formation, a subset of cells liberate cytoplasmic proteins and DNA, which are repurposed to form the extracellular matrix that binds the remaining cells together in large clusters. Using a strain that forms robust biofilms in vitro during growth under glucose supplementation, we carried out a genome-wide screen for genes involved in the release of extracellular DNA (eDNA). A high-density transposon insertion library was grown under biofilm-inducing conditions, and the relative frequency of insertions was compared between genomic DNA (gDNA) collected from cells in the biofilm and eDNA from the matrix. Transposon insertions into genes encoding functions necessary for eDNA release were identified by reduced representation in the eDNA. On direct testing, mutants of some of these genes exhibited markedly reduced levels of eDNA and a concomitant reduction in cell clustering. Among the genes with robust mutant phenotypes were gdpP, which encodes a phosphodiesterase that degrades the second messenger cyclic-di-AMP, and xdrA, the gene for a transcription factor that, as revealed by RNA-sequencing analysis, influences the expression of multiple genes, including many involved in cell wall homeostasis. Finally, we report that growth in biofilm-inducing medium lowers cyclic-di-AMP levels and does so in a manner that depends on the gdpP phosphodiesterase gene.
Di Gioia SA, Connors S, Matsunami N, Cannavino J, Rose MF, Gilette NM, Artoni P, de Macena Sobreira NL, Chan W-M, Webb BD, Robson CD, Cheng L, Van Ryzin C, Ramirez-Martinez A, Mohassel P, Leppert M, Scholand MB, Grunseich C, Ferreira CR, Hartman T, Hayes IM, Morgan T, Markie DM, Fagiolini M, Swift A, Chines PS, Speck-Martins CE, Collins FS, Jabs EW, Bönnemann CG, Olson EN, Olson EN, Carey JC, Robertson SP, Manoli I, Engle EC. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun 2017;8:16077.Abstract
Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk(insT/insT) zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.