Extraocular ectoderm triggers dorsal retinal fate during optic vesicle evagination in zebrafish.

Dorsal retinal fate is established early in eye development, via expression of spatially restricted dorsal-specific transcription factors in the optic vesicle; yet the events leading to initiation of dorsal fate are not clear. We hypothesized that induction of dorsal fate would require an extraocular signal arising from a neighboring tissue to pattern the prospective dorsal retina, however no such signal has been identified. We used the zebrafish embryo to determine the source, timing, and identity of the dorsal retina-inducing signal. Extensive cell movements occur during zebrafish optic vesicle morphogenesis, however the location of prospective dorsal cells within the early optic vesicle and their spatial relationship to early dorsal markers is currently unknown. Our mRNA expression and fate mapping analyses demonstrate that the dorsolateral optic vesicle is the earliest region to express dorsal specific markers, and cells from this domain contribute to the dorsal retinal pole at 24 hpf. We show that three bmp genes marking dorsal retina at 25 hpf are also expressed extraocularly before retinal patterning begins. We identified gdf6a as a dorsal initiation signal acting from the extraocular non-neural ectoderm during optic vesicle evagination. We find that bmp2b is involved in dorsal retina initiation, acting upstream of gdf6a. Together, this work has identified the nature and source of extraocular signals required to pattern the dorsal retina.

Risk factors, management, and outcomes of Acanthamoeba keratitis: A retrospective analysis of 110 cases.

PURPOSE: To evaluate the risk factors, medical and surgical management, and visual outcomes of patients affected by Acanthamoeba keratitis (AK) over a 16-year period. OBSERVATIONS: Records were reviewed retrospectively for all AK patients treated at University of Iowa between 2002 and 2017. Main outcomes measured were risk factors, time to diagnosis, coinfection types, initial and final visual acuities, and treatment outcomes, with failure of medical therapy defined as need for therapeutic keratoplasty (TK). Effects of steroid use on these outcomes were determined. Among all AK cases occurring during the study period (N = 110), the median age of the AK cohort was 31 years (range 8-80 years), and 49.1% were men. Contact lens wear was the primary risk factor for AK (95/100, 86.4%), and the median time to diagnosis was 0.70 (0.23-1.23) months. Forty-four AK patients (40%) failed medical therapy. Vision outcomes were better for AK patients with successful medical therapy compared to those requiring TK (LogMAR 0.00 v. 0.30; p < 0.0001). Corticosteroid use was associated with increased time to diagnosis (1.00 v. 0.50 months; p = 0.002), decreased final vision (LogMAR 0.10 v. 0.00; p < 0.05) and increased need for TK (40/77 v. 4/33; p < 0.001). CONCLUSIONS AND IMPORTANCE: Acanthamoeba keratitis cases have increased over the past two decades at our institution. In this large retrospective study, AK was commonly misdiagnosed with delayed diagnosis and high rates of failed medical therapy. Corticosteroid use before AK diagnosis led to poorer outcomes. Our findings underscore the need for ophthalmologists to suspect Acanthamoeba in the setting of contact lens-associated keratitis before topical steroids are initiated.

Long-Term Follow-Up of Normal Tension Glaucoma Patients With TBK1 Gene Mutations in One Large Pedigree.

PURPOSE: To characterize features of glaucoma associated with a TANK binding kinase 1 (TBK1) gene duplication, which is among the most common molecularly defined causes of normal tension glaucoma (NTG). DESIGN: Retrospective observational case series. METHODS: We conducted a retrospective case series, by reviewing medical records of 7 members of a pedigree with NTG caused by TBK1 gene duplications. Clinical features of these patients at diagnosis, throughout management, and at latest follow-up were identified, including age, intraocular pressure (IOP), central corneal thickness (CCT), optic nerve head appearance, and mean deviation (MD) assessed with Humphrey visual field (HVF) testing protocols. RESULTS: At initial diagnosis, the mean age was 35 ± 7 years, IOP was 16 ± 2.1 mm Hg, cup-to-disc (C/D) ratio was 0.9 ± 0.08, and MD assessed via HVF 30-2 and/or 24-2 testing protocols was -9.0 ± 8.9 (range: -1.8 to -27) dB in the 14 study eyes. At initial diagnosis, 4 of 14 eyes (28%) had no visual field defect, 4 (28%) had early visual field defects, and 6 (43%) had severe visual field defects. Patients had a mean follow-up of 21.5 ± 9.0 years and experienced an average reduction of IOP by 28%. Four of 12 eyes (33%) had stable visual fields throughout follow-up, while 8 eyes (67%) had slow-to-moderate progression. The 30-2 and/or 24-2 HVF tests had an average change in MD of -0.53 ± 0.26 dB/year. No eyes had rapid progression with an MD >1.0 dB/year. At final follow-up, the mean IOP was 11.5 ± 2.9, and C/D ratio was 0.94 ± 0.4. At final follow-up, 3 of 14 eyes (21%) had early visual field defects, 4 (29%) had moderate visual field defects, and 7 (50%) had severe visual field defects. Six of 14 eyes (43%) met criteria for legal blindness. CONCLUSIONS: We provide the first report of the clinical features and long-term clinical course in a family of NTG patients with TBK1 gene duplications. TBK1-associated glaucoma exhibits classic features of NTG. Patients present with severe disease at a relatively early age and most (67%) have slow-to-moderate progression of their visual field defects. The rate of visual field change appears correlated with the magnitude of IOP, suggesting that it may be advantageous to set extremely low IOP targets for some patients with TBK1-associated glaucoma.

Long-term changes in keratometry and refraction after small aperture corneal inlay implantation.

PURPOSE: To assess longitudinal refractive, keratometric, and topographic changes following KAMRA small-aperture inlay implantation. DESIGN AND SETTING: Prospective study at a single site refractive surgery center. METHODS: Fifty patients underwent KAMRA small-aperture corneal inlay implantation for the correction of presbyopia. Uncorrected near visual acuity (UNVA), uncorrected distance visual acuity, manifest refractive spherical equivalent (MRSE), mean keratometry (Km), corneal topography, and surgically induced astigmatism vector analysis assessments were performed preoperatively and at 1, 3, 6, 12, 24, and 36 months postoperatively. RESULTS: The study comprises 50 eyes. An average shift of 0.15±0.63 D (range -1.63 to 2.00 D) occurred between preoperative baseline and 36 months. At 36 months, 54% of patients had hyperopic MRSE and 40% had myopic MRSE compared with baseline. Km was significantly elevated at all postoperative measurements compared with baseline, with the largest Km measured at 12 months. Eighty-six percent of patients had UNVA of 20/32 or better and 88% uncorrected distance visual acuity of 20/25 or better at 36 months. Longitudinal corneal topography revealed a pattern of corneal steepening over the body of the inlay and flattening over the aperture, correlating with a hyperopic shift. There was no significant surgically induced astigmatism. CONCLUSION: KAMRA inlay may cause an increase in Km compared with baseline. Corneal steepening may occur in a specific pattern with steepening over the inlay and flattening over the aperture. This topographic pattern causes a hyperopic shift, which may be relevant for subsequent procedures, such as cataract extraction.

Case of Presumed Transient Light-Sensitivity Syndrome After Small-Incision Lenticule Extraction.

PURPOSE: To report the first presumed case of transient light-sensitivity syndrome (TLSS) after small-incision lenticule extraction (SMILE). METHODS: A 27-year-old male patient was treated for severe photophobic symptoms occurring 7 weeks after undergoing a bilateral SMILE procedure. His comprehensive ocular examination was unremarkable and his visual acuity was unaffected. Treatment was a month-long tapering dose of topical steroids. RESULTS: Photophobic symptoms fully resolved after steroid treatment. TLSS related to SMILE mirrors TLSS after laser in situ keratomileusis in both onset and steroid responsiveness. CONCLUSIONS: TLSS is a rare and minor complication of SMILE. Photophobic symptoms associated with post-SMILE TLSS are fully responsive to topical corticosteroids.

Stereoacuity after small aperture corneal inlay implantation.

PURPOSE: The aim of this study was to compare stereoacuity before and after KAMRA corneal inlay implantation for the correction of presbyopia. PATIENTS AND METHODS: This is a prospective study of 60 patients who underwent KAMRA inlay implantation. Patients were examined before and 6 months after surgery for stereoacuity, uncorrected distance visual acuity (UDVA), and uncorrected near visual acuity (UNVA). RESULTS: The mean stereoacuity before surgery was 29.5±28.1 arcsec (range: 20-200) and at 6 months was 29.8±26.4 arcsec (range: 20-200). The decline in stereoacuity was not statistically significant. At 6 months follow-up, UDVA was 20/25 or better in all 60 patients and UNVA was J2 (20/25) or better in 51 (85%) patients. CONCLUSION: There is no significant change in stereoacuity following KAMRA inlay implantation. The KAMRA inlay is a good treatment option for improving near vision in presbyopic patients while preserving stereoacuity and distance vision.

Cataract Surgery in Patients with a Previous History of KAMRA Inlay Implantation: A Case Series.

INTRODUCTION: The visual outcome of cataract surgery in patients with a previous history of KAMRA inlay implantation is an emerging issue for which limited research exists. The purpose of this study is to describe postoperative visual outcomes in this patient population. METHODS: This is a case series with retrospective chart review. Seven patients underwent cataract surgery following KAMRA corneal inlay implantation. Visual acuity was assessed before and after cataract surgery. Keratometry was measured before and after KAMRA inlay implantation, and optical biometry was performed prior to cataract surgery. RESULTS: Postoperatively, uncorrected distance visual acuity (UDVA) was 20/20 in five (71%) patients and 20/40 or better in seven (100%) patients, corrected distance visual acuity (CDVA) was 20/20 or better in six (86%) patients and 20/25 in seven (100%) patients, and uncorrected near visual acuity (UNVA) was J1 in four (57%) patients, J2 or better in six (86%) patients, and J3 or better in seven (100%) patients. There was no significant change in keratometry after KAMRA inlay implantation. Biometry calculations accurately predicted intraocular lens (IOL) power after cataract surgery. Surgeons did not report a significant change in the surgical technique of cataract surgery. CONCLUSION: Patients who undergo cataract surgery with a previous history of KAMRA inlay implantation have good visual outcomes. Furthermore, intraocular lens (IOL) calculations accurately predict power, and there appears to be no significant change in surgical technique.

Six-month visual outcomes for the correction of presbyopia using a small-aperture corneal inlay: single-site experience.

OBJECTIVE: The objective of this study was to describe 6-month postoperative efficacy and safety outcomes after monocular KAMRA corneal inlay implantation in emmetropic presbyopic patients. STUDY DESIGN: This study followed a retrospective chart analysis. SETTING: This study was performed at Hoopes Vision in Draper, UT, USA. SUBJECTS AND METHODS: Fifty-seven patients met the inclusion criteria of this study and underwent KAMRA corneal inlay implantation following the approval of the United States Food and Drug Association between May 2015 and April 2016 at a single site. Surgery involved femtosecond laser-created corneal pockets of various depths. Efficacy, safety, and patient satisfaction reports were analyzed at 3 and 6 months. RESULTS: At 6 months follow-up, the monocular uncorrected near visual acuity (UNVA) was Jaeger (J) 4 (20/32), the mean uncorrected distance visual acuity was 20/25, and the mean corrected distance visual acuity was 20/20. At 6 months, 71% of patients with a pocket depth of ≥250 µm had a UNVA of 20/20 or better, whereas only 22% of patients with a shallow pocket depth of <250 µm had a UNVA of 20/20 or better. There was no statistical difference in UNVA at 6 months between virgin eyes and post-LASIK eyes. One patient had an explant and five patients underwent inlay recentration, all of which resulted in improved visual acuity. At 6 months, 72% of patients reported some level of satisfaction, 26% of patients reported being "not dependent" on reading glasses, and 62% of patients reported being able to do most things in bright light without reading glasses. CONCLUSION: For patients with emmetropic presbyopia, the KAMRA inlay is a viable treatment option resulting in improved UNVA. Increased pocket depth may be associated with better postoperative outcomes. Safety rates are high, while explantation and recentering rates are low. Overall, patient satisfaction of the KAMRA inlay is good.

Rainbow glare after laser-assisted in situ keratomileusis: a review of literature.

This article reviews the current literature pertaining to rainbow glare (RG), including incidence rate, clinical presentation, etiology, prognosis, and management. RG is a rare optical complication of femtosecond laser-assisted in situ keratomileusis that results in patients seeing an array of spectral bands surrounding point sources of light under mesopic and scotopic conditions. The mechanism is thought to be a consequence of the formation of a transmissive diffraction grating on the posterior surface of the corneal flap created by the FS laser. RG has a good prognosis and is usually self-limiting. Persistent RG with concomitant residual refractive error may warrant lifting the flap and photoablating the posterior surface of the flap. Patients with persistent RG and no residual refractive error should be considered candidates for phototherapeutic keratectomy on the posterior flap surface.

Hearing preservation after middle fossa vestibular schwannoma removal: are the results durable?

OBJECTIVE: To describe 5-year hearing preservation rates following microsurgical excision of vestibular schwannoma (VS) via the middle cranial fossa (MCF) approach. STUDY DESIGN: Case series with chart review. SETTING: This study was performed at a tertiary care academic medical center. SUBJECTS AND METHODS: Fifty-seven subjects with VS underwent resection via an MCF approach between February 1998 and January 2009. Pure-tone average (PTA) and word recognition score (WRS) were obtained preoperatively, immediately postoperatively, and at 5-year follow-up. RESULTS: Preoperative serviceable hearing (American Academy of Otolaryngology-Head and Neck Surgery class A/B) was present in 49 (86%) of the 57 patients, with an average PTA of 23 dB (range, 1-50 dB) and an average WRS of 97% (range, 76%-100%). Immediate postoperative serviceable hearing was maintained in 27 (55%) patients, with an average PTA and WRS of 31 dB (5-50 dB) and 96% (70%-100%), respectively. Five-year follow-up was available for 16 of the 27 patients. Twelve (75%) of the 16 patients maintained serviceable hearing with an average PTA and WRS of 35 dB (4-49 dB) and 95% (84%-100%), respectively. Of the 16 subjects who did maintain class A or B hearing, the mean change in PTA and WRS was 5 dB and 0.4%, respectively. Of the 4 patients who did not maintain class A/B hearing, average change in PTA and WRS was 16 dB (4.5-23 dB) and 16% (0%-40%), respectively. CONCLUSIONS: For patients with VS in whom serviceable hearing is preserved following the MCF approach, the long-term hearing outcome remains durable in most patients.

Rapid and efficient zebrafish genotyping using PCR with high-resolution melt analysis.

Zebrafish is a powerful vertebrate model system for studying development, modeling disease, and performing drug screening. Recently a variety of genetic tools have been introduced, including multiple strategies for inducing mutations and generating transgenic lines. However, large-scale screening is limited by traditional genotyping methods, which are time-consuming and labor-intensive. Here we describe a technique to analyze zebrafish genotypes by PCR combined with high-resolution melting analysis (HRMA). This approach is rapid, sensitive, and inexpensive, with lower risk of contamination artifacts. Genotyping by PCR with HRMA can be used for embryos or adult fish, including in high-throughput screening protocols.

Zebrafish foxP2 zinc finger nuclease mutant has normal axon pathfinding.

foxP2, a forkhead-domain transcription factor, is critical for speech and language development in humans, but its role in the establishment of CNS connectivity is unclear. While in vitro studies have identified axon guidance molecules as targets of foxP2 regulation, and cell culture assays suggest a role for foxP2 in neurite outgrowth, in vivo studies have been lacking regarding a role for foxP2 in axon pathfinding. We used a modified zinc finger nuclease methodology to generate mutations in the zebrafish foxP2 gene. Using PCR-based high resolution melt curve analysis (HRMA) of G0 founder animals, we screened and identified three mutants carrying nonsense mutations in the 2(nd) coding exon: a 17 base-pair (bp) deletion, an 8bp deletion, and a 4bp insertion. Sequence analysis of cDNA confirmed that these were frameshift mutations with predicted early protein truncations. Homozygous mutant fish were viable and fertile, with unchanged body morphology, and no apparent differences in CNS apoptosis, proliferation, or patterning at embryonic stages. There was a reduction in expression of the known foxP2 target gene cntnap2 that was rescued by injection of wild-type foxP2 transcript. When we examined axon pathfinding using a pan-axonal marker or transgenic lines, including a foxP2-neuron-specific enhancer, we did not observe any axon guidance errors. Our findings suggest that foxP2 is not necessary for axon pathfinding during development.