Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice.

Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.

Response to aflibercept as secondary therapy in patients with persistent retinal edema due to central retinal vein occlusion initially treated with bevacizumab or ranibizumab.

BACKGROUND: Recent advances have given practitioners options for the treatment of macular edema secondary to central retinal vein occlusion. These options include steroid injections and implants as well as anti-vascular endothelial growth factor medications. However, there is little in the medical literature to guide secondary therapy when an initial treatment strategy is insufficient. The authors present encouraging results from the treatment of six consecutive cases of central retinal vein occlusion treated with aflibercept as a secondary therapy for macular edema refractory to repeated intravitreal bevacizumab or ranibizumab injections. METHODS: A retrospective review of six consecutive cases of central retinal vein occlusion with persistent macular edema despite regular anti-vascular endothelial growth factor injections that were transitioned to aflibercept was conducted. Optical coherence tomography and visual acuity data were examined. RESULTS: All six eyes from the six patients included showed either complete or near complete resolution of macular edema with one or two injections of aflibercept. The improvement in edema was accompanied by lasting modest visual gains in three of the six patients and in subjective visual improvement in four of the six patients. CONCLUSION: The six eyes in this series all responded favorably to aflibercept as a secondary therapy. Although the sample size is too small to draw definitive conclusions, the results are encouraging.

Prospective observational study of United States (US) Air Force Critical Care Air Transport team operations in Iraq.

BACKGROUND: Current United States (US) military doctrine emphasizes rapid evacuation of casualties to fixed medical facilities remote from the theater of war. To support this strategy, the Air Force has formed Critical Care Air Transport (CCAT) teams consisting of a physician, nurse, and respiratory therapist. STUDY OBJECTIVE: To describe the characteristics of US Air Force CCAT team operations at Balad Air Base, Iraq over a 1-year period. METHODS: Balad Air Base was the primary collection point in Iraq for patients requiring evacuation outside of the country during the study period. The study authors deployed sequentially to Balad Air Base as CCAT team leaders. All patients transported by the authors were enrolled in the study. Injuries, illnesses, demographics, and in-flight data were collected prospectively. RESULTS: There were 133 patients transported on 61 separate flights between Iraq and Germany. Trauma was present in 65% (87/133) of all patients transported. Lower-extremity injuries were the most prevalent among combat-related trauma patients. Cardiac conditions were the most common diagnoses among the medical patients. Fifty-seven percent of patients were mechanically ventilated. Hypotension was the most common in-flight complication, occurring in 17% (22/133) of patients. No flights were diverted or turned back due to an unstable patient. No patient died during flight or in the 24 h after the flight. CONCLUSIONS: US Air Force CCAT teams can safely transport multiple critical patients over long distances while providing intensive care interventions. Medical patients make up over one-third of patients requiring CCAT team transport.

Variation in optineurin (OPTN) allele frequencies between and within populations.

PURPOSE: To evaluate the extent to which mutations in the optineurin (OPTN) glaucoma gene play a role in glaucoma in different populations. METHODS: Case-controlled study of OPTN sequence variants in individuals with or without glaucoma in populations of different ancestral origins and evaluate previous OPTN reports. We analyzed 314 subjects with African, Asian, Caucasian and Hispanic ancestries included 229 cases of primary open-angle glaucoma, 51 cases of juvenile-onset open-angle glaucoma, 33 cases of normal tension glaucoma, and 371 controls. Polymerase chain reaction-amplified OPTN coding exons were resequenced and case frequencies were compared to frequencies in controls matched for ancestry. RESULTS: The E50K sequence variant was identified in one individual from Chile with normal tension glaucoma, and the 691_692insAG variant was found in one Ashkenazi Jewish individual from Russia. The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry. In addition to presenting OPTN allele frequencies for Caucasian and Asian populations that have been the subject of previous reports, we also present information for populations of Hispanic and black African ancestries. CONCLUSIONS: Our study contributes additional evidence to support the previously reported association of the OPTN E50K mutation with glaucoma. After finding an additional 691_692insAG OPTN variant, we can still only conclude that this variant is rare. Combined analysis of our data with data from more than a dozen other studies indicates no association of R545Q with glaucoma in most populations. Those same studies disagree in their conclusions regarding the role of M98K in glaucoma. Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations. It is currently not possible to tell how much of the underlying cause of the allele frequency difference is attributable to demographic, technical, or ascertainment differences among the studies.

Shaggy photoreceptors with subfoveal fluid associated with a distant choroidal melanoma.

Purpose. To describe the enhanced depth imaging optical coherence tomography (EDI-OCT) findings in a patient with an extra macula choroidal melanoma before and after treatment. Methods. Observational case report. Results. A 45 year-old Caucasian male patient was referred to retina clinic for management of choroidal melanoma. Examination revealed a nasal choroidal melanoma while EDI-OCT illustrated subfoveal fluid pocket with elongated shaggy photoreceptors distant and separate from the tumor. The patient was treated with plaque brachytherapy and intravitreal bevacizumab. One week after plaque removal, there was a dramatic reduction in the shaggy photoreceptors. Conclusion. Choroidal melanomas have effects that are not localized to the area of the tumor. This loculated pocket of subretinal fluid and coinciding changes to photoreceptor morphology may be related to global changes in choroidal function or release of tumor related cytokines.

Successful treatment of choroidal neovascularization secondary to persistent placoid maculopathy with intravitreal bevacizumab.

PURPOSE: To report a case of posterior placoid maculopathy with secondary choroidal neovascularization that responded favorably to repeat intravitreal injections of bevacizumab with long-term follow-up. METHODS: Patient data from all clinic visits were reviewed. These include visual acuity measurements and clinical examination findings, optical coherence tomography, color fundus photography, and fluorescein angiography images from the initial visit and follow-up encounters. RESULTS: This patient showed clear evidence of active leakage from choroidal neovascularization on presentation that promptly resolved with treatment. After his initial course of injections, all evidence of active exudation disappeared from his optical coherence tomography scans. However, when treatment was extended beyond 8 weeks, choroidal neovascularization leakage returned. In addition, the patient developed subretinal fibrosis in one eye despite regular treatments. Nevertheless, visual acuity has remained excellent through his most recent encounter. CONCLUSION: Persistent placoid maculopathy is an exceedingly rare clinical entity. In their original descriptive series, Golchet et al revealed that 9 of the 12 eyes went on to develop poor vision from complications of choroidal neovascularization. There is currently only one case in the literature that describes the use of anti-vascular endothelial growth factor medications in the treatment of persistent placoid maculopathy with promising results. This case adds supporting evidence for this treatment modality and highlights the need for continued follow-up and treatment till 18 months from presentation.

Localized retinal manifestations of paraneoplastic autoimmune retinopathy.

PURPOSE: Systemic neoplastic processes can affect the retina through autoimmune retinopathy. This process may present in a variety of patterns. A novel pattern of paraneoplastic autoimmune retinopathy has been described. METHODS: Two patients presented with paraneoplastic vision changes. Optical coherence tomography and multifocal electroretinography were performed, which showed a unique focal retinal change in both patients. Case 1 is a 20-year-old woman with history of cutaneous melanoma. Case 2 is 67-year-old woman with history of breast cancer. RESULTS: Both patients showed a localized area of foveal thinning that corresponded with areas of depression on multifocal electroretinography. Each tested positive for antiretinal antibodies. CONCLUSION: This is a novel manifestation of paraneoplastic autoimmune retinopathy. Previously described cases have all affected the retina diffusely. These cases highlight the need to consider distant neoplastic processes when evaluating patient with similar presentations to those depicted here.

Response to aflibercept in patients with persistent exudation despite prior treatment with bevacizumab or ranibizumab for age-related macular degeneration.

BACKGROUND AND OBJECTIVE: This study examines the clinical response of patients transitioned to aflibercept, the newest anti-VEGF medication, due to persistent evidence of exudation on optical coherence tomography (OCT) despite regular treatment with bevacizumab and/or ranibizumab. PATIENTS AND METHODS: Aflibercept was administered to 111 patients considered for study inclusion. Eyes were included if they were transitioned to aflibercept for treatment of persistent exudation on OCT despite regular treatment with at least three injections of ranibizumab or bevacizumab. Retrospective data were collected from medical records. RESULTS: Complete resolution of exudation was seen in 34% of eyes at final follow-up. Clear improvement in exudation amount or severity without complete resolution was seen in 25%. No improvement was seen in 34%, and 6% demonstrated worsening of exudation. Snellen visual acuity at the time of transition versus final follow-up after aflibercept injection did not appreciably change (logMAR 0.494 to 0.505, Snellen equivalent 20/62 to 20/64; P = .84). The mean center point neurosensory retina thickness decreased from 228.6 to 176.9 µm (P = .001). CONCLUSION: Aflibercept may decrease the amount of exudation in a significant number of patients. However, this reduction did not result in an improvement in Snellen visual acuity.

Migration of ozurdex implant into the anterior chamber.

PURPOSE: The purpose of this study was to report a novel complication of Ozurdex implantation in which the implant migrates into the anterior chamber and to describe the subsequent clinical course. METHODS: After identification of the implant in the inferior anterior chamber, clinical photographs were obtained. Baseline measurements of vision, corneal thickness, and corneal cell counts were likewise collected. The patent was followed for clinical sequelae. RESULTS: After 4 months, the implant was clearly observed to be degrading. Repeat corneal pachymetry, slit-lamp examination, and visual acuity were stable. DISCUSSION: Patients with a patent peripheral iridotomy who received Ozurdex intravitreal implants are at risk for migration of the implant into the anterior chamber. However, the implant itself appears to be benign, causing no detrimental effects to the corneal endothelium.

Severe Guillain-Barré syndrome following primary infection with varicella zoster virus in an adult.

Varicella zoster virus (VZV) infection may trigger Guillain-Barré syndrome (GBS), but this is rare and almost always in the context of reactivation disease from latent VZV, 'shingles'. We report here a case of severe GBS following primary VZV infection in an adult. A 40-year-old man of Indian origin developed features of GBS including quadriplegia, bulbar paralysis, and bilateral facial nerve palsies 14 days after primary VZV infection contracted from a known case in a family member. Nerve conduction studies confirmed acute inflammatory demyelinating polyneuropathy. Anti-ganglioside antibodies were negative. The mechanism of Schwann cell attack following VZV infection is poorly understood but this case suggests that primary VZV infection may be a sufficient stimulus to drive antibody generation and precipitate severe clinical symptomatology. The morbidity associated with the complications of VZV infection in adulthood could be avoided if patients who are seronegative for VZV (frequently from the Asian subcontinent) are offered prophylaxis after an exposure in adulthood.