Occlusive retinal vasculitis: novel insights into causes, pathogenesis and treatment.

PURPOSE OF REVIEW: Occlusive retinal vasculitis (ORV) has a large differential diagnosis and varied therapeutic approaches. This review highlights existing and novel causes and treatment options for ORV. RECENT FINDINGS: Mutations in CAPN5, TREX1, and TNFAIP3 have been associated with dominantly inherited forms of ORV. Various intraocular therapeutics have been shown to occasionally cause ORV; the most recent medications associated with ORV are vancomycin and brolucizumab. In cases of ORV linked to Behçet's disease, clinical trials support the use of tumor necrosis factor alpha inhibitors. SUMMARY: Identification of the underlying etiology of ORV is critical to help guide treatment. Treatment in ORV involves both treatment any underlying infection or autoimmune condition, cessation of the any offending causative agent and local treatment of neovascular complications.

The use of biologics for uveitis associated with spondyloarthritis.

PURPOSE OF REVIEW: The term spondyloarthritis (SpA) encompasses a group of chronic inflammatory disorders of the joints, including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, inflammatory bowel disease, juvenile SpA and undifferentiated SpA. These diseases can also present with uveitis, or intraocular inflammation, which can be controlled with biologics. RECENT FINDINGS: Profound success has occurred with the tumor necrosis factor-α inhibitors infliximab and adalimumab, moderate success with certolizumab pegol and golimumab and less encouraging results with etanercept. Promising results have also been demonstrated with interleukin-17 (IL-17) antagonists, such as secukinumab ixekizumab or combined IL-12 and 23 medications, such as ustekinumab. SUMMARY: In cases of uveitis that require long-term control, biologics are an emerging and valuable class of medications for these patients, and may provide avenues to control both their underlying SpA and uveitis manifestations.

ELLIPSOID ZONE MAPPING AND OUTER RETINAL ASSESSMENT IN STARGARDT DISEASE.

PURPOSE: To quantify and correlate ellipsoid zone and photoreceptor outer segment changes with visual acuity in Stargardt disease. METHODS: An institutional review board-approved study of 32 eyes with Stargardt disease was performed. After spectral domain optical coherence tomography, the macular cube was exported into a novel analysis tool and volumetric assessment from the ellipsoid zone to the retinal pigment epithelium was performed. Using this information, mapping was completed with en face representation of the height between the ellipsoid zone and retinal pigment epithelium. This analysis provided quantification of ellipsoid zone and photoreceptor outer segments, including atrophy (ellipsoid zone to retinal pigment epithelium thickness = 0 µm) and attenuation (ellipsoid zone to retinal pigment epithelium thickness <20 µm). These parameters were compared with visual acuity and controls (n = 12 eyes). RESULTS: Visual acuity ranged from 20/30 to 20/250. The central foveal B-scan area of ellipsoid and photoreceptor outer segments was significantly less than controls (0.13 ± 0.05 mm vs. 0.17 ± 0.03 mm, respectively, P = 0.0074). The central foveal B-scan mean thickness measured 22.52 ± 9.0 µm in Stargardt versus 30.0 ± 5.08 µm (P = 0.0096). Atrophy and attenuation were significantly higher in Stargardt patients (22% vs. 1%, P = 0.005 and 43% vs. 1%, P = 0.0002). Visual acuity directly correlated with ellipsoid zone/outer segment volume (R = 0.57, P < 0.005) and inversely correlated with attenuation and atrophy (R = -0.53 and -0.57; P < 0.005 for all). CONCLUSION: Eyes with Stargardt disease frequently have significant disruption of the ellipsoid zone and outer segments. This degenerative change was successfully quantified with a novel assessment platform and identified correlates with visual function. This software provides the opportunity for quantitative assessment and possible longitudinal surveillance.

Paracanthal "One-Snip" Decompression in a Cadaver Model of Retrobulbar Hemorrhage.

PURPOSE: The authors assess the effectiveness of a modified paracanthal or "one-snip" procedure compared with the traditional lateral canthotomy and inferior cantholysis in the reduction of intraocular pressure (IOP) and proptosis in a human cadaveric model of retrobulbar hemorrhage. METHODS: This study comprised a comparative interventional study in a cadaveric model of retrobulbar hemorrhage. Six orbits of 3 fresh cadavers were included in the study. Baseline measurements of IOP and proptosis were recorded for all 6 orbits before and after simulation of retrobulbar hemorrhage as previously described. Right orbits (n = 3) underwent traditional lateral canthotomy and inferior cantholysis. Left orbits (n = 3) underwent modified paracanthal or "one-snip" procedure. The primary outcome measures were reduction in IOP and proptosis between the 2 techniques. RESULTS: Following lateral canthotomy and inferior cantholysis of each right orbit, the average IOP dropped to 14 mm Hg (range of 11-18 mm Hg), corresponding to a mean decrease of 32 mm Hg. Following the "one-snip" procedure of each left orbit, the average IOP dropped to 19 mm Hg with a range of 16 to 23 mm Hg, corresponding to a mean decrease of 22 mm Hg. There was no statistically significant difference in IOP reduction (p = 0.36) or proptosis reduction (p = 0.23) between the 2 treatment groups. CONCLUSIONS: Compared with traditional lateral canthotomy xand inferior cantholysis, the modified paracanthal or "one-snip" procedure is effective for IOP reduction and led to mild improvement of proptosis in a cadaveric model of retrobulbar hemorrhage. The authors hope this study helps improve orbital compartment syndrome outcomes by providing an option that more providers will feel comfortable performing and therefore decreasing time to surgical decompression.

Choroidal osteoma shows bone lamella and vascular channels on enhanced depth imaging optical coherence tomography in 15 eyes.

PURPOSE: To describe enhanced depth imaging optical coherence tomography findings of choroidal osteoma. METHODS: Retrospective, observational case series of 15 eyes with choroidal osteoma imaged with EDI-OCT. RESULTS: The mean age at presentation was 27 years. There were 10 women and 3 men. The visual acuity ranged from 20/20 to hand motion, with reduced visual acuity secondary to photoreceptor loss in the foveola (n = 5) or subfoveal fluid (n = 1), and additional choroidal neovascular membrane (n = 3). The mean basal tumor diameter was 8.0 mm, and ultrasonographic thickness was 1.5 mm. Using enhanced depth imaging optical coherence tomography, the mean tumor thickness was 589 µm when compared with a matched choroidal region in the unaffected eye of 247 µm (138% increased thickness) (P = 0.009). The tumor surface topography was classified (ultrasonography vs. enhanced depth imaging optical coherence tomography) as flat (87 vs. 13%), dome (13 vs. 40%), or undulating (0 vs. 47%). On enhanced depth imaging optical coherence tomography, unique features included horizontal lamellar lines (presumed bone lamella) (n = 15, 100%) and hyperreflective horizontal lines (presumed cement lines) (n = 8, 53%). Other features included horizontal tubular lamella with optically empty center (presumed Haversian canals or vascular channels) (n = 9, 60%), vertical tubular lamella (presumed Volkmann canals or vascular channels) (n = 2, 13%), and speckled regions (presumed compact or small trabecular bone) (n = 6, 40%). Of the nine eyes with subfoveolar osteoma, the tumor was completely ossified (n = 4), partially deossified (n = 2), or completely deossified (n = 3). Photoreceptor thinning/atrophy was found in all five eyes with deossified osteoma, whereas intact photoreceptor appearance was noted in the four eyes with ossified subfoveal osteoma. CONCLUSION: Enhanced depth imaging optical coherence tomography reveals characteristic surface topography of choroidal osteoma as dome or undulating (87%) with unique intrinsic features of horizontal lamellar lines (100%), horizontal (60%) or vertical (13%) tubules, and speckled regions (40%). Photoreceptor loss was evident in every case of tumor deossification.

Choroidal melanocytosis evaluation with enhanced depth imaging optical coherence tomography.

OBJECTIVE: To assess eyes with unilateral choroidal melanocytosis using enhanced depth imaging (EDI) optical coherence tomography (OCT). DESIGN: Retrospective, observational case series. PARTICIPANTS: Fifteen patients with unilateral choroidal melanocytosis. METHODS: Each patient was evaluated with EDI-OCT, and comparison was made of involved versus uninvolved foveal retinal and choroidal layers. MAIN OUTCOME MEASURES: Enhanced depth imaging OCT features of choroidal melanocytosis. RESULTS: The mean patient age was 28 years (median, 23 years; range, 5-76 years). There were 9 male and 6 female patients. Best-corrected visual acuity ranged from 20/20 to 20/30. All patients had subfoveal involvement with choroidal melanocytosis. Associated features included dermal (n = 6), scleral (n = 9), iris (n = 3), and palate (n = 1) melanocytosis. Spectral domain EDI-OCT revealed normal inner retina (n = 15) and normal outer retina (n = 14). The only retinal abnormality was a defect in both the myoid zone and the ellipsoid junction (n = 1). The affected choroid showed smooth anterior contour (n = 15) and thinned or compressed choriocapillaris (n = 2), thinned (n = 3) or thickened (n = 3) medium vessels, and thinned large vessels (n = 2). The subfoveal choroid was a mean 23% thicker in the involved eye, with a mean thickness of 326.4 µm (median, 326 µm; range, 120-459 µm) compared with 264.4 µm (median, 260 µm; range, 94-462 µm) in the uninvolved eye (P = 0.15). The choroidal perivascular interstitial tissue was 51% thicker in the study eye, enwrapping and silhouetting the medium and large vessels (P = 0.01). The ratio between the perivascular stromal tissue and the subfoveal choroidal thickness was 66% in the study eye and 54% in the normal eye (P = 0.0001). Deep partial (n = 5) or complete (n = 2) tissue shadowing was noted. CONCLUSIONS: Enhanced depth imaging OCT revealed that choroidal melanocytosis shows increased subfoveal choroidal thickness with an apparent increase in the choroidal perivascular stromal tissue and minimal effect on the overlying retina.

Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma.

OBJECTIVE: To analyze our 5-year experience of intra-arterial chemotherapy (IAC) for retinoblastoma as primary or secondary therapy. DESIGN: Retrospective interventional case series. PARTICIPANTS: A total of 70 eyes of 67 patients. INTERVENTION: Ophthalmic artery chemotherapy infusion under fluoroscopic guidance was performed using melphalan (3, 5, or 7.5 mg) in every case, with additional topotecan (1 mg) and/or carboplatin (30 or 50 mg) as necessary. MAIN OUTCOME MEASURES: Tumor control and treatment complications. RESULTS: The mean patient age at IAC was 30 months. The treatment was primary in 36 eyes and secondary in 34 eyes. Those primary therapy eyes were classified according to the International Classification of Retinoblastoma (ICRB) as group A (n = 0), B (n = 1), C (n = 4), D (n = 17), or E (n = 14). The secondary therapy eyes had failed previous intravenous chemotherapy (n = 34) in every case. Each eye received a mean of 3 IAC sessions per eye (median, 3; range, 1-7 sessions). After IAC with a mean follow-up of 19 months, globe salvage was achieved in 72% of primary-treated cases and in 62% of secondary-treated cases. Specifically, primary therapy achieved globe salvage for group B (100%), group C (100%), group D (94%), and group E (36%). Of all 70 eyes, complete regression was achieved for solid tumor in 48 of 51 eyes (94%), subretinal seeds in 40 of 42 eyes (95%), and vitreous seeds in 34 of 39 eyes (87%). After each catheterization (n = 198), the main complications included transient eyelid edema (5%), blepharoptosis (5%), and forehead hyperemia (2%). More lasting complications included vitreous hemorrhage (2%), branch retinal artery obstruction (1%), ophthalmic artery spasm with reperfusion (2%), ophthalmic artery obstruction (2%), partial choroidal ischemia (2%), and optic neuropathy (<1%). Over the past 3 years, the combined incidence of ophthalmic, retinal, and choroidal vascular ischemia was reduced to 1%. There was no patient with stroke, seizure, neurologic impairment, limb ischemia, secondary leukemia, metastasis, or death. CONCLUSIONS: Five-year experience with IAC indicates that this technique is remarkably effective for the management of retinoblastoma as both a primary and a secondary treatment.

Choroidal lymphoma shows calm, rippled, or undulating topography on enhanced depth imaging optical coherence tomography in 14 eyes.

PURPOSE: To describe the features of choroidal lymphoma on enhanced depth imaging optical coherence tomography. METHODS: This retrospective observational case series included 14 eyes of 13 patients, with choroidal lymphoma, studied by enhanced depth imaging optical coherence tomography. RESULTS: The mean age at presentation was 63 years (median, 65 years; range, 32-87 years). Systemic lymphoproliferative disease was present in 2 cases as non-Hodgkin lymphoma (n = 1) or Waldenstrom macroglobulinemia (n = 1). On clinical examination, the choroidal infiltrate was classified as unifocal (n = 3), multifocal (n = 4), or diffuse (n = 7). Enhanced depth imaging optical coherence tomography scans through the tumor epicenter revealed infiltration of the choroid with apparent inward compression of choroidal vascular structures, creating an anterior tumor surface topography that appeared smooth (calm) (n = 7), mini-wavy (rippled) (n = 2), or maxi-wavy (undulating) (n = 5). Greater tumor thickness correlated with increasing tumor surface fluctuation as calm was mean 1.7mm, rippled was 2.8 mm, and undulating surface was 4.1 mm in ultrasonographic thickness. On enhanced depth imaging optical coherence tomography, the mean subfoveolar choroidal thickness, measurable in 9 eyes, was 484 µm (median, 423 µm; range, 156-1,002 µm) (81% greater) versus 267 µm (median, 276 µm; range, 142-501 µm) in the unaffected eye. The mean maximal tumor thickness, measurable in 8 eyes, was 117% greater at 602 µm (median, 538 µm; range, 241-966 µm) compared with the corresponding unaffected choroid in the contralateral eye at 278 µm (median, 245 µm; range, 189-511 µm) (P = 0.046). Inability to measure choroidal thickness was due to dense tumor-induced optical shadowing with inability to visualize the sclerochoroidal junction (P = 0.009). There was no visible infiltration into the overlying retina in any case. CONCLUSION: Enhanced depth imaging optical coherence tomography of choroidal lymphoma revealed 1 of 3 surface topographical patterns resembling an ocean as calm (n = 7), rippled (n = 2), or undulating (n = 5), correlating with increasing tumor thickness.

Combined hamartoma of the retina and retinal pigment epithelium: findings on enhanced depth imaging optical coherence tomography in eight eyes.

PURPOSE: To assess combined hamartoma of the retina and retinal pigment epithelium with enhanced depth imaging optical coherence tomography. METHODS: Retrospective, observational cases series in eight eyes of eight patients, with comparison between affected and unaffected eyes regarding enhanced depth imaging optical coherence tomography features of tumor, fovea, and choroid. RESULTS: The mean age at presentation was 7 years. The tumor was macular (n = 5) or extramacular (n = 3). Enhanced depth imaging optical coherence tomography revealed irregularities in inner retina (n = 8) and/or all retinal layers (n = 3), with epiretinal membrane (n = 8), causing an inner retinal sawtooth (mini-peak) pattern (n = 2), full thickness retinal folds (maxi-peak) (n = 3), or both (n = 3). In the 5 macular tumors, foveal retinal thickness measured mean 608 µm compared with 244 µm in the unaffected eye (P = 0.0004). Mean tumor epicenter retinal thickness in 8 tumors measured 650 µm compared with 327 µm in a corresponding area in the unaffected eye (P = 0.01). In all cases, choroidal thickness beneath the tumor epicenter was decreased at mean 210 µm compared with 328 µm in the corresponding area of unaffected eye (P = 0.009). CONCLUSION: Enhanced depth imaging optical coherence tomography of combined hamartoma revealed epiretinal membrane with vitreoretinal traction in a sawtooth (mini-peak) or folded (maxi-peak) pattern. Combined hamartoma seems to be a thickened retinal mass secondary to focal vitreoretinal traction.

PARACENTRAL ACUTE MIDDLE MACULOPATHY ASSOCIATED WITH COCAINE USE.

BACKGROUND/PURPOSE: To report a case of paracentral acute middle maculopathy in association with cocaine use. METHODS: This is a case report of a 26-year-old man presented with acute vision loss in the left eye following cocaine use. RESULTS: Fundus examination demonstrated faint retinal, whereas optical coherence tomography displayed hyperreflectivity predominantly in the middle retinal layers. Because of associated loss-of-consciousness and vision loss, a stroke work-up was initiated and ruled-out embolic and neurologic causes. The vision loss was attributed to paracentral acute middle maculopathy secondary to cocaine. The vision and retinal alterations on optical coherence tomography improved with observation. CONCLUSION: This case demonstrates a potential unique etiology of paracentral acute middle maculopathy following exposure to cocaine. Paracentral acute middle maculopathy may occur in the setting of cocaine use. Optical coherence tomography evaluation with close surveillance can be helpful to identify the often subtle findings of paracentral acute middle maculopathy in cases of vision loss associated with illicit drug use.

Artificial intelligence chatbot performance in triage of ophthalmic conditions.

BACKGROUND: Timely access to human expertise for affordable and efficient triage of ophthalmic conditions is inconsistent. With recent advancements in publicly available artificial intelligence (AI) chatbots, the lay public may turn to these tools for triage of ophthalmic complaints. Validation studies are necessary to evaluate the performance of AI chatbots as triage tools and inform the public regarding their safety. OBJECTIVE: To evaluate the triage performance of AI chatbots for ophthalmic conditions. DESIGN: Cross-sectional study. SETTING: Single centre. PARTICIPANTS: Ophthalmology trainees, OpenAI ChatGPT (GPT-4), Bing Chat, and WebMD Symptom Checker. METHODS: Forty-four clinical vignettes representing common ophthalmic complaints were developed, and a standardized pathway of prompts was presented to each tool in March 2023. Primary outcomes were proportion of responses with the correct diagnosis listed in the top 3 possible diagnoses and proportion with correct triage urgency. Ancillary outcomes included presence of grossly inaccurate statements, mean reading grade level, mean response word count, proportion with attribution, and most common sources cited. RESULTS: The ophthalmologists in training, ChatGPT, Bing Chat, and the WebMD Symptom Checker listed the appropriate diagnosis among the top 3 suggestions in 42 (95%), 41 (93%), 34 (77%), and 8 (33%) cases, respectively. Triage urgency was appropriate in 38 (86%), 43 (98%), and 37 (84%) cases for ophthalmology trainees, ChatGPT, and Bing Chat, correspondingly. CONCLUSIONS: ChatGPT using the GPT-4 model offered high diagnostic and triage accuracy that was comparable with that of ophthalmology trainees with no grossly inaccurate statements. Bing Chat had lower accuracy and a tendency to overestimate triage urgency.

Longitudinal analysis of aqueous humour cytokine expression and OCT-based imaging biomarkers in retinal vein occlusions treated with anti-vascular endothelial growth factor therapy in the IMAGINE study.

BACKGROUND/OBJECTIVES: Retinal vein occlusion (RVO) is the second most common retinal vascular disorder. Despite promising advances with anti-VEGF therapy, select patients are unresponsive to therapy. A precision medicine-based approach for therapeutic decision-making based on underlying biomarkers may facilitate treatment based on the underlying pathway. This study aims to identify the baseline and longitudinal cytokine profiles of RVO-related macular oedema and correlating these expression profiles with higher order OCT features using a novel retinal segmentation and feature extraction platform. SUBJECTS/METHODS: The IMAGINE study is a post-hoc assessment of aqueous humour cytokines with correlation to higher level analysis of imaging studies. OCT scans underwent machine learning enhanced segmentation of the internal limiting membrane (ILM), ellipsoid zone (EZ) and retinal pigment epithelium (RPE), as well as evaluating volumetric fluid metrics. Samples of aqueous humour were obtained at baseline, as well as months 4 and 9 prior to treatment. These samples were analysed for the expression of multiple cytokines. Patients were divided into Responders and Non-Responders based on OCT profiles. Additionally, patients were categorised as a Rebounder if their CST increased by 50% after initial improvement. RESULTS: Twenty-six eyes were included. The OCT-based response schema identified 21 Responders (81%) and 5 Non-Responders (19%). VEGF levels directly correlated with intraretinal fluid volume and angiogenin was inversely correlated with fluid indices. Multiple cytokines, including ANGPTL4, were directly correlated with ellipsoid zone disruption. The baseline VEGF levels were significantly higher in all responders compared to Non-Responders (p = 0.02). Rebounders tended to have significantly decreased levels of angiogenin and TIMP-1 (p = 0.019, p = 0.015). CONCLUSIONS: Cytokine expression was linked to specific OCT features and treatment response in RVO. Identification of an imaging phenotype that could serve as a surrogate for underlying active disease pathways could enhance treatment decision-making and precision medicine.

Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency.

The higher prevalence of autoimmune diseases in women compared to men could be due to effects of ovarian hormones, pregnancy and/or the presence of a second X chromosome. To elucidate the role of these factors, we investigated the prevalence and spectrum of autoimmune diagnoses in women with primary ovarian insufficiency associated with X chromosome monosomy (Turner syndrome, TS, n = 244) and women with karyotypically normal (46,XX) primary ovarian insufficiency (POI, n = 457) in a prospective study, conducted at the National Institutes of Health. We compared the study group prevalence to normative data for the U.S. population of women. Chronic lymphocytic (Hashimoto's) thyroiditis (HT) occurred in 37% of women with TS vs. 15% with POI (P < 0.0001); HT prevalence in both ovarian insufficiency groups significantly exceeded that in U.S. population of women (5.8%). Inflammatory bowel (IBD, 4%) and celiac disease (CD, 2.7%) were significantly increased in TS, but not in POI. No other autoimmune diagnosis, including Graves' disease or Type 1 diabetes appears to be significantly increased in either group. Women with TS had higher pro-inflammatory IL6 and TGF ß1 levels (p < 0.0001 for both), and lower anti-inflammatory IL10 and TGF ß2 levels (p < 0.005 for both) compared to POI and to normal volunteers. Lifetime estrogen exposure and parity were significantly lower in TS compared to POI, which were in turn lower than the general population of women. The finding that lymphocytic thyroiditis is greatly increased in both women with TS and POI suggests that factors associated with ovarian insufficiency per se promote this form of autoimmunity. The absence of a normal second X-chromosome further contributes to increased autoimmunity in TS.

Perturbation of the transforming growth factor ß system in Turner syndrome.

OBJECTIVE: To measure components of the circulating transforming growth factor ß (TGFß) system in patients with Turner syndrome (TS) compared to relevant controls and to ascertain correlation with endocrine and cardiovascular parameters. METHODS: TGFß1, TGFß2 and endoglin (a vascular TGF receptor component) were measured using enzyme-linked immunoassays in the sera of 40 subjects with TS and 40 healthy volunteer women. The cardiovascular phenotype in TS subjects was extensively characterized by cardiac magnetic resonance (MR) and echo. RESULTS: TGFß1 levels were about 3-fold higher in TS while TGFß2 levels were about 3.5-fold higher in controls (P<0.000 1 for both). Soluble endoglin levels were 25% higher in TS (P<0.000 1). Variation in TGFß system components was not explained by age, blood pressure, platelet count, thyroid function, body proportions or cardiovascular phenotype. CONCLUSION: There is profound perturbation of the TGFß system evident in the circulation of individuals with TS.

Curvularia infection presenting as recurrent conjunctival erosion overlying a scleral-fixated intraocular lens suture.

Purpose: To describe a case of an indolent, chronic Curvularia infection after a ruptured globe injury from an intraocular metallic foreign body in a 38-year old male. Following globe repair and vitrectomy, the patient underwent a sutured scleral-fixated lens. The patient subsequently presented with recurrent painless conjunctival erosion associated with small, pigmented skip lesions of the exposed suture. Observation: Indolent, chronic Curvularia infections can present with subtle signs, including small areas of suture exposure and pigmentation as well as and small ciliary body collections. Conclusion: Recurrent conjunctival erosion in cases of secondary sutured scleral fixated intraocular lenses should prompt evaluation for possible infectious etiology.

Severe retinal complications in Knobloch Syndrome - Three siblings without clinically apparent occipital defects and a review of the literature.

BACKGROUND: Knobloch syndrome results from recessive mutations in COL18A1 and is characterized by retinopathy and occipital scalp, brain and skull defects. METHODS AND MATERIALS: We report three siblings, born to consanguineous parents, two of whom with genetically confirmed Knobloch syndrome due to a homozygous pathogenic variant c.4054_4055del; p.Leu1352Valfs*72 in COL18A1. RESULTS: With the lack of classic occipital findings, an initial diagnosis of familial exudative vitreoretinopathy was entertained in these siblings because of the history of retinal detachments, retinal pigmentary changes and abnormal vitreous. The diagnosis of Knobloch syndrome was eventually made through molecular genetic testing using an extensive panel. In one patient presenting with acute retinal detachment and posteriorly dislocated intraocular lens implant, reattachment surgery was successful in stabilizing vision. CONCLUSION: The clinical diagnosis of Knobloch syndrome can be difficult to reach in the absence of the typical occipital scalp defects. A careful medical history, detailed clinical examination and molecular genetic testing will reveal the correct diagnosis of Knobloch syndrome in atypical cases.

Exploring the angiographic-biologic phenotype in the IMAGINE study: quantitative UWFA and cytokine expression.

BACKGROUND: This study investigates the association of intraocular cytokine expression and ultrawide-field fluorescein angiography (UWFA) quantitative imaging biomarkers and their association with angiographical feature response after antivascular endothelial growth factor (VEGF) therapy in diabetic macular oedema (DME). METHODS: The IMAGINE DME study is a post hoc imaging biomarker and intraocular cytokine assessment from the DAVE study, a prospective DME clinical trial that included aqueous humour sampling and UWFA imaging. Fifty-four cytokines associated with inflammation and angiogenesis were evaluated through multiplex arrays. UWFA parameters were assessed using an automated feature analysis platform to determine ischaemic and leakage indices and microaneurysm (MA) count. Eyes were classified into UWFA responder or non-responder groups based on longitudinal quantitative UWFA parameter improvement. Cytokine expression was correlated with UWFA metrics and evaluated in the context of therapeutic response. RESULTS: Twenty-one eyes were included with a mean age of 55±10 years. Increased panretinal leakage index correlated with VEGF (r=0.70, p=0.0005), angiopoietin-like 4 (r=0.77, p=4.6E-5) and interleukin (IL)-6 (r=0.64, p=0.002). Panretinal ischaemic index was associated with tissue inhibitor of metalloproteinases 1 (TIMP-1, r=0.49, p=0.03) and peripheral ischaemia correlated with VEGF (r=0.45, p=0.05). MA count correlated with increased monocyte chemotactic protein-4 (MCP-4, r=0.60, p=0.004) and platelet and endothelial cell adhesion molecule 1 (PECAM-1, r=0.58, p=0.005). Longitudinal MA reduction was associated with decreased baseline VEGF and urokinase receptor (uPAR) (p<0.05). High baseline VEGF and IL-6 were associated with dramatic reduction in macular leakage (p<0.05). CONCLUSIONS: Baseline and longitudinal quantitative UWFA imaging parameters correlated with multiple aqueous humour cytokine concentrations, including VEGF and IL-6. Further research is needed to assess the possible implications of using these findings for evaluating treatment response.

Pipeline therapies for neovascular age related macular degeneration.

Age related macular degeneration (AMD) is the most common cause of vision loss in the elderly population. Neovascular AMD comprises 10% of all cases and can lead to devastating visual loss due to choroidal neovascularization (CNV). There are various cytokine pathways involved in the formation and leakage from CNV. Prior treatments have included focal laser therapy, verteporfin (Visudyne, Bausch and Lomb, Rochester, New York) ocular photodynamic therapy, transpupillary thermotherapy, intravitreal steroids and surgical excision of choroidal neovascular membranes. Currently, the major therapies in AMD focus on the VEGF-A pathway, of which the most common are bevacizumab (Avastin; Genentech, San Francisco, California), ranibizumab (Lucentis; Genentech, South San Francisco, California), and aflibercept (Eylea; Regeneron, Tarrytown, New York). Anti-VEGF agents have revolutionized our treatment of wet AMD; however, real world studies have shown limited visual improvement in patients over time, largely due to the large treatment burden. Cheaper alternatives, including ranibizumab biosimilars, include razumab (Intas Pharmaceuticals Ltd., Ahmedabad, India), FYB 201 (Formycon AG, Munich, Germany and Bioeq Gmbh Holzkirchen, Germany), SB-11 (Samsung Bioepsis, Incheon, South Korea), xlucane (Xbrane Biopharma, Solna, Sweden), PF582 (Pfnex, San Diego, California), CHS3551 (Coherus BioSciences, Redwood City, California). Additionally, aflibercept biosimilars under development include FYB203 (Formycon AG, Munich, Germany and Bioeq Gmbh Holzkirchen, Germany), ALT-L9 (Alteogen, Deajeon, South Korea), MYL1710 (Momenta Pharamaceuticals, Cambridge, MA, and Mylan Pharmacueticals, Canonsburg, PA), CHS-2020 (Coherus BioSciences, Redwood City, California). Those in the pipeline of VEGF targets include abicipar pegol (Abicipar; Allergan, Coolock, Dublin), OPT-302 (Opthea; OPTHEA limited; Victoria, Melbourne), conbercept (Lumitin; Chengdu Kanghong Pharmaceutical Group, Chengdu, Sichuan), and KSI-301 (Kodiak Sciences, Palo Alto, CA). There are also combination medications, which target VEGF and PDGF, VEGF and tissue factor, VEGF and Tie-2, which this paper will also discuss in depth. Furthermore, long lasting depots, such as the ranibizumab port delivery system (PDS) (Genentech, San Francisco, CA), as well as others are under evaluation. Gene therapy present possible longer treatments options as well and are reviewed here. This paper will highlight the past approved medications as well as pipeline therapies for neovascular AMD.

Current and Future Anti-VEGF Agents for Neovascular Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the most common cause of legal blindness in developed countries. Neovascular (ie, wet) AMD is currently managed with intravitreal therapy. Traditional treatments (ie, bevacizumab, ranibizumab, aflibercept) provide high-efficacy therapy but can also require frequent dosing. Newer and future anti-VEGF therapies aim to decrease injection frequency through eitherlonger half life or port-delivery systems (brolucizumab, conbercept, KSI-301, ranibizumab). This review outlines current anti-VEGF treatments and ways by which their duration might be extended.

Panuveitis Presumed Secondary to Ibrutinib Therapy.

Although a small number of cases of secondary uveitis have been documented in the setting of ibrutinib therapy, panuveitis has not previously been described with this medication. The authors describe a presumed case of panuveitis in a patient on ibrutinib for chronic lymphocytic leukemia. The purpose of this report is to document a case of asymmetric, bilateral panuveitis in the setting of ibrutinib use. Panuveitis may develop in the setting of ibrutinib use, and local steroid therapy can be successfully used for treatment without cessation of systemic cancer therapy. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:160-164.].