A case of Lomentospora prolificans endophthalmitis treated with the novel antifungal agent Olorofim.

PURPOSE: To report a case of endogenous Lomentospora prolificans endophthalmitis treated with the novel antifungal agent Olorofim. CASE REPORT: A 57-year-old man developed disseminated Lomentospora prolificans with right endophthalmitis on the background of immunosuppression following lung transplantation for interstitial lung disease. He was treated with early vitrectomy, intravitreal voriconazole, and systemic Olorofim, voriconazole and terbinafine. His symptoms improved and remained stable in the right eye. Eight weeks later the patient represented with Lomentopora prolificans endophthalmitis in the left eye when systemic voriconazole and terbinafine treatment were withdrawn. Despite aggressive treatment he ultimately succumbed due to vascular complications of extensive disseminated disease. CONCLUSION: We report a rare case of disseminated Lomentosporosis with panophthalmitis in an immunocompromised host with prolonged survival on systemic Olorofim, voriconazole and terbinafine in conjunction with pars plana vitrectomy and intravitreal voriconazole. Early suspicion of an opportunistic fungal infection is critical, as managing disseminated disease is often unsuccessful. Despite presumed inherent resistance, intravitreal and systemic voriconazole appeared to limit disease progression in the right eye. The potential synergistic effects of combined antifungal therapy with orotomides warrant further investigation.

Uveitis masquerade syndromes: An approach to diagnosis.

Uveitis masquerade syndromes are a diverse group of clinical entities which mimic conventional immune-mediated uveitis due to the presence of inflammatory signs but are resistant to anti-inflammatory therapy. Misdiagnosis hinders appropriate management in these conditions and may result in poor outcomes. This review discusses commonly encountered neoplastic and non-neoplastic disease processes that masquerade as intraocular inflammation with a focus on relevant clinical features and adjunctive investigations that are helpful in reaching a correct diagnosis.

Characterising the diagnosis of genetic maculopathies in a real-world private tertiary retinal practice in Australia: protocol for a retrospective clinical audit.

PURPOSE: Accurate diagnosis of macular atrophy is paramount to enable appropriate treatment when novel treatments for geographic atrophy and macular dystrophies become available. Genetic testing is useful in distinguishing between the two conditions but is not feasible for the majority of patients in real-world clinical practice. Therefore, we aimed to investigate the potential misdiagnosis of inherited macular dystrophy as age-related macular degeneration (AMD) in real-world ophthalmic practice to assist in the development of guidelines to improve diagnostic accuracy while minimizing genetic testing for targeted patients. METHODS: Retrospective review of the medical records of patients diagnosed with AMD, which included imaging, between 1995 and 2023 from a large multidisciplinary private ophthalmic practice in Australia. We will use a stepwise method to screen for probable cases of macular dystrophy, followed by a consensus review by an expert panel. The outcomes are (1) to determine the potential misdiagnosis rate of macular dystrophy as atrophic AMD by retinal specialists and general ophthalmologists; (2) to identify clinical imaging modalities that are most useful for differentiating macular dystrophy from atrophic AMD; and (3) to establish preliminary guidance for clinicians to improve the diagnosis of macular atrophy from AMD in practice, and thereby target cost-efficient genetic testing. DISCUSSION: Improving the diagnostic accuracy of both AMD and macular dystrophy, while ensuring cost-efficient genetic testing, will improve the targeted treatment of macular diseases when emerging treatments become available.

Ibrutinib-related uveitis: A case series.

PURPOSE: Four cases of ibrutinib-related uveitis are presented, which are to the best of our knowledge the first in the literature. Possible mechanisms of ibrutinib-mediated uveitis are explored. OBSERVATIONS: Case 1 is a 60-year-old female who had been stable on 1 year of ibrutinib for chronic lymphocytic leukaemia. She was diagnosed with ibrutinib-related uveitis, which responded well to topical steroids. Case 2 is a 63-year-old male diagnosed with uveitis after 2 years of ibrutinib treatment for chronic lymphocytic leukaemia. He responded well to topical and oral steroids; however, he continued to have uveitis relapses after weaning steroids. Case 3 is a 69-year-old male diagnosed with uveitis after 18 months of ibrutinib treatment. He was trialed on topical and intravenous steroids, and restarted ibrutinib without worsening of symptoms. Case 4 is a 66-year-old female who developed uveitis after being stable on ibrutinib for 3 years. She responded well to topical steroids. CONCLUSIONS AND IMPORTANCE: Inflammatory complications of tyrosine kinase inhibitors are well described. While ibrutinib, and other kinase inhibitors, are generally well-tolerated, there are increasing reports of ocular toxicities, including uveitis. It is recommended to monitor patients for potential ocular adverse effects and facilitate rapid ophthalmologic assessment.

UVEITIS CAUSED BY TREATMENT FOR MALIGNANT MELANOMA: A CASE SERIES.

BACKGROUND/PURPOSE: To report the largest case series to date of uveitis occurring in association with immunomodulatory therapy for malignant melanoma. METHODS: A retrospective multicenter case review. Twenty-two patients with uveitis occurring in association with either immunotherapy or targeted immune therapy for malignant melanoma were identified. RESULTS: Of 22 patients, 11 had anterior uveitis in isolation. The remainder showed a variety of clinical features including panuveitis, ocular hypotony, papillitis, cystoid macular edema, and melanoma-associated retinopathy. Most patients responded well to treatment. CONCLUSION: We report the largest case series to date of patients with uveitis secondary to drug treatment for malignant melanoma. These cases are likely to increase in number in the future as newer immunomodulatory therapies for cancers are developed and the indications for these drugs increase. A dilemma arises when patients respond well to these drugs but develop vision-threatening side effects.

The Incidence of Ocular Tuberculosis in Australia Over the Past 10 Years (2006-2015).

PURPOSE: To determine the incidence and clinical phenotype of ocular tuberculosis in Australia based on the mandatory jurisdictional health notification records for TB. METHODS: A whole population retrospective case series (Australia). Patients diagnosed with ocular tuberculosis were identified over the past 10 years (1 January 2006 to 31 December 2015) as recorded by individual Health Department jurisdictions per mandatory health notifications. The incidence rates were calculated based on the available Australian census data. Incidence rates were age and sex standardized. RESULTS: A total of 162 cases of ocular tuberculosis were identified across Australia over a 10-year time period. Of these, 156 participants were overseas born. The 10-year Australian incidence of ocular tuberculosis was 0.77 per 100,000 people. While there has been a downward trend in overall TB annual incidence rates from 2010 to 2015, over the same period the annual incidence of ocular TB has increased compared to the 4 previous years. Descriptive clinical data regarding the ocular manifestations of TB was available in 73/157 patients. In these 73 patients the commonest manifestations of ocular TB were unspecified uveitis (50.1%), focal, multifocal or serpiginous choroiditis or chorioretinitis (12.3%) and retinal vasculitis (11.0%). Of patients with ocular TB, 4/162 (2.47%) had associated pulmonary TB and 8/162 (4.94%) had associated systemic (non-pulmonary) TB. Systemic anti-TB therapy was administered to 161 patients. CONCLUSIONS: The annual Australian incidence of ocular tuberculosis was 0.077 per 100,000 people. Increasing notifications in the past 6 years may demonstrate increased awareness and changing diagnostic criteria of the disease in the Australian population.

Drug-induced Myopia and Bilateral Angle Closure Secondary to Zolmitriptan.

PURPOSE: To describe a unique case of drug-induced transient myopia with angle-closure glaucoma in a patient being treated with zolmitriptan for migraines. METHODS: A 42-year-old woman who had been using increasing amounts of zolmitriptan over the previous 12 months presented with an acute myopic shift and raised intraocular pressures (IOP) with anterior chamber shallowing. Clinical examination findings at presentation and at follow-up visits were reviewed. RESULTS: Initial examination revealed unaided visual acuities of 20/100 in the right eye and 20/125 in the left, with IOP measuring 34 mm Hg bilaterally. Zolmitriptan was ceased and the patient was commenced on topical antiglaucoma medication. Within 2 weeks, IOP had normalized, with deepening of the anterior chambers and complete resolution of her myopia. Her final recorded unaided visual acuities were 20/12.5 in the right eye and 20/16 in the left. When topical antiglaucoma medication was ceased the patient developed pressure-related headaches and selective laser trabeculoplasty was performed to minimize the need for long-term topical medication use. CONCLUSION: Idiosyncratic drug reactions resulting in ciliochoroidal effusion, secondary angle closure, and transient myopia are well described, but they have not been previously reported with zolmitriptan use. An awareness of the various potential causative agents is important, as findings are generally reversible if recognized early and if the offending drug is discontinued.

Keratoconus associated with the Pierre Robin sequence.

A 30-year-old female with known Pierre Robin sequence presented to the emergency department of the Royal Victorian Eye and Ear Hospital, Melbourne, with acute unilateral hydrops as her first presentation of bilateral keratoconus. Initial management consisted of eye patching, hypertonic saline and cycloplegia. However, the long-term prognosis for visual rehabilitation remained poor in this patient because of the presence of a central corneal opacity and inability to comply with contact lenses. She was not an appropriate candidate for keratoplasty due to severe mental retardation. This report highlights an association of keratoconus in patients with the Pierre Robin sequence.

Selective suicide of cross-presenting CD8+ dendritic cells by cytochrome c injection shows functional heterogeneity within this subset.

Cross-presentation as a fundamental pathway of activating CD8(+) T cells has been well established. So far the application of this concept in vivo is limited, and the mechanisms that specialize CD8(+) dendritic cells (DCs) for this task are not fully understood. Here we take advantage of the specific cytosolic export feature of cross-presenting DCs together with the property of cytosolic cytochrome c (cyt c) in initiating Apaf-1-dependent apoptosis selectively in cross-presenting DCs. A single i.v. injection of cyt c in B6 mice produced a 2- to 3-fold reduction in splenic CD8(+) DCs but not in Apaf-1-deficient mice. Functional studies both in vivo and in vitro showed that cyt c profoundly abrogated OVA-specific CD8(+) T cell proliferation through its apoptosis-inducing effect on cross-presenting DCs. More importantly, in vivo injection of cyt c abolished the induction of cytotoxic T lymphocytes to exogenous antigen and reduced subsequent immunity to tumor challenge. In addition, only a proportion of CD8(+) DCs that express abundant IL-12 and Toll-like receptor 3 were efficient cross-presenters. Our data support the hypothesis that cross-presentation in vivo requires cytosolic diversion of endocytosed proteins, conferring cross-presentation specialization to a proportion of CD8(+) DCs. We propose that DCs incapable of such transfer, even within the CD8(+) DC subset, are unable to cross-present. Our model opens an avenue to specifically target cross-presenting DCs in vivo for manipulating cytotoxic T lymphocyte responses toward infections, tumors, and transplants.

The cell biology of cross-presentation and the role of dendritic cell subsets.

The cell biology of cross-presentation is reviewed regarding exogenous antigen uptake, antigen degradation and entry into the major histocompatibility complex class I pathway. Whereas cross-presentation is not associated with enhanced phagocytic ability, certain receptors may favour uptake for cross-presentation for example mannose receptor for soluble glycoproteins. Perhaps, the defining property of the cross-presenting cell is some specialization in host machinery for handling and transport of antigen across organelles. Both cytosolic and vacuolar pathways are discussed. Which dendritic cell (DC) subset is the cross-presenting cell is explored. Cross-presentation is found within the CD8(+) subset resident in lymphoid organs. The role of other DC subsets (especially the migratory CD8(-) DC) and the route of antigen delivery are also discussed. Further consideration is given to antigen transfer between DC subsets and differential presentation to naive vs memory T cells.

NK cells promote peritoneal xenograft rejection through an IFN-gamma-dependent mechanism.

BACKGROUND: Natural killer (NK) cells have emerged as major players in anti-viral and anti-tumour immune responses. Like cytotoxic T lymphocytes (CTL), they express perforin and are potent secretors of gamma-interferon (IFN-gamma). However, there is conflicting evidence about their role in mediating rejection of xenogeneic tissue. METHODS: A pig-to-mouse peritoneal cell model of xenotransplantation was used to investigate the effect of NK deficiency on xenograft recovery and the possible mechanisms behind this NK-mediated graft rejection. gamma c(-/-)RAG(-/-) mice were used as a model of NK deficiency. Additionally, NK cells were depleted in RAG(-/-) mice using anti-asialo GM1. The contributions of IFN-gamma, perforin and NKT cells were studied using knock-out mice that were depleted in vivo of T cells. Mice were injected with 10(7) pig cells intraperitoneally and peritoneal fluid was assessed 5 days later for xenograft recovery and phenotypic analysis. The requirement for NK cells for xenograft rejection was also assessed using luciferase-transfected porcine cells in a renal subcapsular model of transplantation. RESULTS: Pig cell recovery was enhanced in both gamma c(-/-)RAG(-/-) and NK-depleted RAG(-/-) mice when compared with RAG(-/-) control mice. IFN-gamma(-/-) mice depleted of T cells also demonstrated superior graft survival compared with their B6 counterparts. However, there were minimal graft survival differences between Pfp(-/-) and B6 control mice. Similarly, a deficiency in NKT cells did not improve pig xenograft recovery from the peritoneum of these mice. CONCLUSIONS: Therefore, we conclude that NK cells, but not NKT cells, are important mediators of xenograft rejection in the peritoneal cavity, and that their role may be unmasked in the absence of T cells. The mechanism for this xenorejection appears to involve IFN-gamma but is perforin independent.

An unusual cause of heart failure identified by echocardiography in an octogenarian.

Non-compaction of the ventricular myocardium is a rare congenital cardiomyopathy that carries an unfavorable prognosis. It is associated with a high incidence of progressive heart failure, thromboembolism and malignant arrhythmias. Echocardiography currently remains the imaging modality most commonly used for diagnosis. We describe an unusual case of isolated non-compaction of the left ventricle in an octogenarian male to highlight the need for echocardiography in all patients with suspected heart failure, in order to determine aetiology, prognosis and assess treatment.