Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2.

Outer retinal degenerations, including age-related macular degeneration (AMD), are characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. In these blinding diseases, macrophages accumulate at atrophic sites, but their ontogeny and niche specialization remain poorly understood, especially in humans. We uncovered a unique profile of microglia, marked by galectin-3 upregulation, at atrophic sites in mouse models of retinal degeneration and human AMD. In disease models, conditional deletion of galectin-3 in microglia led to phagocytosis defects and consequent augmented photoreceptor death, RPE damage, and vision loss, indicating protective roles. Mechanistically, Trem2 signaling orchestrated microglial migration to atrophic sites and induced galectin-3 expression. Moreover, pharmacologic Trem2 agonization led to heightened protection but in a galectin-3-dependent manner. In elderly human subjects, we identified this highly conserved microglial population that expressed galectin-3 and Trem2. This population was significantly enriched in the macular RPE-choroid of AMD subjects. Collectively, our findings reveal a neuroprotective population of microglia and a potential therapeutic target for mitigating retinal degeneration.

Lasiodiplodia theobromae keratitis: A rare tropical fungal keratitis in a non-tropical climate.

Purpose: We present the clinical and histopathological findings of a geographically unique Lasiodiplodia theobromae fungal keratitis case in North Carolina. L. theobromae is a rare cause of fungal keratitis, and all but one of the 51 previously reported cases have occurred in patients living in the tropics. Observations: A man in his early 50s developed L. theobromae keratitis after being struck in the left eye by a piece of debris while using a flexible-cord weed trimmer. Intracapsular lensectomy and penetrating keratoplasty were necessary when initial antimicrobial therapy was ineffective. The best-corrected visual acuity was 20/40 four years postoperatively. Conclusions and Importance: Our patient is only the second example of L. theobromae keratitis in a patient living in a sub-tropical climate and the first case in the U.S.A. outside of Florida. Additional in-vitro antibiotic sensitivity testing and documentation of more clinical cases are needed to define the optimal therapy for Lasiodiplodia theobromae keratitis.

Microglia at Sites of Atrophy Restrict the Progression of Retinal Degeneration via Galectin-3 and Trem2 Interactions.

Degenerative diseases of the outer retina, including age-related macular degeneration (AMD), are characterized by atrophy of photoreceptors and retinal pigment epithelium (RPE). In these blinding diseases, macrophages are known to accumulate ectopically at sites of atrophy, but their ontogeny and functional specialization within this atrophic niche remain poorly understood, especially in the human context. Here, we uncovered a transcriptionally unique profile of microglia, marked by galectin-3 upregulation, at atrophic sites in mouse models of retinal degeneration and in human AMD. Using disease models, we found that conditional deletion of galectin-3 in microglia led to defects in phagocytosis and consequent augmented photoreceptor death, RPE damage and vision loss, suggestive of a protective role. Mechanistically, Trem2 signaling orchestrated the migration of microglial cells to sites of atrophy, and there, induced galectin-3 expression. Moreover, pharmacologic Trem2 agonization led to heightened protection, but only in a galectin-3-dependent manner, further signifying the functional interdependence of these two molecules. Likewise in elderly human subjects, we identified a highly conserved population of microglia at the transcriptomic, protein and spatial levels, and this population was enriched in the macular region of postmortem AMD subjects. Collectively, our findings reveal an atrophy-associated specialization of microglia that restricts the progression of retinal degeneration in mice and further suggest that these protective microglia are conserved in AMD.

Eccrine Ductal Carcinoma of the Eyelid.

The authors present the third example of an eccrine ductal carcinoma of the eyelid. A woman in her early 70s presented with a lesion of the central right lower eyelid margin in the vicinity where an actinic keratosis was diagnosed by biopsy 2.75 years previously. Her dermatologist and ophthalmologist monitored the area of actinic keratosis, and it was stable for 2.5 years until the area became ulcerated and thickened with the loss of eyelashes. A wedge resection disclosed a squamous cell carcinoma in situ and a separate eccrine ductal carcinoma. The eccrine ductal carcinoma had in situ tumor thickening, an eccrine duct component, and an invasive tumor infiltrating the tarsal plate and replacing the normal meibomian glands. The invasive eccrine ductal carcinoma only mildly thickened the tarsal plate and was most likely an incidental finding in a biopsy prompted by the squamous cell carcinoma in situ. The 5-year relative survival rate for malignant apocrine-eccrine tumors is approximately 97%, and our patient is alive and without evidence of local or distant tumor recurrence 5.5 years following the excision of her eyelid tumor.

Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and remains an important public health issue worldwide. Here we demonstrate that the expression of stimulator of interferon genes (STING) is increased in patients with DR and animal models of diabetic eye disease. STING has been previously shown to regulate cell senescence and inflammation, key contributors to the development and progression of DR. To investigate the mechanism whereby STING contributes to the pathogenesis of DR, diabetes was induced in STING-KO mice and STINGGT (loss-of-function mutation) mice, and molecular alterations and pathological changes in the retina were characterized. We report that retinal endothelial cell senescence, inflammation, and capillary degeneration were all inhibited in STING-KO diabetic mice; these observations were independently corroborated in STINGGT mice. These protective effects resulted from the reduction in TBK1, IRF3, and NF-κB phosphorylation in the absence of STING. Collectively, our results suggest that targeting STING may be an effective therapy for the early prevention and treatment of DR.

Primary Vitreoretinal Lymphoma Masquerading as Post-Operative Endophthalmitis in a Pregnant Patient with Longstanding Idiopathic Panuveitis.

PURPOSE: To report primary vitreoretinal lymphoma after surgical 0.59 mg fluocinolone acetonide implant (FAi) exchange in a patient treated with adalimumab for idiopathic bilateral panuveitis. METHODS: Retrospective case review. RESULTS: A 37-year-old woman with bilateral idiopathic panuveitis, who had favorable responses to previous FAi surgical implants, presented with right eye recurrent intraocular inflammation and cystoid macular edema that partially responded to systemic adalimumab. Her FAi was replaced, given her previous favorable response. She developed post-operative ocular inflammation transiently responsive to two serial vitreous taps and injections of intravitreal antimicrobials and then worsening inflammation and new layered flocculant material. Diagnostic vitrectomy showed a few atypical lymphocytes and cultures were negative. At post-diagnostic vitrectomy month 1, flocculant material recurred. Aqueous cytology and flow cytometry revealed large CD45 positive B-cells suspicious for lymphoma. Post-operatively, she revealed that she was pregnant. She was treated with 8 monthly intravitreal methotrexate injections and post-partum consolidation radiotherapy. Subsequent repeat cytology, flow cytometry, and corneal pathology revealed large B-cells that were CD20 positive, and next generation sequencing detected a dominant monoclonal B-cell population, diagnostic of PVRL. 19 months after FAi exchange, she developed an area of enhancement in the lateral aspect of the right frontal lobe on brain MRI, consistent with central nervous system involvement. CONCLUSION: We present a unique case of PVRL masquerading as post-operative endophthalmitis after FAi exchange in an eye with chronic panuveitis treated with adalimumab immunosuppressive therapy. We hypothesize that there may be a causal relationship between adalimumab and PVRL.

A CASE OF HIGH-RISK CILIARY BODY MELANOMA ARISING IN AN EYE AFTER RESECTION OF AN IRIDOCILIARY MELANOCYTOMA.

PURPOSE: To report a case of a benign iridociliary melanocytoma recurring as malignant melanoma after excision. METHODS: Observational case report with clinical data, slit-lamp examination findings, ultrasound biomicroscopy results, and histopathological and genetic analyses. RESULTS: A 40-year-old African American woman initially presented with a superonasal iridociliary mass with a maximal thickness of 2.5 mm. Visual acuity of the involved eye was 20/25, intraocular pressure was 52 mmHg on maximal pressure-lowering medications, and Humphrey visual field testing revealed an inferior altitudinal defect. Fine-needle aspiration biopsy and incisional biopsy followed by tumor excision confirmed a benign melanocytoma. After 5 years of stability, possible recurrence was detected on ultrasound biomicroscopy as an increase in ciliary body thickness. The new lesion grew to a thickness of 5.1 mm over the next 18 months of observation. Fine-needle aspiration biopsy and gene expression profile of the recurrent lesion diagnosed a malignant melanoma with high metastatic potential (Class 2). The patient underwent plaque brachytherapy and has ongoing regression of the tumor. CONCLUSION: Transformation of benign iridociliary melanocytoma to melanoma is rare. To the best of the authors' knowledge, this is the first documented case of a melanoma arising in an eye after initial excision of a melanocytoma. Close monitoring of these patients is warranted even years after the initial excision.

Spindle Cell/Sclerosing Rhabdomyosarcoma of the Orbit.

A 3-year-old boy developed proptosis over 3 weeks. CT and MRI disclosed a 3.2 × 1.9 cm soft-tissue mass of the right extraconal and intraconal orbit with sphenoid bone erosion. After debulking through an upper eyelid crease incision, the tumor was diagnosed as a spindle cell/sclerosing rhabdomyosarcoma. DNA sequencing was negative for an L122R mutation in MyoD1 . Spindle cell/sclerosing rhabdomyosarcoma is an uncommon variant of this neoplasm, and only 2 patients with orbital tumors have been reported in 2 case series. Spindle cell/sclerosing rhabdomyosarcomas confined to the orbit are considered to have an excellent prognosis when treated with chemotherapy and radiation therapy. Diagnosis and treatment planning rely on histology, immunohistochemistry, and molecular analysis.

Mönckeberg sclerosis with giant cells as a masquerade of giant cell arteritis.

Giant cell arteritis (GCA) is the most common type of vasculitis in adults, which is classified as a large/medium vessel vasculitis. It has a predilection for the ophthalmic circulation and extracranial carotid system. Temporal artery biopsy specimens can show the presence of inflammatory multinucleated giant cells. Here, we report just the third case of Mönckeberg sclerosis with multinucleated giant cells affecting the temporal artery and mimicking GCA. This rare finding in the evaluation of a common vasculitis is important for rheumatologists to be aware of and emphasizes close collaboration between clinicians and pathologists.

A Pruritic Eyelid Lesion Followed by Conjunctival Swelling.

A 54-year-old woman presented with an erythematous right lower eyelid lesion with a vermiform appearance, accompanied by pruritus and pain. She recently had exposure to farm animals, including dogs and cats. What would you do next?

Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma.

The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.

Multiple Cranial Neuropathies as the Initial Presentation of Primary Ductal Adenocarcinoma of the Lacrimal Gland.

Primary ductal adenocarcinoma of the lacrimal gland is a rare, aggressive malignancy that clinically and histologically resembles salivary duct carcinoma. Similar to other malignant epithelial lacrimal gland tumors, ductal adenocarcinoma typically presents with unilateral proptosis, pain, upper eyelid swelling, palpable mass, diplopia, ptosis, and blurred or decreased vision. Rarely, primary malignant epithelial lacrimal gland tumors may first present with multiple cranial neuropathies due to occult spread to the cavernous sinus, as in this case. With such a vast differential diagnosis, a practical yet systematic approach to multiple cranial neuropathies, as guided by clinical history, exam, and neuroimaging, allows for a more targeted diagnostic evaluation, especially when multiple diagnostic tests and interventions return unrevealing. A repeat biopsy or complete excision of the lacrimal gland may be necessary to yield the correct diagnosis.

Subretinal Mononuclear Cells in Coats' Disease Studied with RPE65 and CD163: Evidence for Histiocytoid Pigment Epithelial Cells.

PURPOSE: To evaluate the mononuclear cells in the subretinal exudate in Coats' disease. DESIGN: Retrospective case series. METHODS: Five enucleated globes and 1 cytology sample from a patient with Coats' disease and 1 case of chronic retinal detachment following repair of an open globe injury were examined immunohistochemically to identify intraretinal and subretinal exudative cells. The 2 biomarkers were RPE65 for retinal pigment epithelium and CD163 for histiocytes, each tagged with different chromogens, yellow for pigment epithelium and purple for CD163-positive (CD163+) monocytes/histiocytes. Expression levels were sought from both biomarkers together and singly. A color shift to red in the cells' chromogenic reaction indicated the simultaneous presence of the 2 biomarkers. RESULTS: Most of the mononuclear cells in Coats' disease samples were CD163+ (purple), and a minority were RPE65+ (yellow). An intermediate number of cells were RPE65+/CD163+ (orange-red). The eye with a chronic retinal detachment had an equal distribution of CD163+ and RPE65+/CD163+ cells. CONCLUSIONS: RPE has several well-delineated phenotypes and functions. In normal visual physiology, the pigment epithelium supports photoreceptors and participates in their renewal by phagocytosis of the tips of the photoreceptors. The expression of CD163, a feature of hematopoietically derived monocytes, together with RPE65 in the retinal pigment epithelium, supports differentiation toward histiocytes. Yellow staining of detached pigment epithelial cells were rare. The presence of histiocytoid pigment epithelium at the Bruch membrane probably also has implications for macular degeneration.

Uveal Melanoma Metastatic to the Cavernous Sinus: A Case Report.

A woman in her early 50s previously treated 7 years prior with iodine-125 plaque brachytherapy without a biopsy for gene expression profiling for uveal melanoma in the left eye presented with a 3-week history of intermittent diplopia and headache. Ophthalmic examination was significant for limitation in left eye upward gaze; otherwise, examination revealed a stable, regressed tumor in the left eye, and normal vision, pressure, and pupils in both eyes. Neuroimaging showed a left cavernous sinus lesion, suggestive of a meningioma. Excisional biopsy revealed metastatic melanoma. The patient was treated with radiotherapy, and her diplopia resolved. Slight enlargement of the lesion was noted on neuroimaging 20 months later, and was treated with stereotactic radiosurgery. Serial neuroimaging in the following 6 months did not reveal any recurrences or new metastases. This case demonstrates the importance of investigating persistent diplopia in a patient with a history of uveal melanoma, and the possibility of metastases occurring in organs besides the liver or lung.

Clinical and Morphologic Outcomes of Minimally Invasive Direct Corneal Neurotization.

PURPOSE: To describe clinical outcomes of a minimally invasive technique for direct corneal neurotization to treat neurotrophic keratopathy. METHODS: All cases of corneal neurotization for neurotrophic keratopathy performed by a single surgeon using minimally invasive direct corneal neurotization were reviewed. The supraorbital donor nerve was directly transferred to the cornea through an upper eyelid crease incision using either a combination of endoscopic and direct visualization or direct visualization alone. Detailed ocular and adnexal examinations as well as Cochet-Bonnet esthesiometry of the affected cornea were performed. Corneal histopathology and in vivo confocal microscopy after minimally invasive direct corneal neurotization were reviewed in one patient who underwent simultaneous penetrating keratoplasty. RESULTS: Five consecutive cases in 4 patients were included, with a mean follow up of 15.8 months (range: 11-23 months). Average denervation time was 17.8 months (range: 6-24 months). Baseline corneal conditions were Mackie stage 1 (20%), Mackie stage 2 (40%), and Mackie stage 3 (40%). All patients demonstrated improvements in corneal sensibility and appearance postoperatively. All patients demonstrated stable or improved visual acuity. No patients developed persistent epithelial defects postoperatively, and all achieved return of tactile skin sensation in the donor nerve sensory distribution. In vivo confocal microscopy after minimally invasive direct corneal neurotization and simultaneous penetrating keratoplasty demonstrated regeneration of corneal nerves. Complications included an asymptomatic small bony excrescence lateral to the supraorbital notch in one patient and cataract progression in the patient who underwent penetrating keratoplasty. CONCLUSIONS: Minimally invasive direct corneal neurotization is a safe and effective treatment of neurotrophic keratopathy.

Idiopathic orbital inflammation with bone destruction and extension into the paranasal sinuses.

Idiopathic orbital inflammation developed in the right orbit of a woman in her mid-thirties, causing tearing, photophobia, diplopia, altered depth perception, proptosis, and pain on eye movements. Computed tomography disclosed a mass involving the intraconal and extraconal nasal right orbit, extending to the orbital apex with anterior displacement of the globe, effacement of the medial rectus muscle, portions of the fat plane, and the superior oblique muscle, and bone destruction with extension of the mass through the orbital floor into the superior maxillary sinus and through the lamina papyracea into the ethmoid sinus. Orbital biopsy disclosed dense fibrous connective tissue with numerous lymphocytes and macrophages. Immunohistochemical stains supported a diagnosis of idiopathic inflammatory pseudotumor involving the orbit and sinus mucosa. Treatment with a prednisone taper and a retrobulbar injection of triamcinolone acetonide have relieved her symptoms and diminished her proptosis. This patient highlights the rare potential of idiopathic orbital inflammation to erode though bone into adjacent cranial structures.

Reduction in Mortality after Umbilical Cord Blood Transplantation in Children Over a 20-Year Period (1995-2014).

Infections and graft-versus-host disease (GVHD) have historically resulted in high mortality among children undergoing umbilical cord blood transplantation (UCBT). However, recent advances in clinical practice have likely improved outcomes of these patients. We conducted a retrospective cohort study of children (<18years of age) undergoing UCBT at Duke University between January 1, 1995 and December 31, 2014. We compared 2-year all-cause and cause-specific mortality during 3 time periods based on year of transplantation (1995 to 2001, 2002 to 2007, and 2008 to 2014). We used multivariable Cox regression to identify demographic and UCBT characteristics that were associated with all-cause mortality, transplantation-related mortality, and death from invasive aspergillosis after adjustment for time period. During the 20-year study period 824 children underwent UCBT. Two-year all-cause mortality declined from 48% in 1995 to 2001 to 30% in 2008 to 2014 (P = .0002). White race and nonmalignant UCBT indications were associated with lower mortality. Black children tended to have a higher risk of death for which GVHD (18% versus 11%; P = .06) or graft failure (9% versus 3%; P = .01) were contributory than white children. Comparing 2008 to 2014 with 1995 to 2001, more than half (59%) of the reduced mortality was attributable to a reduction in infectious mortality, with 45% specifically related to reduced mortality from invasive aspergillosis. Antifungal prophylaxis with voriconazole was associated with lower mortality from invasive aspergillosis than low-dose amphotericin B lipid complex (hazard ratio, .09; 95% confidence interval, .01 to .76). With the decline in mortality from invasive aspergillosis, adenovirus and cytomegalovirus have become the most frequentinfectious causes of death in children after UCBT. Advances in clinical practice over the past 20years improved survival of children after UCBT. Reduced mortality from infections, particularly invasive aspergillosis, accounted for the largest improvement in survival and was associated with use of voriconazole for antifungal prophylaxis.