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.

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.

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.

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.

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.

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.

Utility of Autopsy among Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients: One Last Chance to Learn?

Autopsy may confirm clinical diagnoses or identify conditions that were not suspected prior to a patient's death. Previous studies evaluating the utility of autopsy in hematopoietic stem cell transplant (HSCT) recipients yielded conflicting results. We conducted a retrospective cohort study of children (<18 years of age) undergoing allogeneic HSCT at Duke University who died of any cause between January 1, 1995, and December 31, 2016. We evaluated associations between patient characteristics and autopsy performance using chi-square or Fisher exact tests. We reviewed autopsy reports to determine the concordance between preautopsy causes of death and pathological diagnoses identified on autopsy. We classified unexpected diagnoses on autopsy using criteria developed by Goldman et al. We evaluated for temporal changes in the autopsy consent rate and the frequency of unexpected diagnoses on autopsy using Cochran-Armitage tests. During the 22-year study period, 475 patients died and had data available on autopsy performance, and 130 (27%) of these patients underwent autopsy. The autopsy consent rate declined over time (P < .0001), with autopsies being performed for 40% of deaths in 1995 to 1999 and 17% of deaths in 2009 to 2016. White patients were more likely to undergo autopsy than nonwhite patients (P = .03). There were no associations between autopsy performance and patient age, sex, HSCT indication, or HSCT donor. Unexpected diagnoses were identified in 31 (24%) autopsies. The proportion of autopsies with an unexpected diagnosis did not change during the study period (P = .45). However, infectious diagnoses that would have led to a change in management were more frequently identified on autopsies in 1995 to 2003 than in 2004 to 2016 (20% versus 0%; P = .001). The autopsy consent rate for pediatric HSCT recipients at our institution has declined substantially over the past several decades. The utility of autopsy in this patient population remains high despite a reduction in the identification of unexpected infections.

CD163+ macrophages infiltrate axon bundles of postmortem optic nerves with glaucoma.

PURPOSE: Prior research in animal models has shown that macrophages and microglia play an important role in pathogenesis of glaucoma, but the phenotype and distribution of macrophages in human glaucomatous tissue have not been sufficiently characterized. METHODS: We analyzed H&E, CD68-, and CD163-immunostained slides from 25 formaldehyde-fixed, paraffin-embedded autopsy eyes: 12 control eyes and 13 eyes with glaucoma. The diagnosis of glaucoma was made based on a history of glaucoma as reported in the medical record and histological changes characteristic of glaucoma. Glaucoma cases and controls were matched in terms of age, sex, and race. RESULTS: Qualitative analysis of the conventional outflow pathway and the optic nerve revealed that all eyes contained CD163+ cells but a negligible number of CD68+ cells. CD163+ macrophages infiltrated the trabecular meshwork and surrounded Schlemm's canal of normal eyes and eyes with glaucoma, but the pattern was variable and qualitatively similar between groups. In optic nerves of control eyes, CD163+ macrophages were present at low levels and restricted to septa between axon bundles. In glaucomatous optic nerves, the number of CD163+ cells was increased both qualitatively and quantitatively (glaucoma 5.1 ± 0.6 CD163+ cells/mm2, control 2.5 ± 0.3 CD163+ cells/mm2, p < 0.001), with CD163+ cells infiltrating axon bundles in cases of both mild and severe diseases. CONCLUSIONS: The increase in CD163+ cell number in eyes with mild and severe glaucoma is the first demonstration of macrophage infiltration in glaucomatous human optic nerves. This finding supports a role for macrophages in glaucoma pathogenesis and progression.

Seminoma Metastatic to the Orbit.

PURPOSE: Seminomas are solid tumors in young men, but which rarely metastasize to the orbit. The authors review the known literature on seminoma metastatic to the orbit, and describe an additional case in a 33-year-old man. METHODS: A literature search was performed on the MEDLINE database using keywords "seminoma," "testicular germ-cell tumors," "testicular cancer," "testicular neoplasm," "orbital metastasis," and "germ-cell neoplasms." RESULTS: Malignant neoplasms of the testis account for only 1% of cancers in men. None-the-less, testicular germ cell seminoma is the most common solid tumor found in young men between the ages of 15 and 39. Only seven previous cases have been mentioned in the literature. The pathogenesis remains unclear although genetic, environmental, and maternal factors may play a role. The number of cases is too few to determine the best treatment options, but surgical excision and adjunctive orbital radiotherapy appear to be most appropriate. CONCLUSIONS: Although metastases to the orbit are rare, seminoma should be considered in the differential diagnosis of all young men with proptosis.

Endocrine Mucin-Producing Sweat Gland Carcinoma of the Eyelid Associated With Mucinous Adenocarcinoma.

Endocrine mucin-producing sweat gland carcinoma, a rare, low-grade neoplasm with predilection for the eyelids, has been posited as a precursor to invasive mucinous adenocarcinoma. Endocrine mucin-producing sweat gland carcinoma and its concurrence with mucinous adenocarcinoma have received little attention in the ophthalmic literature. The combination of the 2 histologic patterns parallels endocrine ductal carcinoma in situ of the breast and its transition to Type B invasive mucinous carcinoma. The authors describe a 59-year-old man who developed a tumor of the right upper eyelid showing endocrine mucin-producing sweat gland carcinoma in the outer dermis and extensive mucinous carcinoma in the deeper tissue. Immunohistochemical analysis showed positivity for endocrine markers chromogranin, synaptophysin, CD56, estrogen, and progesterone in each histologic component of the tumor. This research was conducted in conformity with the Helsinki Declaration and HIPPA regulations.

Adenocarcinoma of Pigmented Ciliary Epithelium in a Child With Aicardi Syndrome and Congenital Microphthalmia With Cyst.

A 5-year-old girl with Aicardi syndrome and microphthalmia with cyst of the OD presented with progressive enlargement of the cyst causing pain. Microophthalmia with inferior cyst (35 × 25 × 12 mm) was noted at birth, and Aicardi syndrome was diagnosed at 10 months by the presence of the classic triad of callosal agenesis, infantile spasms, and chorioretinal lacunae. She underwent enucleation with cyst resection, and subsequent reconstruction with a dermis fat graft. Histopathologic study revealed adenocarcinoma of the pigmented ciliary epithelium. Full-body metastatic workup was negative. Adenocarcinoma of the pigmented ciliary epithelium is an extremely rare eye tumor with only 4 documented cases in the literature, none arising in a microophthalmic eye with cyst. Aicardi syndrome is also a rare disease that has been associated with increased incidence of malignancy and ocular abnormalities, but has never been described in association with microophthalmia with cyst or with adenocarcinoma of the pigmented ciliary epithelium. Herein, the authors present a review of the case and relevant literature.

Fontana-Masson stain in fungal infections.

BACKGROUND: Fontana-Masson (FM) staining is a histopathology technique used to identify dematiaceous fungi. The result often guides initial species identification and antifungal treatment; however, there is evidence that nondematiaceous fungi might react with this stain. Few studies in the current literature address this issue. OBJECTIVE: Our aim was to classify the FM staining patterns of common fungal pathogens for use by pathologists attempting to accurately identify fungi on histopathologic examination. METHODS: In total, 132 cases of culture proven mycoses were identified. We stained tissue with 2 different FM protocols and recorded the intensity and distribution of results. RESULTS: There was variability in staining, and many nondematiaceous fungi showed positivity, including Zygomycetes, Aspergillus, and Fusarium spp. LIMITATIONS: The study was limited by the number of cases. Of 132 cases identified, 112 cases had adequate tissue left after sectioning deeper into the block. CONCLUSION: Nondematiaceous fungi frequently stained positive with FM. The course of treatment should not be based on the result of this stain alone. Histopathology should be examined in multiple tissue sections, and therapy should be determined on the basis of clinical context and culture results.

Catastrophic antiphospholipid syndrome after cardiac surgery.

We report a case of catastrophic antiphospholipid syndrome in a patient following mitral valve replacement. The pathophysiology and management of this rare condition is discussed.

Abundance of infiltrating CD163+ cells in the retina of postmortem eyes with dry and neovascular age-related macular degeneration.

PURPOSE: Prior research in animal models has suggested that retinal macrophages play an important role in age-related macular degeneration (AMD), but studies have insufficiently characterized the distribution of retinal macrophages in various stages of human AMD. METHODS: In this case series, we analyzed H&E, periodic acid-Schiff, and CD163 and CD68 immunostained slides from 56 formaldehyde-fixed, paraffin-embedded autopsy eyes of patients over age 75: 11 age-matched, normal eyes, and 45 AMD eyes. RESULTS: Qualitative analysis of the macula and retinal periphery revealed that all eyes contained a significant number of CD163+ cells but a negligible number of CD68+ cells. In normal eyes and eyes with thin or infrequent basal laminar deposits, CD163+ cells were restricted to the inner retina. In contrast, in AMD eyes with thick basal deposits, choroidal neovascular membranes, and geographic atrophy, qualitatively there was a marked increase in the number and size of the CD163+ cells in the outer retina, sub-retinal, and sub-retinal pigment epithelium space in the macula. CONCLUSIONS: The changes in number and localization of retinal CD163+ cells in eyes with intermediate-severe AMD support a key role for macrophages in the pathogenesis and progression of the disease. A larger, quantitative study evaluating the distribution of macrophage subpopulations in postmortem AMD eyes is warranted.

Comparative integrated molecular analysis of intraocular medulloepitheliomas and central nervous system embryonal tumors with multilayered rosettes confirms that they are distinct nosologic entities.

Intraocular medulloepithelioma (IO MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. These ocular neoplasms have been compared with intracranial medulloepitheliomas or other histologic variants of CNS embryonal tumor with multilayered rosettes (CNS ETMR) due to their morphological mimicry. We performed comprehensive molecular analysis to explore the histogenetic and biologic relationships between 22 IO MEPL and 68 CNS ETMR. Routinely prepared paraffin-embedded samples were assessed for genome-wide methylation profiles using the Illumina Methylation 450k BeadChip array. We identified strong cytogenetic and epigenetic differences between ocular neoplasms and CNS ETMR. None of the IO MEPL cases displayed the ETMR-specific amplification of the C19MC locus. Instead, cytogenetic analysis of the IO MEPL showed numerous copy number aberrations which involved either whole chromosomes or chromosomal arms; recurrent aberrations in these tumors affected chromosomes 1p, 4, 8 and 16p. DNA methylation patterns were also strikingly different between these two tumor entities, suggesting that they do not share common origins and biological behaviors. Comparative cluster analysis of 198 pediatric CNS tumors and 22 IO MEPL revealed a clear demarcation of the CNS ETMR and IO MEPL profiles from other CNS entities. In conclusion, although IO MEPL shares some histopathological features with CNS ETMR, they manifest striking molecular diversity at the cytogenetic and epigenetic levels. Consequently they deserve a separate nosologic designation in future tumor classifications, where CNS MEPL could be designated as a histological variant of CNS ETMR.

Diagnostic Algorithm for Patients With Suspected Giant Cell Arteritis.

BACKGROUND: To identify clinical and laboratory factors contributing to the diagnosis of giant cell arteritis (GCA) and develop a diagnostic algorithm for the evaluation of GCA. METHODS: Retrospective review of 213 consecutive cases of temporal artery biopsy (TAB) seen at a single academic center over a 10-year period (2000-2009). Pathologic specimens were re-reviewed and agreement between the original and second readings was assessed. A composite clinical suspicion score was created by adding 1 point for each of the following criteria: anterior extracranial circulation ischemia, new onset headache, abnormal laboratory results (erythrocyte sedimentation rate, C-reactive protein (CRP), or platelet count), jaw claudication, abnormal or tender superficial temporal artery, constitutional symptoms, and polymyalgia rheumatica; one point was subtracted if a comorbid condition could explain a criterion. RESULTS: Of the 204 TABs analyzed, pathologic findings were confirmatory in 49 (24.0%) and suggestive in 12 (5.9%). TAB-positive patients were more likely to be older (age 75.2 ± 7.8 vs 69.7 ± 11.0 years, P = 0.0002), complain of jaw claudication (relative-risk = 3.26, P = 0.0014), and have thrombocytosis (relative-risk = 3.3, P = 0.0072) and elevated CRP (relative-risk = 1.8, P = 0.037). None of the patients with a clinical score less than 2 had a positive TAB. Diabetes mellitus and kidney disease were often the explanation for the symptoms and abnormal clinical finding(s) that led to a negative TAB. CONCLUSIONS: We propose a clinical algorithm that is highly predictive for a positive TAB and can be valuable in the evaluation process of suspected cases of GCA.

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.

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.