High-risk human papillomavirus-associated corneal/conjunctival intraepithelial neoplasia in a young patient.

Purpose: To report a case of high-risk human papillomavirus (HPV)-associated corneal/conjunctival intraepithelial neoplasia (CIN) in a 17-year-old fair-skinned male with no other risk factors. Observations: A 17-year-old Caucasian male presented with an 18-month history of left eye pain, redness, itchiness, and decreased vision. Examination revealed a leukoplakic nasal limbal/peripheral corneal lesion resistant to topical antibiotic and anti-inflammatory treatments. Excisional biopsy confirmed the diagnosis of CIN, and RNA in situ hybridization testing for high-risk HPV types 16/18 was positive. Subsequent testing of the patient for human immunodeficiency virus (HIV) returned negative. Conclusions and Importance: The median age of CIN diagnosis in the United States is in the sixth decade of life and is usually associated with a history of ultraviolet (UV) light exposure. There are reports of CIN in young patients with systemic immunodeficiency, immunosuppression, xeroderma pigmentosum, atopic dermatitis, asthma, and vaping. Here we present a case of high-risk HPV-associated CIN in a young, fair-skinned patient with no other identifiable risk factors.

Primary bulbar conjunctival basal cell carcinoma: A clinical-pathologic report and literature review.

Purpose: To enhance the characterization of primary bulbar conjunctival basal cell carcinoma (BCC) clinically and histologically, via report of a case and review of the relevant medical literature. Observations: We report the case of a 73-year-old man with no history of skin cancer who presented with a bulbar conjunctival nodule without connection to the eyelid or caruncle, originally thought to represent a pyogenic granuloma. After one month without improvement on topical prednisolone, excisional biopsy was performed, with routine histopathology and immunohistochemistry. The tumor was found histologically to be primary conjunctival BCC. Immunostaining exhibited negative Ber-EP4 and S100, mostly negative CK7 and EMA, and positive p63. Margins were negative, and the patient had no recurrence six months after excision. Conclusions and Importance: Primary conjunctival BCC must be considered in the differential diagnosis of a conjunctival lesion which may initially appear benign but does not behave as expected clinically. The location of the tumor in the case presented here refutes a prior postulate that primary conjunctival BCC arises from basal adnexal epithelium in the caruncle. Of the immunohistochemical findings, only the Ber-EP4 result differed from the typical immunostaining profile of cutaneous BCC. Further study is needed to determine the frequency of Ber-EP4 positivity in primary conjunctival BCC.

ENDOGENOUS ENDOPHTHALMITIS CAUSED BY GROUP B STREPTOCOCCUS IN A HEALTHY, TERM NEONATE.

PURPOSE: The purpose of this study was to describe an unusual case of unilateral, endogenous endophthalmitis in an otherwise healthy, term neonate. METHODS: A 3-week-old otherwise healthy, term male infant was referred to St. Louis Children's Hospital for a second opinion of presumed panuveitis of the right eye. RESULTS: Diffusion-weighted magnetic resonance imaging demonstrating purulent intraocular contents facilitated the diagnosis of endophthalmitis. Examination of surgical vitreous samples by staining and cytology demonstrated gram-positive bacterial cocci in short chains, thereby confirming endophthalmitis. Polymerase chain reaction testing of vitreous fluid identified Streptococcus agalactiae , despite an unremarkable systemic workup and a negative prepartum maternal Group B streptococcal screen. CONCLUSION: Endogenous endophthalmitis is a rare but devastating cause of vision loss in otherwise healthy, term neonates. Prompt diagnosis may be facilitated by magnetic resonance imaging and diagnostic vitreous biopsy.

Vitreoretinal Lymphoma: Optimizing Diagnostic Yield and Accuracy.

PURPOSE: To determine whether the addition of adjunctive tests, including immunohistochemistry (IHC), cytokine analysis, flow cytometry, and IgH gene rearrangement testing, achieves improved diagnostic parameters compared with cytologic smears alone in the detection of vitreoretinal lymphoma (VRL). To determine which of these tests or combination of tests provide the greatest diagnostic utility. DESIGN: Retrospective review to assess diagnostic value. METHODS: This single university-affiliated tertiary care center study included data from 237 vitreous biopsies performed between 1999 and 2017 in patients with suspected VRL. From 1999 to 2008-2009, cytologic smears were the sole test performed (84 cases). The protocol initiated in 2008-2009 added the 4 additional diagnostic tests (153 cases). The sensitivity, specificity, positive predictive value, negative predictive value, diagnostic accuracy, and diagnostic yield were calculated. Parameters were calculated for tests individually, for all 5 combined, and all possible 2-, 3-, and 4-test combinations. For cytologic smears, diagnostic parameters were calculated both before and after the addition of adjunctive tests to our protocol and for the entire cohort. RESULTS: Of the 237 vitreous biopsies, 50 samples (21%) were from patients with confirmed central nervous system lymphoma and/or actively treated central nervous system, systemic, or intraocular lymphoma. Diagnostic yields (95% CI) were 90% (85%-93%) for smears, 82% (72%-89%) for IHC, 91% (85%-96%) for cytokine analysis, 76% (67%-84%) for IgH gene rearrangement, and 50% (40%-60%) for flow cytometry. For smears, the sensitivity pre-protocol was 73% (39%-94%), compared with 87% (69%-96%) post-protocol. IgH gene rearrangement was the only test exhibiting low sensitivity (40%). The combination of smears, IHC, and cytokine analysis exhibited the highest diagnostic parameters, with sensitivity 92%, specificity 98%, and diagnostic yield 100%. CONCLUSIONS: The combination of cytologic smears, IHC, and cytokine analysis seems to be a reasonable and sufficient protocol for the diagnosis of suspected VRL. IgH gene rearrangement and flow cytometry may be the most expendable tests from our protocol.

Compositional Analysis of Extracellular Aggregates in the Eyes of Patients With Exfoliation Syndrome and Exfoliation Glaucoma.

Purpose: Exfoliation syndrome (XFS) is a condition characterized by the production of insoluble fibrillar aggregates (exfoliation material; XFM) in the eye and elsewhere. Many patients with XFS progress to exfoliation glaucoma (XFG), a significant cause of global blindness. We used quantitative mass spectrometry to analyze the composition of XFM in lens capsule specimens and in aqueous humor (AH) samples from patients with XFS, patients with XFG and unaffected individuals. Methods: Pieces of lens capsule and samples of AH were obtained with consent from patients undergoing cataract surgery. Tryptic digests of capsule or AH were analyzed by high-performance liquid chromatography-mass spectrometry and relative differences between samples were quantified using the tandem mass tag technique. The distribution of XFM on the capsular surface was visualized by SEM and super-resolution light microscopy. Results: A small set of proteins was consistently upregulated in capsule samples from patients with XFS and patients with XFG, including microfibril components fibrillin-1, latent transforming growth factor-ß-binding protein-2 and latent transforming growth factor-ß-binding protein-3. Lysyl oxidase-like 1, a cross-linking enzyme associated with XFS in genetic studies, was an abundant XFM constituent. Ligands of the transforming growth factor-ß superfamily were prominent, including LEFTY2, a protein best known for its role in establishing the embryonic body axis. Elevated levels of LEFTY2 were also detected in AH from patients with XFG, a finding confirmed subsequently by ELISA. Conclusions: This analysis verified the presence of suspected XFM proteins and identified novel components. Quantitative comparisons between patient samples revealed a consistent XFM proteome characterized by strong expression of fibrillin-1, lysyl oxidase-like-1, and LEFTY2. Elevated levels of LEFTY2 in the AH of patients with XFG may serve as a biomarker for the disease.

Corneal perforation in ocular graft-versus-host disease.

PURPOSE: Corneal perforation is a rare, vision-threatening complication of ocular graft-versus-host disease (GVHD) and is not well understood. Our objective was to examine the clinical disease course and histopathologic correlation in patients who progressed to this outcome. METHODS: This study is a retrospective case series from four academic centers in the United States. All patients received a hematopoietic stem cell transplant (HSCT) prior to developing ocular GVHD. Variables of interest included patient demographics, time interval between HSCT and ocular events, visual acuity throughout clinical course, corticosteroid and infection prophylaxis regimens at time of corneal perforation, medical/surgical interventions, and histopathology. RESULTS: Fourteen eyes from 14 patients were analyzed. Most patients were male (86%) and Caucasian (86%), and average age at time of hematopoietic stem cell transplant was 47 years. The mean interval between hematopoietic stem cell transplant and diagnosis of ocular graft-versus-host disease was 9.5 months, and between hematopoietic stem cell transplant and corneal perforation was 37 months. Initial best-corrected visual acuity was 20/40 or better in 9 eyes, and all eyes had moderate or poor visual outcomes despite aggressive management, including corneal gluing in all patients followed by keratoplasty in 8 patients. The mean follow-up after perforation was 34 months (range 2-140 months). Oral prednisone was used prior to perforation in 11 patients (79%). On histopathology, representative specimens in the acute phase demonstrated ulcerative keratitis with perforation but minimal inflammatory cells and no microorganisms, consistent with sterile corneal "melt" in the setting of immunosuppression; and in the healed phase, filling in of the perforation site with fibrous scar. CONCLUSIONS: In these patients, an extended time interval was identified between the diagnosis of ocular graft-versus-host disease and corneal perforation. This represents a critical window to potentially prevent this devastating outcome. Further study is required to identify those patients at greatest risk as well as to optimize prevention strategies.

Severe Corneal Hydrops With Suspected Posterior Stromal Rupture Managed With Ultrathin Descemet-Stripping Automated Endothelial Keratoplasty.

PURPOSE: To describe severe acute corneal hydrops in a patient with previously undiagnosed keratoconus, in which anterior segment optical coherence tomography (AS-OCT) revealed a protruding ridge of tissue on either side of Descemet membrane (DM) break, treated successfully with ultrathin Descemet-stripping automated endothelial keratoplasty (UT-DSAEK). METHODS: A case report. RESULTS: A 32-year-old man presented with severe corneal hydrops in OS. He was treated conservatively with hypertonic saline. Serial AS-OCT revealed persistent edema and haze overlying a break in DM, with a ridge of protruding tissue on either side. Based on these findings, UT-DSAEK was performed. Intraoperatively, the ridge of tissue remained firmly adhered after DM removal and was felt to possibly represent posterior stroma. The patient's uncorrected visual acuity improved to 20/80. Literature review revealed 1 case with similar AS-OCT findings who underwent penetrating keratoplasty; histopathology was reported to show Descemet scrolls on either side of the break, but our analysis of this and other reports suggest that an additional layer of tissue is contained within the scroll along with DM. CONCLUSIONS: This case demonstrates severe corneal hydrops in the setting of keratoconus, in which AS-OCT revealed a ridge of protruding tissue on either side of a break in DM. UT-DSAEK led to resolution of corneal edema and improvement in stromal haze and visual acuity. Further research is required to determine the precise role of endothelial keratoplasty and potential role of posterior stromal rupture in some cases of acute corneal hydrops.

Atypical presentation of Cat Eye Syndrome in an infant with Peters anomaly and microphthalmia with cyst.

PURPOSE: To describe a unique ocular presentation of Cat Eye Syndrome and review the ocular and systemic findings associated with the syndrome. METHODS: Case report with multimodal imaging. RESULTS: A newborn female presented with a unilateral Peters anomaly with contralateral microphthalmia with cyst. The patient's other systemic findings included a hypoplastic right heart, persistent ductus arteriosus, intrauterine growth retardation, bilateral anotia, preauricular ear pits and skin tags, micrognathia, hypoplastic female genitalia, and unilateral cranial nerve VII palsy. Chromosomal microarray testing showed tetrasomy of chromosome 22 in the q11.1-q11.21 region consistent with Cat Eye Syndrome. The patient ultimately underwent a successful optical iridectomy on one side and orbitotomy with excision of the cystic mass on the other. CONCLUSIONS: The co-occurrence of unilateral Peters anomaly with contralateral microphthalmia with cyst in Cat Eye Syndrome is rare and demonstrative of the syndrome's phenotypic variability. The medical and surgical management of these patients may require a multidisciplinary approach and must be tailored to the individual findings and overall systemic health of the patient.

Efficient Coding by Midget and Parasol Ganglion Cells in the Human Retina.

In humans, midget and parasol ganglion cells account for most of the input from the eyes to the brain. Yet, how they encode visual information is unknown. Here, we perform large-scale multi-electrode array recordings from retinas of treatment-naive patients who underwent enucleation surgery for choroidal malignant melanomas. We identify robust differences in the function of midget and parasol ganglion cells, consistent asymmetries between their ON and OFF types (that signal light increments and decrements, respectively) and divergence in the function of human versus non-human primate retinas. Our computational analyses reveal that the receptive fields of human midget and parasol ganglion cells divide naturalistic movies into adjacent spatiotemporal frequency domains with equal stimulus power, while the asymmetric response functions of their ON and OFF types simultaneously maximize stimulus coverage and information transmission and minimize metabolic cost. Thus, midget and parasol ganglion cells in the human retina efficiently encode our visual environment.

Histopathologic Analysis of Explanted KAMRA Corneal Inlays Demonstrating Adherent Fibroconnective Tissue Scar Formation.

OBJECTIVE: To investigate the histologic composition of opaque membranes associated with corneal intrastromal inlays implanted for the surgical treatment of presbyopia. METHODS: This is an observational case series of KAMRA corneal inlays explanted due to the presence of adherent opaque membranes associated with peri-inlay corneal stromal haze and sent for histopathologic analysis. Routine histology was performed in addition to immunohistochemical staining with myofibroblast and keratocyte markers. RESULTS: Eleven explanted inlay specimens were received, of which, after histologic processing, four demonstrated suf-ficient cellular material for histopathologic analysis. The opaque membranes surrounding the explanted inlays were composed of fibroconnective tissue, and myofibroblasts (positive for smooth muscle actin immunostain) were the predominant cell type. Immunostaining for the keratocyte marker CD34 was negative, confirming that the membranes were the result of a reactive scar-tissue formation process and not simply normal corneal stroma adherent to the explant. CONCLUSIONS: Corneal inlay implantation can lead to the formation of an adherent fibroconnective tissue membrane, suggesting keratocyte-to-myofibroblast transdifferentiation and reactive fibroconnective tissue scar formation that could potentially impact visual potential. Prospective patients should be counseled regarding the risk of this complication, as this may be associated with some risk of incomplete reversibility of the procedure.

Intraocular Dissemination of Uveal Melanoma Cells Following Radiotherapy: Evolving Management Over the Past Decade.

BACKGROUND AND OBJECTIVE: To describe the presentation and the authors' evolving management strategy for intraocular dissemination of uveal melanoma cells following radiotherapy during the past decade. PATIENTS AND METHODS: Patients with uveal melanoma who developed intraocular dissemination of pigmented cells following radiotherapy. Histopathology was available in two cases. RESULTS: Four patients underwent treatment for progressive intraocular dissemination of uveal melanoma cells at 9 to 41 months following I-125 plaque radiotherapy (three patients) or proton beam radiotherapy (one patient). Treatments included primary enucleation (one patient), vitrectomy followed later by enucleation (one patient), and vitrectomy followed by intravitreal chemotherapy (two patients). Enucleated eyes demonstrated diffuse invasion of intraocular tissues by viable melanoma cells. No patient has developed systemic metastasis to date. CONCLUSIONS: Intraocular dissemination of pigmented cells following radiotherapy for uveal melanoma should raise suspicion for viable invasive melanoma cells. Prompt vitrectomy with intravitreal chemotherapy can be effective in avoiding enucleation in selected cases. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:573-579.].

Corneal keloid presenting forty years after penetrating injury: Case report and literature review.

A 64-year-old Caucasian man had been diagnosed with presumed ocular surface squamous neoplasia in the left eye and started on topical interferon alpha 2b drops. When we saw him, he provided a history of penetrating corneal injury more than forty years before. Slit lamp examination revealed a large, elevated, opaque lesion involving the left cornea. High-definition anterior segment optical coherence tomography revealed a hyperreflective lesion involving the anterior stroma with a relatively normal overlying epithelium. Based on the clinical history, slit lamp, and anterior segment optical coherence tomography findings, a giant corneal keloid was suspected, and the interferon drops were discontinued. He subsequently underwent a penetrating keratoplasty, and histopathologic analysis was consistent with corneal keloid. Corneal keloids may be seen decades after the initial trauma, and anterior segment optical coherence tomography can be a useful tool in differentiating these tumor-like lesions from other neoplasia.

Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis.

A 21-year-old man experienced unilateral vision loss associated with multiple atrophic chorioretinal lesions. He was treated for a presumptive diagnosis of acute retinal necrosis, but his vision did not improve with antiviral therapy. Over the course of several weeks, his symptoms progressed to involve both eyes. The fellow eye showed characteristic yellow-white placoid lesions, prompting treatment with oral corticosteroids for acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Despite high-dose therapy with prednisone 80 mg daily, the patient developed the acute onset of mental status changes within the next several days. Neuroimaging revealed multifocal large-vessel strokes associated with cerebral edema; these infarcts led to herniation and death. Postmortem histopathologic examination confirmed granulomatous inflammation in both ocular and cerebral vasculatures. Together with findings from multimodal imaging obtained throughout this patient's clinical course, our findings support the notion that granulomatous choroiditis is the mechanism of the ocular lesions seen in APMPPE. This granulomatous inflammation can also affect cerebral vessels, leading to strokes.

Bioinspired Fibrillary Hydrogel with Controlled Swelling Behavior: Applicability as an Artificial Vitreous.

The vitreous humor of the eye is mainly composed of fibrillary collagen and semiflexible hyaluronic acid (HA). To mimic this macromolecular composition of the vitreous, we previously developed an injectable two-component hydrogel composed of a fibrillary gellan and a semiflexible polyelectrolyte, poly[methacrylamide-co-(methacrylic acid)], both endowed with thiol cross-linkers. We optimized the hydrogel formulations for optical, physical, mechanical, and transport properties approximating those of the vitreous. Here, we studied 11 hydrogel formulations with varying concentrations of each component, and, as expected, we found that they all swelled in physiological solution. The two formulations that most closely matched the vitreous properties were investigated further. Judged against nonsurgical control and silicone oil, a clinically accepted vitreous replacement, both hydrogel formulations were biocompatible in rabbits for 30 days. Both hydrogels maintained optical clarity, physiological intraocular pressure, and intact retinal layers that displayed normal electroretinography. The swelling behavior of the gel led us to postulate that the native vitreous may also exhibit controlled swelling, where ionic HA's swelling capacity is restricted by fibrillary collagen. In conclusion, the two hydrogels merit further in vivo evaluation as an artificial vitreous for an extended duration and additionally in mini-pigs for their similarity to human eyes in size.

Extrascleral Tumor Extension Associated with Localized Scleral Melt following Plaque Brachytherapy for Uveal Melanoma: Clinical and Histologic Findings.

BACKGROUND/AIMS: Our study aims to better characterize the clinical and histopathologic features of eyes with extrascleral uveal melanoma associated with scleral melt following brachytherapy. METHODS: A retrospective review was performed on patients who had undergone 125I (iodine-125) brachytherapy for uveal melanoma at our institution between 1992 and 2015. Patients with postradiation scleral necrosis who required enucleation were identified, and an analysis including a review of histopathology results was performed on those cases. RESULTS: A total of 301 patients underwent plaque brachytherapy for uveal melanoma, of whom 31 required eventual enucleation. The histologic analysis showed extraocular extension through full-thickness scleral discontinuities in 6 cases. All but 1 (5 of 6) of these eyes exhibited either mitotic figures or Ki-67 positivity. Mitotic figures were noted in 4 specimens, including 3 eyes exhibiting mitoses within or adjacent to the extrascleral portion of the tumor. Two eyes exhibiting mitoses, as well as the case with Ki-67 positivity, also had clinical evidence of tumor regrowth. CONCLUSION: We found evidence of mitotic activity at the area of scleral discontinuity in some eyes with and in some without clinical evidence of tumor regrowth. Protruding pigmented material in areas of scleral necrosis after plaque brachytherapy may represent actively proliferating tumors even without internal evidence of tumor regrowth.

Successful treatment of metastatic congenital intraocular medulloepithelioma with neoadjuvant chemotherapy, enucleation and superficial parotidectomy.

PURPOSE: To report a case of metastatic intraocular medulloepithelioma successfully treated with neoadjuvant chemotherapy, superficial parotidectomy, and enucleation. OBSERVATIONS: A 5-year-old male with history of cataract surgery, glaucoma drainage device, endocyclophotocoagulation, scleral patch grafting, and chronic posterior "inflammation" in a blind left eye presented with a rapidly enlarging painful mass under the left upper eyelid. Biopsy of the conjunctival mass and fine needle aspiration of an enlarged preauricular lymph node revealed medulloepithelioma, which was also seen in the left parotid gland on positron emission tomography (PET) scan. The patient's father refused exenteration, so the patient received 3 cycles of vincristine, cisplatin, cyclophosphamide, and etoposide per a retinoblastoma protocol. Repeat magnetic resonance imaging (MRI) showed regression of ocular extension, and an enucleation was performed, histologically confirming the diagnosis of malignant, non-teratoid medulloepithelioma. The child later underwent superficial parotidectomy and received an additional round of chemotherapy. There has been no evidence of recurrence for 9 years. CONCLUSIONS AND IMPORTANCE: There is no standard treatment for metastatic intraocular medulloepithelioma. The neoadjuvant chemotherapy regimen used in our patient led to regression of the extrascleral extension of the tumor, allowing for enucleation rather than a more disfiguring exenteration, as well as likely improving his prognosis. We believe that it is reasonable to consider neoadjuvant chemotherapy for patients with extrascleral and/or metastatic medulloepithelioma.

Extramedullary Relapse of Acute Myelogenous Leukemia Presenting as a Large Serous Retinal Detachment.

BACKGROUND/AIMS: To describe the rare presentation of a large, unilateral, serous retinal detachment as an extramedullary manifestation of acute myelogenous leukemia (AML) recurrence without bone marrow or central nervous system involvement after more than 1 year of follow-up. METHODS: Case report. RESULTS: A teenage patient with AML, previously treated with multiple courses of systemic chemotherapy, radiation, and bone marrow transplant, presented with acute vision loss. Ophthalmic workup revealed a large, unilateral, bullous, serous retinal detachment. Ultimately, he underwent subretinal fluid biopsy, which was found to be positive for leukemic blast cells. Cytologic markers matched his initial bone marrow biopsy, and therefore were diagnostic of extramedullary AML relapse. CONCLUSIONS: Leukemia can cause various ophthalmic manifestations. Autopsy studies suggest that choroidal infiltration is relatively common, but clinical progression to serous retinal detachment is quite uncommon. Furthermore, serous retinal detachment is generally shallow, posterior, and much more often reported in acute lymphocytic leukemia. The ophthalmologist plays a critical role in identifying leukemic ocular involvement. This case demonstrates the potential for ocular biopsy to secure the diagnosis of extramedullary relapse in order to initiate prompt treatment and systemic workup.