Immunohistochemical study of epiretinal membranes in patients with uveitis
© The Author(s) 2012
Received: 28 December 2011
Accepted: 26 March 2012
Published: 25 April 2012
The purpose of this study is to report two cases of idiopathic uveitis with secondary epiretinal membrane (ERM) formation in order to describe histologic and immunohistochemical features that may help distinguish uveitic from idiopathic ERMs.
The study utilized a clinical case series and histopathological and immunohistochemical findings.
There was no identifiable etiology of inflammation in either case. Histology and immunohistochemistry demonstrated a mixture of abundant inflammatory cells, including lymphocytes, histiocytes, plasma cells, and occasional eosinophils, among a stromal matrix composed of glial elements and condensed vitreous, but no retinal pigment epithelium (RPE) was present. The relative proportions of the various inflammatory cell types were assessed with immunohistochemistry, and among the lymphocyte population, T cells predominated over B cells. In one of the cases, there was an abundance of histiocytes, consistent with granulomatous uveitis, which was later confirmed on histology of the enucleated globe.
Idiopathic ERM formation is thought to be secondary to glial cell migration that may require some involvement of RPE cells. The absence of RPE and abundance of inflammatory cells may be used to identify ERMs as secondary to uveitis.
Epiretinal membranes (ERM) are fibrocellular proliferations over the internal limiting membrane that can lead to significant macular pathology when associated with contraction . When these membranes contract, patients often complain of metamorphopsia and loss of visual acuity. Early histopathologic studies characterized ERMs from a variety of diseases; however, immunohistochemical studies were not performed [2, 3]. While there is little understanding as to how idiopathic ERMs form, there is even less information regarding the formation of ERMs in chronic uveitis. To better understand the formation of these membranes, we aim to characterize the immunohistochemistry of ERMs from two patients with chronic idiopathic uveitis.
Case report 1
A 50-year-old woman was referred for intraocular inflammation in the right eye with decreased vision for 2 days. She had no past medical history, and on exam, her vision was 20/400 in the right eye and 20/40 in the left. Dilated fundoscopic examination revealed 1+ vitreous cell and inferior snowballs and vitreous debris with a chorioretinal scar in the right eye. Examination of the left eye revealed nuclear sclerotic cataract and was otherwise normal. She was started on azithromycin for the possibility of toxoplasmosis-related chorioretinitis, and a systemic work-up was initiated, which was negative for infectious, inflammatory, and vasculitic processes. Over the next 2 months, her vision improved to 20/150 with a combination of topical prednisolone acetate 1 % and empiric therapy for toxoplasmosis. However, the amount of inflammation remained largely unchanged, and she underwent vitreous biopsy with the hope of identifying a causative agent.
Case report 2
A 57-year-old woman with high myopia and a remote history of a prior retinal tear in the left eye treated with focal laser photocoagulation underwent pneumatic retinopexy and cryotherapy for a retinal tear in the right eye. She was referred for sudden onset of decreased vision 32 days after the recent procedure in the right eye. Her past medical history was significant for osteoarthritis and breast cancer treated with bilateral mastectomy 6 years prior to this presentation. Her vision had dropped from 20/25 to count fingers at 2 ft. Slit lamp examination revealed 2+ anterior chamber and vitreous cells without hypopyon. The retina was attached in all four quadrants, and the chorioretinal scarring from the cryotherapy procedure was seen inferotemporally. She was started on topical steroid therapy with prednisolone acetate 1 % with improvement in the inflammation, and her vision improved to 20/50 after 4 weeks of topical therapy. The steroid drop was slowly tapered; however, after 2 weeks, the inflammation worsened, and her vision declined to 2/200. A systemic work-up was initiated, and her topical steroid regimen increased. She returned 4 weeks later with no inflammation and 20/30 vision. Her systemic work-up was negative for infectious, inflammatory, and vasculitic processes known to cause intermediate and pan-uveitis. Her steroid drop was tapered, but 2 months later, she returned with 2+ cell and flare in the anterior chamber and vitreous cell, again without hypopyon. It was then decided to perform a vitreous biopsy to further investigate the cause of her recurrent inflammatory condition.
Some of the early series describing the histology of ERMs were done over 30 years ago [4, 5]. The formation of a simple ERM is thought to be secondary to glial cell migration from the nerve fiber layer. GFAP expression in simple ERMs further demonstrates that the majority of these membranes derive from glial cells as originally described . Early studies also suggested that RPE cells are generally necessary for ERM formation and likely accentuate ERM formation when in combination with glial cells . These observations were confirmed in a recent study of internal limiting membranes from idiopathic macular holes . While ERMs of different presumed etiologies were studied, characterization of the less common forms was minimally pursued.
Given the complexity of ERM formation, Snead et al. attempted to classify ERMs by histology and etiology, subdividing them into three categories: simple, tissue repair, and neovascular ERMs . While not stated directly in the paper, uveitic ERMs would likely fall under the tissue repair category, in which the biological mediators are thought to involve the NF-κB pathway specifically driven by TGFβ, IL-6, and PDGF. Interestingly, IL-6 to IL-10 ratios from the vitreous biopsies in these two cases were extremely elevated, possibly suggesting some direct or indirect relationship between IL-6 levels and ERM formation in chronic uveitis. In vivo studies indeed suggest that IL-6 is an inducer of gliosis in the retina through changes in the transcription profile of glial cells .
The membranes in this series both lacked RPE cells but contained abundant inflammatory cells that distinguished them from simple ERMs. These features can help differentiate simple ERMs from uveitic ERMs. While glial cells are present in both, it is possible that the original observations by Kampik et al. were correct in that ERM formation requires some combination of glial, inflammatory, and/or RPE cell types. The lack of RPE and presence of inflammatory cells may be used to classify ERMs as secondary to uveitis when there is a question as to their etiology.
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