Ehsan Rahimy

Age-related T-cell cytokine profile parallels corneal disease severity in Sjögren’s syndrome-like keratoconjunctivitis sicca in CD25KO mice

OBJECTIVES IL-2ralpha (CD25)(-/-) mice develop autoimmunity and lymphoproliferative disorders, including SS-like disease. The objective of this study was to evaluate the severity of corneal epithelial disease and T-cell cytokine profile in the ocular surface tissues of CD25KO mice. METHODS CD25KO mice were evaluated at 8, 12 and 16 weeks of age. Corneal epithelial smoothness and corneal permeability were measured. Phenotype of infiltrating lymphocytes was evaluated by immunohistochemistry. Th-1, -2 and -17 associated factors were measured by real-time PCR in cornea and conjunctiva and by Luminex immunobead assay in tears. RESULTS Compared with 8-week-old wild-type (WT) mice, CD25KO mice of the same age had significantly greater corneal irregularity and a significant increase in the number of CD4(+) and CD8(+) T cells infiltrating the conjunctiva. CD25KO mice had significantly higher levels of IL-6, TGF-beta1, IL-23R, IL-17A, IL-17F, IL-21, CCL20, IL-10, GATA-3 and IFN-gamma mRNA transcripts in their cornea and conjunctiva than WT mice at 8 weeks. IL-17A and IL-17F mRNA transcripts peaked at 12 weeks, whereas IFN-gamma spiked at 16 weeks in CD25KO mice. Increased expression of IL-17A and IL-17F at 12 weeks in CD25KO mice was accompanied by a worsening of corneal surface parameters and an increase of CD4(+) T cell infiltrating the cornea. CONCLUSIONS Disruption of IL-2 signalling in CD25KO mice results in age-dependent SS-like autoimmune lacrimal-keratoconjunctivitis. A mix of Th-1 and Th-17 cytokines was detected. The peak severity of corneal epithelial disease corresponded to the peak of IL-17 expression.

Baseline Choroidal Thickness as a Predictor for Response to Anti–Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema

PURPOSE To determine the association between baseline subfoveal choroidal thickness and short-term response to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in diabetic macular edema (DME). DESIGN Retrospective, consecutive case series. METHODS Fifty-three eyes from 42 patients diagnosed with treatment-naïve DME were treated with 3 monthly intravitreal injections of ranibizumab or bevacizumab. Serial enhanced depth imaging optical coherence tomography scans were used to measure subfoveal choroidal thickness and central macular thickness (CMT). Anatomic response (CMT decrease ≥ 50 μm) and functional response (best-corrected visual acuity gain ≥ 1 line) were assessed at 3 months follow-up using univariate and multivariate analyses. RESULTS After 3 monthly anti-VEGF treatments, subfoveal choroidal thickness decreased significantly (225 μm at baseline, 201 μm at 3 months, P < .0001). The anatomic responder group (32 eyes) had a greater baseline choroidal thickness (243 ± 15 μm) than the nonresponder group (21 eyes, 198 ± 13 μm, P = .03). Similarly, the functional responder group (28 eyes) tended to have a greater baseline subfoveal choroidal thickness (239 ± 12 μm) than the nonresponder group (25 eyes, 211 ± 16 μm, P = .08). Multivariate analyses revealed that a greater baseline subfoveal choroidal thickness was associated with a better anatomic (odds ratio = 1.12 for every 10 μm increase, P = .03) and functional response (odds ratio = 8.45 for >200 μm vs ≤ 200 μm, P = .008). CONCLUSION Baseline subfoveal choroidal thickness may help predict which patients with DME will respond more favorably in the short term to intravitreal anti-VEGF pharmacotherapy. In this study, eyes with a thicker baseline subfoveal choroidal thickness had better short-term anatomic and functional responses.

Spectrum of Retinal Vascular Diseases Associated With Paracentral Acute Middle Maculopathy.

PURPOSE To evaluate the spectrum of retinal diseases that can demonstrate paracentral acute middle maculopathy and isolated ischemia of the intermediate and deep capillary plexus. DESIGN Retrospective, multicenter, observational case series. METHODS This is a retrospective case series review of 9 patients (10 eyes) from 5 centers with paracentral acute middle maculopathy lesions and previously unreported retinal vascular etiologies. Case presentations and multimodal imaging, including color photographs, near-infrared reflectance, fluorescein angiography, spectral-domain optical coherence tomography (SD OCT), and orbital color Doppler imaging, are described. Baseline and follow-up findings are correlated with clinical presentation, demographics, and systemic associations. RESULTS Five men and 4 women, aged 27-66 years, were included. Isolated band-like hyperreflective lesions in the middle retinal layers, otherwise known as paracentral acute middle maculopathy, were observed in all patients at baseline presentation. Follow-up SD OCT analysis of these paracentral acute middle maculopathy lesions demonstrated subsequent thinning of the inner nuclear layer. Novel retinal vascular associations leading to retinal vasculopathy and paracentral acute middle maculopathy include eye compression injury causing global ocular ischemia, sickle cell crisis, Purtschers retinopathy, inflammatory occlusive retinal vasculitis, post-H1N1 vaccine, hypertensive retinopathy, migraine disorder, and post-upper respiratory infection. CONCLUSION Paracentral acute middle maculopathy lesions may develop in a wide spectrum of retinal vascular diseases. They are best identified with SD OCT analysis and may represent ischemia of the intermediate and deep capillary plexus. These lesions typically result in permanent thinning of the inner nuclear layer and are critical to identify in order to determine the cause of unexplained vision loss.

Paracentral acute middle maculopathy in nonischemic central retinal vein occlusion.

PURPOSE To better characterize a novel spectral-domain optical coherence tomography (OCT) presentation, termed paracentral acute middle maculopathy, to describe this finding in patients with nonischemic central retinal vein occlusion (CRVO), and to support a proposed pathogenesis of intermediate and deep retinal capillary ischemia. DESIGN Retrospective observational case series. METHODS Clinical histories, high-resolution digital color imaging, red-free photography, fluorescein angiography, near-infrared reflectance, and spectral-domain OCT images of 484 patients with acute CRVO from 2 centers were evaluated for the presence of coexisting paracentral acute middle maculopathy. RESULTS Of 484 patients diagnosed with CRVO, 25 (5.2%) demonstrated evidence of concurrent paracentral acute middle maculopathy. Patients averaged 51 years of age and presented with complaints of paracentral scotomas. All patients demonstrated hyper-reflective plaquelike lesions at the level of the inner nuclear layer by spectral-domain OCT and showed corresponding dark-gray lesions on near-infrared reflectance and perivenular deep retinal whitening on color fundus photography. There was no fluorescein angiographic correlate to these lesions. On follow-up spectral-domain OCT imaging, the lesions had resolved into areas of inner nuclear layer atrophy with persistence of scotomas. CONCLUSIONS Paracentral acute middle maculopathy refers to characteristic hyper-reflective spectral-domain OCT lesions involving the middle layers of the retina at the level of the inner nuclear layer that may develop in response to ischemia of the intermediate and deep capillary plexuses. This series is the largest to describe this spectral-domain OCT finding to date, and it is the first to associate it with nonischemic CRVO.

Prospective evaluation of the incidence and risk factors for the development of RPE tears after high- and low-dose ranibizumab therapy.

Purpose: To prospectively determine the incidence and risk factors for retinal pigment epithelial (RPE) tears in eyes with vascularized pigment epithelial detachments (PED) and exudative age-related macular degeneration receiving antivascular endothelial growth factor therapy. Methods: Eyes were prospectively randomized into 1 of 4 arms: 1) 0.5 mg of ranibizumab monthly for 12 months; 2) 0.5 mg of ranibizumab monthly for 3 months and then pro re nata on the basis of clinical and optical coherence tomography–guided indications; 3) high-dose 2.0 mg of ranibizumab monthly for 12 months; or 4) 2.0 mg of ranibizumab monthly for 3 months and then pro re nata thereafter. All PEDs were measured for height, greatest linear diameter, and surface area at baseline. The incidence of RPE tears in the entire 4-arm cohort was determined at the end of 12 months. Eyes were divided into two groups (tear vs. nontear) and statistically compared to determine risk factors for the development of RPE tear. Results: Of 37 eyes, a total of 5 developed postranibizumab RPE tears during the course of the study (incidence 14%). Four of the 5 tears occurred in the high-dose 2.0-mg groups. Baseline PED height, surface area, and greatest linear diameter were significantly greater in the group that developed RPE tears versus the nontear group (P = 0.018, 0.031, and 0.048, respectively). There were significantly more eyes with PED height >550 microns in the RPE tear group (4 of 5, 80%) compared with the nontear group (9 of 32, 18%) (P = 0.042). The presence of PED height >550 microns was associated with an increased tear rate from 14% to 31%. Furthermore, retrospective identification of a ring sign or Grade 1 tear at baseline, in addition to PED height >550 microns, was associated with a further increase in the tear rate to 67%. Conclusion: In this study, the prospective incidence of RPE tears was ∼14%. A baseline PED height >550 microns and presence of a Grade 1 tear, or positive ring sign, were identified as high-risk factors for the subsequent development of an RPE tear.

Paracentral acute middle maculopathy spectral-domain optical coherence tomography feature of deep capillary ischemia.

Purpose of Review To describe the novel spectral-domain optical coherence tomography (SD-OCT) finding of paracentral acute middle maculopathy (PAMM) that can be associated with acute macular neuroretinopathy (AMN) or retinal vasculopathy, and that may indicate an underlying pathogenesis related to ischemia of the retinal deep capillary plexus (DCP). Recent Findings With the advent of high-definition SD-OCT imaging, we are now able to detect deep capillary ischemia. Although cotton wool spots are caused by ischemia of the superficial capillary plexus, PAMM is caused by ischemia of the DCP, and appears as hyper-reflective, band-like lesions in the middle retina, extending from the inner nuclear layer (INL)/outer plexiform layer junction to involve the full-thickness INL. Over time, these lesions resolve with atrophy of the INL, resulting in persistent paracentral scotomas for the patient. Originally, PAMM was identified in isolation and thus classified into a subcategory of AMN. Subsequent reports have demonstrated PAMM lesions in the setting of coexisting retinal vascular disease, notably nonproliferative diabetic retinopathy and central retinal vein occlusion. Summary PAMM refers to a recently described class of characteristic SD-OCT lesions involving the middle layers of the retina at the level of the INL. If a patient presenting with PAMM is young and healthy without any other vascular disease, this may represent a novel variant of AMN. However, if the patient has an underlying retinal vascular disease, such as diabetic retinopathy or retinal vascular occlusion, one would refer to the lesion as PAMM complicating the underlying retinal vascular disease.

Optical Coherence Tomography Angiography and En Face Optical Coherence Tomography Features of Paracentral Acute Middle Maculopathy

PURPOSE To characterize the optical coherence tomography (OCT) angiography, en face OCT, and microperimetry features of paracentral acute middle maculopathy in both the acute phase and after resolution, and to propose a classification of distinct subtypes of this entity. DESIGN Retrospective observational case series. METHODS Clinical histories, high-resolution digital color imaging, spectral-domain OCT images, fluorescein angiography, OCT angiography images, and en face OCT images of 16 patients with paracentral acute middle maculopathy were evaluated. Microperimetry was available in 6 patients. RESULTS The most common referring diagnoses were isolated branch retinal arterial occlusion (5/16), combined central retinal vein and cilioretinal artery occlusion (4/16), and isolated central retinal vein occlusion (4/16). All patients demonstrated hyperreflective plaque-like lesions at the level of the inner nuclear layer on spectral-domain OCT, with no fluorescein angiographic correlate. OCT angiography demonstrated variable areas of capillary dropout within the superficial and deep retinal capillary plexi in these areas. En face OCT highlighted confluent areas of middle retina hyperreflectivity corresponding to these lesions. Three distinct en face OCT patterns were observed: arteriolar, fern-like, and globular. Microperimetry demonstrated relative scotomas mapping to the area of middle retinal hyperreflectivity seen on en face OCT. CONCLUSIONS Paracentral acute middle maculopathy may be best evaluated with the use of en face OCT imaging, which corresponds to subjective and objective visual field defects. En face OCT appearance may be used to classify paracentral acute maculopathy into distinct subtypes.

Paracentral Acute Middle Maculopathy: What We Knew Then and What We Know Now.

What We Knew Then and What We Know Now In 2013, we characterized a novel presentation of hyperreflective band-like spectral-domain optical coherence tomography (SD-OCT) lesions at the level of the inner nuclear layer (INL) in a clinical series of 6 eyes from 5 patients. We descriptively termed this finding paracentral acute middle maculopathy (PAMM) due to the parafoveal position of the causative gray lesion with near-infrared reflectance imaging, the acute onset of the resulting scotoma, and the SD-OCT localization of involvement to the middle layer (INL) of the retina. Localized retinal capillary ischemia was proposed as the mechanism underlying the development of these lesions. Since then, a growing body of knowledge regarding PAMM has led to a greater understanding of this entity, and this review will serve to update the clinical associations and pathogenic mechanisms of this abnormality while distinguishing it from similar disorders.

Multilayered pigment epithelial detachment in neovascular age-related macular degeneration.

Purpose: To describe the spectral domain optical coherence tomography findings in eyes with chronic fibrovascular pigment epithelial detachment (PED) receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. Methods: Retrospective observational case series of patients with chronic fibrovascular PEDs receiving serial intravitreal anti-VEGF therapy. Corresponding spectral domain optical coherence tomography scans of chronic PEDs were studied in detail over multiple visits. The internal structure within the sub-PED compartment was analyzed, characteristic features were identified, and then correlated with visual outcome. Results: Thirty-eight eyes of 34 patients with fibrovascular PEDs were included. Mean and median Snellen visual acuity was 20/50 (range, 20/20–20/400). Eyes received a mean of 28.2 intravitreal anti-VEGF injections (median, 23.0; range, 3–70) administered over a mean of 36.9 months (median, 37.5; range, 6–84). A fusiform, or spindle-shaped, complex of highly organized layered hyperreflective bands was noted within each PED. Nineteen eyes demonstrated heterogenous, dilated, irregular neovascular tissue adherent to the undersurface of the retinal pigment epithelium. Additionally, 25 eyes demonstrated a hyporeflective cavity separating the choroidal neovascularization complex from the underlying choroid. Conclusion: Chronic fibrovascular PEDs receiving serial anti-VEGF therapy demonstrate a characteristic fusiform complex of highly organized, layered, hyperreflective bands, termed a “multilayered PED,” which is often seen in conjunction with neovascular tissue adherent to the undersurface of the retinal pigment epithelium monolayer. On the basis of previous histopathologic correlations, these bands may represent a fibrous tissue complex with contractile properties. An associated hyporeflective space, termed a “pre-choroidal cleft,” separates the fusiform complex from the underlying choroid and may be due to contraction, the exudation of fluid, or both. Many of these eyes maintain good visual acuity, presumably because the neovascular and cicatricial process is suppressed within the sub-retinal pigment epithelium space by chronic anti-VEGF therapy, thus permitting the viability of the photoreceptor population through preservation of the retinal pigment epithelium.

Pharmacological Cholinergic Blockade Stimulates Inflammatory Cytokine Production and Lymphocytic Infiltration in the Mouse Lacrimal Gland

PURPOSE To investigate the effects of cholinergic blockade on inflammatory cell infiltration and cytokine production in the mouse lacrimal gland (LG). METHODS C57BL/6 mice were untreated (UT) or received subcutaneous injections of either scopolamine hydrobromide (SCOP; 0.5 mg/0.2 mL) or saline (SAL) four times daily for 2 or 5 days (2D, 5D). This was followed by a 7-day rest period in separate groups. Tear volume (cotton thread) and tear epidermal growth factor (EGF, by ELISA) concentrations were measured. Extraorbital LGs were surgically excised and sectioned or lysed for gene expression analysis. Immunohistochemistry evaluated immunophenotype of infiltrating cells. Expression of EGF and T helper (Th)-1, -2, and -17-associated cytokines in LGs was evaluated by real-time PCR. Goblet cell density was evaluated in periodic acid Schiff-stained conjunctival sections. RESULTS Tear volume and EGF protein levels were significantly reduced in SCOP5D mice compared with controls, indicating that cholinergic blockade decreased LG secretory function. LGs of SCOP2D and SCOP5D mice showed an increased density of CD4(+), CD11c+, CD11b+, and myeloperoxidase+ cells compared with UT controls. At day 5, these cells were significantly elevated compared with SAL-treated counterparts. Elevated levels of IL-17A, IL-17R, IFN-γ, IL-12Rβ1, IL-2, IL-13, IL-6, IL-1β, and TNF-α transcripts were noted in SCOP2D mice and IFN-γ, TGF-β1, and IL-18R transcripts in SCOP5D mice. CONCLUSIONS Pharmacological blockade of lacrimal secretion induced a significant CD4(+) infiltration in the LG, mimicking Sjögrens syndrome. The mRNA expression profile revealed elevations of a mix of inflammatory cytokines and Th-1-associated factors.