To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA).
The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 μg) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area.
The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months.
Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. (ClinicalTrials.gov number, NCT00766649.)
Subconjunctival sirolimus was investigated as a treatment in geographic atrophy in a Phase I/II trial. The study drug was well tolerated but was not associated with any positive anatomic or functional effects.
age-related macular degeneration; geographic atrophy; sirolimus; rapamycin; clinical trial
Diabetic macular edema (DME) is a leading cause of blindness in the developed world. Sirolimus has been shown to inhibit the production, signaling, and activity of many growth factors relevant to the development of diabetic retinopathy. This phase I/II study assesses the safety of multiple subconjunctival sirolimus injections for the treatment of DME, with some limited efficacy data.
In this phase I/II prospective, open-label pilot study, five adult participants with diabetic macular edema involving the center of the fovea and best-corrected ETDRS visual acuity score of ≤74 letters (20/32 or worse) received 20 μl (440 μg) of subconjunctival sirolimus at baseline, month 2 and every 2 months thereafter, unless there was resolution of either retinal thickening on OCT or leakage on fluorescein angiography. Main outcome measures included best-corrected visual acuity and central retinal thickness on OCT at 6 months and 1 year, as well as safety outcomes.
Repeated subconjunctival sirolimus injections were well-tolerated, with no significant drug-related adverse events. There was no consistent treatment effect related to sirolimus; one participant experienced a 2-line improvement in visual acuity and 2 log unit decrease in retinal thickness at 6 months and 1 year, two remained essentially stable, one had stable visual acuity but improvement of central retinal thickness of 1 and 3 log units at 6 months and 1 year respectively, and one had a 2-line worsening of visual acuity and a 1 log unit increase in retinal thickness at 6 months and 1 year. Results in the fellow eyes with diabetic macular edema, not treated with sirolimus, were similar.
Subconjunctival sirolimus appears safe to use in patients with DME. Assessment of possible treatment benefit will require a randomized trial.
Sirolimus; Diabetic retinopathy; Macular edema; mTOR
Primary vitreoretinal lymphoma is a high-grade in-traocular malignancy that presents as a vitritis with creamy subretinal lesions. In cases where the vitritis is dense, the characteristic subretinal lesions can be dif-ficult to see on clinical examination. Novel high-definition imaging techniques that allow for deeper penetration through opaque media could have diagnostic utility in such cases. The authors present a case of a patient who presented with a dense vitritis that precluded visualization of fundus details. Spectral-domain optical coherence tomography using high-definition raster imaging demonstrated subretinal deposits along with outer retinal atrophy. These findings were suggestive of primary vitreoretinal lymphoma and prompted diagnostic vitrectomy. Pathological examination of the vitreous specimen confirmed the diagnosis of primary vitreoretinal lymphoma.
There have been several published reports of inflammatory ocular adverse events, mainly uveitis and scleritis, among patients taking oral bisphosphonates. We examined the risk of these adverse events in a pharmacoepidemiologic cohort study.
We conducted a retrospective cohort study involving residents of British Columbia who had visited an ophthalmologist from 2000 to 2007. Within the cohort, we identified all people who were first-time users of oral bisphosphonates and who were followed to the first inflammatory ocular adverse event, death, termination of insurance or the end of the study period. We defined an inflammatory ocular adverse event as scleritis or uveitis. We used a Cox proportional hazard model to determine the adjusted rate ratios. As a sensitivity analysis, we performed a propensity-score–adjusted analysis.
The cohort comprised 934 147 people, including 10 827 first-time users of bisphosphonates and 923 320 nonusers. The incidence rate among first-time users was 29/10 000 person-years for uveitis and 63/10 000 person-years for scleritis. In contrast, the incidence among people who did not use oral bisphosphonates was 20/10 000 person-years for uveitis and 36/10 000 for scleritis (number needed to harm: 1100 and 370, respectively). First-time users had an elevated risk of uveitis (adjusted relative risk [RR] 1.45, 95% confidence interval [CI] 1.25–1.68) and scleritis (adjusted RR 1.51, 95% CI 1.34–1.68). The rate ratio for the propensity-score–adjusted analysis did not change the results (uveitis: RR 1.50, 95% CI 1.29–1.73; scleritis: RR 1.53, 95% CI 1.39–1.70).
People using oral bisphosphonates for the first time may be at a higher risk of scleritis and uveitis compared to people with no bisphosphonate use. Patients taking bisphosphonates must be familiar with the signs and symptoms of these conditions, so that they can immediately seek assessment by an ophthalmologist.
To evaluate the safety and efficacy of finasteride, an inhibitor of dihyroxytestosterone (DHT) synthesis, in the treatment of chronic central serous chorioretinopathy (CSC).
Five patients with chronic CSC were prospectively enrolled in this pilot study. Patients were administered finasteride (5mg) daily for 3 months, following which study medication was withheld and patients were observed for 3 months. Main outcome measures included best-corrected visual acuity (BCVA), center-subfield macular thickness and subretinal fluid volume as assessed by optical coherence tomography (OCT). Serum DHT, serum testosterone, and urinary cortisol were also measured.
There was no change in mean BCVA. Mean center-subfield macular thickness and subretinal fluid volume reached a nadir at 3 months, and rose to levels that were below baseline by 6 months. The changes in both OCT parameters paralleled changes in serum DHT level. In four patients, center-subfield macular thickness and/or subretinal fluid volume increased following discontinuation of finasteride. In the remaining patient, both OCT parameters normalized with finasteride and remained stable when the study medication was discontinued.
Finasteride may represent a novel medical treatment for chronic CSC. Larger controlled clinical trials are needed to further assess the efficacy of finasteride for the treatment of CSC.
Pilot study to evaluate finasteride for treatment of chronic central serous chorioretinopathy suggests efficacy and tolerability.
Finasteride; Chronic Central Serous Chorioretinopathy; Retina; Optical Coherence Tomography
Ocular Inflammation; Retinal Vasculitis; Sarcoidosis; Gallium Scintigraphy
To determine if optical coherence tomography (OCT) device-type influences clinical grading of OCT imaging in the context of exudative age-related macular degeneration (AMD).
Ninety-six paired OCT scans from 49 patients with active exudative AMD were obtained on both the time-domain Stratus™ OCT system and the spectral-domain Cirrus™ OCT system at the same visit. Three independent graders judged each scan for the presence of intraretinal fluid (IRF) or subretinal fluid (SRF). The degree of grader consensus was evaluated and the ability of the systems to detect the presence of disease activity was analyzed.
Cirrus™ OCT generated a higher degree of inter-grader consensus than Stratus OCT with higher intraclass correlation coefficients (ICC) for all parameters analyzed. A pair-wise comparison of Cirrus™ OCT to Stratus™ OCT systems revealed that Cirrus™-based gradings more frequently reported the presence of SRF and IRF and detected overall neovascular activity at a higher rate (p<0.05) compared to Stratus™-based gradings
The choice of time-domain (Stratus™) versus spectra-domain (Cirrus™) OCT systems has a measurable impact on clinical decision making in exudative AMD. Spectral-domain OCT systems may be able to generate more consensus in clinical interpretation and, in particular cases, detect disease activity not detected by time-domain systems. Clinical trials employing OCT-based clinical evaluations of exudative AMD may need to account for these inter-system differences in planning and analysis.
Age-related macular degeneration; Optical coherence tomography; Clinical trials; neovascularization; anti-angiogenic treatment
Pseudoxanthoma elasticum (PXE) is a systemic disease with characteristic findings on fundus examination. The fundus findings may be difficult to detect with ophthalmoscopy. A case report is described as follows. A PXE patient had subtle retinal findings on fundoscopy that were more prominently seen using a combination of both fundus autofluorescence (FAF) imaging and indocyanine green (ICG) angiography. The fundus features visualized using each of these two modalities appeared different from each other. FAF imaging and ICG angiography may be able to more prominently detect pathology at the level of the retinal pigment epithelium and Bruch’s membrane, respectively. The use of these imaging modalities together may be complementary and useful in the evaluation of patients with PXE.
Angiography; Autofluorescence; Fluorescein; Indocyanine green; Pseudoxanthoma elasticum
To characterize the fundus autofluorescence (FAF) findings in patients with white dot syndromes (WDSs).
Patients with WDSs underwent ophthalmic examination, fundus photography, fluorescein angiography, and FAF imaging. Patients were categorized as having no, minimal, or predominant foveal hypoautofluorescence. The severity of visual impairment was then correlated with the degree of foveal hypoautofluorescence.
Fifty-five eyes of 28 patients with WDSs were evaluated. Visual acuities ranged from 20/12.5 to hand motions. Diagnoses included serpiginous choroidopathy (5 patients), birdshot retinochoroidopathy (10), multifocal choroiditis (8), relentless placoid chorioretinitis (1), presumed tuberculosis-associated serpiginouslike choroidopathy (1), acute posterior multifocal placoid pigment epitheliopathy (1), and acute zonal occult outer retinopathy (2). In active serpiginous choroidopathy, notable hyperautofluorescence in active disease distinguished it from the variegated FAF features of tuberculosis-associated serpiginouslike choroidopathy. The percentage of patients with visual acuity impairment of less than 20/40 differed among eyes with no, minimal, and predominant foveal hypoautofluorescence (P<.001). Patients with predominant foveal hypoautofluorescence demonstrated worse visual acuity than those with minimal or no foveal hypoautofluorescence (both P<.001).
Fundus autofluorescence imaging is useful in the evaluation of the WDS. Visual acuity impairment is correlated with foveal hypoautofluorescence. Further studies are needed to evaluate the precise role of FAF imaging in the WDSs.
To quantify photoreceptor outer segment (PROS) length in patients with diabetic macular edema (DME) using spectral domain optical coherence tomography (OCT), and to describe the correlation between PROS length and visual acuity in this group of patients.
Twenty-seven consecutive patients (30 eyes) with DME.
Three SD-OCT scans were performed on all eyes during each session using Cirrus™ HD-OCT. A prototype algorithm was developed for quantitative assessment of PROS length. Retinal thicknesses and PROS lengths were calculated for three parameters; macular grid (6mm × 6mm), central subfield (1mm), and center foveal point (0.33mm). Intrasession repeatability was assessed using coefficient of variation (CVW) and intraclass correlation coefficient (ICC). Association between retinal thickness and PROS length with visual acuity was assessed using linear regression and Pearson correlation analyses.
Main Outcome Measure
Intrasession repeatability of macular parameters, and correlation of these parameters with visual acuity.
Mean retinal thickness and PROS length were 298-381 μm and 30-32 μm, respectively, for macular parameters assessed in this study. CVW values were 0.75-4.13% for retinal thickness, and 1.97-14.01% for PROS length. ICC values were 0.96-0.99 and 0.73-0.98 for retinal thickness and PROS length, respectively. Slopes from linear regression analyses assessing the association of retinal thickness and visual acuity were not significantly different from zero (p>0.20), whereas the slopes of PROS length and visual acuity were significantly different from zero (p<0.0005). Correlation coefficients for macular thickness and visual acuity ranged from 0.13 to 0.22, while coefficients for PROS length and visual acuity ranged from -0.61 to -0.81.
PROS length can be quantitatively assessed using Cirrus™ HD-OCT. Although the intrasession repeatability of PROS measurements was less than that of macular thickness measurements, the stronger correlation of PROS length with visual acuity suggests that PROS measures may be more directly related to visual function. PROS length may be a useful physiologic outcome measure, both clinically and as a direct assessment of treatment effects.
To evaluate visual acuity outcomes after cataract surgery in patients with varying degrees of age-related macular degeneration (AMD).
A total of 4757 participants enrolled in the Age-Related Eye Disease Study (AREDS), a prospective, multicenter, epidemiological study of the clinical course of cataract and AMD and a randomized controlled trial of antioxidants and minerals.
Standardized lens and fundus photographs, performed at baseline and annual visits, were graded by a centralized reading center using standardized protocols for severity of AMD and lens opacities. History of cataract surgery was obtained every 6 months. Analyses were conducted using multivariate logistic regression.
Main Outcome Measure
The change in best-corrected visual acuity (BCVA) after cataract surgery compared with preoperative BCVA.
Visual acuity results were analyzed for 1939 eyes that had cataract surgery during AREDS. The mean time from cataract surgery to measurement of postoperative BCVA was 6.9 months. After adjustment for age at surgery, gender, type, and severity of cataract, the mean change in visual acuity at the next study visit after the cataract surgery was as follows: Eyes without AMD gained 8.4 letters of acuity (P<0.0001), eyes with mild AMD gained 6.1 letters of visual acuity (P<0.0001), eyes with moderate AMD gained 3.9 letters (P<0.0001), and eyes with advanced AMD gained 1.9 letters (P = 0.04). The statistically significant gain in visual acuity after cataract surgery was maintained an average of 1.4 years after cataract surgery.
On average, participants with varying severity of AMD benefited from cataract surgery with an increase in visual acuity postoperatively. This average gain in visual acuity persisted for at least 18 months.
A retrospective case series was undertaken to evaluate nine eyes of six patients with active CMV retinitis. Patients were evaluated with a comprehensive ophthalmic examination, fundus autofluorescence imaging, and fundus photography. Oral valganciclovir, intravitreal ganciclovir, intravitreal foscarnet, or a ganciclovir implant was administered as clinically indicated.
Clinically significant changes in the concentrations of intraocular cytokines following treatment with intravitreal bevacizumab are described.
Several complications after intravitreal bevacizumab (IVB) treatment have been described including tears of the retinal pigment epithelium and tractional retinal detachment. The etiology of these complications remains unclear. The purpose of this study was to characterize changes in the intraocular levels of inflammatory cytokines after IVB as a possible explanation for these complications.
Twenty-nine patients with proliferative diabetic retinopathy (PDR) undergoing pars plana vitrectomy (PPV) for vitreous hemorrhage (VH) with IVB pretreatment were prospectively enrolled. Aqueous humor samples were taken at the time of IVB pretreatment and approximately 1 week later at the time of PPV. Multiplex cytokine arrays were used to assay 20 different cytokines. Multivariate general linear regression was performed to determine differences in cytokine levels between the two study visits. Proportional hazards regression was performed to determine the relationship between cytokine levels at PPV and postoperative outcomes.
After treatment with IVB, vascular endothelial growth factor (VEGF) concentrations in the aqueous humor decreased (P = 0.0003), whereas the concentrations of IL-8 and transforming growth factor (TGF)-β2 increased after IVB (P < 0.03). The level of IL-8 at the time of PPV was associated with the occurrence of recurrent VH after surgery (hazard ratio, 1.32; P = 0.02).
Alterations in the intraocular inflammatory cytokine milieu occur after IVB injection, possibly as a compensatory mechanism in response to VEGF inhibition. The increased concentrations of inflammatory cytokines after IVB may be clinically significant and may be responsible for some of the complications after IVB.
Hypoxia‐inducible factor (HIF) is a common transcription factor for many angiogenic proteins. Retinal pigment epithelial (RPE) cells are an important source of angiogenic factors in the retina. The expression of HIF, its regulation by proline hydroxylase (PHD) enzymes, and its downstream regulation of angiogenic factors like vascular endothelial growth factor (VEGF) and erythropoietin (EPO) was studied in RPE cells in order to determine some of the molecular mechanisms underlying ischaemic retinal disease.
ARPE‐19 cells were cultured for various times under hypoxic conditions. Cellular HIF and PHD isoforms were analysed and quantified using western blot and densitometry. VEGF and EPO secreted into the media were assayed using enzyme‐linked immunosorbent assay (ELISA). Messenger RNA (mRNA) was quantified using real‐time quantitative reverse transcriptase polymerase chain reaction (qPCR). RNA interference was achieved using siRNA techniques.
HIF‐1α was readily produced by ARPE‐19 cells under hypoxia, but HIF‐2α and HIF‐3α could not be detected even after HIF‐1α silencing. HIF‐1α protein levels showed an increasing trend for the first 24 h while HIF‐1α mRNA levels fluctuated during this time. After 36 h HIF‐1α protein levels declined to baseline levels, a change that was coincident with a rise in both PHD2 and PHD3. Silencing HIF‐1α significantly decreased VEGF secretion. Significant production of EPO could not be detected at the protein or mRNA level.
HIF‐1α appears to be the main isoform of HIF functioning in ARPE‐19 cells. Under hypoxia, HIF‐1α levels are likely self‐regulated by a feedback loop that involves both transcriptional and post‐translational mechanisms. VEGF production by human RPE cells is regulated by HIF‐1α. EPO was not produced in significant amounts by RPE cells under hypoxic conditions, suggesting that other cells and/or transcription factors in the retina are responsible for its production.
diabetic retinopathy; VEGF; erythropoietin; hypoxia‐inducible factor; proline hydroxylase
To employ multiple modality imaging to described patients with type 2 idiopathic macular telangiectasia (IMT) at different disease severity stages so as to characterize and categorize disease progression through the full spectrum of disease phenotypes.
Observational case series.
Twelve patients with type 2 IMT (22 eyes) with type 2 IMT examined with fundus photography, angiography, optical coherence tomography (OCT) imaging, fundus autofluorescence (FAF), and microperimetry (MP) testing in an institutional setting.
Eyes examined by multiple modality imaging were classified into five proposed categories (0–4): Category 0 (fellow) eyes were normal on all imaging modalities. Category 1 eyes had increased foveal autofluorescence on FAF imaging as the only imaging abnormality. Category 2 eyes had increased foveal autofluorescence together with funduscopic and angiographic features typical of type 2 IMT. Category 3 had additional evidence of foveal atrophy on OCT and while category 4 has all the above features plus clinically evident pigment clumping. FAF signal increased in intensity in the foveal region from category 0 through category 3, while category 4 eyes demonstrated a mixed pattern of increased and decreases FAF signal.
The findings here outline a sequence of progressive changes seen with multiple imaging modalities in advancing stages of disease. Increases in foveal autofluorescence is an early anatomical change in type 2 IMT that may precede typical clinical and angiographic changes. Loss of macular pigment density in the fovea and a changing composition of flurophores in the retinal pigment epithelium may underlie these changes in FAF in the fundus.
To evaluate CD4+Foxp3+ regulatory T cell populations in uveitis patients and to determine if T-regulatory cell populations are associated with disease features.
Uveitis patients were evaluated for CD4+Foxp3+ T-regulatory cells by flow cytometry. Systemic and ocular diagnoses, disease activity, and the presence of cystoid macular edema were reviewed. CD4+Foxp3+ lymphocyte percentages were compared for patients with inactive versus active disease, systemic versus ocular diagnoses, and the presence or absence of cystoid macular edema. RT-PCR testing was performed on two patients with extremely low CD4+Foxp3+ cell populations to assess Foxp3 mRNA.
20 patients with intermediate, posterior and panuveitis were evaluated. Mean age was 40.6 years and mean visual acuity was 20/57. CD4+Foxp3+ cell percentages were lower in patients with active uveitis compared to inactive disease (p<0.05). No differences in T-regulatory cells were observed between the other subgroups. Two patients with recalcitrant uveitis who demonstrated <1% CD4+Foxp3+ lymphocytes showed extremely low or absent Foxp3 mRNA.
T-regulatory cells were reduced in patients with active disease compared to inactive patients. Severe depletion of CD4+Foxp3+ T-cells and Foxp3 mRNA in two patients with severe uveitis suggests that loss of T-regulatory cells of uveitis may be a salient feature in certain patients.
Uveitis; Foxp3; regulatory T-cell; cystoid macular edema; intermediate uveitis; posterior uveitis; panuveitis; Wegener’s granulomatosis; sarcoidosis; birdshot retinochoroidopathy
To describe a case of orbital mucosa-associated lymphoid tissue (MALT) lymphoma masquerading as unilateral panuveitis.
Retrospective chart review.
A 53-year-old female patient with unilateral vitritis and exudative retinal detachment refractory to immunosuppressive treatment was eventually diagnosed with orbital MALT lymphoma. Following treatment with radiotherapy and rituximab, the patient's intraocular inflammation and retinal detachment resolved.
Orbital MALT lymphoma can masquerade as refractory unilateral panuveitis with exudative retinal detachment and appears to respond to a combination of radiotherapy and specific B-cell-targeted systemic therapy.
MALT lymphoma; orbital MALT lymphoma; Rituximab; uveitis; masquerade syndrome
To describe tachyphylaxis to intravitreal bevacizumab (IVB) in patients with exudative age-related macular degeneration (AMD).
We retrospectively reviewed the records of 59 consecutive patients treated with IVB at the National Eye Institute over a 14 month period, and identified cases demonstrating loss of treatment efficacy as revealed by spectral domain optical coherence tomography. We defined tachyphylaxis as a loss of therapeutic response to IVB 28±7 days after administration in an eye which had previously demonstrated a therapeutic response in the same time interval.
Five patients (6 eyes) were identified as developing tachyphylaxis following repeated treatment with IVB. High-dose IVB (2.50mg) did not restore therapeutic response in these patients. Bilateral tachyphylaxis to IVB was seen following an episode of unilateral post-injection anterior uveitis. After the first treatment of IVB, the median time taken to develop tachyphylaxis was 100 weeks (range: 31-128 weeks), and the median number of IVB treatments to the development of tachyphylaxis was 8 treatments (range: 5-10).
Tachyphylaxis can occur following long-term intravitreal use of bevacizumab in patients with AMD. The precise mechanism of tachyphylaxis is unclear, but both local and/or systemic factors may be involved.
Age-related macular degeneration; anti-angiogenic treatment; bevacizumab; intravitreal injection; neovascularization; optical coherence tomography; tachyphylaxis; vascular endothelial growth factor
To evaluate macular thickness and volume measurements and their intrasession repeatability in two optical coherence tomography (OCT) systems: the Stratus OCT, a time domain system, and the Cirrus HD-OCT, a spectral domain system (both by Carl Zeiss Meditec, Inc., Dublin, CA), in the context of diabetic macular edema (DME).
Thirty-three eyes of 33 diabetic patients with clinically significant macular edema (CSME) were scanned in a single session by a single operator on both OCT systems. Macular thickness measurements of nine standard macular subfields and total macular volume were obtained and analyzed. Bland-Altman plots were constructed to assess agreement in macular measurements. Intraclass correlation coefficients (ICCs), coefficients of repeatability (CRW), and coefficients of variation (CVW) were used to assess intrasession repeatability.
Macular thickness in nine retinal subfields and macular volume were significantly higher in the Cirrus HD-OCT system compared with the Stratus OCT system. Subfield thickness and total volume measurements, respectively, were 30 to 55 μm and 3.2 mm3 greater for the Cirrus HD-OCT system compared with the Stratus OCT system. Both Stratus OCT and Cirrus HD-OCT systems demonstrated high intrasession repeatability, with overlapping ranges for CRW, CVW, and ICC. Repeatability measures (CRW and CVW) differed significantly between systems in only one of nine subfields (outer temporal subfield).
Absolute measures of macular thickness and volume in patients with DME differed significantly in magnitude between the Stratus OCT and Cirrus HD-OCT systems. However, both OCT systems demonstrated high intrasessional repeatability. Although the two systems may not be used interchangeably, they appear equally reliable in generating macular measurements for clinical practice and research.
Although myelin autoimmunity is known to be a major factor in the pathogenesis of multiple sclerosis (MS), the role of nonmyelin antigens is less clear. Given the complexity of this disease, it is possible that autoimmunity against nonmyelin antigens also has a pathogenic role. Autoantibodies against enolase and arrestin have previously been reported in MS patients. The T-cell response to these antigens, however, has not been established.
Thirty-five patients with MS were recruited, along with thirty-five healthy controls. T-cell proliferative responses against non-neuronal enolase, neuron-specific enolase (NSE), retinal arrestin, β-arrestin, and myelin basic protein were determined.
MS patients had a greater prevalence of positive T-cell proliferative responses to NSE, retinal arrestin, and β-arrestin than healthy controls (p < 0.0001). The proliferative response against NSE, retinal arrestin, and β-arrestin correlated with the response against myelin basic protein (p ≤ 0.004). Furthermore, the proliferative response against retinal arrestin was correlated to β-arrestin (p < 0.0001), whereas there was no such correlation between non-neuronal enolase and NSE (p = 0.23).
There is accumulating evidence to suggest that the pathogenesis of MS involves more than just myelin autoimmunity/destruction. Autoimmunity against nonmyelin antigens may be a component of this myriad of immunopathological events. NSE, retinal arrestin, and β-arrestin are novel nonmyelin autoantigens that deserve further investigation in this respect. Autoimmunity against these antigens may be linked to neurodegeneration, defective remyelination, and predisposition to uveitis in multiple sclerosis. Further investigation of the role of these antigens in MS is warranted.
Enolase; arrestin; multiple sclerosis (MS); T lymphocytes; autoimmunity
To characterize foveal atrophy in a heterogeneous group of uveitis patients using clinical findings and high-definition optical coherence tomography (HD-OCT).
Cross-sectional, retrospective case series.
HD-OCT scans of 140 patients seen in a tertiary referral center were reviewed and 23 patients (33 eyes) with foveal atrophy were identified. All patients with foveal atrophy were diagnosed with intermediate uveitis, posterior uveitis, or panuveitis. The status of the photoreceptor layer as visualized with HD-OCT was associated with significant differences in mean visual acuity (p<0.0001). Clinical findings associated with foveal atrophy included atrophy of the retinal pigment epithelium (RPE) and/or choroid (91%), macular ischemia (39%), cystoid macular edema (15%), choroidal neovascularization (12%), retinal detachment involving the macula (6%), and serum antiretinal antibodies (6%).
Foveal atrophy can be a complication of intraocular inflammation in a variety of uveitic syndromes. The etiology of foveal atrophy is multi-factorial and may include dysfunction and atrophy of the RPE and/or choroid, cystoid macular edema, macular ischemia secondary to occlusive retinal vasculitis, choroidal neovascularization, retinal detachment, and possibly antibody-mediated damage directed against photoreceptors. Careful observation of the photoreceptor layer using HD-OCT may help to identify patients who are at risk for visual loss secondary to foveal atrophy.
The ocular pathology of autoimmune retinopathy is demonstrated in a 62-year-old female patient with systemic lupus erythematosus (SLE) who presented with typical clinical autoimmune retinopathy. Macroscopically, there were multiple depigmented lesions in the peripheral retina and choroid and scattered pigmentary bone-spickling at the equator and periphery. Microscopically, there were generalized loss of photoreceptors and thinning of the outer plexiform layer. Many peripheral retinal vessels were sclerotic and occluded, some surrounded by pigment granules and RPE cells. Cobblestone degeneration was prominent in the periphery. Macrophages were seen in the retina, particularly in areas of photoreceptor degeneration. Rare, scattered T- lymphocytes were present in the retina and choroid, while B-cells were notably absent. The optic nerve showed loss of axons and thickened septae. Serum autoantibodies against normal retinal nuclei were detected. These pathological changes represent both known SLE-associated ocular complications as well as possible features of autoimmune retinopathy secondary to SLE.