Inflammatory cystoid macular edema Aniki Rothova Purpose of review The aim of this article is to update our current understanding and management of inflammatory cystoid macular edema. Recent findings Cystoid macular edema is a common cause of visual loss in uveitis, which occurs predominantly in older patients with chronic uveitis forms and might be heralded by subclinical changes on optic coherence tomography. Cystoid macular edema is emerging as a major cause of visual loss in HIV-infected patients with immune recovery uveitis. Elevated levels of proinflammatory cytokines and vascular endothelial growth factor were found in all types of cystoid macular edema. Treatment with anti-inflammatory and anti-vascular endothelial growth factor drugs is widely applied for all forms of cystoid macular edema and usually has a beneficial, but temporary effect. So far, there are no clear guidelines for the treatment of subclinical cystoid macular edema in uveitis. The effect of vitrectomy in inflammatory cystoid macular edema is not yet clear and might become more important in the future. Recent advances in management include intravitreal drug delivery systems of cystoid macular edema-modifying drugs. Summary This review summarizes current thoughts on inflammatory cystoid macular edema focusing on the new, clinically relevant findings. Upcoming data on aqueous constituents in cystoid macular edema and imaging with the new generation of optic coherence tomography offer the hope that a better treatment strategy will soon be established. Keywords cystoid macular edema, uveitis Curr Opin Ophthalmol 18:487–492. ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins. Department of Ophthalmology, University Medical Center, Utrecht, The Netherlands Correspondence to Aniki Rothova, MD, PhD, Department of Ophthalmology, University Medical Center Utrecht, E.03-136, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Fax: +31 30 2505417; e-mail: [email protected] Current Opinion in Ophthalmology 2007, 18:487–492 Abbreviations CME CMV IOP IRU IVTA OCT RPE VEGF cystoid macular edema cytomegalovirus intraocular pressure immune recovery uveitis intravitreal triamcinolone acetonide optic coherence tomography retinal pigment epithelium vascular endothelial growth factor ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-8738 Introduction The huge negative impact of inflammatory cystoid macular edema (CME) on visual acuity has become evident in recent years [1,2,3,4]. CME develops regularly in the wake of diverse diseases affecting the inner or outer blood–retina barrier and represents a complication with a final pathway common to all these various disorders [3]. This review focuses on the recent literature about inflammatory CME, its treatment and currently gained insights into its pathogenesis. CME represents a major cause of visual loss in uveitis [1,3]. In a large cross-sectional survey of 581 patients with uveitis, 35% of all uveitis eyes had a visual acuity of 20/60 or less, of which CME had caused 42% [1]. Clinically significant CME developed in 30% of patients with uveitis. The mean visual acuity for eyes with CME was significantly worse than for eyes without CME. Although CME represented the most common cause of visual loss in adults, the most frequent causes of visual loss in children with uveitis were retinal scars and glaucoma [5,6]. In contrast to adult patients, CME does not frequently develop in children. The higher resistance of young tissues to external damage could in part explain this phenomenon [7]. The standard prognosticators of poor visual outcome in uveitic eyes with CME are a prolonged duration of uveitis and of CME itself, a large foveal avascular zone as well as the presence of incomplete vitreous detachment [1,2,3]. Recently, the increased macular thickness on optic coherence tomography (OCT) was also linked to poor outcome and in addition, the advanced age of patients was identified as an independent factor for the early development and poor outcome of CME in uveitis [2,8,9]. Pathogenesis Several hypotheses have been proposed to explain how the diverse diseases may lead to the formation of CME. The initial factors might be entirely different and include mechanical forces, various toxic effects on the retinal cells, vessels and retinal pigment epithelium (RPE) as well as a release or diffusion of inflammatory mediators in the eye. Following these events, the leakage of fluids across the retinal vessel wall and through RPE occurs and leads to the accumulation of fluid in the macular area with a characteristic distribution of fluid usually located in the outer plexiform layer. The inflammatory mediators play probably the essential initiating role in the development of inflammatory CME, but the exact factors and events 487 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 488 Ocular manifestations of systemic disease responsible for further CME development and its chronicity have not yet been identified. Recent progress in aqueous analysis, in particular multiplexed bead immunoassays and proteomics analyses, have facilitated the measurements of intraocular cytokines and chemokines present in uveitis with and without CME [10,11]. So far, these studies have repeatedly shown that elevated intraocular levels of diverse proinflammatory cytokines [12,13,14], specifically vascular endothelial growth factor (VEGF) and IL-6, were correlated with the presence of CME, not only in uveitis [15,16], but also in CME of noninflammatory origins where the intraocular levels of VEGF and IL-6 correlated with the severity of CME [17,18]. In uveitis, CME was not yet linked to a characteristic pattern of intraocular cytokines [16]. It should be taken into account, however, that all previous studies included only a limited number of samples of uveitis from various origins. Future studies containing large numbers of patients and uniform etiologic groups are essential for the further understanding of CME pathogenesis. It is clear that the integrity of the retinal vessels and RPE is essential for the intricate macular functions. The presence of inflammation, however, does not explain the apparent arbitrariness of uveitis patients developing CME. Concurrent cardiovascular disease, hypertension, hyperlipidemia, albuminuria and smoking contributed to the development of CME in diabetes mellitus and vascular occlusions [19]. Not surprisingly, also in uveitis, microalbuminuria and advanced age in patients (independent of the duration of the uveitis) were associated with the presence of CME. Coexisting cardiovascular disease in uveitis was associated with an early onset of CME [2,20]. These observations suggest that the presence of systemic vascular disease in patients with inflammatory CME might be a predisposing factor for the (early) development of CME [21]. It might be possible that a vascular wall already damaged by whatever means induces a higher vulnerability to further pathogenic stimuli such as a release of inflammatory mediators in uveitis. Three months’ use of angiotensin-converting enzyme inhibitor (10 mg lisinopril), however, had no effect on chronic CME although the effect on hypertension and microalbuminuria was noted [21]. Several drugs may induce CME, including the topical applications of prostaglandin analogues, the systemic use of nicotinic acid, zidovudine and rifabutin. Clinical manifestations The clinical features of CME are well known [3]. Recently, contrast sensitivity, reading acuity and reading speed were recognized as more impaired functions than distance visual acuity [4,22]. These observations suggest that contrast sensitivity and reading functions might become important parameters when following patients with CME and evaluating the treatment regimens. Yellow tinted filters gave a slight improvement in contrast sensitivity and visual acuity in uveitic CME [22]. According to anatomical types, intermediate and panuveitis had the highest frequency of CME (60 and 66%, respectively); panuveitis was associated with a more severe CME with poor visual outcome [1]. Specific uveitis entities linked to the frequent development of CME included birdshot chorioretinopathy, sarcoidosis and acute retinal necrosis. OCT exhibited a persistence of CME in uveitic eyes long after the uveitis has been quiescent and clinical signs of CME disappeared [23,24]. The concurrent optic disc leakage, present also in phakic patients, is of unknown origin and might be in part caused by vitreoretinal traction [2,6,25]. The reliable prognostic factors distinguishing CME eyes with a potential for improvement from the eyes with definitively damaged visual acuity, are not yet known. The beneficial effect of treatment was noted for patients with pinhole and interferometric acuity exceeding the initial Snellen acuity. Poor contrast sensitivity, impaired color vision, chronicity of CME and advanced age of patients were all associated with impaired visual outcomes as well as the macular ischemia and flat OCT indicating thin and atrophic macula. AIDS and cystoid macular edema Cytomegalovirus (CMV) and other opportunistic ocular infections have decreased in the era of highly active antiretroviral therapy (HAART). Patients with regressed CMV retinitis, however, may still lose vision from CME, epiretinal membranes and complications secondary to immune recovery uveitis (IRU) [26,27,28]. Eyes with IRU have a several times higher risk of CME and epiretinal membrane than eyes affected by other types of uveitis. The presence of IRU was associated with the intraocular production of IL-12, whereas in eyes with active CMV elevated levels of IL-6 were found [29,30]. The treatment of CME in IRU is not different from CME in nonHIV infected, even intravitreal triamcinolone acetonide (IVTA) was successfully used [31]. Intraocular infections following IVTA, even a case of CMV retinitis, however, were reported in immunocompetent patients [32]. Diagnostic tests The OCT quickly replaced fluocinolone acetonide as a main (and a less aggressive) diagnostic tool for CME. Moreover, OCT characterized the morphologic changes associated with macular edema, especially the vitreomacular relationship and subclinical serous macular detachment (SMD). SMD, the pathogenesis of which is not yet known, occurred in about 50% of uveitic CME and did not correlate with poor visual acuity [33]. Contradictory findings were published on the association of macular Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Inflammatory cystoid macular edema Rothova 489 thickening and visual acuity [9], which is not surprising as visual acuity depends on diverse factors including the duration of macular edema, and photoreceptor impairment as well as media opacities. The role of the tractional component in uveitic CME has not yet been systematically studied [25]. New generations of OCT will undoubtedly further recognize the vitreomacular adherence changes in uveitis. Treatment of cystoid macular edema There are no official guidelines for the treatment of uveitic CME. The definition of clinically significant CME, frequently used in diabetes mellitus, is essential for comparison studies, but was never an indication for treatment in patients with uveitis. CME responsible for severe decrease of visual acuity will usually be treated, but there is no management consensus for various subclinical CME forms, without significant or any decrease in visual acuity. It is my opinion that, in uveitis, any CME should be carefully followed and eventually treated until disappearance. Since the crucial mechanisms involved in the development and persistence of uveitic CME have not yet been established, the treatment possibilities are limited to anti-inflammatory drugs, carbonic anhydrase inhibitors and the release of traction and removal of possible toxic mediators. In active inflammation, antiinflammatory treatment is imperative. Recent OCT study [8] documented a more rapid decrease of CME with oral administration than with periocular steroid injections, so an initial treatment with oral steroids might be preferred when the rapidity of recovery is essential. In recent years, new administrations of corticosteroids became available and anti-VEGF administration has been embarked on, but so far, significant progress in the treatment of uveitic CME has not been made. The potential role of topical forms of carbonic anhydrase inhibitors on CME in uveitis has not yet been investigated. IVTA used in variable dosages had a short-term effect on CME and improved vision transiently but, despite repeated injections, most patients had no sustained improvement of acuity compared with baseline [34–36]. The side-effect profile of IVTA is significant with corticosteroid-induced intraocular pressure rises. The rate of posterior subcapsular cataract formation is higher than previously reported, and there is a small but potential risk of endophthalmitis [37]. The rise in intraocular pressure is more common in relatively young patients with uveitis than in elderly patients with other reasons for CME, and increases with multiple injections [38]. Intravitreal application of 4 mg triamcinolone in diabetic patients with already abnormal electroretinographic findings showed no additional evidence of a retinotoxic effect [39]. In contrast, benzyl alcohol at concentrations slightly higher than what is present in commercial triamcinolone preparations caused histological changes to retinal elements of the outer retina in rabbits [40]. Therefore the removal of preservatives from commercial preparations of triamcinolone has been recommended before the IVTA application [40,41]. Macular thickness and edema were reduced as early as 1 h after IVTA and this early effect was hypothetically attributed to immediate intraocular pressure (IOP) rise [42,43]. Although the immediate IOP rise may last only for a few minutes, it still may cause damage to fragile retinal structures. Although the guidelines do not recommend routine paracentesis before intraocular injections, the discussion on this topic is still ongoing [44]. Intraocular sustained drug release via implantable devices or injectable microparticles has been investigated for treating uveitis and CME [45,46]. An intraocular sustained release implant containing fluocinolone acetonide has been developed and assessed in a prospective randomized study [47] (278 patients with recurrent noninfectious posterior uveitis) using a 0.59 mg or 2.1 mg fluocinolone acetonide implant. The fluocinolone acetonide implants significantly reduced uveitis recurrences, improved visual acuity, and decreased the need for adjunctive therapy. The most common side effects included increased IOP and cataract progression. Of 110 patients with CME, 25% of implanted eyes had a 3-line or greater increase in visual acuity at 34 weeks. The subsequent complications and infections have already been reported [48]. The dexamethasone drug delivery system (DDS) is composed of a biodegradable copolymer of lactic acid and glycolic acid. As dexamethasone is released, the polymer slowly degrades into carbon dioxide and water. Since the implant dissolves completely, sequential implants can be placed into the eye over time without the need for surgical removal. A single intraocular application of 700 mg of dexamethasone had a good effect on visual acuity at the 3-month follow-up in patients with CME of various origins including nine patients with uveitis [49]. The development of intraocular DDS using a biodegradable implant with CME-modifying drugs might become a preferred treatment for uveitic CME in the future. Surgical treatments for inflammatory cystoid macular edema The advantageous effect of pars plana vitrectomy (PPV) on CME has been regularly reported in the noncontrolled studies; large randomized trials have so far not been performed [50,51]. A randomized pilot study [52] (23 eyes) established that PPV had a beneficial effect on visual function and angiographic findings compared to a slighter effect of systemic treatment with steroids and immunosuppressants. Internal limiting membrane peeling did not affect the vision outcomes in patients with diabetic CME, but was not yet assessed in uveitis [53,54]. Further, a novel surgical technique consisting of cystoid macular edema Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 490 Ocular manifestations of systemic disease puncture was attempted in eight patients with longstanding diabetic or vascular CME refractory to standard treatments. Although an anatomical improvement was noted for all, functional improvement was not observed [55]. Anti-vascular endothelial growth factor, interferons, anti-tumor necrosis factor-a and somatostatin analogues VEGF is a major regulator of angiogenesis and vascular permeability and is strongly implicated in the development of CME of various origins. The anti-VEGF drugs inhibit the breakdown of the blood–retinal barrier and intravitreal applications of bevacizumab were associated with shortterm improvement in visual acuity and decreased retinal thickness in CME of various causes, including uveitis. Unfortunately, the beneficial effect was of short duration [56,57]. The histological and electroretinography studies showed no retinal toxicity after intravitreal administration of bevacizumab in rabbits, but some inflammatory cells were found in the vitreous after the 5 mg intraocular dose [58]. Although several cases of uveitis occurring after bevacizumab injections were reported, no inflammatory response was detected clinically and by the laser flare meter following the 61 injections in patients with neovascular age-related macular degeneration [59,60]. Ranibizumab also showed a beneficial effect in diabetic CME, but in several cases mild to moderate ocular inflammation developed following the injections [61]. Ranibizumab was associated with subsequent development of uveitis from 0.7 to 1.3% [62,63]. Treatment trial [64] with a high dose of vitamin E, which blocks the effector mechanisms of VEGF that lead to vascular permeability, did not find any apparent benefit to either visual acuity or retinal thickening. Interferons are implicated in inducing as well as in treating autoimmunity and reduced intraocular inflammation, especially in Behcet’s disease [65,66]. German studies have shown promising results of IFNa in eight patients with CME and inactive uveitis. Side effects of the IFNa treatment are frequent and include flu-like symptoms, fatigue, hepatotoxicity and psychological disturbances [67]. In addition, a beneficial effect of IFNb on uveitic CME was noted in a retrospective study [68] of 13 patients with multiple sclerosis-associated intermediate uveitis. In contrast, 12 patients undergoing treatment with IFNa for diverse systemic diseases including hepatitis C developed ischemic microangiopathy of the retina and optic nerve several weeks after the start of interferon therapy [69]. Therefore monitoring of interferon therapy by an ophthalmologist, especially of patients with systemic vascular risk factors, was recommended. Anti-tumor necrosis factor (TNF)-a biological agents are considered a major advance in the treatment of noninfectious inflammations and their effect on inflammatory CME is to be expected [70,71]. The place of anti-TNF in the treatment of CME has not yet been identified. Somatostatin analogues such as octreotide may be effective in the treatment of CME by blocking the local and systemic production of growth hormone, insulin-like growth factor and VEGF, which were all associated with angiogenesis and endothelial cell proliferation. Somatostatin is a small neuropeptide that is produced in the central nervous system, where it acts as a neurotransmitter and is also a potent inhibitor of hormone release. In the eye, it is probably being produced by retinal cells [72]. Octreotide resulted in marked improvement or complete resolution of CME in seven of nine uveitic eyes [73]. Conclusion The precise indications and treatment strategies for inflammatory CME have not yet been identified. At present, intraocular sustained drug release via implantable devices or injectable microparticles are being investigated for treating of uveitic CME. With upcoming data on CME pathogenesis using new generation of OCT images and studies of intraocular fluids and tissues it is hoped that a more optimal treatment strategy will soon be established. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 518). 1 Lardenoye CW, van Kooij B, Rothova A. Impact of macular edema on visual acuity in uveitis. Ophthalmology 2006; 113:1446–1449. This study identified CME as a major cause of visual loss in patients with uveitis and reported poor visual outcome of CME associated with the advanced age of the patients, chronic inflammation, and various specific uveitis entities. 2 van Kooij B, Probst K, Fijnheer R, et al. Risk factors for cystoid macular oedema in patients with uveitis. Eye 2006; 6 Oct [Epub ahead of print]. 3 Tranos PG, Wickremasinghe SS, Stangos NT, et al. Macular edema. Surv Ophthalmol 2004; 49:470–490. Kiss CG, Barisani-Asenbauer T, Maca S, et al. 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