MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity

A new class of chemotherapeutic agents, MEK inhibitors, has recently been developed and is proving to be an effective treatment for a number of cancers. A pattern of ocular adverse events has followed these drugs through clinical trials and their association with retinopathy is only just beginning to be recognized. We present two cases of MEK inhibitor-associated retinopathy followed by a review of the current literature on ocular toxicity associated with MEK inhibitors. Patients undergoing treatment with MEK inhibitors appear to have high rates of multifocal serous retinal detachments as well as retinal vein occlusions. We present the first report of cystoid macular edema associated with MEK inhibitor use. The mechanism of these adverse events is still unclear though they seem to be related to oxidative stress and blood retinal barrier breakdown. Management of the ocular toxicity can range from observation to topical treatments or intravitreal injections. Fortunately most ocular adverse events appear to be self-limited and do not require discontinuing the MEK inhibitor. Discontinuation or decreased dosing of MEK inhibitors may be reserved for cases of severe sight-threatening ocular toxicity.     

Epidemiology of Macular Edema in Uveitis

Purpose: To describe the epidemiology of macular edema (ME) in patients with uveitis.

Methods: Review of articles listed on PubMed pertaining to uveitic ME.

Results: Reported rates of uveitic ME ranging from 20% to 70%, depending on the ancillary tests used (fundus examination, fluorescein angiography, optical coherence tomography). Macular edema might develop due to uveitis itself, or occur as an adverse effect of drugs taken for different diseases. It is more frequently observed in adults than in children, in chronic uveitis, and in intermediate uveitis. Males with ankylosing spondylitis are more prone to develop ME than females. Three patterns of uveitic ME are observed, either isolated or in combination: cystoid ME, the most frequently encountered pattern seen in up to 80% of cases, diffuse ME and serous retinal detachment.

Conclusion: Older age, chronicity of uveitis and intermediate uveitis are risk factors for the development of ME in patients with uveitis.     

Long-term results of treatment of macular complications in eyes with immune recovery uveitis using a graded treatment approach

PURPOSE: To evaluate the results of a graded treatment approach in a cohort of eyes with macular complications of immune recovery uveitis. METHODS: A cohort of 18 eyes of 13 patients representing all eyes with these complications at the University of California, San Diego AIDS Ocular Treatment Unit was studied. Eyes were classified into three groups and treated according to a graded protocol. RESULTS: Eyes with mild disease (macular edema and vision of 20/30 or better) were observed. These six eyes maintained good vision with only one dropping to 20/40. In eyes with worse macular edema and vision of 20/30 or worse (10 eyes of 9 patients), repository sub-Tenon steroid injections were used repeatedly. There were no complications of steroid use but visual improvement occurred in only 40% of eyes. Macular edema persisted. In eyes with structural macular changes, such as epiretinal membrane, vitrectomy resulted in vision improvement in three of four eyes. The cystoid macular edema persisted despite surgery. CONCLUSION: Mild cases of immune recovery uveitis and macular edema may be observed. In eyes with reduction of vision due to cystoid macular edema, there was only a modest treatment effect using repository corticosteroids. Eyes with immune recovery uveitis that develop epiretinal membrane undergo some visual improvement after removal of the membrane. The macular edema of immune recovery uveitis is resistant to corticosteroid treatment.     

光学相干断层扫描在中间葡萄膜炎性黄斑病变中的诊断应用

目的 探讨光学相干断层扫描（OCT）图像在中间葡萄膜炎黄斑病变中的诊断应用。方法 用OCT检测中间葡萄膜炎合并黄斑病变患者17例33只眼并进行资料分析。结果 11例22只眼呈现程度不同的黄斑囊样水肿（CME）特征;3只眼可见黄斑区视网膜前膜增生,同时合并神经上皮层增厚及CME病变;2只眼出现黄斑裂孔;6只眼黄斑区可见玻璃体部分后脱离,并能清晰地显示出玻璃体对视网膜的细小牵引。结论 OCT能客观、精确、有效、方便地对中间葡萄膜炎黄斑病变进行类似病理学的检查。     

Inflammatory cystoid macular edema

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.     

Cataract surgery in patients with retinal disease.

Retinal disease and cataracts frequently are associated with one another. Cataract formation can occur following pars plana vitrectomy and pneumatic retinopexy. Conversely, cataract surgery may exacerbate existing retinal disease, such as diabetic retinopathy, macular degeneration, and uveitis. Finally, cataract surgery can lead to retinal disease de novo, such as cystoid macular edema. A review of the medical literature was performed for all articles published between August 1st, 2000 and July 31st, 2001 on the topic of cataract surgery in patients with retinal disease. The authors selected ten articles that were most relevant to the practicing ophthalmologist for inclusion in this review. Topics of interest included age related macular degeneration, retinal detachment, macular hole, diabetic retinopathy, uveitis, and cystoid macular edema.     

慢性葡萄膜炎黄斑病变的玻璃体手术治疗

目的探讨玻璃体手术对慢性葡萄膜炎合并黄斑病变的治疗价值.方法16例（16眼）反复发作6月以上的慢性迁延性葡萄膜炎,其中合并囊样黄斑水肿6眼,黄斑前膜5眼,玻璃体黄斑牵引综合症4眼,黄斑孔性视网膜脱离1眼,采用玻璃体切除联合人工玻璃体后脱离,内界膜剥离等.术后随访12～30月.结果12眼（75.00%）术后视力明显提高,视力不变或下降4眼为囊样黄斑水肿;视网膜脱离复位;16例术后全身用药减少,炎症得到控制.结论玻璃体手术是治疗慢性葡萄膜炎黄斑病变的有效手段,可以明显提高患者视力,减少全身用药量.     

Ocular side effects of checkpoint inhibitors

The incidence and impact of ocular side effects in patients treated with checkpoint inhibitors are not clearly defined.We reviewed prospective phase III clinical trials of checkpoint inhibitors applied in lung cancer, renal cell cancer, and melanoma. Case reports of the occurrence of ocular toxicities in patients receiving immune checkpoint inhibitors were also included. Of the 35 articles corresponding to phase III clinical trials with checkpoint inhibitors, ocular toxicity was described in four. Forty-six clinical cases of ocular toxicity after therapy with checkpoint inhibitors have been reported. The most frequently described ocular toxicities are uveitis, inflammatory orbital disease, and alterations of the ocular surface. Ocular toxicity is underestimated in checkpoint inhibitors clinical trials. Early ophthalmic examination and treatment with corticosteroids may improve the visual prognosis in these patients.     

曲安奈德玻璃体腔注射治疗难治性黄斑水肿的研究进展

黄斑水肿是造成多种眼病视力丧失的常见原因。尽管传统药物治疗、激光以及玻璃体手术有不同程度的疗效,但黄斑水肿的治疗还存在诸多问题。近年来有关玻璃体腔注射曲安奈德治疗黄斑水肿的研究成为热点。对曲安奈德的药物动力学、眼内毒性、注射方法、治疗效果以及不良反应等进行综述。     

Macular edema

Macular edema is the final common pathway of many intraocular and systemic insults. It may develop in a diffuse pattern where the macula appears generally thickened or it may acquire the characteristic petaloid appearance referred to as cystoid macular edema. Although macular edema may be associated with protean underlying conditions, it is most commonly seen following intraocular surgery, venous occlusive disease, diabetic retinopathy, and posterior segment inflammatory disease. As well as clinical suspicion, a wide range of investigations may lead to the diagnosis of macular edema. Fluorescein angiography and optical coherence tomography provide enhanced visualization of the geometry and distribution of macular edema. A variety of approaches to the treatment of macular edema have been attempted, with a variable degree of success. These options have included topical and systemic steroids, topical and oral non-steroidal anti-inflammatory agents and laser photocoagulation treatment. More recently other therapeutic modalities, including immunomodulators, intravitreal injection of triamcinolone, and pars plana vitrectomy have also been employed. Clinical trials are currently looking into the use of a steroid slow-release intravitreal device for the management of macular edema secondary to uveitis and diabetes. This article reviews the clinical entity of macular edema focusing on the current therapeutic strategies for its management.     

葡萄膜炎合并黄斑囊样水肿的临床表现和治疗

目的 探讨后葡萄膜炎患者并发黄斑囊样水肿(CME)的发生频率 、临床表现和荧光素眼底血管造影(FFA)特征。 方法 自2002年7月至200 5年6月，连续收集在我院行FFA检查的各类后葡萄膜炎患者67例106只眼，观察CME的临床表现、FFA特征和治疗效果。 结果 有18例患者28只眼(26.4%)出现CME改变 。男7例，女11例，平均年龄（42.5±10.8）岁。FFA早期表现为黄斑区水肿遮挡脉络膜荧光而呈片状暗区，随之出现点片状渗漏，静脉期可见毛细血管扩张渗漏，后期可见荧光素蓄积在黄斑区各个小囊腔内，形成特有的花瓣状外观。18例患者分别给予糖皮质激素、非甾体抗 炎药和碳酸酐酶抑制剂治疗后，黄斑水肿程度减轻，视力有不同程度改善。 结论 葡萄膜炎是一种严重影响视功能的眼病，其中CME明显致视力损害。早期发现和及时干预，可防止发生永久性视力损害。 (中华眼底病杂志， 2006， 22：394-396）     

Managing cystoid macular edema after cataract surgery

Cystoid macular edema (CME) is a common problem after cataract extraction. It can occur after uncomplicated surgery in patients with otherwise healthy eyes, after complicated surgery, or after surgery in patients with ocular diseases such as uveitis or diabetic retinopathy. Usually vision loss from cystoid macular edema is temporary and responds to treatment with topical anti-inflammatory medications. However, some cases respond poorly to conservative treatment and may develop permanent visual loss. A review of the medical literature was performed for all articles published in English between August 1, 2001 and July 31, 2002 on the topic of cystoid macular edema after cataract surgery. The authors selected nine articles that were most relevant to the practicing ophthalmologist for inclusion in this review. Topics of interest included vitreous loss, retained lens fragments, diabetes, uveitis, retinitis pigmentosa, ocular hypotensive lipids, internal limiting membrane peeling, and intravitreal triamcinolone injection.     

Aqueous humor and plasma vascular endothelial growth factor in uveitis-associated cystoid macular edema.

PURPOSE: To determine the association between cystoid macular edema and vascular endothelial growth factor concentration in the aqueous humor and plasma of uveitis patients. METHODS: Cross-sectional study. Vascular endothelial growth factor concentrations were measured by enzyme-linked immunosorbent assay in the aqueous humor of 20 uveitis patients (9 with and 11 without cystoid macular edema), and in the plasma of 40 uveitis patients (20 with and 20 without cystoid macular edema) and 20 healthy volunteers. RESULTS: Mean aqueous humor vascular endothelial growth factor concentrations for uveitis patients with and without cystoid macular edema were 152.3 and 109.5 pg/ml, respectively, P =.044. Mean plasma vascular endothelial growth factor concentrations in uveitis patients with and without cystoid macular edema and in healthy volunteers were 32.2, 29.6, and 55.0 pg/ml, respectively. Uveitis patients had lower plasma vascular endothelial growth factor levels than did healthy volunteers, P =.0002. CONCLUSION: In uveitis patients, vascular endothelial growth factor concentration is increased in the aqueous humor of eyes with cystoid macular edema. It may be useful to investigate vascular endothelial growth factor antagonists as a treatment for uveitis-associated cystoid macular edema.     

不同剂量IVTA治疗葡萄膜炎黄斑囊样水肿的疗效观察

目的:观察两种不同剂量曲安奈德玻璃体腔注射(intravitreal triamcinolone acetonide,IVTA)治疗葡萄膜炎黄斑囊样水肿的效果,并对其治疗结果和并发症情况进行比较。方法:分析研究2010-01/2012-01在我院确诊为双眼葡萄膜炎黄斑囊样水肿的患者6例12眼,每例患者双眼随机分为A,B两组进行曲安奈德玻璃体腔注射治疗,A组玻璃体腔注射4mg曲安奈德,B组玻璃体腔注射2mg曲安奈德。术后观察两组视力、眼压、黄斑中心凹厚度、晶状体透明度以及葡萄膜炎复发等。数据比较采用配对t检验。结果:术后视力均有大幅提高,术后OCT显示12眼(100%)黄斑囊样水肿均消失,黄斑中心凹厚度减低,与术前相比差异有统计学意义(P<0.01)。术前与术后两组间视力、黄斑区厚度相比差异无统计学意义(P>0.05)。两组术后各出现眼压升高3例3眼(50%),A组药物控制后眼压平均为44.33±7.51mmHg,B组为23.33±2.52mmHg,术后两组间眼压差异有统计学意义(P=0.01)。2例患者双眼随访期间发生并发性白内障,2例患者双眼葡萄膜炎黄斑囊样水肿复发。结论:IVTA是治疗葡萄膜炎黄斑囊样水肿的有效方法。并发症有眼压升高和并发性白内障。玻璃体腔注射4mg和2mg曲安奈德治疗葡萄膜炎黄斑囊样水肿的疗效相同,后者眼压升高的并发症易于应用药物控制。     

Uveitis bei multipler Sklerose

The association of uveitis and multiple sclerosis (MS) is less well known than the association between optic neuritis and MS even though MS patients suffer ten times more often from uveitis than the normal population. In this group of patients, intermediate uveitis presenting with periphlebitis and “snowbanks” or “snowballs”, as well as granulomatous anterior uveitis play an important role. Simultaneous occurrence of MS and uveitis could be due to the fact that both neural and ocular tissues have the same embryological origin or could be the consequence of an immunological reaction following an Epstein-Barr virus infection. The aim is to find a drug for these patients that treats both MS and uveitis. Currently various studies with different drugs already used successfully in MS patients are under investigation for use in the treatment of uveitis. There is some evidence that interferon beta is effective in macular edema associated with uveitis. Other substances, such as daclizumab, natalizumab and fingolimod also seem to be promising.     

Fluorescein angiography findings in intermediate uveitis

The present paper describes the results of angiographic examinations of 48 eyes (29 patients) with intermediate uveitis. More than 50% of the cases displayed pathologic changes of the retinal blood vessels, such as increased fluorescein staining of the vessel walls and leakages of the retinal veins or venules, respectively. Some 20% of the eyes manifested cystoid macular edema and/or edema of the optic disk which had gone undetected by ophthalmoscopy. These findings suggest that vascular changes may play a role in the pathogenesis of intermediate uveitis. The question as to whether this disease might be caused rather by retinal vasculitis than by uveitis is discussed.     

The role of carbonic anhydrase inhibitors in the management of macular edema

Medical treatment of cystoid macular edema (CME) with carbonic anhydrase inhibitors has been known for over a decade. Initial observations were based on experimental data which suggested that acetazolamide can increase fluid absorption across the retinal pigment epithelium. Carbonic anhydrase inhibitors (CAI) have also been shown to have other direct effects both on retinal and retinal pigment epithelial cell function by inducing an acidification of the subretinal space, a decrease of the standing potential as well as an increase in retinal adhesiveness. It is thought that acidification of the subretinal space is finally responsible for the increase in fluid resorption from the retina through the RPE into the choroid. Several clinical studies have suggested that patients with cystoid macular edema due to retinitis pigmentosa and uveitis may react more favorably to CAI treatment than other etiologies such as diabetic maculopathy or macular edema after retinal vein occlusion. The present working hypothesis is that diffuse leakage from the RPE responds more readily to CAI treatment than leakage from retinal vessels. This may be due to the modulation of membrane- bound CA IV in the RPE which may have lost its polarised distribution in the presence of macular edema. A normal clinical starting dose of CAI is 500 mg/day which should be continued for at least one month to see an effect. This dose may be reduced by the patients over the course of therapy. Metaphylaxis to the drug may occur with a rebound of the edema despite continuation of treatment. This revised version was published online in July 2006 with corrections to the Cover Date.     

Interferon alpha 2b in the Treatment of Uveitic Cystoid Macular Edema

Purpose: To determine the efficacy of interferon alpha 2b in the treatment of refractory, uveitic cystoid macular edema (CME).

Methods: Retrospective chart review of 4 patients attending the uveitis clinic at the Casey Eye Institute, Oregon Health & Science University.

Results: All 4 patients had uveitis and refractory CME, resistant to a variety of immunosuppressants. All patients, except one with severe scleral thinning, had tried and failed therapy with locally injected corticosteroids. Treatment with systemic interferon alpha 2b produced dramatic improvement in CME (central macular thickness: 563 to 267?µm, p?=?.002) and visual acuity (logMAR: +0.81 to +0.45, p?=?.0004) in all 4 cases. All patients have been able to reduce the interferon dosage, but none has discontinued it completely. All patients had some mild adverse response that did not necessitate stopping therapy.

Conclusions: Interferon alpha 2b is an effective option to treat refractory CME secondary to uveitis.     

Corneal endothelial cell loss, cystoid macular edema, and iris-supported intraocular lenses

Endothelial cell loss, persistent cystoid macular edema and a chronic low-grade uveitis may complicate intracapsular cataract extraction combined with iris supported intraocular lenses. Clinical examination of 19 eyes of 17 patients, at 1.1 to 5 years after cataract surgery, and correlation with wide field specular microscopy and fluorescein angiography, documents this problem. The mean central corneal endothelial cell count was 497 cells/mm2 (standard deviation, 119). In ten cases, focal edema was localized to the corneal periphery. Cystoid macular edema was present in all but one case. Intermittent cornea/implant touch or low-grade intraocular inflammation, possibly from iris/implant contact, may explain the natural history of the endothelial cell loss and cystoid macular edema. Monitoring endothelial cell counts and macular function in patients with iris-supported implants may afford the early recognition of this problem. In such cases, early implant removal may alter the natural history and preserve corneal and macular function.     

Disease of the Year: Differential Diagnosis of Uveitic Macular Edema

Uveitic cystoid macular edema (UME) is an important cause of visual morbidity among patients with both infectious and non-infectious uveitis. UME may be associated in more than 30% cases of active uveitis. However, even patients with minimal features of intraocular inflammation may develop recurrent or chronic UME. Therefore, the evaluation and management of UME in patients with uveitis may be challenging. A number of vitreoretinal pathologies may result in UME and accumulation of fluid in the intra- or subretinal space. These need to be carefully distinguished from each other so that appropriate management can be initiated. All types of uveitis, including anterior uveitis (where the primary site of inflammation is not in the posterior segment) can present with UME. Other conditions such as diabetes, and surgery, can present with macular edema. This index review highlights various differential diagnoses of UME and provides illustrative case examples with multimodal imaging evaluation.