Continuing Education Activity

Uveitic macular edema is a complication of acute or chronic uveitis. Characterized by the accumulation of fluid in the retinal layers or the subretinal space, it is the leading cause of visual impairment in cases with uveitis. This activity outlines the evaluation and treatment of uveitic macular edema and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Describe the pathophysiology of uveitic macular edema.
• Explain the common physical findings associated with uveitic macular edema.
• Outline the typical imaging findings associated with uveitic macular edema.
• Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by uveitic macular edema.

Introduction

Uveitis is the inflammation of the uveal tract that may be classified according to the predominant site of inflammation into anterior, intermediate, posterior, or panuveitis (standardization of uveitis: SUN classification).[1]

Uveitic macular edema (UME) is defined as the accumulation of fluid within the retinal layers as cystoid spaces or diffuse retinal thickening or in the subretinal space between the neurosensory retina and retinal pigment epithelium. This results mostly from the breakdown of the blood-retina barrier subsequent to inflammation. UME can be associated with any of the uveitic entities and is the most common cause of diminution in vision in cases with posterior uveitis (around one-third of cases).[2]

Thus early diagnosis and management can be instrumental in preventing long-term ocular morbidity. Uveitis is the cause of legal blindness in around 20% of cases in developed countries.[3]

Etiology

Uveitic macular edema is mostly associated with noninfectious causes of posterior, intermediate, and panuveitis. In patients with anterior uveitis, macular edema is mostly seen in anterior uveitis due to HLA B27, as it has a strong association with the development of macular edema. Otherwise, UME is not common with anterior uveitis. A few infectious disorders also lead to UME.

Common causes of UME include the following:[4]

1. Anterior uveitis: HLA B27, juvenile idiopathic arthritis, idiopathic
2. Posterior uveitis: Birdshot retinochoroidopathy, toxoplasmosis, retinal vasculitis, CMV retinitis, acute retinal necrosis
3. Panuveitis: Vogt-Koyanagi-Harada disease (VKH), sympathetic ophthalmia (SO), Adamantiades-Behcet disease, endophthalmitis, sarcoidosis, multifocal choroiditis and panuveitis, immune recovery uveitis, immunological causes
4. Intermediate aveitis: Pars planitis, sarcoidosis, multiple sclerosis, tuberculosis, Lyme disease
5. Drug-induced: topical medications like brimonidine, metipranolol, prostaglandin analogs, glucocorticosteroids.
6. Systemic: sulfonamides, cidofovir, rifabutin, bisphosphonates, sulfonamides, tumor necrosis factor inhibitors [TNF-a]
7. Irvine–Gass syndrome: macular edema develops after cataract surgery
8. Intraocular tumors: primary CNS or ocular non-Hodgkin lymphoma
9. History of travel
10. Recent administration of immunomodulatory therapy: fingolimod, paclitaxel, taxane[5]

Epidemiology

Uveitic macular edema is mostly seen with posterior uveitis, panuveitis, and intermediate uveitis and less frequently with anterior uveitis. The frequency of ME in patients with anterior uveitis is between 9% and 28%, most commonly associated with HLAB27 anterior uveitis. Intermediate uveitis is most commonly associated with UME found in 20 to 75% of cases. In cases with posterior uveitis, the reported incidence of UME ranges from 19 to 34%. Panuveitis cases have a reported incidence of 18 to 66%.[6][7][8]

In non-infective cases, UME is the commonest sight-threatening complication, as noted in around one-tenth of the patients. This is followed by epiretinal membrane and glaucoma.

Pathophysiology

In the normal anatomical state, the neurosensory retina is attached to the retinal pigment epithelium. This is due to the following reasons:

• Interphotoreceptor matrix
• The cell junction between photoreceptor and retinal pigment epithelium
• The active pumping of fluid from the retina to the choroid by the retinal pigment epithelium

There are two blood-retina barriers present which prevent efflux of fluid in retinal layers: the inner barrier is due to the non-fenestrated endothelium of capillaries secured by zonula occludens, and the outer barrier is due to tight junctions between the retinal pigment epithelial cells, which prevents leakage of fluid from the choroid to the retina.

In the presence of uveitis, there is a breakdown of this blood-retina barrier due to the release of various factors in the presence of inflammation: vascular endothelial growth factor (VEGF), TNF-a, TGF-β, angiotensin 2, IL-1, adenosine, histamine, and glucose. Thus, there is leakage of fluid into the retinal tissue, which forms cystic spaces in the outer plexiform layer, or within all layers of the retina. Defective retinal pigment epithelium function leads to accumulation beneath the neurosensory retina.

Muller cells also maintain the structural integrity of retinal layers and metabolic hemostasis. In the uveitic state, the function is also affected, leading to the release of VEGF and other inflammatory mediators, dysfunction of potassium rectifying channels, and swelling of Muller cells that leads to cytotoxic macular edema. This is also the mechanism of macular edema after surgery as there is an increase in arachidonic acid metabolites that affects Muller cells.

The third cause is the tractional component that leads to stretching of retinal layers and subsequent ooze from the blood vessels and thus edema. Traction can be from the epiretinal membrane or vitreous traction.

History and Physical

When a patient with uveitis complains of a decrease in vision, uveitic macular edema is the most frequent cause. In the early stages, the edema may be subclinical, and there may not be any visual disturbance.[6] Other symptoms of UME are a disturbance in contrast sensitivity, difficulty in reading, metamorphopsia, micropsia, and a positive relative scotoma.

A slit-lamp examination with a 90D or a 78D lens supplemented by biomicroscopy (direct or indirect) is performed. It may reveal an increase in macular thickness, loss of normal foveal reflex, with cystic spaces perceived in a few cases, and an associated epiretinal membrane may be present in some cases. An overlying vitreous haze may be present and surrounding signs of inflammation like vasculitis, chorioretinitis, choroiditis, disc edema, inferior snowballs, snow banking, vitreous traction must be looked for. Cystic spaces and edema are better appreciated using a red-free light. When the edema is subclinical (central macular thickness <300 μm), it is difficult to appreciate it clinically and is diagnosed on the investigations discussed below.[6]

Evaluation

In patients with uveitis with a drop in vision and a clinical suspicion of macular edema, the diagnosis is confirmed by performing optical coherence tomography (OCT) and on fundus fluorescein angiography (FFA). These modalities are also helpful in diagnosing subclinical macular edema.

OCT can reveal the presence of cystic spaces in the outer plexiform layer at the fovea, diffuse retinal thickening, cystic spaces involving all retinal layers, and subfoveal subretinal fluid. One should look at the features of tractional components like the presence of epiretinal membrane and vitreous traction. Underlying choroiditis or surrounding chorioretinitis may also be evident in OCT. This serves as the confirmatory test and gold standard for UME and also helps in the follow up of patients on treatment for resolution or recurrence.[9]

FFA: There can be dilatation of perifoveal capillaries leading to subsequent pooling of dye in the cystoid spaces at the foveola, arranged in petaloid patterns due to the radial arrangement of cells in the outer plexiform layer. Some cases may reveal diffuse leakage of choriocapillaris at the fovea. Enlargement of the foveal avascular zone due to ischemia will affect the vision. There may be dye leakage at the optic disc due to active inflammation. Surrounding signs of active or inactive vasculitis, chorioretinitis, and areas of capillary nonperfusion and neovascularization are also noted.[10]

Treatment / Management

The treatment of uveitic macular edema is initially with steroids, and then it is modified with the help of other drugs depending upon the response of the patient. Following are the treatment options available:[4][11][12]

1. Corticosteroids: These are the mainstay of treatment. Systemic steroids are given for binocular uveitis or uniocular involvement not improving with peri-ocular injections: oral prednisolone 1 to 2 mg/kg is started, which is slowly tapered. Peri-ocular steroids (posterior subtenon or transseptal) may be administered with triamcinolone acetonide (2 to 4 mg/0.1ml). Methylprednisolone acetate (40 to 80 mg) injection is indicated in unilateral cases of UME or where systemic steroids are contraindicated. Intravitreal triamcinolone (2 to 4 mg/0.1ml) or steroid implants are also used in recalcitrant cases. Fluocinolone (590 micrograms) implants slowly release the drug for up to 30 months. Dexamethasone (700 micrograms: duration of effect is around three months) is used quite often when the patient is not responding to periocular injections or for recurrent CME.
2. Topical steroids: Topical steroids do not have much role in macular edema control but can be added to control anterior segment inflammation. Of all the drugs, difluprednate has superior posterior segment penetration.
3. Topical nonsteroidal anti-inflammatory drugs: Though their role has not been effectively proven to control uveitic macular edema, they may have a synergistic action with steroids, e.g., bromfenac and nepafenac eye drops.
4. Immunomodulator agents: Antimetabolites like azathioprine and methotrexate may be used. Azathioprine, a nucleoside analog, interferes with DNA replication and RNA transcription (dose up to 2 mg/kg/day). Methotrexate is a folic acid analog that inhibits dihydrofolate (starting 10 to 15 mg/week gradually increasing to 15 to 25 mg/week). Mycophenolate mofetil is an inosine monophosphate inhibitor (1 to 1.5 grams). Another group is T-cell inhibitors such as cyclosporine, an IL-2 inhibitor (1 to 5 mg/kg/day).
5. Biological agents: These have been used in refractory cases of uveitis associated with UME in consultation with a rheumatologist. These are etanercept (TNF alpha receptor blocker) and infliximab (TNF alpha inhibitor).
6. Intravitreal anti-vascular endothelial growth factor (VEGF): Bevacizumab (1.25 mg/0.05ml) and ranibizumab (0.5 mg/0.05ml) have been used as off-label in the treatment of UME. They have the disadvantage that they do not control inflammation and may sometimes worsen it and have a shorter duration of action. The advantage is that they do not cause glaucoma or cataract. AntiVEGF agents have a definite well-proven role in treating inflammatory choroidal neovascular membranes that can lead to retinal edema.[13]
7. Surgical: Uveitic CME in the presence of hyaloid traction on the macula and the presence of dense epiretinal membranes may require surgical intervention.

Differential Diagnosis

Uveitic macular edema needs to be differentiated from other causes of edema in case of uveitis. These are uveitis secondary to a choroidal neovascular membrane, underlying active choroiditis lesion, and secondary to disc edema. Traction due to the epiretinal membrane or vitreous traction can also lead to edema. The OCT is used for diagnosis as management is surgical.

Prognosis

Patients with uveitis associated with macular edema are at risk of developing severe to profound vision loss. The visual prognosis also depends upon the associated uveitis features. Association with posterior uveitis has the worst prognosis as the lesion and subsequent scarring involves the macula. With newer treatment options as long-acting intravitreal corticosteroid implants and immunomodulatory therapy, the visual prognosis has improved dramatically.[14] It is important to consider the ocular and systemic side effects of long-term steroid therapy and immunosuppressive agents. A decrease in visual acuity <20/60 has been reported in around 35 to 50% of cases due to UME. Other patients may have vision loss due to UME and cataracts.[15]

Complications

If the macular edema persists for a longer duration (more than six months), the retinal architecture can have visually disturbing changes. There may be cyst formation, occurrences of a lamellar hole, or, uncommonly, a full-thickness macular hole, schitic spaces, fibrosis, and scarring both from edema and underlying uveitis. Once fibrosis and scarring occur, visual prognosis is usually poor. Therefore, one should aim at treating edema earlier to prevent long-term sequelae.[16]

Deterrence and Patient Education

Uveitic macular edema is the most common cause of loss of visual acuity in patients with posterior uveitis, panuveitis, and also if there is recurrent or chronic intermediate uveitis or anterior uveitis. In the presence of a progressive drop in vision or perception of metamorphopsia or decreased contrast sensitivity, a detailed ophthalmic assessment is vital. The entity needs timely diagnosis and treatment as long-term persistence can lead to permanent visual disturbance. Confirmatory tests like optical coherence tomography and fundus fluorescein angiography, in addition to routine hematological examinations for diagnosing uveitis, will be needed. Treatment may be in the form of steroids or immunomodulatory therapy; injections may be given in the eye. Rarely one may need surgery.

Enhancing Healthcare Team Outcomes

UME may develop in the acute or chronic phase of the disease. The health care team's responsibility is to make the patient understand that there will be a need for several investigations from an ocular and systemic standpoint before any diagnosis may be made and treatment initiated. The interprofessional team constituting the ophthalmologist, physician, rheumatologist, radiologist, hematologist, optometrist, nurses, and hospital administration need to build a well-chained network for patient investigation and management.

Uveitis may be a manifestation of a systemic disease entity that needs a thorough evaluation by the physician and rheumatologist in conjunction with evidence from imaging and hematology reports. The initiation and long-term continuation of steroid and immunosuppressive therapy, along with the need for alteration in drugs depending on the ocular response, need good teamwork between the ophthalmologist, physician, and rheumatologist. In addition, underlying infective or non-infective conditions need simultaneous treatment to prevent the UME from becoming non-responsive to treatment and turn chronic.