25 Noninfectious Chorioretinal Inflammatory Conditions
Numerous types of noninfectious posterior segment ocular inflammation exist. Most are thought to be autoimmune in nature. Infectious uveitis, toxicity reactions, and cancer, especially primary intraocular lymphoma, can masquerade as noninfectious uveitis and are essential to identify early because specific treatment of these diseases is critical to optimize outcomes. The remaining noninfectious, non-neoplastic causes are all treated with systemic and/or local inhibition of the immune response. This chapter outlines commonly used treatment approaches for posterior segment ocular inflammatory disease, starting with intermediate uveitis and then examining approaches to self-limiting, acute, and chronic posterior segment inflammation. Although beyond the scope of this chapter, a broad familiarity with the many types of noninfectious posterior segment uveitides is required to avoid improper treatment of masquerading conditions and to treat with therapy that is adequate while avoiding unnecessary side effects. Our goal is to provide an outline of the most commonly used treatment modalities.
The mainstay of therapy for uveitis remains corticosteroids. 1 Topical steroids are the first-line approach to anterior uveitis, but are better used as adjunctive therapy for intermediate or posterior inflammation. Periocular corticosteroids are useful in the treatment of intermediate uveitis and uveitic macular edema. Many patients will require systemic immunosuppression to control their inflammation. This can be a short course of high-dose corticosteroids to control acute, severe inflammation or, in patients with chronic inflammation, systemic corticosteroids may be required initially to control the symptoms followed by long-term corticoid-sparing immunosuppression. As a general rule, systemic corticosteroids must be used in limited amounts, if they are to be used chronically, due to systemic side effects. The American College of Rheumatology, for example, recommends that prednisone not be used at doses higher than 10 mg/day for over 2 months. 2 , 3 In patients in whom systemic immunosuppression is relatively contraindicated (unilateral disease, patient intolerance to immunosuppressants), sustained release corticosteroid implants are available. These therapeutic options are discussed in detail later.
25.2 Intermediate Uveitis
Intermediate uveitis is a noninfectious entity of unknown etiology that affects otherwise young, healthy individuals, typically between the ages of 5 and 65 years. 4 Most patients with intermediate uveitis present with reduced visual acuity and floaters. Reduced visual acuity may be caused by cystoid macular edema (CME), cataract, vitreous opacities, and rarely vitreous hemorrhage and rhegmatogenous retinal detachment. Most cases tend to be asymmetric at presentation but often become symptomatically bilateral with time. Men and women are affected equally. There is no racial predilection. Intermediate uveitis is associated with multiple sclerosis. 5 , 6 Up to one-fourth of patients with multiple sclerosis may have intermediate uveitis with retinal venous sheathing. However, among patients with intermediate uveitis, fewer than 15% have a demyelinating disorder resembling multiple sclerosis. 6 , 7 Diagnosis is based on clinical manifestations of vitritis, CME, and pars plana snowbank, the pathognomonic sign of intermediate uveitis (Fig. 25-1 and Fig. 25-2). The main findings on optical coherence tomography (OCT) are related to uveitic CME, consisting of retinal thickening, intraretinal fluid, and subretinal fluid (the latter appearing especially in the initial phases of inflammation). 8 , 9 , 10 Anterior segment manifestations may include variable amounts of anterior chamber flare and cell. Children with intermediate uveitis may have episodes of acute fibrinous iridocyclitis. There may be evidence of posterior synechiae, particularly in children. End-stage cases of intermediate uveitis may be associated with rubeosis. Posterior subcapsular cataracts are the most common anterior segment complication of intermediate uveitis. Glaucoma can occur but is uncommon. 11
Intermediate uveitis is a chronic disease and occasionally may have a mild course. Therefore, to optimize the risk–benefit ratio of the various treatments, therapy has traditionally been approached in a logical, stepwise fashion and initiated when the visual acuity drops to 20/40 level or worse. Corticosteroids are the treatment of choice for intermediate uveitis. They may be used in a periocular fashion or systemically. Topical corticosteroids can help control anterior segment inflammation, but alone will not typically have any significant effect on vitritis or CME. Periocular injections of 40 mg of triamcinolone given up to every 2 weeks and repeated four times in each eye may be an adequate first course to control intraocular inflammation. This is the preferred route of treatment for children with intermediate uveitis. Systemic corticosteroids may be utilized at 1 mg/kg daily with a taper based on response for intraocular inflammation and CME. Treatment with systemic corticosteroids may be required for 6 or more months. The side effects of both oral and periocular corticosteroids are well known and are not discussed here. 1
If corticosteroids do not control inflammation or are not tolerated by the patient, cryoretinopexy of the snowbank may be performed. Cryopexy using a double freeze–thaw technique over the snowbank with one freeze width of treatment extension into normal retina and uninvolved ciliary body may be performed. Complications may include progressive inflammation posterior to the area of cryopexy, vitreous hemorrhage, tractional retinal detachments, and hypotony. 4 , 12
In cases of recalcitrant intraocular inflammation or inability to lower steroid dose to an acceptable level, systemic steroid-sparing immunosuppressive therapy may be utilized. Systemic methotrexate, cyclosporine, azathioprine, or anti–tumor necrosis factor (TNF) biologics in low doses may be utilized in conjunction with systemic corticosteroids to gain control of chronic intraocular inflammation and chronic CME. Intravitreal injections with triamcinolone, sustained-release dexamethasone, or anchored fluocinolone implant in severe cases are often successful in treating CME, but almost always result in cataract and often in ocular hypertension or even glaucoma. 13 , 14
The retinal complications of intermediate uveitis can be difficult to manage. Panretinal laser photocoagulation is typically used to promote regression of retinal or disc neovascularization. 12 Traction retinal detachments that do not involve the macula may be followed up closely for signs of progression. If macular involvement does occur, pars plana vitrectomy surgery (combined with scleral buckling surgery if a rhegmatogenous component is present) should be considered. The presence of active intraocular inflammation increases the risk for proliferative vitreoretinopathy in these patients. 15
Pars plana vitrectomy and lensectomy are often preferred as a treatment for chronic, recalcitrant, intermediate uveitis associated with cataract and CME. The anterior and posterior hyaloid and epiretinal membranes should be removed to relieve retinal traction, and peripheral neovascularization should be treated with intraoperative scatter laser photocoagulation or cryotherapy. This aggressive approach appears to be associated with visual improvement and good long-term visual prognosis, but controlled, prospective data are not available.
Intermediate uveitis has a highly variable course and outcome. Some patients have benign disease that requires little or no treatment. In other patients, particularly children, severe disease develops that can result in blindness and phthisis in one or both eyes. Patients with a benign course and no significant exacerbations are uncommon and account for 10 to 15% of cases. The vast majority, representing about 50% of patients, have a chronic, smoldering course without significant exacerbations. Approximately one-third of cases have a chronic, smoldering course with occasional severe exacerbations. 4 , 16 , 17
The long-term prognosis of untreated intermediate uveitis is not well known. The severity rather than the duration of inflammation appears to be the stronger prognostic indicator of visual outcome. The development of macular complications is associated with a poorer visual prognosis. CME develops more commonly in those patients who have definite pars plana exudates and vitritis. 4 , 16 , 17
25.3 Self-Limiting Posterior Uveitis Often Not Requiring Treatment
Some posterior segment inflammatory disorders such as multiple evanescent white dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), or punctate inner choroiditis (PIC) may not require any treatment. All these entities fall into a group of diseases grouped together as white dot syndromes (Table 25-1 and Table 25-2).
25.3.1 Multiple Evanescent White Dot Syndrome
MEWDS is a well-defined posterior segment inflammatory disease typically presenting with unilateral photopsias and vision loss in young patients with a female predilection. Numerous small white dots are always seen throughout the peripheral retina. Subfoveal retinal pigment epithelium (RPE) changes in the involved eye may lead to central macular stippling, often termed peau d’orange changes. The diagnosis of MEWDS is confirmed by fluorescein angiography (FA) findings of late-phase hyperfluorescent lesions with central hypofluorescence. Indocyanine green angiography (ICG) shows multifocal hypofluorescent lesions (Fig. 25-3). OCT shows focal defects in the ellipsoid zone and RPE alterations in the fovea. 25 This is a self-limited condition that resolves in 4 to 8 weeks and does not require treatment. Rare cases may be recurrent or have features of more aggressive, vision-threatening disease, such as multifocal choroiditis, and require prednisone treatment. 25 , 26 , 27 , 28 , 29 , 30 , 31
25.3.2 Acute Posterior Multifocal Placoid Pigment Epitheliopathy
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a bilateral inflammatory disease that affects the choriocapillaris, RPE, and outer retina. It occurs in otherwise healthy, young adults in the second to third decades of life. There is no gender predilection. A flulike syndrome precedes the onset of ocular disease in about one-third of patients. 32 , 33 Symptoms of myelomeningeal encephalitis, such as meningismus, headaches, and hearing loss, may be seen after the viral prodrome in some patients. 34 , 35 Most patients present with sudden onset of painless visual loss in both eyes. Retinal examination reveals few, if any, vitreous cells and multiple yellow or gray, flat placoid lesions of variable size in the posterior pole. 32 Episcleritis, disc hyperemia, and, rarely, exudative retinal detachment have been reported. 34 , 36 FA demonstrates early hypofluorescence and late hyperfluorescence of the active lesions 32 , 33 (Fig. 25-4). OCT findings include early elevation and disruption in the ellipsoid layer with accumulation of hyperreflective material and subretinal fluid. The ellipsoid layer becomes separated from the RPE with concomitant thickening of the outer nuclear layer. These findings resolve as visual acuity improves. 37
25.3.3 Punctate Inner Choroiditis
Punctate inner choroiditis (PIC) is a rare inflammatory condition affecting the choroid and RPE. It presents in young (median age: 30 years) women (> 90% of the cases) who are myopic (mean refraction: -4.6D). Patients present with photopsias, scotomata, and blurred vision. It is bilateral in 50 to 88% of cases. There is an absence of intraocular inflammation, and fundus examination reveals multiple, small (100–300 µm), white or yellow lesions in the posterior pole (Fig. 25-5). The lesions resolve in a few weeks, progressing into atrophic or hyperpigmented chorioretinal scars. The main vision threatening complication is choroidal neovascularization which has been reported to occur in 69 to 75% of patients, leading to subretinal fibrosis in up to 56% of patients. Acute lesions show disturbances in the sub-RPE space and ellipsoid zone. 38 A study of OCT findings in 35 eyes with inactive PIC demonstrated that half of PIC lesions consisted of focal atrophy of the outer retina and RPE, a third of lesions consisted of sub-RPE hyperreflective deposits, and the remainder consisted of focal RPE elevations with underlying hyporeflective space. 39 Treatment for the inflammatory lesions (mainly with systemic steroids) can be considered if they are very close to fixation, but most lesions resolve with a good visual prognosis. Treatment with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections is recommended for choroidal neovascularization. 40
25.3.4 Acute Posterior Uveitis
Many patients suffer from acute inflammation of the posterior segment. When the pattern of inflammation can be differentiated, often a diagnosis of an acute exacerbation of a chronic disease can be made, for example, a bout of retinitis and vitritis in Behçet’s disease, or a bout of vasculitis in sarcoidosis. The acute exacerbations of the condition are treated as described below and then followed by chronic steroid-sparing treatment as outlined in the next section. Alternatively, some patients may not need chronic immunosuppression and may need only a short course of treatment as detailed in this section.
Corticosteroids remain the mainstay for the treatment of acute uveitis because of their rapid potent effect. Prednisone is the most frequently used oral corticosteroid. Prednisolone, which is the active form of prednisone, can be prescribed in patients with liver dysfunction. Initial therapy is typically 0.5 to 1 mg/kg/day of prednisone followed by a slow taper when the inflammation has been controlled. Corticosteroids should be tapered slowly (over the course of at least 3–4 weeks) to prevent rebound inflammation, except in short 1-week courses used for anterior uveitis. If the disease recurs, a higher dose should be used for another month and slowly tapered again. Initial treatment must be aggressive. In cases of acute vision-threatening inflammation (such as bilateral serous retinal detachment), intravenous methylprednisolone at a dose of 500 to 1,000 mg/day for 3 days may be used, followed by oral corticosteroid therapy. An immunosuppressive drug should be considered if an adequate response in not seen with 2 to 4 weeks of high-dose corticosteroids or if, after 3 months of adequate treatment and taper, the disease in not controlled on less than 10 mg of prednisone a day.
Complications of systemic steroids include altered mood (and, in severe cases, psychosis), systemic hypertension, elevated blood glucose, leukocytosis, hypokalemia, acne, osteoporosis, avascular necrosis of the hip, weight gain, and pancreatitis. Prolonged use in children should be avoided, as delayed growth can be observed even with 0.4 mg/kg of prednisone 41 and may be irreversible. 42 Cataract formation with systemic steroids is dose and duration dependent; 83% of patients will develop cataract if taking corticosteroids (even maintenance doses) for more than 4 years. 43 Blood pressure and blood glucose should be monitored every 3 months, and bone density and cholesterol levels should be checked on an annual basis. Calcium and vitamin D supplementation is advised, as well as weight-bearing exercises.
25.4 Posterior Uveitis Requiring Chronic Treatment
Immunosuppressive drugs should be considered when an unacceptably high dose of corticosteroids is required to control inflammation (i.e., > 10 mg/day of corticosteroids after 3 months) or if there is an inadequate response to high-dose corticosteroids. Additionally, in some diseases, immunosuppressive drugs are indicated at presentation because of poor prognosis when treated with appropriate dose of corticosteroid alone. These include Behçet’s disease with posterior involvement, serpiginous choroidopathy, sympathetic ophthalmia, and birdshot chorioretinopathy. Some authors recommend early treatment with immunosuppressive drugs in multifocal choroiditis with panuveitis and Vogt-Koyanagi-Harada’s (VKH) syndrome. 44
25.4.1 Behçet’s Disease
Behçet’s disease is a systemic disorder that produces occlusive vasculitis in the skin, circulatory system, and central nervous system, including the eyes. 45 Diagnosis of Behçet’s disease is based on the involvement of one or more of these organ systems. The etiology of this disorder is unknown. It tends to affect men more commonly than women. It is particularly common in Japan, Southeast Asia, the Middle East, and the Mediterranean region. 45 Behçet’s disease is associated with panuveitis. The nonocular features of Behçet’s disease can dominate and precede the ocular involvement. Oral aphthous ulcers occur in up to 98% of patients. They typically heal within 1 week and are recurrent. Genital lesions may occur in 80% of patients. Cutaneous lesions occur in up to 90% of patients. Central nervous system involvement is seen in more than 50% of patients. These patients often have no ocular involvement. 46
Patients with ocular manifestations of Behçet’s disease may present with pain, photophobia, redness, and reduced vision. Ocular manifestations occur in up to 70% of patients with Behçet’s disease, but fewer than 25% of patients complain about the manifestation. 46 Hypopyon iridocyclitis is seen in one-third of patients with ocular manifestations. 45 , 46 It is usually transient and is associated with pain, photophobia, and reduced vision. Posterior segment inflammation is marked by retinal vascular sheathing and retinal venous and arteriolar occlusions. Branch retinal vein occlusions with intraretinal hemorrhages, retinal venous sheathing, and associated macular edema are typical and characteristic. However, vision may be more severely affected if concomitant retinal arteriolar involvement is present. In these cases, white necrotic infiltrates of the inner retina may be seen along with intraretinal hemorrhages (Fig. 25-6). Vitritis is variable but can be severe. Recurrent attacks of retinal vasculitis can result in severe ischemia and retinal neovascularization. Ischemic changes and recurrent ocular inflammation causes thinning of the outer retinal layers and loss of the ellipsoid layer in the fovea and throughout the macula on OCT. 47 , 48 Like the nonocular manifestations, the ocular manifestations of Behçet’s disease follow a cyclical course punctuated by exacerbations of uveitis. 45 , 46
25.4.2 Sympathetic Ophthalmia
Sympathetic ophthalmia is a rare, bilateral granulomatous panuveitis that occurs only after penetrating ocular injury or ocular surgery, especially full-thickness, glaucoma-filtering procedures. It occurs in fewer than 1% of patients with penetrating ocular injuries and in 0.01% of patients who have undergone intraocular surgery. 49 , 50 , 51
Inflammation characteristically occurs as early as 4 to 8 weeks following the ocular insult. The interval between the injury and the onset of intraocular inflammation varies. It may be as short as 5 days or as long as 42 years. 49 , 50 , 51 When inflammation develops in the sympathizing eye, patients often present with pain, photophobia, and decreased vision in that eye. The granulomatous anterior segment inflammation manifests with mutton fat keratic precipitates, iris nodules, and anterior chamber cell and flare. In the acute phases of the illness, optic disc edema is present. In the retina, multiple, deep, yellow lesions (Dalen-Fuchs’s nodules) can be seen, particularly in the inferior periphery of the fundus (¦Chapter 32¦, ¦Fig. 32.23¦) (Fig. 25-7). These nodules represent aggregates of epithelioid cells at the level of Bruch’s membrane. Serous retinal detachments may also be present. Serous retinal detachments, cystoid intraretinal fluid with retinal thickening, and irregularity of the ellipsoid layer are common spectral domain optical coherence tomography (SD-OCT) findings. 52 The choroid is greatly thickened and there is RPE undulation proportional to the degree of inflammation, which improves with treatment. 53 Dalen-Fuchs’s nodules are seen as hyperreflective lesions at the level of the RPE with disruption of the ellipsoid layer. 54 Diffuse choroidal thickening from inflammatory infiltrates is a consistent finding, best demonstrated by ultrasonography (see later). Occasionally, cutaneous and neurologic manifestations similar to those of VKH syndrome occur. 50
25.4.3 Vogt-Koyanagi-Harada’s Syndrome
Vogt-Koyanagi-Harada’s (VKH) syndrome is a bilateral granulomatous panuveitis associated with dermatologic and neurologic extraocular manifestations. 55 VKH syndrome affects darkly pigmented races, including Asians, Hispanics, American Indians, Asian Indians, and blacks. 50 , 55 , 56 Female patients predominate, particularly in the Hispanic population, where the female–male ratio is 3:1. 55 The patients are typically between the ages of 20 and 50 when affected, although patients of younger age have been reported with the disease. The extraocular manifestations appear to vary widely between Japanese and Hispanic patients. Hispanic patients do not typically tend to have extraocular manifestations of vitiligo, alopecia, and poliosis. However, they do tend more commonly to have meningismus and cerebrospinal fluid pleocytosis, the neurologic manifestations of the disease. 55 , 56
VKH syndrome can be divided into four distinct phases. 55 The prodromal phase is characterized by a flulike illness associated with meningismus, headache, tinnitus, and dysacusis. Cerebrospinal fluid pleocytosis can occur in this phase. The second, or uveitic, phase is associated with an acute onset of bilateral granulomatous iridocyclitis, vitritis, optic disc edema, and multiple serous retinal detachments. OCT will show the characteristic serous retinal detachments of VKH (Fig. 25-8). These detachments are not continuous, but are made of multilobular pools of subretinal fluid, separated by septa that seem to arise from splitting off of the outer segments of photoreceptors from the inner segments and binding of inflammatory products. 57 Choroidal thickness increases markedly in the acute phase of VKH and decreases quickly after systemic corticosteroid therapy. 58 In long-standing VKH, the choroid is significantly thinner and thickness is inversely correlated with disease duration. 59 Pain, photophobia, and sudden vision loss are common symptoms. This phase lasts for 2 to 6 weeks. The third, convalescent phase, is associated with subsiding uveitis but depigmentation of skin and uveal structures. These manifestations can include vitiligo, poliosis, and diffuse depigmentation of the choroid. Perilimbal vitiligo is called Sugiura’s sign and is often seen along with the development of a “sunset glow” appearance to the fundus. In the absence of depigmentation, the structure of the retina and choroid are preserved. In contrast, eyes with severe depigmentation have significantly thinner choroids on OCT. 60 In the inferior far periphery of the retina, well-circumscribed, white-yellow, punched-out chorioretinal scars, representing resolved Dalen-Fuchs’s nodules, are usually present. This appearance is very similar to that of sympathetic ophthalmia. The final phase is the chronic, recurrent inflammatory phase. This is characterized by recurrent anterior segment inflammation and is associated with the major ophthalmic complications of VKH syndrome, including cataracts, glaucoma, and choroid neovascularization. 55
25.4.4 Serpiginous Choroiditis
Serpiginous choroiditis has also been called helicoid and geographic choroidopathy. It is an acute and chronic recurrent inflammatory disease affecting the RPE, choriocapillaris, and choroid. The name of the disease is derived from the serpentine progression of the choroiditis in the posterior pole. The disease tends to affect men and women equally and manifests between the second and seventh decades of life. It is unilateral or very asymmetric at presentation, but significant involvement of both eyes eventually ensues. 61 , 62 , 63 , 64 , 65
Patients with serpiginous choroiditis usually present with some degree of vision loss and associated central or paracentral scotomas in one or both eyes. There is variable anterior chamber and vitreous cellular reaction, the latter of which is present in about one-third of cases. Active choroiditis appears ophthalmoscopically as well-circumscribed, gray-white, geographically shaped lesions at the level of the RPE and choriocapillaris that involve the peripapillary region or macula of both eyes 61 , 62 , 65 , 66 (Fig. 25-9). Some sensory retinal thickening can usually be appreciated overlying these areas of active choroiditis. OCT typically demonstrates retinal atrophy, subretinal fibrosis, varying degrees of intraretinal fluid, and marked attenuation of the ellipsoid layer. 67
The lesions enlarge over a period of months with progression in a characteristic serpentine fashion from their origin. Activity classically resides at the leading edge of the lesion, and with enlargement, an increasing area of chorioretinal atrophy is left in its wake. With recurrences, the process eventually ends up involving the entire posterior pole. Furthermore, choroid neovascularization can develop in eyes with serpiginous choroiditis at some point in the course of disease, potentially causing further vision loss from the associated exudative changes and subsequent subretinal fibrosis. 61 , 62 , 65