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Diagnosis is based on the anatomic location of ocular inflammation: vitreous and peripheral retina with macular edema.
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Frequently associated with a systemic or infectious disease.
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Pars planitis is a subtype of intermediate uveitis.
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Complications include macular edema, epiretinal membrane, vitreous hemorrhage, retinal detachment, and glaucoma.
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Treatment involves corticosteroids, immunosuppressive agents, or biologics.
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Cryoretinopexy and vitrectomy my be beneficial for some patients.
Intermediate uveitis is a diagnosis based on the anatomic location of ocular inflammation; it is not a distinct clinicopathologic condition. The diagnosis of intermediate uveitis is made when ocular inflammation primarily involves the vitreous and peripheral retina. Intermediate uveitis was first described as chronic cyclitis by Fuchs in 1908. The clinical description of intermediate uveitis was further elucidated by Schepens in 1950, when he described patients with a peripheral uveitis characterized by inflammation centered around the vasculature and exudative changes in the retinal periphery. In 1960, Brockhurst and colleagues described additional patients with peripheral vascular abnormalities and an exudate along the ora serrata and pars plana, and Welch and colleagues used the term pars planitis to describe an inflammation characterized by the white accumulation on the pars plana. Other terms used in the literature to describe patients with intermediate uveitis include vitreitis, peripheral exudative retinitis, cyclochorioretinitis, chronic posterior cyclitis, and peripheral uveoretinitis. Unfortunately, there is still confusion and controversy, even among uveitis specialists, on how to classify patients with this anatomic distribution of intraocular inflammation. Grouping conditions with the anatomic features of intermediate uveitis does provide value as it helps with developing a differential diagnosis and in determining response to therapy and long-term prognosis.
We use the term intermediate uveitis, as suggested by the International Uveitis Study Group, to classify patients with intraocular inflammation predominantly involving the vitreous and peripheral retina. Some specialists use this diagnosis only if a more specific diagnosis cannot be made. Specific diseases such as sarcoidosis and multiple sclerosis are known to cause an intermediate uveitis, and we will often classify patients as having an intermediate uveitis associated with sarcoidosis or associated with multiple sclerosis, when an underlying disease can be identified. The reason for this is that diseases like sarcoidosis can also present with other manifestations, such as a predominant retinitis, and these patients will respond differently to therapy. We also use the term pars planitis to describe a subset of patients with intermediate uveitis when a white opacity (commonly called a snowbank) occurs over the pars plana and ora serrata. Although pars planitis probably does not represent a clinical entity distinct from intermediate uveitis, patients with pars planitis often have worse vitreitis, more severe macular edema, and a worse prognosis than patients with intermediate uveitis who do not have a pars plana exudate.
Epidemiology
Intermediate uveitis accounts for approximately 4–8% of cases of uveitis in a referral practice. In approximately 15% of patients with uveitis referred to us at the National Institutes of Health (NIH), intermediate uveitis is diagnosed. In a retrospective, population-based cohort study the incidence of pars planitis was 2.077 per 100 000 persons (95% confidence interval, 1.43–2.62). Although the incidence of uveitis in children is low, intermediate uveitis may account for up to 25% of cases. Intermediate uveitis has been reported in both young children and the elderly, but it tends to mostly affect people in their teens to their 40s. There appears to be no gender or race predilection.
There have been occasional reports of intermediate uveitis occurring in families, suggesting that either hereditary or environmental factors may predispose one to develop the disease. HLA associations have been identified in patients with multiple sclerosis and intermediate uveitis, but there is debate about whether there are other HLA haplotypes associated with intermediate uveitis. In 1963, Kimura and Hogan first reported multiple family members with intermediate uveitis. There are only about 20 instances of familial intermediate uveitis of which we are aware, and a number of these have been reported. In one instance of familial pars planitis, the two affected brothers were not twins but had identical HLA haplotypes. There have also been cases of intermediate uveitis of the pars planitis subtype in identical twins. Some of the familial occurrences of intermediate uveitis are associated with demyelinating disease. , Studies have indicated a possible association of intermediate uveitis with HLA-A28, HLA-DR15, HLA-DR51, and HLA-DR17 haplotypes.
Clinical manifestations
Most patients present with blurred vision and/or floaters. Pain and photophobia are rare. Early in the course of the disease, visual acuity is often reduced to the 20/40 range as a result of a moderate vitritis and cystoid macular edema. However, if inflammation is not well controlled severe visual loss can ensue, associated with chronic cystoid macular edema, glaucoma, inflammatory changes in the retina, and retinal detachment. We have seen sudden loss of vision in several patients after vitreous hemorrhage. Bilateral involvement is seen in 70–80% of patients at the time of presentation, and approximately one-third of patients who have unilateral disease initially will later develop bilateral involvement. ,
Most adults with intermediate uveitis have minimal anterior segment inflammation; the exception is patients with intermediate uveitis associated with multiple sclerosis, who typically develop a granulomatous anterior uveitis with formation of mutton-fat keratic precipitates. Anterior segment inflammation is more common in children with uveitis, when there may be a moderate degree of anterior chamber cells with posterior synechiae. Brockhurst and colleagues noted peripheral anterior synechiae in 24% of patients and posterior synechiae in 18%. Band keratopathy may be seen in children. Occasionally patients may present with significant anterior segment inflammation with pain and photophobia and only later develop signs typical of an intermediate uveitis.
Autoimmune endotheliopathy is a rare finding associated with pars planitis. Khodadoust and colleagues reported four of 10 patients with pars planitis who demonstrated areas of peripheral corneal edema with keratic precipitates arranged linearly on the border between edematous and normal cornea. This morphologic finding was reminiscent of a corneal graft endothelial rejection line. Although other investigators have not observed this finding as frequently as Khodadoust and associates, the possible association of an autoimmune phenomenon is intriguing.
Glaucoma has been described as a cause of severe visual loss in patients with intermediate uveitis. In a study of 182 eyes with intermediate uveitis, glaucoma was diagnosed in 15 (8%). However, 11 of the 15 cases were thought to be related to corticosteroid use, and only four of the 182 eyes (2%) had disease-induced glaucoma. Cataract is a more common finding in these patients; it develops as a result of the ocular inflammatory disease and corticosteroid therapy. Similar to other cataracts in patients with uveitis, posterior subcapsular cataract is the most common lenticular opacity found in patients with intermediate uveitis.
The most characteristic findings in this disease are in the vitreous and peripheral retina. Cells are always present in the vitreous in active intermediate uveitis. Some patients may only have 1+ vitreous cells, but the absence of cellular activity in the vitreous precludes a diagnosis of an active intermediate uveitis. White and yellow-colored aggregates of inflammatory cells called vitreous snowballs tend to accumulate in the inferior vitreous. Occasionally, the vitreitis is dense enough to obscure the retina entirely. This dense vitreitis must be differentiated from vitreous hemorrhage that may also occur as a result of neovascularization, usually in the vitreous base or peripheral retina.
Brockhurst and colleagues described the early stages of peripheral uveitis as the accumulation of yellow-gray exudates at the ora serrata. Although this clinical finding is not required for a diagnosis of intermediate uveitis, it is the major clinical feature in the subset of intermediate uveitis that we call pars planitis. Not all patients with intermediate uveitis have a snowbank, and because some patients may have it in one eye only, the inferior white snowbank is an important finding but not an absolute requirement. As the disease progresses, Brockhurst and colleagues note that these exudates coalesce to form the material commonly referred to as a snowbank. This is usually located inferiorly only, but in rare patients it can extend for 360°. The snowbank may be discontinuous. It may form a fine band along the ora serrata or be broad and extend onto both the peripheral retina and the pars plana. It can be dense and extend several millimeters into the vitreous, and is usually best seen with scleral depression (see Fig. 3-16 ). However, a high dense snowbank on the pars plana can often be better seen with the indirect ophthalmoscope without using the 20-diopter lens while the patient looks down. Although this material has been termed an exudate, it is probably a fibroglial mass and not a true protein exudate, as will be discussed later. When a snowbank is observed, the area should be carefully examined for the presence of neovascularization because these areas are a source of potential vitreous hemorrhage.
The peripheral retinal vascular abnormalities may be obscured by the dense vitreal inflammation in some patients. When the vitreous is fairly clear, sheathing or obliteration of the small peripheral venules can be seen. Periarteritis of the small arteries is found less commonly. The perivasculitis is often associated with whitish infiltrates of the peripheral retina. In rare patients the peripheral neovascularization can evolve into a vascular cyclitic membrane ( Fig. 21-1 ).
Many patients have a mild course of intermediate uveitis or pars planitis and have no loss of visual acuity and may not require treatment. However, when visual acuity does decrease early in the disease process, cystoid macular edema is the most common cause; these patients usually warrant therapy. Fluorescein angiography or clinical examination frequently reveals cystoid macular edema. In addition, there is often diffuse retinal vascular leakage and optic disc edema when the disease is active. Interestingly, optic disc edema occurs in 50% of children with this entity.
Vitreous hemorrhage from peripheral neovascularization may occur in a small percentage of patients. It occurs more frequently in intermediate uveitis of the pars planitis subtype, and appears to be more common in children, occurring in 28% of children compared to 6% of adults in one case series. Vitreous hemorrhage has also been reported as a characteristic finding of intermediate uveitis associated with multiple sclerosis. In many eyes the hemorrhage will resolve, but some will require surgical intervention to remove a persistent vitreous hemorrhage. We have observed one patient in whom the neovascularization extended well into the posterior pole, leading to recurrent vitreous hemorrhages ( Fig. 21-2 ). Rhegmatogenous retinal detachment can occur from vitreoretinal traction; it is seen in 3.7–22% of patients, depending on the published series. , In our experience, rhegmatogenous retinal detachment is an uncommon complication of intermediate uveitis that occurs in less than 3% of patients. Retinal detachments, when they occur, tend to develop later in the disease process, because persistent vitreal inflammation leads to vitreal contraction and retinal traction. In addition to rhegmatogenous retinal detachments, Brockhurst and colleagues described nonrhegmatogenous retinal detachments associated with choroidal detachments.
Although macular edema is the most common cause of visual loss in patients with intermediate uveitis and is present in most of the patients who are referred to us, other series have reported an incidence of macular edema ranging from 28% to 50%. Epiretinal membranes have been reported in 36% of eyes with intermediate uveitis. Long-standing macular edema can lead to the development of retinal pigment epithelial stippling in the macula and may be a subtle sign of previous edema in patients with chronic intermediate uveitis. Unfortunately, this postcystoid macular degeneration can be a cause of severe visual loss in these patients.
Disc edema, optic atrophy, and optic disc neovascularization have been reported in patients with intermediate uveitis. Neovascularization of the disc is associated with severe retinal ischemia but responds to panretinal laser photocoagulation. Phthisis bulbi may be the final outcome for an eye with chronic poorly controlled intermediate uveitis. Oftentimes these eyes have had total retinal detachments, proliferative vitreoretinopathy, or a cyclitic membrane leading to ciliary body traction and hypotony.
Prognosis
Brockhurst and colleagues originally described five possible types of intermediate uveitis; 28% of their patients had a benign course during which the inflammation subsided with good visual outcome. In fact, Schlaegel stated that 80% of patients with intermediate uveitis of the pars planitis subtype need no therapy, and we have seen a number of patients with intermediate uveitis with or without pars plana exudates who have low-grade inflammation but never develop macular edema or decreased visual acuity. However, patients in the second group of Brockhurst and colleagues developed choroidal and serous retinal detachments. Patients in the third group developed vascularized high snowbanks that eventually formed cyclitic membranes that led to retinal detachments or glaucoma. Patients in the fourth group had significant vascular obliteration that led to visual field loss and optic atrophy. The fifth group, accounting for 46% of his patients, developed chronic smoldering inflammation.
In a later article, Brockhurst and Schepens condensed the classification into four groups: benign (31%), mild chronic (49%), severe chronic (15%), and relentlessly progressive (10%). In an article published 5 years later, Smith and colleagues found that 19% of patients with intermediate uveitis had mild disease, 42% had moderate inflammation, and 39% had severe inflammation. Clearly, the exact percentage of patients in any given category depends on the patient populations of the institutions in which the studies are performed. Tertiary referral centers will have more severe disease than primary care institutions. For example, Brockhurst and Schepens reported retinal detachments in 50% of their patients; however, patients with intermediate uveitis and retinal detachments were probably preferentially referred to their retina practice. We have found retinal detachment to occur rarely in patients with intermediate uveitis, but this may reflect the positive effect of therapy with corticosteroids.
Long-term prognosis varies greatly based on treatment and development of complications including epiretinal membrane and glaucoma. At the time of presentation, one half of patients have a visual acuity of 20/30 or better. Nevertheless, the disease can produce long-term visual disability in more than one third of patients. Schlaegel and Weber found that two-thirds of eyes in patients treated with corticosteroids maintained visual acuity of 20/40 or better, and other studies have noted that long-term prognosis for vision is often good with strict control of inflammation and proper management of complications. In a 20-year cohort study, mean visual acuity after 10 years of follow-up was 20/30, with 75% of patients maintaining a visual acuity of 20/40 or better. One-third of patients in this study maintained normal visual acuity without treatment. The presence of pars plana exudation or snowbanks may be of some prognostic value. Henderly and colleagues observed that eyes with pars plana exudates had more vitreitis and macular edema, although the difference was not statistically significant. In addition, severity of disease appears to be more related to visual outcome than duration of disease. ,
Although inflammatory disease does remit in some patients, Smith and colleagues found only a 5% remission rate in patients followed from 4 to 26 years. Similarly, Hogan and colleagues reported only one remission in 56 patients followed from 1 to 9 years. Patients with intermediate uveitis are often told that their disease will ‘burn out’ after a number of years, and although many patients may maintain useful vision, the disease is usually characterized by either a chronically active course or a course of exacerbations interrupted by apparent remissions. In fact, Aaberg stated that ophthalmologists rarely observe a permanent spontaneous resolution of the disease.
Differential diagnosis
Although intermediate uveitis may exist as an isolated idiopathic disorder, a number of underlying diseases are associated with this condition. Evidence of systemic disorders can be found in up to one-third of patients with intermediate uveitis, depending on the study. In one study of 83 patients, 10 had presumed sarcoidosis, six had multiple sclerosis, two had optic neuritis, two had inflammatory bowel disease, four had thyroid abnormalities, and two had histories consistent with Epstein–Barr virus infection. Recently, infectious diseases have been associated with intermediate uveitis. It has been reported in patients with Lyme disease, , human T-cell lymphoma virus type 1 (HTLV-1) infection, cat scratch disease, and hepatitis C. The diagnoses associated with intermediate uveitis are listed in Box 21-1 . Many of these disorders are discussed in detail elsewhere in this book. Sarcoidosis is discussed in Chapter 22 , Lyme disease in Chapter 10 , toxocariasis in Chapter 16 , intraocular lymphoma in Chapter 30 , and iridocyclitis with Irvine–Gass syndrome in Chapter 18 . Intermediate uveitis associated with multiple sclerosis is discussed later in this chapter. Other autoimmune disorders can cause an intermediate uveitis in the eye, including Crohn’s disease. Although specific diseases associated with intermediate uveitis can be identified in many patients, clinical investigation often fails to yield an exact diagnosis despite clinical findings that may suggest a unique condition. We reported 19 phakic patients with vitreitis, cystoid macular edema, retinal periphlebitis, and good visual outcome in whom no specific disease could be discerned.
Sarcoidosis
Multiple sclerosis
Inflammatory bowel disease
Lyme disease
Toxocariasis
Intraocular lymphoma
Retinoblastoma
Whipple’s disease
Iridocyclitis
Multifocal choroiditis
Irvine–Gass syndrome
Amyloidosis
Interstitial nephritis and uveitis syndrome
HTLV-1 infection
Cat scratch disease
Hepatitis C
Crohn’s disease
Our diagnostic evaluation of patients with intermediate uveitis includes a thorough evaluation for sarcoidosis, including a chest X-ray, a serum angiotensin-converting enzyme (ACE) level, serum calcium level, pulmonary function testing, and a gallium scan. Patients with a history of chronic or bloody diarrhea are referred to a gastroenterologist for evaluation for inflammatory bowel disease. A neurologic history and examination are performed and a magnetic resonance imaging (MRI) scan is performed in patients suspected of having multiple sclerosis. For patients with a history of a rash who live in an area endemic for Lyme disease, and especially those with a history of chronic arthritis, a serologic test for Lyme disease is performed. If the inflammation is unilateral, a serologic test for Toxocara is performed especially in younger patients. Intraocular lymphoma is suspected in older patients, who undergo a MRI scan of the brain, a lumbar puncture for cytologic evaluation of the cerebral spinal fluid, and a diagnostic vitrectomy. Other tests are ordered on the basis of a clinical suspicion of a specific disorder.
We usually obtain a fluorescein angiogram for these patients for two reasons: to assess the presence and extent of cystoid macular edema, and to examine the retinal vasculature for signs of perivasculitis, including staining of the vessel wall and vascular leakage of dye ( Fig. 21-3 ). Ultrasonography can demonstrate cyclitic membranes or the extent of vitreous debris when the view of the posterior pole is obscured by cataract. Ultrasound biomicroscopy may reveal vitreoretinal adhesions that are not observed clinically.
