Fuchs Heterochromic Iridocyclitis (Fuchs Heterochromic Uveitis) 

Updated: May 09, 2017
Author: Neerav Neel Lamba, MD, MBA; Chief Editor: Hampton Roy, Sr, MD 

Overview

Background

First described by Fuchs in 1906, Fuchs heterochromic iridocyclitis (FHI; also known as Fuchs heterochromic uveitis and Fuchs uveitis syndrome) is a chronic, unilateral iridocyclitis that is characterized by iris heterochromia.[1, 2, 3] Fuchs speculated that an unknown process leads to the development of abnormal uveal pigment with chronic low-grade inflammation and eventually causes iris atrophy and secondary glaucoma. Later, he described 38 cases and reported the histopathology of 6 eyes.

The uveitis typically occurs in the lighter-colored eye of a young adult with minimal ocular symptoms and typically presents with no pain or redness of the external eye or miosis; in addition, no related systemic disease is present. Gradual progression of the disease is associated with cataract formation, glaucoma, and, occasionally, vitreous cellular infiltrates. Although it typically presents as a unilateral condition, 7.8%-10% of affected patients have bilateral disease.[2]

Like many syndromes of unknown etiology, the defining characteristics of FHI have expanded over time. Some atypical findings in patients with FHI include absence of heterochromia, reversed heterochromia, and small foci of peripheral choroiditis. FHI is a diagnosis of exclusion. Other forms of infectious and noninfectious uveitis should be suspected and evaluated in patients with unilateral uveitis.

Pathophysiology

The trigger for inflammation of the iris and the ciliary body is currently unknown. Several unsubstantiated theories have been proposed, including Toxoplasma gondii infection, an immune dysfunction, infiltration of sensitized lymphocytes, and chronic herpetic infection.[4, 5, 6, 7] Additionally, because iris heterochromia occurs in congenital Horner syndrome, a neurogenic factor contributing to inflammation and structural changes has been proposed.

Infectious causes leading to FHI have been extensively studied. Both FHI and ocular toxoplasmosis have well-defined clinical features, and unequivocal diagnoses can often be made. A strong association between FHI and ocular toxoplasmosis has been documented. T gondii has been suggested as a possible etiologic agent. In Brazil and France, 60% of patients with FHI are reported to have chorioretinal lesions consistent with toxoplasmosis.[4]

Toledo de Abreu and coworkers reported chorioretinal scars characteristic of ocular toxoplasmosis in 13 of 23 patients with FHI. All of these patients had characteristic features of both toxoplasmosis and FHI, with positive serum immunofluorescent reactions for toxoplasmosis.[8] Among 25 patients studied by Schwab, 16 had fundus lesions suggestive of ocular toxoplasmosis; 13 of these patients had a positive serologic test for toxoplasmosis, suggesting a significant association between FHI and the chorioretinal scars of toxoplasmosis.[4] La Hey and associates analyzed the association between FHI and toxoplasmosis by studying humoral and cell-mediated immunity against T gondii in blood and aqueous humor in patients with FHI. They found no association between toxoplasmosis and FHI. However, there were no active chorioretinal lesions in the patients with FHI at the time the blood samples were taken.[9]

Rubella virus, which is well known for causing German measles, has been postulated to be involved in the pathogenesis of FHI. The exact molecular mechanisms still remain a topic for research, but the clinical spectrum of rubella uveitis resembles Fuchs heterochromic uveitis (FHU) in many aspects.[10, 11, 12] Two cases of FHI in otherwise healthy men aged 26 years and 29 years have been described by de Groot-Mijnes and associates. These patients tested positive for the antirubella antibody from aqueous humor isolates. However, no nucleic acid was isolated for any known pathogen from the anterior chamber of these patients.[13, 14] Quentin and Reiber reported evidence of intraocular production of antibodies against rubella virus in patients with FHI. They compared aqueous humor samples from patients with FHI with those from patients with other acute and chronic ocular inflammatory conditions and cataract control subjects to determine antibody reactivity against various organisms (eg, rubella virus, varicella zoster virus, herpes simplex virus [HSV], Toxoplasma infection). They calculated an antibody index for each antigen to determine the fraction of specific antibody to total immunoglobulin G (IgG). They found an increased antibody index against rubella in all 52 patients with FHI compared with cataract control subjects and patients with other uveitides.[15]

There has been an isolated case report regarding the detection of HSV DNA via polymerase chain reaction (PCR) in the aqueous humor of a patient with FHI and a possible role for HSV in the pathogenesis. Teyssot and associates reported a case of a 24-year-old woman relating FHI with unilateral ocular Toxocara canis. The isolated findings of HSV and T canis in association with FHI are likely to be insignificant.[16] There have been 12 case reports of FHI associated with retinitis pigmentosa, 2 of which were bilateral FHI.

No significant positive human leukocyte antigen (HLA) associations have been found. Immunologic theories attempting to explain the cause of FHI have been put forward. Elevated aqueous interleukin 6 (IL-6) levels have been found in patients with Fuchs uveitis syndrome (FUS) when compared with control subjects. The predominant cell type in FHI is the T lymphocyte. Phenotypes of the cells and cytokines present in the aqueous humor and blood of patients with FHI and idiopathic anterior uveitis (IAU) were compared. Differences were found, including higher CD8 T cells and interferon levels and lower interleukin 12 (IL-12) levels in FHI compared with IAU. Cytokine profiles in the aqueous humor also differed, with higher interleukin 10 (IL-10) and interferon-gamma levels and lower IL-12 levels in FHI compared with IAU. These findings point to a T helper 1 (Th1)–subtype response in FHI.[17]

Labalette and associates showed the presence of a CD8-positive CD28-negative T-cell population, suggesting an antigen-driven process. However, because of the small number of patients examined, this finding requires further investigation. Antibodies against various ocular antigens, including retinal S antigen and corneal antigens, have been reported in subsets of patients with FUS. Their significance remains unclear.[18]

Using ELISA, elevated levels of IgG subclass 1 in the aqueous have been reported when compared to that in patients with other uveitides and cataract control subjects. An antigenic stimulus may lead to local immune dysfunction with IgG subclass 1 production, which may play a role in the pathogenesis.

A suggestive association of FHI with cytotoxic T cell antigen 4 gene polymorphism has been described by Spriewald and associates. This may potentially be a candidate gene for FHI.[19]

Epidemiology

Frequency

In the United States, FHI is uncommon in the general ophthalmic practice. Because of a lack of symptoms and minimal signs of inflammation, the disease is probably underdiagnosed. In surveys, 2%-11% of patients with uveitis have FHI, while 2%-17% of patients with anterior uveitis have FHI.[4, 20, 21, 22, 23]

No ethnic, racial, or sexual predilection has been found. The age at presentation ranges from 20-60 years, and the mean age is 40 years.[2]

 

Presentation

History

FHI may be detected in the asymptomatic patient during a routine eye examination.[24] The most common reported symptoms include floaters cause by vitreous opacities and visual deterioration caused by cataract formation, while pain and perilimbal injection are rare. Some patients may present with symptoms of acutely elevated intraocular pressure (eg, mild pain, blurry vision, colored haloes around lights).

Physical Manifestations

Iris heterochromia develops as a result of gradual, progressive, irreversible atrophy of the iris stroma. Heterochromia can be subtle or even absent in patients with darkly pigmented irides and in patients with bilateral involvement.[25, 26, 27] Heterochromia is caused by atrophy of the anterior border of the iris. Progressive atrophy makes the brown iris appear less brown, whereas inflammation causing atrophy of a light colored iris will result in an apparent deepening of the color secondary to revealing the underlying iris pigmented epithelium.[28]

Anterior chamber inflammation is unilateral in 90% of patients and bilateral in 10%.[1, 2, 29] Inflammation, when present, is usually mild, and keratic precipitates are essentially pathognomonic for FHI. The keratic precipitates in FHI are small, stellate, nonpigmented, and translucent and scattered over the entire corneal endothelium.[1, 2, 29] In occasional cases, inflammation flares up to a moderate level, requiring a short course of topical corticosteroid therapy. High-dose or long-term topical corticosteroids are generally not beneficial to patients with FHI. In fact, long-term therapy hastens the development of complications, such as cataracts and glaucoma.

Cataract formation is a common cause of decreased visual acuity in FHI and usually commences as a posterior subcapsular cataract. It matures at variable speeds depending on the amount of inflammation present and frequency of corticosteroid use.[2]

The prevalence of secondary glaucoma is reported to be as high as 59%, and it is the most common cause of permanent visual loss in patients with FHI. The presence of elevated intraocular pressure is multifactorial in origin. Degenerative changes of the trabecular meshwork are the most common cause of secondary glaucoma. Other factors leading to the development of secondary glaucoma include inflammation of the trabecular meshwork, long-term corticosteroid therapy, inhibition of uveoscleral outflow mechanisms, presence of peripheral anterior synechiae, and neovascularization of the trabecular meshwork.[2]

Iris nodules may be present at the pupillary margin or throughout the stroma of the iris.[25] Posterior synechiae do not usually occur in patients with FHI.[30] Rubeosis over the anterior chamber angle and iris surface has also been reported. The blood vessels found in the iridocorneal angle and iris may sheer and lead to hyphema after any surgical intervention involving the anterior chamber. This is known as Amsler sign.[31]

 

DDx

 

Workup

Laboratory Studies

No laboratory studies are useful to the clinician in making the specific diagnosis of Fuchs heterochromic iridocyclitis (FHI). The diagnosis is based on both the clinical history and the physical examination. When the presentation is not typical of FHI, selected laboratory evaluation may be useful to rule out other forms of uveitis that share some clinical characteristics.

Angiotensin-converting enzyme (ACE) may be useful to the clinician in diagnosing sarcoid uveitis.

A microhemagglutinin test for Treponema pallidum aids in the diagnosis of syphilis.

Purified protein derivative (PPD) is beneficial to the clinician in diagnosing tuberculosis.

Imaging Studies

Imaging studies are not useful in the evaluation of Fuchs heterochromic uveitis (FHU). However, chest radiography may be beneficial in helping to diagnose sarcoid uveitis.

Other Tests

Fluorescein angiography and optical coherence tomography are used in patients with cystoid macular edema.

Procedures

Previously, anterior chamber paracentesis was considered a diagnostic test for FHI. This procedure is no longer indicated for this purpose.

Histologic Findings

Pathological studies show a combination of inflammatory, degenerative, and atrophic changes. The iris and the ciliary body have a low-grade chronic inflammatory cell infiltration of lymphocytes and plasma cells. Although lymphocytes are the predominant infiltrating cells, plasma cells, eosinophils, mast cells, and Russell bodies have all been described. Russell bodies may correlate clinically with the appearance of minute, globular iris crystals that are typical of FUS. The iris and the ciliary body are atrophic with fibrosis and obliteration of the vascular endothelium with a reduced number of melanocytes. Degenerative changes have been observed in the inner wall of the Schlemm canal and in nerve fibers. Electron microscopy of iridectomy specimens from FHI has shown abnormal melanocytes with loss of dendritic processes and damaged myelinated nerve fibers.[3, 32]

 

Treatment

Medical Care

In general, treatment is not necessary for patients with the typical low-grade inflammation. Symptomatic flare-ups may require short-term topical corticosteroids; however, long-term therapy is not indicated. Unlike other uveitides, topical steroids should not be used to eliminate cells from the anterior chamber as part of the cells and flare is contributed by the breakdown of the blood-aqueous barrier and leakage of inflammatory infiltrate.

Surgical Care

Surgical decisions are related to the development of cataracts and glaucoma in patients with FHI.

Cataracts associated with Fuchs heterochromic uveitis

Overall, the surgical outcome of patients with FHI is equivalent to patients with age-related cataracts. Patients with FHI tend to have better outcomes following cataract extraction than patients with other forms of uveitis. Preoperative and postoperative control of inflammation with topical steroids is of paramount importance for a successful surgical outcome. Topical prednisolone acetate 1%, 4 times per day, for several days before and after surgery may blunt the inflammation associated with procedure.

A small group of patients with FHI are at a higher risk for complications. Risk factors for complications include the following:

  • Rubeosis irides that lead to hyphema
  • Glaucoma may be more difficult to control following surgery.
  • Severe iris atrophy with transillumination defects tends to have worse postoperative inflammation.
  • Dilation of the pupil may be difficult.
  • Phacoemulsification tends to have a better outcome in terms of complications when compared to cataracts removed by extracapsular cataract extraction.

In planning for cataract extraction in patients with FHI, small incision surgery is recommended to reduce surgical trauma. Clear corneal incision is preferred to avoid blood vessels in the anterior chamber angle. Slow decompression of intraocular pressure is indicated to reduce the risk of hemorrhage from abnormal iris blood vessels. Peripheral iridectomy is not indicated.

An acrylic intraocular lens implant is preferred over a silicone lens to decrease the amount of pigment adhering to the lens postoperatively and to prevent uveitis relapse. If possible, the lens should be placed within the capsular bag.[29, 33, 26]

Glaucoma associated with Fuchs heterochromic iridocyclitis

The incidence of glaucoma ranges from 15%-59%. Antiglaucoma medications may be required later in the course of the disease, as repeated bouts of inflammation may permanently damage the trabecular meshwork and lead to a slow rise in intraocular pressure over time. Argon laser trabeculoplasty does not appear effective in improving the outflow where trabecular sclerosis and peripheral anterior synechiae are present.[1, 21]

La Hey and colleagues found that medical treatment alone was unsuccessful in effectively lowering the intraocular pressure to acceptable levels in 73% of patients with FHI. Patients with FHI whose intraocular pressure is not effectively controlled with topical medications may require glaucoma filtration surgery. Glaucoma filtering procedures in patients with FHI are less successful than in patients with primary open-angle glaucoma. The intraocular inflammation may lead to bleb failure; therefore, strict control of the inflammation with topical steroids during the perioperative period may improve the surgical outcome. Use of antimetabolites also may improve surgical results. Trabeculectomy with antimetabolites is successful in 60%-70% of patients 2 years postoperatively.[34] Glaucoma drainage implants yield a 90% success rate 1 year postoperatively and a 50% success rate after 4 years.[35]

Management of symptomatic vitreous opacities

Vitrectomy is advisable for visually significant vitreous infiltrates. It successfully eliminates symptoms of floaters and is associated with a better visual outcome when compared to vitrectomy in other uveitides.[2]

 

Medication

Medication Summary

The inflammatory activity in the anterior chamber is generally mild and can fluctuate over time. With minimal inflammation in an asymptomatic patient, chronic use of topical steroids is not indicated. However, FHI can be associated with pain, floaters, increased anterior segment inflammation, and elevated intraocular pressures. These cases may warrant short-term treatment with a topical corticosteroid.[2]

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects; they modify the body's immune response to diverse stimuli.

Prednisolone acetate suspension 1% (Pred Forte)

Generic preparations may be significantly less potent because of markedly larger particle sizes, approximately 10 µm in diameter. The larger particles decrease the effective exposure of drug to ocular surfaces, reducing absorption and potency. Rebounds may occur when switching from proprietary to generic prednisolone acetate 1% suspension on a dose-for-dose basis.

Initial dosage is titrated according to the degree of inflammation, and the therapeutic goal is to reduce the inflammation to the level prior to the flare-up.

Drops should be spaced at least 5 min apart to avoid dilution effects. Gentle eyelid closure or punctal occlusion can significantly decrease upper airway irritation and systemic absorption. A second drop given immediately after the initial drop does not increase potency because the conjunctival cul-de-sac only holds about 10 microliters, and each drop contains 40 microliters.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Class Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic, anti-inflammatory, and antipyretic effects. Their mechanism of action is not known but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms also may exist, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Topical formulations provide reasonable anti-inflammatory therapeutic effect without the major adverse effects of steroids. Although very potent analgesics, NSAID drops are generally far less potent than steroids.

Diclofenac ophthalmic (Voltaren)

Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors. May facilitate outflow of aqueous humor and decrease vascular permeability.

Ketorolac ophthalmic (Acular)

Inhibits prostaglandin synthesis by decreasing activity of the enzyme cyclooxygenase, resulting in decreased formation of prostaglandin precursors, which, in turn, results in reduced inflammation.

 

Follow-up

Further Outpatient Care

Patients should receive follow-up care as needed.

Complications

See the list below:

  • Cataracts

  • Secondary glaucoma

  • Vitreous debris that obscures vision

  • Dilated pupil

  • Corneal edema (rare)

  • Retinal detachment (rare)

Prognosis

The low-grade inflammation smolders over decades. Initially, vision is not significantly impaired.

All patients eventually develop cataracts that require surgical removal. Generally, the outcome of cataract surgery with posterior chamber intraocular lens implantation is good. Some patients develop increased inflammation and transient increased intraocular pressure during the postoperative period. Particular care should be given to placement of the intraocular lens within the capsular bag and the use of minimally adherent intraocular lens materials most compatible with uveitis. Acrylic intraocular lenses and surface modified polymethylmethacrylate (PMMA) intraocular lenses appear to be the most desirable materials, while first-generation silicone may create more cellular adhesion and, thus, more inflammation postoperatively.

Secondary glaucoma is not uncommon. This may require surgical therapy if antiglaucoma medications do not control the disease. The success for glaucoma surgery is less than that for primary open-angle glaucoma.

Severe vitreous inflammatory debris not only obscures vision but also may create a capacitance for inflammatory mediators. Thus, elective pars plana vitrectomy may not only improve vision but also reduce long-term inflammatory damage to the posterior segment. Vitrectomy may be performed concomitantly with cataract extraction and intraocular lens implantation or as a subsequent procedure.