eMedicine Specialties > Ophthalmology > Iris & Ciliary Body

Uveitis, Fuchs Heterochromic

Author: Mansoor Arif, MB, BS, Research Officer, Department of Ophthalmology, Aga Khan University Medical College
Coauthor(s): C Stephen Foster, MD, FACS, FACR, FAAO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution; Ira G Wong, MD, MS, Associate Director, Clinical Affairs, Uveitis Service, The Francis I Proctor Foundation for Research in Ophthalmology, University of California at San Francisco; Clinical Professor, Department of Ophthalmology, University of California at San Francisco and Stanford University School of Medicine
Contributor Information and Disclosures

Updated: Dec 11, 2008

Introduction

Background

First described by Fuchs in 1906, Fuchs heterochromic iridocyclitis (FHI) is a chronic, unilateral iridocyclitis 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, eventually causing 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, no pain, and redness of the external eye or meiosis; no related systemic disease is present. Gradual progression of the disease is associated with cataract formation; glaucoma; and, occasionally, vitreous cellular infiltrates. Although typically presenting as a unilateral condition, 7.8-10% of patients have bilateral disease.

Like many syndromes of unknown etiology, the defining characteristics for 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 unknown. Several unsubstantiated theories have been proposed, including infection from Toxoplasma gondii, 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.

Iris heterochromia develops as a result of gradual, progressive, irreversible atrophy of the iris stroma. However, some patients with lightly colored irides present with a darkening of the affected eye, because the stromal atrophy allows more visualization of the darkly pigmented iris pigment epithelium posteriorly.⁸

Frequency

United States

FHI is uncommon in the general ophthalmic practice. Because of a lack of symptoms and minimal signs of inflammation, the disease probably is underdiagnosed. In surveys, 2-11% of patients with uveitis have FHI, while 2-17% of patients with anterior uveitis have FHI.^4,9,10,11,12

International

A multicenter study in Spain reports the prevalence of FHI to be 1.3%.

Race

No ethnic or racial predilection exists.

Sex

No sexual predilection exists.

Age

The age at presentation ranges from 20-60 years; the mean age is 40 years.

Clinical

History

The condition may be detected in the asymptomatic patient during a routine eye examination.

• Patients may have symptoms of floaters from vitreous inflammation or decreased vision from secondary cataracts.
• Symptomatic patients report blurry vision or myodesopsia.
• Inflammation is unilateral in 90% of patients and bilateral in 10% of patients.^1,2,14
  • Low-grade inflammation usually persists over many years and generally does not require treatment.
  • In a few patients, inflammation flares up to a moderate level, requiring a short course of topical corticosteroid therapy. High-dose or long-term topical corticosteroids generally are not beneficial to patients with FHI. In fact, long-term therapy will hasten the development of complications, such as cataracts and glaucoma.
  • FHI eventually leads to cataract formation and the development of secondary glaucoma.
    • The cataract initially is of the posterior subcapsular type.
    • Secondary glaucoma 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.

Physical

• The classic triad is heterochromia, cataract, and keratitic precipitates (KPs).15,16
• Conjunctiva and sclera: In most patients, the conjunctiva is uninflamed with no ciliary flush or conjunctival hyperemia; however, prominent conjunctival, episcleral, and scleral vessels may be observed.
• Cornea: Small, nonpigmented, translucent, star-shaped KPs are numerous and are nearly pathognomonic; they have fine filament projections, and, unlike the KPs seen in most patients with uveitis, those in FHI are distributed over the entire posterior corneal surface. Stellate KPs can also be seen in uveitis associated with toxoplasmosis, herpes simplex, herpes zoster, and cytomegalovirus (CMV).
• Anterior chamber: There is minimal anterior chamber cells and flare. Paracentesis may result in the appearance of a filiform hemorrhage (Amsler sign). Amsler sign is not pathognomonic and can occur in other uveitides.
• Iris  
  • Heterochromia is present in most patients. Inflammation is often present in the lighter colored iris; however, reversed heterochromia may be seen, with inflammation present in the eye with the darker colored iris. Initially, heterochromia may not be detectable in patients with a thick iris. Flattening of the anterior iris architecture is seen, resulting from loss of the anterior iris border layer and iris stroma, especially in the peripupillary area. Heterochromia is present in 75-90% cases. It is difficult to see in bilateral cases (5-10%). In unilateral cases, the hypopigmented eye is usually the affected eye. It is difficult to see in very pale blue or very dark brown irides and is no longer essential for diagnosis. It is best detected in daylight or bright overhead light, not at the slit lamp.
  • Iris sphincter atrophy may cause an irregular shaped pupil. Patchy atrophy occurs in the posterior pigment epithelial layer of the iris. There is iris stromal smoothing with loss of the normal corrugated texture.
  • Normally, a lighter colored eye becomes darker when extensive loss of iris stroma occurs, exposing the darker pigment epithelial layer.
  • White iris nodules may be seen along the pupillary border (Koeppe nodules) and in the iris stroma (Busacca nodules).
  • Posterior synechiae are never present. The presence of posterior synechiae should strongly suggest another diagnosis.
  • Iris atrophy and, possibly, iris ischemia lead to fine rubeoticlike vessels on the iris surface, especially in the angle. Fluorescein angiography of the iris demonstrates early leakage and, in some cases, vascular occlusion. Transillumination defects are also present in some cases.
  • Neovascularization of the iris and the anterior chamber angle (radial and circumferential) occurs in 6-22% of cases.
• Trabecular meshwork: Fine blood vessels on the trabecular meshwork may bleed unexpectedly when the intraocular pressure suddenly drops during surgery or paracentesis (Amsler sign).
• Lens: In a 9-year follow-up period, 80-90% of cases developed a posterior subcapsular cataract, which matured rapidly.
• Vitreous: Whitish vitreous cellular infiltrates, varying from dustlike to stringy veils are observed. They are not inflammatory snowballs as seen in intermediate uveitis. They may interfere with sight and require vitrectomy.
• Retina: The absence of cystoid macular edema distinguishes FHI from other uveitis syndromes with chronic vitritis. Chorioretinal scars have been reported in some patients. Cases of retinal breaks and retinal dialysis have been reported.17 A causal relationship has not been identified, but the incidence of retinal dialysis in FHI was reported as almost twice that of the general population. This suggests that a thorough retinal examination is essential in patients suspected of having FHI.
• Intraocular pressure: Secondary glaucoma is a frequent complication and can be present in 15-59% of cases.

Causes

The cause of FHI is not known; however, there are a variety of theories.

• The sympathetic/neurogenic theory supports the idea of adrenergic dysfunction leading to iris hypopigmentation by reduced innervation to iris stromal melanocytes. Abnormal innervation to iris vasculature may account for the breakdown in the blood-aqueous barrier observed with secondary leakage of proteins, cells, and inflammatory mediators into the anterior chamber. This can be supported by the fact that electron microscopy of iridectomy specimens from patients with FHI showed changes in myelinated nerves and associated changes in melanosomes.
• Infectious causes leading to FHI have also 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.¹⁸
  • In 25 patients studied by Schwab, 16 patients 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
  • Two cases of FHI in otherwise healthy men, aged 26 years and 29 years, respectively, 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.19
• Quentin and Reiber 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).20,21
  • 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. These findings have been supported by de Groot-Mijnes and associates.
  • There has been an isolated case report regarding the detection of HSV DNA by polymerase chain reaction (PCR) in the aqueous humor of a patient with FHI and a possible role for HSV in the pathogenesis.
  • A case of a 24-year-old woman relating FHI with unilateral ocular Toxocara canis has been reported by Teyssot and associates. The isolated findings of HSV and T canis in association with FHI are likely to be insignificant.²²
• There have been 12 case reports of FHI being associated with retinitis pigmentosa, 2 of them with bilateral FHI. However, 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.
• 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.²⁴
• 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.²⁵

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