Fuchs Heterochromic Iridocyclitis (Fuchs Heterochromic Uveitis)

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

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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]

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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]

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