AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

First described by Fuchs in 1906, Fuchs heterochromic iridocyclitis (FHI) is a chronic, unilateral iridocyclitis characterized by iris heterochromia. 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. 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.

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.

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

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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.
• Inflammation is unilateral in 90% of patients and bilateral in 10% of patients.
• • 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 chronic topical corticosteroids generally are not beneficial to patients with FHI. In fact, chronic 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, chronic corticosteroid therapy, inhibition of uveoscleral outflow mechanisms, presence of peripheral anterior synechiae, and neovascularization of the trabecular meshwork.

Physical

• Classic triad is heterochromia, cataract, and keratitic precipitates (KPs).
• 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.
• 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.
• 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.
• • Toledo de Abreu and coworkers reported chorioretinal scars characteristic of ocular toxoplasmosis in 13 of 23 patients with FHI. All these patients had characteristic features of both toxoplasmosis and FHI, with positive serum immunofluorescent reactions for toxoplasmosis.
  • 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.
• 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).
• • 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 recently 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.
• 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.
• 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.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Intermediate uveitis
Hemosiderosis
Ocular ischemia
Pars planitis
Heterochromia without inflammation
Congenital Horner syndrome
Iris nevus syndrome

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• No laboratory studies are useful to the clinician in making the specific diagnosis of 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.
  • 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 patients with Fuchs heterochromic uveitis.
• Chest x-ray may be beneficial in diagnosing those patients with sarcoid uveitis.

Other Tests

• Fluorescein angiography and ocular 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

The loss of pigment from the anterior stroma with hyalinization of blood vessel walls and cellular infiltration was described by Fuchs in 1906. 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, which 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.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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, chronic 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.
  • 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, consider the following:
    • 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.
    • Topical prednisolone acetate 1% four times per day for several days before and after surgery may blunt the inflammation associated with procedure.
• Glaucoma associated with FHI
• • The incidence of glaucoma ranges from 15-59%. Fortunately, most secondary glaucoma associated with FHI can be controlled with antiglaucoma medications. In the severe case, where 2 or 3 types of antiglaucoma medications cannot achieve control, surgical treatment should be considered.
  • In planning glaucoma surgery in patients with FHI, consider the following:
    • Argon laser trabeculoplasty does not appear effective in improving the outflow where trabecular sclerosis and peripheral anterior synechiae are present.
    • Glaucoma filtering procedures in patients with FHI are less successful compared with that for 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.
    • Glaucoma drainage implants may improve the outcome of glaucoma surgery for patients with uveitic glaucoma.
• 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.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

For the infrequent episodes when inflammation increases to a moderate level, the use of a topical ophthalmic corticosteroid solution or suspension for a short period of time is warranted. Cycloplegics are not generally required.

Drug Category: Corticosteroids

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

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Have analgesic, anti-inflammatory, and antipyretic activities. 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.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Outpatient Care

• Patients should receive follow-up care as needed.

Complications

• 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.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

• Jones NP. Fuchs heterochromic uveitis: An update. Surv Ophthalmol. Jan-Feb 1993;37(4):253-72. [Medline].
• Jones NP. Fuchs Heterochromic Uveitis: A reappraisal of the clinical spectrum. Eye. 1991;5 (Pt 6):649-61. [Medline].
• Labalette P, Caillau D, Grutzmacher C. Highly focused clonal composition of CD8(+) CD28(neg) T cells in aqueous humor of Fuchs heterochromic cyclitis. Exp Eye Res. Sep 2002;75(3):317-25. [Medline].
• Liesgang TJ. Fuchs uveitis syndrome. In: Pepose JS, Holland GS, Wilhelmus KR, eds. Ocular Infection & Immunity. 1995:495-506.
• Loewenfeld IE, Thompson HS. Fuchs heterochromic cyclitis: A critical review of the literature. I. Clinical characteristics of the syndrome. Surv Ophthalmol. May-Jun 1973;17(6):394-457. [Medline].
• Loewenfeld IE, Thompson HS. Fuchs heterochromic cyclitis: A critical review of the literature. II. Etiology and mechanisms. Surv Ophthalmol. 1973;18:2-61.
• Melamed S, Lahav M, Sandbank U. Fuch''s heterochromic iridocyclitis: an electron microscopic study of the iris. Invest Ophthalmol Vis Sci. Dec 1978;17(12):1193-9. [Medline].
• Mohamed Q, Zamir E. Update on Fuchs' uveitis syndrome. Curr Opin Ophthalmol. Dec 2005;16(6):356-63. [Medline].
• Murray PI, Hoekzema R, van Haren MA. Aqueous humor interleukin-6 levels in uveitis. Invest Ophthalmol Vis Sci. May 1990;31(5):917-20. [Medline].
• Quentin CD, Reiber H. Fuchs heterochromic cyclitis: rubella virus antibodies and genome in aqueous humor. Am J Ophthalmol. Jul 2004;138(1):46-54. [Medline].
• Schwab IR. The epidemiologic association of Fuchs' heterochromic iridocyclitis and ocular toxoplasmosis. Am J Ophthalmol. Mar 15 1991;111(3):356-62. [Medline].
• Teyssot N, Cassoux N, Lehoang P. Fuchs heterochromic cyclitis and ocular toxocariasis. Am J Ophthalmol. May 2005;139(5):915-6. [Medline].
• Toledo de Abreu M, Belfort R, Hirata PS. Fuchs' heterochromic cyclitis and ocular toxoplasmosis. Am J Ophthalmol. Jun 1982;93(6):739-44. [Medline].
• de Groot-Mijnes JD, de Visser L, Rothova A. Rubella virus is associated with fuchs heterochromic iridocyclitis. Am J Ophthalmol. Jan 2006;141(1):212-214. [Medline].

Article Last Updated: Sep 26, 2006