Continuing Education Activity

Fuchs uveitis syndrome (FUS) is a chronic and typically unilateral form of mild anterior uveitis characterized by a distinctive clinical feature known as heterochromia, observed in approximately 13.9% of affected individuals. First described by Ernst Fuchs in 1906, its precise origin remains elusive, with various theories proposed over time, though the infectious theory remains one of the more plausible explanations. This condition leads to changes in vision, primarily due to ensuing complications (eg, cataracts and glaucoma), often affecting patient prognosis. Notably, heterochromia arises from anterior iris stromal atrophy, resulting in the lightening of the affected eye—a phenomenon more pronounced in individuals with lighter-colored irises than those with darker irises, where the atrophy's visibility is reduced.

The demographics of FUS patients exhibit variability across geographic regions, showcasing differences in incidence rates, onset age, and complication frequencies among distinct subpopulations. This CME activity reviews the uncertain etiology of FUS, its diverse epidemiological patterns, proposed pathophysiological mechanisms, clinical manifestations, and the interprofessional team's management of both the syndrome and its associated complications. By exploring these facets, healthcare practitioners can enhance their understanding and approach to effectively address FUS and its diverse clinical implications for patient care.

Objectives:

• Identify the etiology of Fuchs uveitis syndrome (FUS).

• Assess the theorized pathophysiology of FUS.

• Interpret the findings that differentiate FUS from other common causes of uveitis.

•  

  Collaborate with the interprofessional team to educate, treat, and monitor patients with FUS to improve patient outcomes.

Introduction

Fuchs uveitis syndrome (FUS) is a chronic, typically unilateral, mild anterior uveitis that was first described by Ernst Fuchs in 1906. FUS is also referred to as Fuchs heterochromic uveitis and Fuchs heterochromic iridocyclitis. The exact etiology of FUS is unknown. Fuchs had many theories about what caused this unique pathology; however, these have been largely disproven over the years, with the infectious theory remaining one of the more probable causes.

The patient population demographics vary by geographic location, with different incidence rates, symptom presentation age, and complication rates depending on the subpopulation studied. Most patients with FUS experience changes in vision mainly due to secondary complications, such as cataracts and glaucoma. Treatment of these complications leads to a good prognosis.[1][2][3][4]

Nonhereditary heterochromia, present in about 13.9% of patients with FUS, is caused by anterior iris stromal atrophy.[4][5] As a result, the patient will notice a lightening in the affected eye. Heterochromia is predominantly seen in patients with a lighter-colored iris. Patients with a darker-colored iris have more pigment cells in the anterior border layer of the iris, making the atrophy in the iris less apparent. Consequently, these patients are less likely to develop heterochromia.[3][4][6]

This article will discuss the etiology, epidemiology, proposed pathophysiology, clinical presentation, and management of FUS and its complications.

Etiology

The initial studies on FUS hypothesized its etiology ranging from adrenergic denervation, as in Horner syndrome, to infectious causes such as herpes simplex virus (HSV) and Toxoplasma gondii. One of the landmark studies by Quentin and Reiber proposed the now-predominant theory that FUS is caused by an inflammatory process involving rubella. The study analyzed the presence of intraocular antibody synthesis driven by rubella, HSV, varicella-zoster, measles, and toxoplasmosis. The results showed rubella oligoclonal antibodies in every sample of aqueous humor collected from patients with FUS, leading to a diagnostic criterion of 100% sensitivity.[7]

Subsequently, multiple studies analyzed the presence of rubella RNA or rubella antibodies in the aqueous humor of patients with FUS.[5][7][8] These studies concluded that patients with FUS have the persistent presence of immunoglobulin G (IgG) oligoclonal rubella antibodies in the affected eye and that the presence of rubella viral RNA in the aqueous humor is not associated with the progression of FUS.[9][10][11][12][13]

The initially proposed mechanisms of FUS consisted of sympathetic nerve dysfunction, hereditary, ocular toxoplasmosis, vascular, and immunological theories, all of which have largely lost favor.[14] Other diseases theorized to manifest with FUS are retinitis pigmentosa, Usher syndrome, and chikungunya; however, other theories have limited support in the literature since the studies involve clinical diagnosis with no aqueous humor antibody analysis. No specific human leukocyte antigen (HLA) is associated with FUS.[15][16][17][18]

Epidemiology

In most studies conducted around the world, the age range of diagnosis is from 27 to 44.5 years, with no significant difference between genders.[19][20][21][22][23][24][25] In a cohort of 131 patients at the University of Illinois Eye and Ear Infirmary, the mean age of patients diagnosed with FUS was 43.9, plus or minus 14.3 years.[25]

In this study, 4.48% of patients presenting to the clinic from 1919 to 1958 had FUS before and after rubella vaccination.[25] The decade after the rubella vaccination was introduced in 1969, only 1.18% of patients had FUS, with decreasing rates in the subsequent decades.[25] Even though the rubella vaccination decreased the overall incidence of FUS, the proportion of patients diagnosed with FUS born outside the United States has increased.

Pathophysiology

New studies have led to the infectious pathway, which has gained increasing traction within the scientific community. It has been proposed that patients with FUS harbor rubella infection, leading to chronic inflammation manifested as chronic anterior or intermediate uveitis.[7] A study that focused on analyzing the cellular infiltrates identified the presence of mainly T-lymphocytes of CD8⁺ phenotype, further enforcing the theory of a viral pathological mechanism.[26][27] Even though the exact mechanism of FUS is unknown, the relationship between rubella oligoclonal antibodies and CD8⁺ T-lymphocytes in the aqueous humor sheds light on the pathway.[7][11][12][27]

History and Physical

FUS usually occurs in the third to the fourth decade of life. Due to the insidious nature of this condition, coupled with a mild chronic course, most patients will be unaware of the subtle changes in their eyes. Patients are usually asymptomatic, with most FUS diagnoses detected during a routine ocular examination. Lightening of the iris of the affected eye is a unique complaint by patients. Occasionally, both eyes will be affected. Another pertinent finding in a patient’s history is decreasing visual acuity primarily caused by cataract formation. Patients may also complain of floaters, one of the more common presenting symptoms. Some patients may also experience symptoms of increased intraocular pressure (IOP), such as blurry vision, mild pain, and colored haloes around lights.[5][19]

On slit-lamp examination, minimal inflammatory signs are present, with quiet conjunctiva and no ciliary injection. Even though heterochromia is a unique feature in FUS, many factors affect this finding, including anterior stromal atrophy, iris color, and the amount of pigment in the iris’s epithelium. This unique clinical finding is caused by the irreversible and progressive atrophy of the anterior stroma. Individuals with darker-colored irises may not manifest heterochromia, whereas others may experience a lightening of the iris of the affected eye. However, those with a lighter iris will experience a deepening of the color. The more consistent finding is that white stellate keratic precipitates are distributed throughout the endothelium, described as sharply circumscribed and small to medium in size.

The trabecular meshwork and iris will display abnormal vessels with variable vitreous inflammation. In some cases, patients have iris nodules in the pupillary margin, known as Koeppe’s nodule, or on the iris’s surface, known as Busacca nodules. The iris sphincter can also atrophy, leading to an irregularly shaped pupil exhibiting poor light reflex. Due to the insidious nature of the disease, many patients with FUS will present to the clinic with advanced disease. These patients often have a posterior subcapsular cataract, eventually evolving into total opacification and increased intraocular pressure.[5][19]

Evaluation

The diagnosis of FUS is primarily clinical, based on history and complete eye examination. Alternative methods of examining the eye can prove useful with an atypical presentation. Anterior chamber paracentesis can be done to analyze the aqueous humor. Finding rubella-specific antibodies in the aqueous humor is nonspecific, but in their absence, it would decrease the probability of the patient having FUS.[7][12]

In vivo, confocal microscopy (IVCM) is a noninvasive procedure that can help observe ocular structures on the cellular level. A study published in 2009 that focused on observing patients with FUS using IVCM provided high-resolution images of the cornea’s endothelium and the consistent keratic precipitates that patients with FUS experience. The images were compared to those of uveitis caused by an infectious etiology, and both images shared various similarities, further enforcing the infectious cause of FUS. Even though IVCM helped identify the possible etiology of FUS, this noninvasive procedure is not routinely used.[28]

Further imaging studies such as enhanced-depth imaging optical coherence tomography (EDI-OCT) have also been used to evaluate the morphology present in FUS. FUS eyes had a decreased thickness of the iris compared with eyes without pathology, as well as statistically significant extra-foveal and subfoveal choroidal thinning. Although studies regarding different imaging modalities have primarily been used in an attempt to refine the knowledge concerning FUS, none have changed the diagnostic criteria.[29][30][31]

Treatment / Management

In FUS, a short course of corticosteroids can be used to treat symptomatic exacerbation of the patient’s uveitis. Topical corticosteroids are typically preferred in patients with anterior uveitis exacerbation because the steroids can only penetrate the anterior segment of the patient’s eyes.[32] Systemic corticosteroids are commonly used when the inflammation involves all uveal layers and, subsequently, the optic nerve.[32]

However, long-term use of anti-inflammatory therapy is not indicated. Patients still experience flares even with chronic corticosteroids, which can lead to cataract formation and glaucoma. Occasionally, since FUS has a similar clinical presentation to other uveitides of other etiologies, a trial of short-course topical corticosteroid therapy may be used to help differentiate the other inflammatory pathologies. The patient requires treatment for secondary complications such as cataracts or glaucoma, which occur in most patients leading to visual deterioration in this disease.[5][14][33]

Differential Diagnosis

FUS shares similar clinical features with other inflammatory processes, such as Posner-Schlossman syndrome (PSS). Both diagnoses are made clinically, with PSS having the characteristics of mild, nongranulomatous, anterior uveitis with recurrent attacks of increasing intraocular pressure. Patients with PSS may experience unilateral mild eye discomfort, pain, or blurred vision, but it can also be asymptomatic. Epithelial corneal edema and small keratic precipitates will be seen.

FUS and PSS share the unique features of an atrophied iris and heterochromia. In between attacks, the patients will have open angles with normal IOP. PSS responds well to steroids, with most cases only resulting in surgery if refractory glaucoma develops. FUS can be differentiated from PSS through history, physical examination, and a trial of steroid medication.[34]

Herpes keratouveitis (HKU) may be considered in the differential diagnosis. Patients with HKU have the clinical features of iridocyclitis, like those of FUS; however, these patients will have stromal edema along with pigmented keratic precipitates and endotheliitis. Other eye findings of posterior synechiae, sphincter damage, and sectoral iris atrophy can also be seen. HKU can be differentiated from FUS by the typical herpetic lesions and diagnostic tests. Viral culture and a viral antigen test can detect the presence of HSV-1 or HSV-2 in ocular fluids.[35]

Alternative differential diagnoses that are common etiologies of chronic uveitis, such as a varicella-zoster virus (VZV) and cytomegalovirus (CMV), should also be considered. These infectious etiologies usually have reduced corneal sensitivity and skin manifestations that help differentiate them from FUS.[36]

FUS may be distinguished from the various causes of increased IOP. A common cause of increased IOP would be acute angle-closure glaucoma, which would have the unique characteristics of a fixed and dilated pupil paired with severe pain, nausea, and vomiting, all of which would be absent in a patient with FUS.

Prognosis

The prognosis for patients who undergo cataract surgery is favorable, with an overall 85% success rate defined as 20/40 or better visual acuity.[2] These rates are better than other uveitis cases. A study done in Italy showed that 33.3% of patients who had cataract surgery subsequently developed posterior capsule opacification, leading to treatment with YAG laser capsulotomy.[19] The prevalence of posterior capsule opacification in FUS after cataract removal is similar to that of the same complication after senile cataract removal, ranging between 20% and 40%.[19][37][38] It is theorized that this percentage can be decreased through aggressive treatment of removing all the cortex.[37]

In a report by La Hey et al, as many as 73% of patients failed maximal medical therapy for glaucoma.[39] Other studies have shown better outcomes with medical management, with Jones reporting a failure in only 37% of patients.[14][40] Surgery is required in about 47% to 66% of patients with glaucoma, with most patients gaining back their baseline visual acuity.[1][14][21][24]

In a retrospective study by Al-Mansour et al, patients diagnosed with FUS showed worsening visual acuity in only 10% of the eyes in the follow-up period after being diagnosed with FUS, with most eyes having improved or unchanged visual acuity.[4]

Complications

One of the most serious complications of FUS is secondary glaucoma, which may cause permanent visual loss in patients. Secondary glaucoma has a prevalence of 15% to 59%.[39][41] Medical therapy is rarely adequate in controlling the elevated IOP for those who have FUS and who subsequently develop secondary glaucoma. When medical management is unsuccessful, surgical intervention is needed, primarily trabeculectomy.[3][4]

Trabeculectomy is the standard surgical procedure displaying the highest success rate. Adjunctive treatment with mitomycin C has proven successful in lowering the average IOP in patients after trabeculectomy; however, bevacizumab was not as successful as an adjunctive treatment in a study by Elgin et al.[39][42][43]

The major cause of poor vision in FUS patients is cataract formation, with a prevalence of 23% to 90.7%.[4] The clinical and visual outcomes of patients are good with various types of cataract extraction strategies consisting of phacoemulsification and small-incision cataract surgery. Both surgical techniques provide lower postoperative and intraoperative complication rates than extracapsular cataract extraction.[4][14][44][45]

Deterrence and Patient Education

Patients with FUS should be informed about the alarming symptoms of sudden increased IOP. Both pain and a decrease in visual acuity should lead the patient to seek medical care immediately to prevent permanent vision loss. If the patient is diagnosed with FUS early in the disease process, they should become aware of the high probability of acquiring a cataract, the likely need for cataract removal, and prompt surgical treatment for refractory glaucoma.

Pearls and Other Issues

FUS is a unique pathology with many theorized pathophysiological mechanisms. It is a chronic anterior uveitis that is primarily unilateral but can be bilateral. FUS is associated with the presence of oligoclonal rubella antibodies in the aqueous humor. Even though the etiology is unclear, the prognosis in patients diagnosed with the pathology is good when secondary complications of cataracts and glaucoma are treated. 

Management of FUS primarily consists of managing secondary complications of cataracts and glaucoma that occur during the disease. Physicians should be able to diagnose patients with this pathology through history and physical examination. FUS may be misdiagnosed due to its similarity to other inflammatory conditions or uveitides.

Enhancing Healthcare Team Outcomes

Management of FUS could be improved with early recognition of signs and symptoms. The eye care specialist, nurse, and technician should always ask the patient if visual acuity has decreased or floaters are noted. A thorough history and physical examination should be taken. The eye care team should take note of any significant difference in iris color between the eyes and perform a complete eye examination.

The prognosis for most patients will be good with proper communication and patient education.[4] The ophthalmologist should weigh the risks and benefits of doing medical management over surgical management. All interprofessional team members involved in the case must be able to communicate with other team members regarding their observations and interventions, and documenting these interactions in the patient's medical record is also essential.