Introduction

Fuchs uveitis syndrome (FUS) also known as Fuchs heterochromic iridocyclitis, is a chronic form of uveitis characterized by mild inflammation typically in one eye, often asymptomatic during routine ocular examinations1,2.

FUS ranks as the second most common non-infectious uveitis in some reports3. While the incidence of FUS spans between 1.8 and 22.7% in developed countries, it remains lower, ranging from 0 to 5.6%, in developing nations4,5. Certain regions report FUS patients constituting up to 22.7% of overall uveitis cases, or up to 45% when restricted to anterior uveitis instances6. In our earlier investigation at an Iranian Tertiary Eye Center, FUS accounted for over a third of anterior uveitis cases7.

Classic clinical manifestations of FUS encompass heterochromia, keratic precipitates (KP), mild iridocyclitis, and iris atrophy without posterior synechiae or cystoid macular edema, although chronic inflammation persists. Patients commonly report heterochromia in the affected eye, and vision changes are typically attributed to secondary complications such as cataracts and glaucoma2,8,9,10.

While the exact cause of FUS remains elusive, diagnostic reliance remains on clinical assessment, despite the appeal of a single etiological agent and a sensitive laboratory test2,11. Over time, numerous proposed etiological theories have been discredited, with infectious theories such as CMV and Rubella virus persisting as a plausible cause12.

Previous studies have suggested variations in the clinical spectrum of FUS in different populations3,13,14,15. Limited clinical data on unique FUS patterns, including pediatric FUS, bilateral cases, and misdiagnosed instances, have been documented16,17,18,19.

Epidemiologic studies with a relatively considerable number of patients for FUS in Iran are scarce7,18. To the best of our knowledge, the present study is one of the few large-scale studies on various clinical and epidemiological features of FUS. The present study aimed to draw attention to various clinical and epidemiological features of FUS in Iran.

Materials and methods

Patients and setting

This was a retrospective study of patients with a diagnosis of FUS at the referral outpatient clinic of Uveitis in a referral ophthalmology center affiliated to Isfahan University of Medical Sciences, Isfahan during 2003–2021. The study protocol was sanctioned by the Ethics Committee of Isfahan University of Medical Sciences, Iran (Code: IR.MUI.MED.REC.1398.72) and all methods were performed in accordance with the relevant guidelines and regulations. Informed consent has been taken from patients to use their data for research purposes.

Eligibility criteria encompassed patients definitively diagnosed with FUS, each with at least a 2-year follow-up period. The Kimura et al. criteria were employed for FUS diagnosis, encompassing specific ocular findings1,11,20.

Exclusion criteria were lack of diagnosis of FUS in the medical record on discharge, confirmation of an alternate diagnosis, incompatible clinical assessment, doubtful diagnosis, and insufficient information.

Data collection

Data from medical records of all subjects including patients’ sex, age, previous medical history, drug history, clinical and ocular symptoms, presence of any systemic diseases, management strategies, and clinical course were reviewed. Ophthalmological data consisted of slit-lamp biomicroscopy findings, Goldmann applanation tonometry, and indirect ophthalmoscopy findings. As warranted, additional tests were employed to assess underlying diseases.

Statistical methods

Frequency distribution tables were used to report categorical variables, and numerical variables were described with median and range. The relationship between each categorical variable and age group and sex was assessed by Chi-square test or Fisher exact test. Statistical analysis was performed with SPSS-18 software at a 95% confidence level.

Ethics approval

The protocol for this study was approved by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran (Code: IR.MUI.MED.REC.1398.72).

Results

Five hundred and seven eyes from 466 patients with a final diagnosis of FUS were included in the study. Forty-one patients (9.8%) had bilateral FUS. The mean age of the patients was 34.01 ± 11.25 years and there were 243 females (52.1%). The most common chief complaints were blurred vision (70.4%), floaters (15.6%), and incidental (10.3%). Iris atrophy, small- to medium-sized stellate KPs, and vitritis were noted in 497 (98%), 496 (97.8%), and 408 (80.5%) eyes, respectively. Iris heterochromia was observed in 40 (7.9%) eyes. Reversal of iris heterochromia was seen in one patient with blue eyes. Sixty-five patients had raised IOP (12.8%), of which 6 patients needed glaucoma surgery. Cataract and history of cataract surgery were recorded in 221 (43.6%) and 124 (24.5%) eyes, respectively (Table 1).

Table 1 Comparison of demographic and clinical characteristics between patients/eyes correctly diagnosed as FU and patients/eyes initially misdiagnosed as other uveitis.
Full size table

Eighteen eyes of 13 patients had initially misdiagnosed as other uveitis. The initial diagnosis of these patients before follow up were pars planitis (PP) (8/13), toxoplasmosis (2/13), posterior scleritis (1/13), Posner–Schlossmann syndrome (1/13), and undiagnosed case (1/13). Table 1 presents a comparison of demographic and clinical characteristics between patients/eyes correctly diagnosed as FUS and patients/eyes initially misdiagnosed as other uveitis. Bilateral involvement was more common in the group with an initially wrong diagnosis (P = 0.005). Iris atrophy and cataract in the misdiagnosed group had a lower rate compared to the corrected diagnosis group (P < 0.001 and P = 0.003, respectively). In addition, patients in the misdiagnosed group had a higher rate of glaucoma (P = 0.02) (Table 1).

Comparison of clinical findings between pediatrics/adults and male/female are summarized in Table 2. Iris atrophy was more common in adult patients (98.3% in adults versus. 92% in pediatrics; P = 0.08).

Table 2 Comparison of clinical findings between pediatrics/adults and male/female in patients with FUS.
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Eight patients with FUS were misdiagnosed as having Behcet disease (BD) and were on immunosuppressive therapy when referred to our referral center. Table 3 presents concurrent findings and diseases in FUS patients. The most common concurrent diseases were toxoplasmosis (30 eyes of 18 patients) and multiple sclerosis (6 patients). The most common concurrent ocular findings were epiretinal membrane (15 patients), amblyopia (12 patients), and retinal detachment (RD) (5 patients) (Table 3).

Table 3 Concurrent findings and diseases in FUS patients.
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Discussion

The result of our study identified several differences between the FUS in our population compared to others. Iris heterochromia was an uncommon clinical feature and PP was the most common causes of mistaken diagnosis in our study. The most common concurrent diseases in our study were toxoplasmosis and multiple sclerosis (MS).

Differences in the clinico-epidemiological pattern of FUS can be attributed to geographic, ethnicity, and genetic/epigenetic factors. These findings can provide new insights into the clinical and epidemiological aspects of FUS.

Although there are some differences between the results of our study and previous studies, major demographic data and most clinical characteristic of FUS were similar to other studies14,15,21,22,23. Consistent with the previous study in another Iranian population18, in our study iris heterochromia was an uncommon clinical feature. In contrast, studies from European countries showed that heterochromia is a more common finding in FUS24,25,26. A possible explanation for this contrast can be attributed to oculocutaneous phenotype. In fair phenotype due to pigmentary dilution of iris, the pigmentary changes related to the FUS may be more apparent.

FUS varies widely in differential diagnosis and can be considered as a great imitator in differential diagnosis of uveitis. FUS may be misdiagnosed due to its similarity to other inflammatory conditions or uveitis. FUS should be considered in all patients with uveitis, especially in patients with a history of uncertain clinical criteria for other differential diagnoses. Similar to previous studies, PP was the most common cause of misdiagnosis in our study18,27,28. Existence of iris changes, bilateral involvement, cataract, and glaucoma were four factors that differed between accurate and mistaken diagnoses of FUS in our study. In challenging cases, attention to changes in iris pigment, unilateral involvement, and existence of cataract can be helpful parameter for true diagnosis of FUS.

In our study, there is a possible important linkage between FUS with Toxoplasmosis. Many authors have looked for a link between toxoplasmosis and FUS29. For example in the study of Toledo de Abreu et al. association of FUS with ocular toxoplasmosis was seen in 13 patients in FUS30.

It is unclear whether this relatively high co-incidence of FUS and these conditions are related to the high prevalence of toxoplasmosis in our area, up to 43% seroprevalence according to some reports31, or a direct association32. Although it cannot be excluded that in some patients with FUS, the observed Toxoplasmosis may represent a co-incidence of two diseases, there is some hypothesis for a potential association between Toxoplasmosis and FUS.

In addition, regarding a possible association between toxoplasmosis and FUS, six patients had FUS co-existing with MS. Regarding the high prevalence of MS in our area, Isfahan, Iran33,34, further investigation is necessary for the identification of possible association of MS and FUS and possible etiopathogenesis pathway or incidental co-occurrence.

The frequency of RD in FUS is not well defined. Five patients in our study had RD. Severe inflammation of the vitreous may lead to vitreous traction causing the tractional and rhegmatogenous retinal detachment35.

FUS is a great imitator and a wide range of differential diagnoses should be considered for accurate diagnosis. In our study 8 patients were referred to us with clinical impression of BD, while on exact ocular examination and re-checking of the clinical criteria, the primary diagnoses of BD were ruled out, and patients were considered as FUS. On the other hand, eight patients had diagnoses of FUS and with long-term follow-up, alternative diagnoses were confirmed.

FUS is a disease of young adults and childhood FUS is a rare condition17. In our study, 25 patients had childhood FUS. On one hand, the relatively higher patient count can be ascribed to a selection bias stemming from the referral center's focus on uveitis. On the other hand, FUS might initiate during early childhood, yet its clinical manifestations might not manifest at the disease's outset. Consequently, diagnosis could potentially be postponed for several years17.

Although our study had some limitations including the retrospective nature of the study, current study, which included 507 eyes from 466 patients, can provide some references for the difference of FUS between Iranian subjects and others. Note that the number of cases in our study in comparison with others is considerable.

Conclusion

The current study demonstrated several differences between Iranian FUS patients and others, including clinical features, misdiagnosis patterns, and concurrent diseases. In challenging cases, attention to changes in iris pigment, unilateral involvement, and existence of cataract can be helpful parameter for the true diagnosis of FUS.