Fuchs Heterochromic Iridocyclitis and Secondary Glaucoma
Also known as Fuchs’ uveitis syndrome (FUS), FHI was first described in 1906 by Ernst Fuchs who reported a series of 38 patients with iris heterochromia, cyclitis, and cataract.1
While the exact etiology of FHI remains unknown, several associations have been proposed, suggesting a multi-factorial disease process.
Sympathetic dysfunction has been proposed as an etiology, given that sympathetic lesions may be followed by iris hypochromia.2,3,4 Decreased innervation to stromal melanocytes may result in iris hypopigmentation.3 Additionally, abnormal innervation can lead to breakdown of the blood-aqueous barrier with subsequent leakage of protein, cells, and other inflammatory byproducts into the anterior chamber. One retrospective study found only 25 of 1746 (1.4%) FHI cases to be associated with Horner’s syndrome and summarily dismissed this association.5
Toxoplasmosis has been suggested as a possible etiology of FHI, given the similarities in chorioretinal lesions between the two entities. The prevalence of peripheral chorioretinal scars in FHI varies from 7-65% of cases, with most studies reporting a prevalence of 10%.4 Several studies have reported that Toxoplasma-like chorioretinal scars are noted in a significantly higher proportion of FHI patients compared to control groups.6,7 However, La Hey and colleagues reported that Toxoplasma antibodies were not found in aqueous humor samples from FHI patients, with the caveat that none of the patients examined had active chorioretinal lesions at the time of sampling.8
Herpes simplex virus (HSV) has also been linked to FHI. One case report identified HSV DNA in the aqueous humor of a patient with FHI, suggesting a role in the pathogenesis.9 However, this finding has not been reproduced in subsequent studies, and the association remains tenuous at best.10,11
The most recent theory was proposed by de Groot-Mijnes and colleagues in 2006.11 Briefly, 46 patients with a clinical diagnosis of either FHI, herpetic anterior uveitis, or ocular toxoplasmosis had aqueous humor samples drawn to measure intraocular IgG production against rubella virus (RV), HSV, VZV, and Toxoplasma gondii. Of the fourteen patients with FHI, thirteen demonstrated intraocular antibody production (Goldmann-Witmer coefficient >3) against RV. None of the fourteen FHI patients had intraocular antibody production against HSV, VZV, or Toxoplasma gondii. Furthermore, none of the controls had positive intraocular RV titers. The authors concluded that RV, but not HSV, VZV, or T gondii, may be associated with FHI.
FHI accounts for 2-11% of all uveitides, although the actual prevalence may be higher, as the entity is probably underdiagnosed given the lack of symptoms in the majority of patients.3,11,12,13 There is no race or sex predilection.14 It affects both genders equally and is typically manifested in young to middle adulthood.
Although patients may be aware of their iris heterochromia, they are often asymptomatic for many years prior to presentation and, unlike other uveitides, typically will have no pain, redness, or photophobia. Presenting complaints are usually secondary to cataract symptoms or floaters.
Classically, patients will present with unilateral (although 5-10% can be bilateral) iris heterochromia and atrophy, keratic precipitates, low-grade Iridocyclitis, and cataract in the absence of posterior synechiae.3,12
Iris Heterochromia: seen in 75-90% of patients.14 The lighter-colored iris usually, but not invariably, indicates the affected eye (Figure 1). In patients with lightly colored irides, one may note inverse heterochromia, whereby loss of pale anterior stroma leads to exposure of darker iris pigment epithelium. Thus, the iris in the affected eye appears darker. In patients with darkly colored irides, hypochromia can be absent or very subtle.
Iridocyclitis: low-grade inflammatory reaction (1-2+ cells) that is not responsive to steroid therapy. The cells and flare seen in FHI are thought to be due to breakdown of the blood-aqueous barrier with resultant leakage of cells rather than active inflammation. Despite the persistent inflammation, posterior synechiae are characteristically absent. A mild vitritis is also commonly seen without the presence of cystoid macular edema.
Keratic Precipitates (KP): usually fine and stellate and are interconnected by fibrin bridges. In contrast to other types of anterior uveitides where KP tend to cluster inferiorly within Arlt’s triangle, KP in FHI tend to involve the entire endothelial surface. However, all types and distributions of KP have been described in FHI (Figure 2).3
Cataract: although often seen in all types of uveitis, it is particularly frequent in FHI. Three quarters are of the posterior subcapsular variety.12 FHI should be considered in the differential diagnosis of any unilateral cataract in a young patient in the absence of trauma or steroid use.
Iris Nodules: Koeppe (pupillary margin) and Busacca (iris surface) nodules can also be seen in FHI and may initially lead to a misdiagnosis of granulomatous uveitis.
Iris Rubeosis: fine rubeotic vessels can be seen on the iris surface. Gonioscopy should be performed in these eyes as some of these vessels may traverse over the trabecular meshwork (Figure 3). Furthermore, sclerosis of trabecular meshwork can result, and an inflammatory membrane can form over the angle. Although not pathognomonic for FHI, Amsler’s sign occurs when a hyphema results after paracentesis during cataract surgery, rupturing the vessels crossing the trabecular meshwork. These fragile vessels may also lead to hyphema secondary to pressure from gonioscopy or applanation tonometry during clinical examination.
Chorioretinal Scar: While chorioretinal scars seem to have a higher prevalence in patients with FHI versus other types of anterior uveitis, there is still no definitive link between toxoplasmosis and FHI.
The diagnosis is based on the constellation of clinical findings, as there is no diagnostic test for FHI. Some have proposed using rubella titers as a diagnostic lab test for FHI, but this has not gained widespread acceptance or practice. Workup should be performed to rule out other causes of uveitis.
Posner-Schlossman Syndrome (glaucomatocyclitic crisis): characterized by recurrent, unilateral spikes in intraocular pressure which are associated with a certain degree of anterior chamber inflammation and keratic precipitates. Patients can have a certain degree of iris heterochromia. In this condition, the inflammation responds to steroids with resolution of elevated intraocular pressure spikes.
Other causes of anterior uveitis should be ruled out, including herpes simplex uveitis, which has been associated with heterochromia and diffuse KP.
Other causes of heterochromia should be ruled out, including congenital Horner’s syndrome, Waardenburg’s syndrome, ocular melanosis, diffuse iris melanoma, and herpes simplex uveitis.
Inflammation: most cases do not require therapy, with patients generally having a good prognosis despite the persistent inflammation. The expected sequelae of chronic uveitis (posterior synechiae, persistent cystoid macular edema) are usually not seen in FHI. Since most of the cell and flare seen is a result of blood aqueous barrier breakdown and not inflammation, corticosteroids are generally ineffective in eliminating the low-grade anterior chamber reaction in FHI and should not be used aggressively. Some advocate a short-course of topical steroids to differentiate FHI from Posner-Schlossman syndrome, but long-term steroids are not indicated.3,12
Cataract: patients with FHI have equivocal or better visual results following cataract extraction compared to other forms of chronic uveitis. Studies have shown phacoemulsification with posterior chamber intraocular lens implantation to be a safe and effective procedure in patients with FHI.15 The peri-operative management of inflammation varies in FHI, with most placing patients on topical steroids.3 Some clinicians even recommend pre-operative systemic steroids. Markers of severe disease and a more guarded post-operative prognosis included severe iris atrophy with transillumination defects, glaucoma, and iris vasculature abnormalities.13
Vitreous opacification: patients with FHI can present with vitreous floaters from inflammatory debris, most often in the anterior vitreous. Should these floaters become visually significant, pars plana vitrectomy (PPV) has been shown to be exceedingly effective in improving vision in FHI.16 In fact, PPV had better results in FHI patients than in those with other forms of uveitis, likely as a result of the less aggressive inflammatory course and lack of cystoid macular edema in FHI.
Glaucoma: As outlined below
Glaucoma is the most sight threatening and challenging complication of FHI. The prevalence of secondary glaucoma has been reported to be anywhere from 9- 59% in FHI patients.12,17,18,19 As is the case in primary open angle glaucoma, black patients may be at increased risk for developing secondary glaucoma from FHI.20 Patients with FHI are prone to wide fluctuations of intraocular pressure. Therefore, it is critical to detect glaucoma early in these patients and baseline optic disc photos and visual fields should be obtained and repeated regularly to closely monitor progression.
In most cases, the drainage angle is open on gonioscopy, and the etiology is thought to be similar to that of chronic open-angle glaucoma. In some cases, active trabeculitis with various inflammatory cell types may play a role in aqueous outflow obstruction and secondary glaucoma. Other rare mechanisms include peripheral anterior synechiae and angle closure, lens-induced glaucoma such as phacolytic glaucoma, steroid induced glaucoma, and neovascular glaucoma from iris and angle rubeosis.18
The risk of developing glaucoma following cataract surgery in FHI patients has been a topic of considerable debate. Some believe this to be a common complication of cataract surgery, as the intraocular pressure rise post-operatively may further compromise susceptible FHI eyes into overt glaucoma.18 Others contend that the development of glaucoma following cataract surgery may simply be a manifestation of the natural history of the disease, given that the incidence of glaucoma in eyes following cataract surgery is roughly equal to that in unoperated eyes.21
Glaucoma in the setting of FHI is a particularly recalcitrant form, with 73% failing to respond to maximal medical therapy.17 Additionally, glaucoma typically does not respond to corticosteroid therapy in these patients. Argon laser trabeculoplasty is ineffective in these eyes given the inflammatory nature of this disease, alterations in the angle anatomy from presence of peripheral anterior synechiae, neovascularization of the angle, or presence of a transparent, inflammatory membrane covering the angle recess. Trabeculectomy in any type of uveitic glaucoma has been demonstrated to have limited success due to excessive scarring, with a 5 year success rate of 54% without adjuvant anti-metabolite therapy and 67% with a one-time does of 5-fluorouracil.22,23 As such, glaucoma drainage implant devices (e.g. Ahmed, Baerveldt, Molteno) are the preferred initial surgical option, with first year success rates ranging from 77-94%.24,25,26 However, four-year success rates with Ahmed valves in uveitic glaucoma -have been reported to be modest, 50-76%.
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