Continuing Education Activity

Aniridic fibrosis syndrome is a rare complication of invasive intraocular surgery (especially cataract extraction with intraocular lens implantation) that may occur in patients with congenital aniridia. It is characterized by a progressive fibrotic membrane within the anterior chamber that occurs after ocular surgery. In this activity, we review the clinical presentation and management of aniridic fibrosis syndrome. We also discuss the pathophysiology, risk factors, and differential diagnosis.

Objectives:

• Summarize the pathophysiology and histopathology associated with aniridic fibrosis syndrome
• Describe the physical examination findings in a patient with aniridic fibrosis syndrome
• Outline the treatment regimen for patients affected with aniridic fibrosis syndrome
• Identify the differential diagnoses to consider in a patient with apparent aniridic fibrosis syndrome

Introduction

Aniridic fibrosis syndrome was first described by Tsai et al. in 2005.[1] It is a rare complication of invasive intraocular surgery (especially cataract extraction with intraocular lens implantation) that may occur in patients with congenital aniridia. It is characterized by a progressive fibrotic membrane within the anterior chamber that occurs after ocular surgery. The membrane may grow over the ciliary body (leading to hypotony), disrupt the placement of intraocular lenses (IOLs), and contribute to retinal pathologies. Those who are affected typically have a history of multiple ocular surgeries to address sequela associated with the underlying congenital aniridia.[1] At present, there are seventeen reported cases with ages ranging from eight months to 71 years.[2][3]

Aniridic fibrosis syndrome occurs in the setting of congenital aniridia or the absence of the iris. Aniridia is an intricate congenital syndrome that can arise in an inherited or sporadic manner.[4][5] The iris is responsible for regulating the amount of light that enters the posterior structures of the eye. In aniridia, the iris may be completely or partially absent and may be associated with other ocular manifestations, most commonly foveal hypoplasia and nystagmus.[6][7] Other ocular manifestations may include glaucoma, cataract formation, keratopathy, and optic nerve coloboma with possible hypoplasia. [1][4][5] These diseases may require surgical intervention and the insertion of implantable devices.[4][8][9] Aniridia and its potential ocular comorbidities can result in poor visual acuity, typically 20/100 to 20/200, with foveal hypoplasia as the most significant limiting factor for these patient’s visual acuity.[4][1] Aniridia is most commonly associated with various PAX6 gene mutations, and the specific mutation can have considerable effects on the observed phenotype and resultant pathologies.[3] Some PAX6 mutations may also be part of various clinical syndromes (e.g., WAGR, or WAGRO syndromes), but other genetic mutations (e.g., FOXC1, PITX2, PITX3) and sporadic cases have been reported to cause aniridia.[4]

Etiology

The etiology of aniridic fibrosis syndrome is still unknown. This progressive fibrosis appears to occur only in patients with congenital aniridia that have undergone intraocular surgery, especially with some implanted device. However, a history of such is not entirely necessary.[1][2][3] The fibrosis appears to originate from the primitive iris root, often initially surrounding the IOL. It slowly progresses anteriorly to cover the entire anterior chamber and posteriorly to cover the ciliary body and anterior retina if surgical intervention is not employed.[1]

Risk factors have not been fully identified because of limited reported cases of aniridic fibrosis syndrome. However, of the seventeen cases published in the literature, 88% have been female.[1][2][3] In Tsai et al.’s initial study, all had undergone cataract surgery (with all but one having an acrylic IOL placed in the ciliary sulcus), and six of the seven had glaucoma drainage implants. Additionally, four of the eyes had a history of penetrating keratoplasty with limbal stem cell transplantation.[1] Additional reports also indicate similar potential risk factors.[3] Therefore, implantable devices, multiple surgeries, and female gender may affect incidence. As more cases are published, additional contributing risk factors may prove to have links to specific surgical techniques, other implantable devices, or yet unspecified predisposing genetic mutations.

Epidemiology

Congenital aniridia has been reported to have an incidence between 1:64000 and 1:100000.[10] However, to our knowledge, there are no extensive epidemiologic reports of aniridic fibrosis syndrome in patients with congenital aniridia. In one study, seven cases out of 155 eyes with aniridia were found (4.5%).[1]

Pathophysiology

The pathophysiology that causes aniridic fibrosis syndrome is unknown. However, observations from published literature can give us clues into the underlying mechanisms. In reported cases, the fibrotic membrane appears to originate from the rudimentary iris and is first noticeable as a growth on the posterior chamber (PC) IOL. The membrane may pull the PCIOL anteriorly, and progressive growth in late-stage disease reportedly causes additional tilting of the PCIOL and eventual contact with the cornea.[1][3] Posterior progression of the fibrosis covers the ciliary body and results in hypotony.[1]

Histopathology

Three surgically extracted samples in Tsai et al.’s study were examined for histopathologic changes. The membrane was composed of hypocellular fibrous tissue with bundles of immature collagen bundles mixed in with mature collagen fibers. Mild vascularity was noted in two of the three, and no other ocular cell type was observed in the fibrosis. Additionally, T-cells and macrophages were scarce in two of three samples, indicating a lack of inflammation that may be associated with other anterior chamber membranes.[1] One other histopathologic examination of a membrane in aniridic fibrosis syndrome revealed similar findings.[2] Of note, the poor wound healing that may accompany fibrous ingrowth was reportedly absent in one case series.[3] Tsai et al. hypothesized that contact or proximity of intraocular structures to immature vessels on the rudimentary iris might provide either a scaffold or a stimulus for the initiation and extension of the fibrotic membrane. Additionally, variant PAX6 mutations could also predispose patients to fibrotic membranes and could be the root cause.[1] However, a case of aniridic fibrosis syndrome in an infant without intraocular implants (but positive for prior Descemet stripping endothelial keratoplasty) has been reported, which challenges this theory.[2]

History and Physical

Patients with aniridic fibrosis syndrome will likely have decreased baseline best-corrected visual acuity. However, the presenting complaint has been recorded as an additional decrease in their visual ability. On ocular examination, a fibrous membrane may be observed to grow from the remnants of the patient’s iris. As patients are accustomed to poor visual acuity, they may delay making an appointment with their physician. With time, the membrane may grow to affect the IOL, ciliary body, and retina; and may become more evident on examination. In addition, patients with aniridic fibrosis syndrome may present with endothelial decompensation.[1]

Evaluation

Patients with aniridic fibrosis syndrome will, of necessity, have a preexisting diagnosis of aniridia; and will likely have multiple associated ocular procedures. Although there are continually improving genetic tests to detect patients with various causes of aniridia [11], there is currently no test or clinical study to determine if a patient is at risk for postsurgical fibrotic complications. The diagnosis is made clinically in patients with appropriate examination findings consistent with the disease.

Regular evaluation of the anterior segment and IOP are essential for the early detection of associated comorbidities. Slit lamp, gonioscopy, and indirect ophthalmoscopy can all be useful in the evaluation of the extent of fibrosis. Visual acuity often decreases with the progression of the fibrotic membrane.[3]

Treatment / Management

Initially, aniridia is typically managed medically; however, surgical intervention eventually becomes necessary to preserve or restore the best-corrected baseline visual acuity and achieve desirable cosmetic effects.[12][13] Likely related to these surgeries, aniridic fibrosis syndrome can develop. Regular evaluation and early surgical intervention (e.g., penetrating keratoplasty and membranectomy with PCIOL explantation or exchange) is the most recommended treatment modality in patients with aniridic fibrosis syndrome, because the membrane is likely to grow, thereby increasing the severity of accompanying intraocular complications.[1] Close monitoring after surgery is recommended since fibrosis may recur based on a report of recurrence in 40% of patients who underwent membranectomy with PCIOL exchange. However, recurrence was not noted after an IOL explant. Intraocular device reduction should be considered before surgical intervention.[1] The Boston KPro type 1 has been shown to improve visual acuity without recurrence of the membrane in patients with aniridic fibrosis syndrome.[3] The authors proposed that its success may stem from its location away from the iris root, the presumed location for the irritation, and initiation of the fibrosis.[3] Other procedures may be performed at this time to address surgically correctable issues that may be related to the fibrous overgrowth (e.g., retinal detachment repair).[1]

Differential Diagnosis

The differential diagnosis for patients with suspected aniridic fibrosis syndrome includes other sequelae of PAX6 mutations, diseases associated with underlying aniridia, and other causes of retrocorneal or intraocular membranes. Peter anomaly, also associated with PAX6 gene mutation, has been observed to have a similar type of fibrosis in patients with intraocular surgery.[1] Iridocorneal syndrome (ICE) can also present with an intraocular membrane and can be distinguished from cases of aniridia by specular microscopy.[14] Additionally, other unknown causes of peri pseudophakic membranes have been reported.[15] Another differential includes an inflammatory based response in patients with chronic uveitis after cataract surgery that has a cocoon-like membranous envelopment of the IOL.[3]

Prognosis

The prognosis for patients with aniridia is often poor, with decreased baseline visual acuity.[4] However, the surgical prognosis for patients with aniridic fibrosis syndrome who receive early detection and intervention is associated with improved visual acuity approximating their baseline acuity, in the absence of additional complications.[3]

Complications

As previously stated, fibrous growth may recur following membranectomy, though no cases of recurrence have been reported in patients with IOL extraction or Boston KPro type 1 implants.[1][3] Underlying aniridia, in general, has numerous associated pathologies, including systemic manifestations, which may impact the quality of life.[4]

Deterrence and Patient Education

Patients with aniridia will, almost of necessity, undergo ocular surgical procedures to restore or improve vision. Of these, some may develop postsurgical fibrotic membranes, which can cause intraocular damage and decreased visual acuity. Patients with aniridia should be counseled to maintain frequent and regular follow up with their ophthalmologist.

Pearls and Other Issues

• Aniridic fibrosis syndrome is a fibrotic membranous overgrowth retrocorneally that may occur in patients with congenital aniridia, likely secondary to multiple intraocular procedures and intraocular implants
• Genetic testing can be done to assess for aniridia, but no test or presurgical imaging can assess for the likelihood of postsurgical fibrosis.
• The fibrosis begins at the rudimentary iris and extends over intraocular structures, including an IOL, if in the posterior capsule.
• If left untreated, the membrane may extend anteriorly (pulling the IOL forward into contact with the cornea) and posteriorly (potentially covering the ciliary body and anterior retina).
• Treatment is membranectomy, and consideration for a decrease in intraocular structures should be considered. Surgical intervention is generally successful. Recurrence is rare and associated with IOL replacement as opposed to removal.

Enhancing Healthcare Team Outcomes

Patients with congenital aniridia should be referred to an ophthalmologist promptly. The broad scope of potential ocular complications in aniridia requires a team of ophthalmic subspecialists to provide optimal ocular care, as well as other providers, forming an interprofessional team. It has been recommended that only the best surgeons operate on the eyes of aniridic patients due to the potential complication of aniridic fibrosis syndrome.[5] Also, one provider should serve as an ‘aniridia guide’ to help the patient navigate the social and educational barriers in addition to the medical aspects of their care.[5] Genetic counseling should also be provided to both patients and their parents where applicable. Medical management should include the nurse, who will monitor the patient, answer questions, and verify compliance with the treatment plan. These interprofessional actions will help drive better patient outcomes. [Level 5]