Corneal epithelial and fibrovascular downgrowth postcataract surgery with intrastromal bleed: a rare case study with multimodal imaging

Abstract

A woman in her 60s presented with diminution of vision and redness in her right eye (OD) 1.5 months duration, 10 months post cataract surgery. The best-corrected visual acuity (BCVA) on the OD was fingers counting at 0.5 m. The anterior section of the OD demonstrated superior pre-Descemet’s intrastromal bleeding, superior dense fibrovascular growth in the corneal mid-stroma and superior fibrovascular downgrowth measuring 5×5 mm in the anterior chamber. Along with topical prednisolone acetate (1%) suspension 4 times per day on a tapering dose, antivascular endothelial growth factor therapy was administered intrastromally and subconjunctivally in the superior bulbar conjunctiva near limbus (0.05 mL of 2.5 mg/0.1 mL at each site). Over the course of a week, the intrastromal bleed had completely stopped. Three months later, at the final follow-up, the BCVA had marginally improved to fingers counting 2 m, with a lingering 4×4 mm nebulomacular scar.

Background

Corneal epithelial downgrowth and intrastromal fibrovascular growth with bleed are a rare but potentially vision-threatening complication seen most commonly after a penetrating trauma or an intraocular surgery.^1–3 Corneal complications after cataract surgery include striate keratopathy, corneal stromal oedema, Descemet’s membrane detachment, corneal decompensation, punctate epithelial microerosions, sterile corneal ulcerations in dry eye patients and epithelial or fibrous downgrowth.⁴ Poor visual recovery after cataract surgery, secondary glaucoma and corneal decompensation are all caused by the descent of corneal epithelial cells into the anterior chamber.

Epithelial downgrowth can occur following cataract surgery in 0.08%–0.12% of cases and after penetrating keratoplasty in up to 0.25% of cases.^{3 5} It is possible for epithelial sheets, cysts or pearls to form as a result of epithelial cells entering through a lesion, adhering to the posterior side of the cornea and then moving into the anterior chamber. A white line over the endothelium can also signify this process.^{6 7} The occurrence of an epithelial downgrowth post phacoemulsification is uncommon with only five cases reported previously in literature. It can occur weeks to months postcataract surgery.

Clinical examination, specular microscopy, anterior segment optical coherence tomography (AS-OCT) and confocal microscopy aid in the diagnosis of epithelial and/or fibrovascular downgrowth. Although the pathophysiology of this condition is yet unknown, it has been suggested that sutures often used during intracapsular and extracapsular cataract excision may cause retrograde flow of epithelial cells.⁷ Patient usually presents with diminution of vision, redness, along with an uncontrolled intraocular pressure and inflammation leading to severe pain and discomfort.

Case presentation

A woman in her early 60s, presented to our centre with complaints of progressive diminution of vision in her right eye (OD) from postoperative day 1 of cataract surgery (10 months earlier) associated with redness of 1.5 months duration. The patient was conscious, co-operative and well oriented to time and person. Her vital signs including pulse rate, temperature and blood pressure were within normal limits. Systemic examination of cardiac, respiratory and abdominal system was within normal limits.

She had cataract surgery in OD 2 years prior and presented to us 10 months later. Her old medical records showed an immediate postoperative vision of counting fingers close to face with microcystic epithelial oedema and bullae, Descemet’s membrane folds, pigments on endothelium, quiet anterior chamber with posterior chamber intraocular lens with dense cortical matter behind it. Intraocular pressure in the OD was 40 mm Hg for which intravenous injection mannitol 100 mL was given. Oral prednisolone 40 mg/day for 1 week was initiated and tapered weekly over 1 month with 30 mg/20 mg/10 mg weekly tapering, topical prednisolone acetate (1%) suspension and antiglaucoma medications topical eye drop timolol maleate (0.5%) was prescribed to the patient. Subsequently a few months later, she had also undergone neodymium-yttrium aluminium garnet (Nd:YAG) laser capsulotomy in OD.

Due to her vision impairment, the patient was referred to a higher centre for further management. Eye evaluation at our centre showed best-corrected visual acuity (BCVA) in OD was counting fingers at 0.5 m, and 20/40 in the left eye (OS). Right eye slit lamp examination revealed diffuse conjunctival hyperaemia, superior small incision cataract surgery scleral scar, diffuse corneal microcystic epithelial oedema, dense superior fibrovascular growth with pre-Descemet’s bleed measuring around 5×5 mm, intrastromal nebulomacular opacity involving the visual axis under the bleed, diffuse several moderate Descemet’s membrane folds, a thin membrane adherent to the endothelium inferiorly from limbus at around 6 0’clock (side-port entry wound) to 4 mm till mid-periphery of corneal endothelium suggestive of epithelial downgrowth and an anterior chamber reaction of flare+ and cells+, peripheral anterior synechiae (PAS) superiorly from 11 to 2 o’clock, with a posterior chamber intraocular lens in situ (figure 1). B-scan ultrasonography showed a normal posterior segment (figure 2). Left eye examination revealed a grade 3 nuclear sclerosis cataract and normal posterior segment. Intraocular pressure in both eyes were within normal limits with Perkin’s tonometer (OD-18 and OS-13 mm Hg).

Figure 1.

Slit lamp images: at presentation. (A) Diffuse slit lamp image showing diffuse epithelial and stromal oedema (blue arrow), 5×5 mm central intrastromal (pre-Descemet’s) fresh bleed with surrounding nebulomacular stromal opacity extending from superior limbus (11 to 2 o’clock) to centre of cornea (orange arrow), with deep vascularisation from 11 to 2 o’clock. (B) Diffuse slit lamp image showing moderate diffuse bulbar conjunctival congestion and hyperaemia. (C) Slit view image showing stromal oedema (increase in stromal thickness) (orange arrow), pre-Descemet’s fibrovascular growth (blue arrow), Descemet’s membrane detachment (yellow arrow), iris pigments on endothelium, epithelial downgrowth (white arrow). (D) Diffuse slit lamp image showing scarred inner lip of small incision cataract surgery with vessels originating (red arrow).

Figure 2.

Ultrasound B scan (Compact Touch, Lumibird Medical, Cournon d’Auvergne Cedex, France) of the right eye with 90 dB gain showing clear vitreous cavity (double red arrow), attached retina (yellow arrow) and optic nerve shadow (red circle) indicating normal posterior segment.

Table 1.

Summary of the treatment modalities adopted for epithelial ingrowth following different ocular procedures^47–66

Study	Surgical procedure/condition	Number of cases	Treatment modality	Outcome
Stark47	NA	12	Photocoagulation on the iris followed by excision of involved iris tissue Vitrectomy Transcorneal and transscleral cryotherapy An intraocular air bubble was used to provide an insulating effect and a more effective, controllable freeze	Visual acuity of 6/12 (20/40) or better
Naumann and Küchle48	NA	NA	Complete excision of all epithelial layers with a full-thickness corneoscleral graft	NA
Nagra and Raber49	Corneal transplant	1	Argon laser photocoagulation applied to the surface of the iris Intraoperative peeling of the epithelial membrane from the surface of the lens ECCE with PCIOL via an open-sky technique through a repeat PKP opening in the cornea	16 months corneal transplant was clear with no signs of rejection or epithelialisation across the endothelial surface, iris or intraocular lens
Tomlins et al50	Cataract surgery	1	Intracameral 5-FU failed Diode laser cycloablation	Poor visual prognosis
Vinciguerra et al51	Cataract surgery		Irrigation/Aspiration phaco probe Copious irrigation with BSS Ethanol for 1 min Diluted 0.02% mitomycin Continuous 10–0 nylon suture	1 week Visual acuity remained 20/50
Lindfield et al52	LASIK	2	Nd:YAG laser	Complete resolution with no recurrence
Kucukevcilioglu and Hurmeric53	LASIK	1	Nd:YAG laser	15 months Total regression
Thulasi et al54	SMILE		Multiple failed interventions such as two flap lifts, epithelial scrapings and flap edge suturing After removal of the epithelial cells from the surface, periphery and interface, the liquid sealant (ReSure; Ocular Therapeutix, Bedford, Massachusetts, USA) was applied to the flap edges using a foam-tipped applicator. Solidification of the sealant then occurred within 20 s, becoming a soft, pliable hydrogel	Decreased corneal haze and no recurrence
Ni et al55	Cataract surgery and subsequent uneventful (DSAEK) ACIOL	2	Anterior chamber 5-FU in a concentration of 1000 μg/0.1 mL was mixed with 0.1 mL of viscoelastic Two injections of 5-FU	Epithelial downgrowth resolved but recurred after 2 months and treated with PKP GDD DSAEK 5 months later no recurrence
Chen et al56	LASIK	12	Mechanical debridement of the ingrowth and placement of fibrin tissue glue	No complications No loss of vision
Chan et al57	SMILE	1	Scrapping and irrigation of the interface pocket Adjuvant collagen crosslinking	Corneal haze subsided and became visually insignificant
Kymionis et al58	LASIK	1	Combined PRK and CXL	12 months no recurrence or progression of ectasia
Gupta et al59	Chronic corneal neovascularisation	14	Intrastromal bevacizumab (0.05–0.1 mL of 2.5 mg/0.1 mL) 1–3 injections/eye prior to corneal grafting	No evidence of recurrence of neovascularisation or graft rejection in the transplant group
Khurana et al60	Pterygium surgery and phacoemulsification	1	No treatment	NA
Jenkins et al61	Combined cataract and DMEK	1	Nd:YAG laser	Four months No recurrence
Hata-Mizuno et al62	PKP Cataract surgery	1	PKP	↑IOP postoperatively, and glaucoma drops were applied Ahmed glaucoma valve (FP-7 model) Third PKP
Kankariya et al63	SMILE	3	Manual debridement after fashioning a flap using the CIRCLE software	No recurrence in all three cases
Dua et al64	NA	NA	Mechanical removal with alcohol swab application	Risk for infection
Salari et al65	Glaucoma surgery	1	One dose of weekly intracameral MTX (400 mg/0.1 mL)	No recurrence
de Rojas Silva et al66	SMILE	1	De-epithelialisation of an area of 6 mm	One month 20/20

ACIOL, anterior chamber intraocular lens; BSS, balanced salt solution; CXL, corneal crosslinking; DMEK, Descemet's membrane endothelial keratoplasty; DSAEK, Descemet’s stripping automated endothelial keratoplasty; ECCE, extracapsular cataract extraction; 5-FU, 5-fluorouracil; GDD, glaucoma drainage device; Iˆ, Increased; IOP, intraocular pressure; LASIK, laser in situ keratomileusis; MTX, methotrexate; NA, not applicable/not available; Nd:YAG, neodymium-yttrium aluminium garnet; PCIOL, posterior chamber intraocular lens; PKP, penetrating keratoplasty; PRK, photorefractive keratectomy; SMILE, small incision lenticule extraction.

Investigations

Anterior-segment Optical Coherence Tomography(AS-OCT) using Tomey Casia 2 SS-1000 of the cornea/anterior segment which revealed superior and central pre-Descemet’s hypo-reflective homogenous area suggestive of a pre-Descemet’s bleed and hyper-reflective fibrovascular downgrowth in superior anterior chamber with inferior retrocorneal epithelial cysts. Corneal stromal oedema was noted with increase in stromal thickness of 621 μm (figure 3). In vivo confocal microscopy using Heidelberg LSC210 showed multiple blood vessels of different sizes and blood in the corneal stroma (figure 4).

Figure 3.

Anterior-segment optical coherence tomography images (A) using Tomey Casia 2 SS-1000 of the cornea/anterior segment showing homogenous hyper-reflective biconvex lesion in pre-Descemet’s layer suggestive of pre-Descemet’s bleed (blue arrow), stromal oedema (increase in corneal thickness)—(double-headed white arrow) and (B) retrocorneal heterogenous hyper-reflective lesion suggestive of fibrovascular downgrowth and stromal oedema (blue red arrow), retrocorneal heterogenous hyper-reflectivity with few hypo-reflective spaces suggestive of epithelial downgrowth with cysts (white arrow) and increase in corneal thickness (double-headed red arrow).

Figure 4.

In vivo confocal microscopy images. at presentation using Heidelberg LSC210 showing (A) increase in corneal thickness (783 μm) with pre-Descemet’s showing diffuse hypoechoic area suggestive of bleed (orange arrow) and (B) multiple hyperechoic dots suggestive of iris pigments on endothelium (707 μm) (white arrow).

Differential diagnosis

The differential diagnosis includes healed cases of perforated microbial keratitis, corneal ulcers with hypopyon, and penetrating ocular trauma with epithelial and fibrovascular downgrowth. Epithelial downgrowth is a rare complication of intraocular surgery or trauma characterised by invasion of surface epithelial cells into the anterior chamber of the eye.⁸ The membranous spread of these conjunctival or corneal epithelial cells can be difficult to control and lead to devastating consequences including end-stage glaucoma and permanent vision loss.³ Fibrous downgrowth is a similar but somewhat less aggressive condition characterised by fibrovascular connective tissue invading into the eye. Patients with these conditions can present with decreasing visual acuity, pain, tearing, photophobia, foreign body sensation or flashes of light.³

Prior to the surgery, the patient had only cataract in OD without any co-existing ocular disorders. Post cataract surgery, patient developed raised intraocular pressure and epithelial ingrowth. The clinical findings were confirmed with AS-OCT (Tomey Casia 2 SS-1000) and in vivo confocal microscopy (Heidelberg LSC210).

Treatment

The patient had been prescribed topical prednisolone acetate (1%) suspension eye drops 4 times/day on tapering dose, sodium chloride 5% eye drops 4 times/day and sodium chloride 6% eye ointment at night, hypromellose eye drops 4 times/day and homatropine 2% eye drop two times per day to OD. At our centre, a special informed consent was taken from the patient in her own language after explaining the risks, benefits, alternatives and complications of intrastromal bevacizumab. Superior intrastromal and superior subconjunctival injection of antivascular endothelial growth factor (VEGF) (bevacizumab) of 0.05 mL of 2.5 mg/0.1 mL at each site was given under topical anaesthesia to the patient under all aseptic precautions in OD.

Outcome and follow-up

Over two follow-up visits of the patient over 1 week, the intracorneal bleed resolved with a persisting thin fibrovascular network with resolution of the stromal oedema. At 3 months follow-up, BCVA in OD was fingers counting close to 2 m and anterior segment examination of the cornea showed a persistent nebulomacular corneal opacity involving the visual axis. There was complete resolution of the intrastromal bleed and reduction of anterior chamber flare was noted (figure 5). Patient was eventually lost to follow-up after 3 months. The financial concerns of the patient would be important as she was from a very remote area with barriers to transportation and finances.

Figure 5.

Slit lamp images at final follow-up. (A) Diffuse slit lamp image showing 4×4 mm nebulomacular scar extending from superior limbus (11 to 2 o’clock) to centre of cornea, with deep faint vascularisation from 11 to 2 o’clock (blue arrow), with resolved pre-Descemet’s bleed (black arrow). (B) Slit view image pre-Descemet’s resolving fibrovascular growth with resolved bleed (blue arrow) and Descemet’s membrane detachment (yellow arrow).

Discussion

Epithelial downgrowth and fibrovascular downgrowth with bleed occur due to migration of epithelial cells onto the posterior surface of cornea. It is a rare complication of intraocular surgery or penetrating ocular trauma leading to a significant ocular morbidity most commonly after cataract surgery, and after penetrating keratoplasty, trabeculectomy, glaucoma drainage surgery, transcorneal sutures and rarely after pterygium excision.^{8 9} The most commonly suggested aetiology for epithelial downgrowth formation include¹⁰:

1. Implantation of epithelial cells following trauma or intraocular surgery/manipulation.

2. Incorporation of a conjunctival flap through a traumatic or surgical wound.

3. Delayed closure of a traumatic or surgical wound.

The other mechanisms following extracapsular cataract surgery predisposing epithelial ingrowth include incomplete or delayed wound healing,^{2 11–18} fistula,^{2 12–14} iris incarceration,^13–15 lens material¹³ or vitreous in the wound,^{13 19} implantation of epithelial cells with instruments^{2 17 19} and through-and-through sutures, creating a tract for epithelial invasion.^{13 14 20}

Wound dehiscence after cataract surgery can cause a fistula which contained an incarcerated anterior capsular flap leading to epithelial downgrowth.²¹ In this patient, a Nd:YAG posterior capsulotomy was performed before it was realised that posterior capsule opacification was associated with epithelial downgrowth.²¹ Our patient also had similar consequences following cataract surgery.

Episcleral blood vessels or conjunctival epithelium invading the cornea after postoperative cataract surgery could have occurred later in our patient. The patient who was treated elsewhere was started on antiglaucoma medications immediately after the surgery as the intraocular pressure was high from the first day post operation.

Glaucoma after diffuse epithelial ingrowth is multifactorial. The aqueous humour drainage may be blocked by the aberrant conjunctival goblet cells in the trabecular meshwork.^{22 23} The epithelial proliferation and inflammation will lead to PAS, trabeculitis and trabecular necrosis further impeding the aqueous flow. Pupillary block may also occur due to vitreous-pupillary adhesion. Topical steroids used intensively for this condition can also lead to glaucoma.^{22 23}

Glaucoma surgeries are also associated with epithelial or fibrous downgrowth.^24–28 A case of epithelial versus fibrous downgrowth identified 10 months after trabeculectomy and was successfully treated with a staged medical and surgical approach has been reported.²⁴ Ruderman et al in their retrospective series of trabeculectomies had reported a single case of epithelial downgrowth after trabeculectomy with mitomycin C.²⁵ In their case, a leak at the flap was seen and treated with a pressure patch, subsequently conjunctival leak was found and the patient declined further treatment and the eye eventually became phthisical.²⁵

Epithelial downgrowth after implantation of a glaucoma drainage device has also been reported. Jewelewicz et al described a case of tissue confirmed epithelial downgrowth in a patient aged 84 years seen 4 months after Ahmed FP7 implantation.²⁶ Hu et al described a case of epithelial downgrowth presenting as a peritubular vascular membrane after Ahmed FP7 implantation.²⁷ Giaconi et al reported epithelial downgrowth presenting as a cyst after goniotomy and Ahmed valve revisions in a child with congenital glaucoma that was treated by ab externo drainage and repeated cryotherapy after recurrence.²⁸

According to previous studies, around 17%–26% of enucleations were associated with an epithelial downgrowth postcataract surgery.^29–35 A 30-year clinicopathological review at the Massachusetts Eye and Ear infirmary, by Weiner et al,³ the predisposing factors, diagnostic features and investigations and results of various types of treatment was studied. A retrocorneal membrane was seen in 45% of patients, glaucoma in 43%, corneal oedema in 21% and a positive Seidel test in 23%. They also emphasised on the fact that mode of presentation in an epithelial downgrowth can be inclusive of corneal stromal vascularisation, stromal downgrowth and damage to underlying endothelium. They suggested that corneal vascularisation can be an important source of nutrition for the downgrowth of the epithelium that can be present up to 6 mm up to the tract of the wound.³⁶ In case of a corneal vascularisation, there is an imbalance between angiogenic and anti-angiogenic factors, with upregulation of VEGF. VEGF belongs to the gene family of that includes VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor. It is responsible for increase in vascular leakage, promoting chemotaxis and generating proliferative signals in inflammatory pathway.

The other causes of corneal vascularisation can include chemical burns, infection, ischaemia, trauma, inflammation. The various methods of treatment of corneal neovascularisation include topical steroidal and non-steroidal anti-inflammatory medications, photodynamic therapy, fine needle diathermy, laser photocoagulation, conjunctival, limbal and amniotic membrane transplantation.^37–39 The hypothesis of anti-VEGF in corneal vascularisation was done following delivery of a murine-soluble VEGF receptor protein, mFlt (1–3)-immunoglobulin G and noting decreased corneal angiogenesis secondary to herpes simplex virus.⁴⁰ The various types of administration for corneal neovascularisation includes subconjunctival, intraocular and topical bevacizumab.^41–45

The pathway of angiogenesis involves multiple factors including growth factor-1 and fibroblastic growth factor-2, matrix metalloproteases, angiostatin, endostatin, pigment endothelium-derived factor, thrombospondin, insulin-like growth factor and platelet-derived growth factor (PDGF). A monotherapy of anti-VEGF or a combination therapy targeting anti-VEGF and above-mentioned other factors can be used in non-resolving case. Therapy targeted against PDGF-B receptors antibody and pegaptanib showed a greater reduction in neovascularisation than the monotherapy treatment groups in mice, according to the study done by Jo et al.⁴⁶Table 1 Summary of the treatment modalities adopted for epithelial ingrowth following different ocular procedures.^47–66

Another non-excisional treatment with 5-fluorouracil, a pyrimidine-analogue antimetabolite that inhibits cellular proliferation, has been used as an alternative for epithelial downgrowth. The antimetabolite has been used widely in ophthalmology for conjunctival neoplasia, pterygium and trabeculectomy because of its ability to inhibit cellular proliferation, fibrosis and excessive scarring.¹⁰ 5-Fluorouracil can be used in a wide range of cases from epithelial cysts to extensive epithelial downgrowth for which excision is not feasible or would lead to hypotony and phthisis.¹⁰

In our patient, as there were no prominent feeder vessels seen near the small incision cataract surgery scar, cauterisation of the vessels following a localised peritomy was excluded. All the fibrovascular growth was in the mid-to-posterior stroma, therefore anti-VEGF eyedrop treatment was not considered. Hence, the option of localised intrastromal and subconjunctival anti-VEGF was chosen in our case. We found that monotherapy with one single dose of anti-VEGF given subconjunctivally and intrastromally resolved the bleed and reduction in neovascularisation was noted.

Patient’s perspective.

I was shocked to see a dark layer in front of my right eye one and half months earlier with blurred vision. I came to know that it was blood in front of the eye. It was looking gory. I was told that there will be scarring despite treatment and reduction of blood. I agreed to the treatment and am now pain free and can see slightly better.

Learning points.

• To prevent epithelial and fibrovascular downgrowth, a water-tight wound closure of Small Incision Cataract Surgery tunnel and side port entry are required.

• Corneal suture to be considered when required for tight wound closure.

• Timely management with topical steroids, antiglaucoma medications and intrastromal antivascular endothelial growth factor or referral to higher centre at the earliest can restore the vision and save the eye.

• Investigation tools aid us in complete evaluation of the entity, to reach proper diagnosis and for appropriate treatment when media is hazy.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).