Corneal Ring Infiltrate Following Micropulse Cyclophotocoagulation

Introduction

Neurotrophic keratitis (NK) is a corneal disease characterized by loss of corneal sensation, leading to decreased tear production, impaired epithelial healing, and corneal ulceration and perforation. It can develop secondary to systemic and ocular conditions like diabetes mellitus and herpes virus ocular infection. Ocular procedures that result in thermal damage to the perilimbal nerve plexus can also be associated with the development of NK. Here, we report a case of neurotrophic keratopathy following micropulse CPC that presented as a ring-shaped corneal infiltrate with diagnostic and therapeutic challenges. To the best of our knowledge, there are few studies describing this complication following MP-CPC.

Case Report

A 36-year-old woman was referred to the cornea clinic at King Khaled Eye Specialist Hospital (KKESH) with a diagnosis of ring infiltrate in the right eye. Her past medical history included a diagnosis of diabetes mellitus without a known peripheral neuropathy or nephropathy. Her past ocular history included a diagnosis of proliferative diabetic retinopathy (PDR) in both eyes and neovascular glaucoma (NVG) in the right eye. One month prior to presenting to our clinic, she underwent a panretinal photocoagulation (PRP) and intravitreal bevacizumab injection to the right eye. Her intraocular pressure (IOP) was uncontrolled despite using full topical anti-glaucoma drops dorzolamide 2% TID (Trusopt 2% eye drops, Merck & Co., Inc., Rahway, NJ, USA), brimonidine tartrate 0.15% TID (Alphagan P; Allergan Inc., Dublin, Ireland), and bimatoprost 0.01% qhs (Lumigan RC, Allergan Inc, Dublin, Ireland), necessitating a micropulse cyclophotocoagulation (MP-CPC) procedure to the right eye a few days after the retina management plan was implemented. During the MP-CPC procedure, the probe was placed on the conjunctiva 1 mm from the limbus, and 360 degrees were treated over 110 seconds, sparing the 3 and 9 o’clock positions (Power 2000 mW, duty cycle 31.3%, duration of 60 and 50 seconds at inferior and superior hemispheres, respectively). The patient tolerated the procedure well and she had an unremarkable anterior segment exam on days 1 and 7 postoperatively.

One month later, a regular follow-up in the glaucoma clinic found a new onset of inferior corneal epithelial defect and a ring-like corneal opacity. Apart from mild photophobia, the patient was comfortable and without pain or ocular discharge. She denied any history of trauma, use of contact lens, topical non-steroidal anti-inflammatory drugs (NSAIDs), or anesthetic eye drops. Her best corrected visual acuity was 3/200 in the right eye and 20/25 in the left eye. IOP was 14 and 12 mmHg. Slit lamp examination of the right eye showed a mild conjunctival injection, trace anterior chamber cells, and an inferior corneal epithelial defect (CED) measuring 8×11 mm, with corneal edema and descemet membrane folds. Additionally, a ring-like anterior stromal corneal opacity was noticed inferiorly extending around the 6 o’clock position and separated from the limbus with a 1-mm area of corneal thinning (Figure 1A, 1B). There were no keratic precipitates or hypopyon. A fundus exam showed a cup-to-disc ratio of 0.8 and examination of the fellow eye was unremarkable. Corneal sensitivity testing using a wisp of cotton showed a reduced corneal sensation in the right eye, more pronounced inferiorly compared to the left cornea (tested by gently touching the cornea with a wisp of cotton and assessing the blink reflex in comparison to the sensation of the other eye).

Corneal scrapings were obtained, including those to identify atypical pathogens as fungi and acanthamoeba, and the patient was started on moxifloxacin 6×/day and preservative-free artificial tears hourly. Corneal cultures and smears were all negative. Testing of herpes simplex virus (HSV) using polymerase chain reaction (PCR) was negative and a confocal microscopy imaging showed no signs of acanthamoeba infection. A presumptive diagnosis of a sterile ring infiltrate in a neurotrophic keratopathy was made. Moxifloxacin was tapered to QID and she was advised to continue frequent use of lubricating drops and lubricating eye ointment (white petrolatum/mineral oil). She was re-assessed 3 days later and showed improvement in terms of CED healing (8×5 mm), and thus was kept on the same treatment regimen. She had a follow-up 3 days later for reassessment, with a plan to start a low-frequency topical steroid to reduce the inflammatory component of the ulcer. Due to social reasons, the patient was lost to follow-up and could not present back for reassessment until 6 months later, where she presented off topical medications with a clinical picture of a scarred cornea with neovascularization and a persistent CED measuring (3.5×5 mm) (Figure 2) Due to expected poor compliance to follow-up, the patient underwent amniotic membrane grafting (AMT) in which 2 layers of AMT were placed over the cornea, with an inlay (stroma side down) followed by an overlay (epithelium side down) and secured in place using 8-0 Vicryl suture. Eight weeks later, slit lamp examination showed complete healing of the corneal epithelium, with resorbed AMT and residual inferior scarring and neovascularization.

Discussion

Neurotrophic keratitis (NK) is a serious corneal disease characterized by decreased or absent corneal sensation, leading to epithelial breakdown, impaired epithelial healing, corneal ulceration, and perforation. Common ocular and systemic causes include herpetic keratitis, long-term use of topical medication, and diabetic neuropathy [1,2]. Many ocular surgeries and procedures are also associated with the development of NK, including extensive panretinal photocoagulation (PRP) and cyclophotocoagulation (CPC) [3,4]. Regardless of its underlying etiology, neurotrophic keratitis presents initially as punctate keratitis progressing into persistent epithelial defects, corneal edema, Descemet’s folds, corneal ulcer, and stromal lysis [2]

Corneal ring infiltrate has a broad differential diagnosis of infectious and non-infectious causes, including bacterial keratitis (particularly gram-negative rods) [5], viruses like herpes simplex virus (HSV) [6], fungi [7], acanthamoeba (AK) [8], and sterile immune ring infiltrates, as in contact lens wearers [9], and topical anesthetic abuse [10].

Contact lens and topical anesthetic abuse were excluded by obtaining a careful history. The initial presentation of a ring stromal infiltrate with an overlying corneal epithelial defect necessitated ruling out an infectious etiology by obtaining corneal scrapes for culture and sensitivity. The absence of suppurative discharge and signs of severe ocular inflammation, in addition to negative smears and absence of early growth on cultures, made a diagnosis of bacterial keratitis unlikely. The patient had no history of recurrent previous attacks, the clinical exam was negative for iris atrophy or keratic precipitates, and she had a negative HSV PCR, which made a diagnosis of HSV keratitis less likely. Rings in Acanthamoeba are a late sign and take weeks to develop; this plus a painless presentation, absence of contact lens use, and an unremarkable confocal microscopy for AK signs ruled out this etiology.

The lack of pain and the ability to open eyes comfortably, despite having a large epithelial defect, gave a clue to the neurotrophic nature of the cornea, which was confirmed clinically. Neurotrophic keratitis (NK) can be triggered by MP-CPC secondary to thermal damage to the perilimbal nerve plexus, affecting the integrity and function of the cornea [4]. A handful of case reports detail the onset of NK following MP-CPC, with and without other underlying etiologies such as diabetes mellitus [4,11,12]. Multiple risk factors may have an additive effect to the onset of NK in the reported case. Uncontrolled diabetes mellitus is a known risk factor for NK and is reported to be associated with cases of NK after traditional treatments [13] and MP-CPC [4].

Corneal sensitivity reduction was reported in 15 out of 18 dogs with glaucoma that underwent MP-CPC in a protocol similar to human glaucoma patients. NK developed in 6 out of 18 dogs and healed by an average of 1 month [14]. Similar studies on human eyes are lacking and are of paramount importance in identifying the population at risk and understanding the etiopathogenesis behind this complication. A clinical picture similar to the present case but with an earlier onset was reported for an otherwise healthy patient after receiving MP-CPC combined with phacoemulsification, where a large new-onset corneal epithelial defect was noticed 5 days postoperatively, in addition to absent corneal sensation. Amniotic membrane grafting was required to heal the persistent epithelial defect despite conservative medical management [15].

Perez et al described 2 diabetic patients who presented with corneal epithelial defects ~1 month after MP-CPC. The first successfully healed after the application of a bandage contact lens, but the second had a persistent CED and required a temporary tarsorrhaphy. Of note, both had a recurrent epithelial defect 3 months postoperatively, indicating poor recovery of the neurotrophic corneal function after nerve injury [4].

Although multiple intravitreal injections of anti-vascular endothelial growth factor (VEGF) were found to reduce the corneal sensitivity and subbasal nerve plexus parameters assessed by in vivo confocal microscopy [16], the single injection in our patient is unlikely to have had a major effect on the neurotrophic statues of the cornea. Subsequent injections should be planned carefully due to risk of further impairment of corneal nerve function. Undergoing a subsequent plan of panretinal photocoagulation for proliferative diabetic retinopathy, followed by a micropulse cyclophotocoagulation for an uncontrolled intraocular pressure within 3 days, is assumed to cause massive thermal injury to the ciliary nerve plexus, resulting in a marked decline in the cornea’s neurotrophic function.

Wessely stromal immune ring is another distinctive type of sterile corneal ring infiltrate, caused by a type 3 hypersensitivity mechanism [17]. It involves an interaction of foreign antigens with antibodies, leading to immune complex deposition, mostly at the peripheral corneal stroma, due to its close proximity to the blood and lymphatic vessels in the conjunctiva. The peripheral cornea contains an abundance of immune cells, such as antigen-presenting cells and polymorphonuclear leukocytes, which makes it more vulnerable to immune and hypersensitivity reactions. Activation of the complement system leads to recruitment of polymorphonuclear cells, mainly neutrophils, into the corneal stroma [17]. It was suggested that removal of the corneal epithelium may be a trigger for an immune reaction to occur, and this has explained the development of Wessely ring following different ophthalmic procedures that disturbs the epithelial integrity, like phototherapeutic keratopathy (PTK), laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), and corneal collagen cross linking (CXL) [18–20].

In addition to a neurotrophic cornea, a secondary underlying immune component is a plausible etiology, as damaging the neurosensory function of the cornea and disturbing its epithelial integrity after MP-CPC can trigger the release of a trapped antigen and a subsequent immune reaction. Unlike the present case, in which the patient presented 1 month after undergoing MP-CPC), previously reported cases of Wessely immune ring had an earlier onset of ulcer, within a week or less following ophthalmic procedures [18–20]. Early introduction of topical steroids to the management plan, after ruling out an infectious etiology, could have hastened the clinical improvement, but this was limited by suboptimal patient follow-up and compliance.

Medical management of neurotrophic keratopathy aims to promote epithelial healing and prevent progression of corneal damage using intensive topical therapy such as preservative-free lubricants and autologous serum tears [1]. To promote epithelial healing, a bandage contact lens can be applied after an infectious etiology is ruled out. Moreover, replacement of preserved anti-glaucoma drops with preservative-free alternatives can lessen the ocular toxicity and improve re-epithelization. Topical recombinant human nerve growth factor (rhNGF) is a promising treatment for moderate to severe neurotrophic keratopathy, which was proven to be safe and effective [21]. Alhajraf et al reported a case in which an 8-week course of Cenegermin was administered for treatment of a neurotrophic corneal ring ulcer secondary to uncontrolled diabetes, with a decreased central ring density and complete healing of the epithelial defect noted up to 4 months after cessation of treatment [3].

Surgical interventions are often required in refractory cases of NK and are especially pertinent in patients with poor compliance to medical management or to follow-up, as with our patient. AMT effectively promotes corneal epithelial healing, reduces vascularization, and alleviates ocular surface inflammation [22]. A randomized control study demonstrated that the time required for complete epithelialization was comparable between AMT and traditional treatments like tarsorrhaphy or bandage contact lenses [23].

Beside amniotic membrane transplant, tarsorrhaphy is considered a cornerstone surgical approach for NK refractory to medical treatment, as it provides a moist environment for epithelial healing and decreases friction with the eyelid [24]. In NK patients with expected poor follow-up, amniotic membrane grafting or temporary lateral tarsorrhaphy should be considered early in the management plan to prevent the occurrence of unfavorable sequalae such as scarring.

In the event of a confirmed neurotrophic sterile ring ulcer, initiating topical steroids early in the course of treatment with careful follow-up is important to lessen inflammation and limit subsequent corneal damage. Unfortunately, our patient’s management and clinical course were complicated by a poor follow-up, which hindered the initiation of steroids in early stages.

Conclusions

As NK after MP-CPC is more frequently encountered, we suggest that this complication should be discussed preoperatively, with proper patient counselling. We recommend a routine preoperative assessment of corneal sensation, especially in patients at risk, such as diabetics, as well as a close postoperative monitoring of ocular surface health to prevent serious ocular complications such as corneal scarring, melting, or perforation. Customized treatment protocols such as shortening the treatment time may be considered in high-risk patients. Routine use of lubricating eye drops should be advocated for patients with MP-CPC.