Neurotrophic Keratopathy in Marfan Syndrome Patient After Micropulse Transscleral Cyclophotocoagulation: A Call for Risk Stratification

Background

Micropulse transscleral cyclophotocoagulation (MP-TCP) is a form of non-invasive laser treatment used in glaucoma treatment to lower intraocular pressure (IOP) [1]. MP-TCP was proposed after witnessing the wide range of complications associated with continuous-wave transscleral cyclophotocoagulation (CW-CPC). MP-TCP uses repetitive alteration of on and off diode laser cycles targeting the pigmented ciliary epithelium. During the on period, the thermal energy is mainly absorbed by the melanin in the pigmented epithelium and to lesser extent by the non-pigmented ciliary epithelium (area of aqueous production), while during the off period the surrounding tissues cools, minimizing the thermal damage [2]; therefore, it has a better safety profile than CW-CPC and has comparable efficacy [3–5]. However, several complications have been reported with MP-TCP, the most frequent being persistent anterior chamber inflammation, hypotony, loss of best-corrected visual acuity, cystoid macular edema, and cataract progression [3]. One of the rarely reported complications is neurotrophic keratopathy (NK). In this case report, we highlight this complication study a unique population that may be at increased risk of developing NK when undergoing MP-TCP.

Case Report

SURGICAL APPROACH:

After administering local anesthesia, gonioscopic gel was applied to the patient’s sclera. Then, the MP3 micropulse probe (IRIDEX, Inc.) was placed 1 mm posterior to the limbus with the notch facing toward the limbus and the probe perpendicular to the surface of the globe. Laser settings were 2000 mW with a duty cycle of 31.3%. One hundred eighty degrees were treated over 90 seconds, sparing the 3 and 9 o’clock positions. The other hemisphere was then treated using the same technique to accomplish 360° of treatment in both eyes. Postoperatively, prednisolone acetate 1% was given every 2 hours with a weekly taper over 6 weeks. Atropine 1% BID, prophylactic topical ofloxacin QID, and all previously used glaucoma medications were continued.

POSTOPERATIVE PERIOD:

On postoperative day 1, the best-corrected visual acuity was 20/200 in the right eye and hand motion “HM” in the left eye. IOP was 19 mmHg in the right eye and 16 mmHg in the left eye. A slit lamp examination revealed a small corneal epithelial defect in the right eye, corneal edema in the left eye, and significant anterior chamber inflammation in both eyes. B-scan ultrasonography results were unremarkable, and the decision was made to increase the topical application of prednisolone acetate 1% from every 2 hours to every 1 hour for both eyes.

On postoperative day 4, the patient had a painless corneal epithelial defect in both eyes, approximately 5 mm vertica×5 mm horizontal, with rolled edges in the right eye and 3 mm vertical×3 mm horizontal in the left eye. Corneal sensation was reduced when tested in both eyes. B-scan ultrasonography showed 360° peripheral choroidal detachment in both eyes. The patient was admitted, corneal cultures were obtained, atropine 1% was continued, and prednisolone acetate 1% was tapered off and then discontinued. Fortified ceftazidime and cefazolin, along with preservative-free artificial tears and eye drops, were added.

A week later, a mild improvement of the corneal epithelial defect was noticed, reaching 4 mm vertical×4 mm horizontal with rolled edges in the right eye and 2 mm vertical×1 mm horizontal in the left eye (Figure 1). Moreover, anterior chamber inflammation also improved. The results of the culture were negative for infection, so fortified topical antibiotics were discontinued. Prophylactic moxifloxacin 0.5%, medroxyprogesterone acetate 1%, and serum BSS 50% were started, and a bandage contact lens was applied for each eye.

On postoperative day 10, the corneal epithelial defect mildly improved in the right eye, measuring 3.5 mm vertically and 2.5 mm horizontally (Figure 2), and healed in the left eye. B-scan ultrasonography showed improved peripheral choroidal detachment in both eyes. During postoperative month 1, since the epithelial defect was the same in the right eye, the option of amniotic membrane transplant was discussed, but the patient refused, and the decision was made to start Endoret (plasma rich in growth factor) in the right eye along with the other topical drops.

During postoperative month 2, the vision improved to 20/200 in the right eye and 20/70 in the left eye. IOP was 16 mmHg in the right eye and 10 mmHg in the left eye without antiglaucoma drops. The epithelial defect had mildly improved in the right eye with stromal opacity, but the patient was still refusing any further surgical intervention (Figure 3). B-scan ultra-sonography showed resolved choroidal detachment.

During postoperative month 6, the best-corrected vision was 20/80 in the right eye and 20/60 in the left eye. IOP was 9 mmHg in both eyes without antiglaucoma drops. The epithelial defect was healed in the right eye with a dense inferior and paracentral corneal scar associated with a large-caliber stromal vessel (Figure 4). Corneal sensation returned to normal in both eyes when tested. Cyclosporine (CSA 1%) eye drops have been started for the right eye, with a possible corneal transplant in the future.

Discussion

NK is a serious, vision-threatening condition that can lead to stromal melting and corneal perforation [6]. A neurotrophic ulcer usually develops because of injury to the long ciliary nerves that originate from the nasociliary nerve, a branch of the trigeminal nerve. Ciliary nerves are responsible for corneal sensation and play a role in blink reflex and tear production [6,7]. Several risk factors for NK have been reported, including herpetic keratitis, prior ocular surgery involving corneal incisions, chemical burns, long-term use of topical medications, and any ocular or systemic conditions that damage the trigeminal nerve [6,8]. Multiple reports of NK have previously emerged with the use of traditional CPC since the continuous nature of the emitted diode laser damages the long ciliary nerves [9–11]. Consequently, it is important to avoid the 3 and 9 o’clock positions where the long ciliary nerve presides. On the other hand, with the MP-TCP there were only 4 reported cases of NK and almost all had predisposing risk factors for it [12–14]. Perez et al reported 2 cases in which both patients developed painless NK after undergoing MP-TCP approximately 1 month before [12]. Both patients had diabetes; diabetic patients have been shown to have decreased corneal sub-basal nerve fibers by confocal microscopy and thus considered a risk factor for NK [6]. Another risk factor that both patients shared was prior ocular surgeries; depending on the ocular surgery involved, the effect on the corneal nerves can vary [15]. In general, ocular surgery that involves corneal incision can lead to direct damage to the ciliary nerves. In contrast, in our case, the patient had a history of AC IOL implantation in both eyes, which is done through a scleral tunnel. Sitompul et al have tested corneal sensation in a similar surgery, which is small-incision cataract surgery (SICS), which employs a scleral incision, similar to our patient’s surgery. After SICS, they have demonstrated that these patients had no decrease in corneal sensation at 2 weeks postoperatively [15,16]. In regards to our patient, he had developed NK relatively faster (on day 4 postoperatively) compared to previously reported cases; this may allude to the fact that our patient was at high risk of developing NK, possibly since Marfan syndrome is characterized by thin sclera, which leads to higher absorption of energy from the laser, thereby damaging the long ciliary nerves. From a histological perspective, it has been demonstrated that individuals with Marfan syndrome exhibit thinning of the sclera; the cause of this thinning is the presence of abnormal fibrillin-1 gene in Marfan syndrome patients [17]. Fibrillin-1 is a glyco-protein that forms the main component of extracellular micro-fibrils. These microfibrils are thought to be important in the formation of elastic fibers in connective tissues [17,18]. These abnormal fibrillins are found in the sclera between the collagen lamellae, leading to scleral thinning [19]. Other causes of thin sclera include Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, and previous ocular surgeries.

Apart from the thin sclera found in Marfan syndrome, our patient had history of long-term use of topical combination eye drops containing beta-blockers. Ranno et al have shown with confocal microscopy that glaucoma patients treated with beta-blockers or prostaglandin analog have fewer corneal nerve fibers and it was reported previously in the literature that patients using topical beta-blockers have corneal hypoesthesia as an adverse effect [20–22]. However, there have been no reports of NK developing in patients with only topical beta-blockers use as the sole risk factor. This leaves high uncertainty about the association between NK and beta-blockers use. That uncertainty leads to the following question: below what degree of corneal hypoesthesia does NK develop? Hsu et al have attempted to address this uncertainty by conducting a retrospective analysis of patients with corneal anesthesia who consequently developed NK. They found that the threshold for developing NK, measured using a Cochet-Bonnet esthesiometer, is 3 mm [23]. Corneal sensation was not tested before the MP-TCP in our patient. Large observational studies are needed to evaluate corneal sensation in glaucoma patients with long-term use of antiglaucoma before undergoing MP-TCP to look for a link between the degree of corneal sensation measured and subsequent NK development.

The management of NK is complex, but the goal is to stop corneal epithelial breakdown and promote healing. The first step is usually to use preservative-free lubrication and ointment, stop any unnecessary topical medications, and use prophylactic antibiotics to prevent secondary infections [6]. Next, using topical collagenase inhibitors such as N-acetylcysteine or topical medroxyprogesterone acetate 1% is advised to prevent stromal melting [24]. In addition, systemic administration of tetracycline or medroxyprogesterone can be considered. The use of autologous serum eye drops is encouraged since they contain growth factors and vitamins that are important for maintaining the epithelium [8]. Surgical options are reserved for severe refractory cases, and they include amniotic membrane transplantation and tarsorrhaphy to promote corneal epithelial healing [6,24,25].

In conclusion, awareness of groups at high risk for developing NK after MP-TCP is crucial to adjust the power of MP-TCP and duration of exposure when treating these patients, to avoid the devastating outcomes of NK.

Conclusions

NK, a vision-threatening condition, is a rare complication of MP-TCP. Being aware of high-risk groups and using lower power and duration when treating these patients could help mitigate this increased risk.