Eyewash with balanced salt solution after intravitreal methotrexate injection in a case of vitreoretinal lymphoma: a simple but effective way to prevent ocular surface toxicity

Abstract

Intravitreal methotrexate injection (400 µg/0.1 mL) is the current mainstay for managing vitreoretinal lymphoma. Various complications associated with intravitreal methotrexate are cataract, keratopathy, maculopathy, sterile endophthalmitis, optic atrophy, vitreous haemorrhage, etc. The most common adverse effect of intravitreal methotrexate is keratopathy occurring in more than half of cases. The severity may range from diffuse punctate keratopathy to severe epitheliopathy leading to photophobia, pain, visual blurring, epiphora, etc. This may become a reason for reduced compliance with treatment. The management of these complications includes oral folic acid, topical folinic acid supplementations and reduced frequency or cessation of methotrexate intravitreal injections. Here, we report a simple method of eyewash in a large amount of balanced salt solution after the intravitreal injection procedure to reduce the severity of keratopathy, which helped the patient tolerate the treatment.

Background

There are no optimal guidelines for the management of vitreoretinal lymphoma. Intravitreal methotrexate and rituximab injections are the current mainstays of management. Intravitreal methotrexate (400 µg/0.1 mL) is used in three phases: induction (twice a week for 4 weeks), consolidation (weekly for the next 8 weeks) and maintenance (monthly for the next 9 months).¹ Various complications associated with intravitreal methotrexate are cataract, keratopathy, maculopathy, sterile endophthalmitis, optic atrophy, vitreous haemorrhage, etc.² The most common adverse effect of intravitreal methotrexate is keratopathy occurring from half to all cases.^{3 4} The severity may range from diffuse punctate keratopathy to severe epitheliopathy leading to photophobia, pain, visual blurring, epiphora, etc. This may become a reason for reduced compliance with treatment. The management of these complications includes oral folic acid, topical folinic acid supplementations and reduced frequency or cessation of methotrexate intravitreal injections.^{1 2} Methotrexate is a cheaper (than rituximab) and effective drug for managing vitreoretinal lymphoma. Here, we report a simple method of eyewash in copious amounts of balanced salt solution (BSS) after the intravitreal injection procedure to reduce the severity of keratopathy, which helped the patient tolerate the treatment.

Case report

A man in his late 30s presented to our outpatient department with painless progressive vision loss in the right eye (RE) for a duration of ten days. He was a known case of diffuse large B-cell lymphoma and had completed chemotherapy (Rituximab, Cyclophosphamide, Hydroxydaunomycin, Oncovin, Prednisone/ R-CHOP) with remission 5 months ago. The corrected distance visual acuity was counting fingers in RE and 6/6 in the left eye (LE). Anterior segment examinations were normal in both eyes. RE fundus examination showed dense vitreous infiltration of lymphomatous cells over the disc and macula. LE fundus was normal. Cerebrospinal fluid analysis was normal, and MRI did not reveal any involvement of CNS. We diagnosed it as a case of vitreoretinal lymphoma. The patient was advised for intravitreal injection of methotrexate (400 µg/0.1 mL) under topical anaesthesia. He had pain, photophobia and epiphora the day after the first injection. Examination showed diffuse conjunctival congestion and marked punctate corneal epitheliopathy (Oxford grade IV) (figure 1A–D).⁵ There was no sign of inflammation in the anterior chamber.

Figure 1.

Shows diffuse conjunctival congestion (A–C) and marked diffuse punctate keratopathy (D) 1 day after intravitreal methotrexate injection. After postprocedural washing of the ocular surface with the balanced salt solution, significant improvement was noticed. After eight intravitreal methotrexate injections in the first month, conjunctival congestion was absent (E–G), and mild punctate keratopathy was present (H).

Treatment

The patient was given oral folic acid (5 mg/day) supplementation and artificial teardrop (sodium hyaluronate 0.1%) eight times/day. Eye-drop moxifloxacin (0.5%) was continued as per postintravitreal injection guidelines.

Outcome and follow-up

Over the next 2 days, the punctate corneal epitheliopathy improved marginally. The patient felt mild symptomatic improvement. The second intravitreal methotrexate injection was given on the third day after the first dose, causing worsening symptoms. The previous treatment was continued. The third intravitreal methotrexate injection was planned after 3 days. During the procedure, after injecting the methotrexate, the injection site was kept pressed with a bud tip, and the ocular surface was irrigated with about 200 mL of BSS. The same procedure was done each time methotrexate was injected. Drugs were continued as before. The symptoms and signs of keratopathy were reduced significantly and did not worsen even on continuing twice weekly injection regimen. At the end of 4 weeks (eight doses of intravitreal methotrexate), the keratopathy had improved to Oxford grade II (figure 1E–H).⁵ The patient received twice weekly intravitreal methotrexate for the first month, followed by once weekly for the second month, followed by once monthly injections for the next 2 months. However, due to a subnormal therapeutic response to methotrexate, he was subsequently shifted to intravitreal rituximab injections.

Discussion

Methotrexate is a dihydrofolate reductase inhibitor that interferes with DNA and RNA synthesis. Tissues with a high rate of mitosis are affected by it. The corneal toxicity after intravitreal injection of methotrexate is believed to be due to the local spillage of the drug during the procedure. The mitotically active limbal stem cells are affected, leading to temporary limbal stem cell deficiency, which causes corneal epithelial breakdown.² Also, due to the antimitotic property, frequent intravitreal injections affect the corneal epithelium in a dose-dependent manner.⁶ Smith reported mild keratopathy in 58% of cases, which generally resolved spontaneously or after treatment with artificial tear drops.³ Whereas Frenkel et al reported keratopathy in all cases, with severity ranging from superficial punctuate to severe epitheliopathy. In most cases, the keratopathy appeared after the third injection.⁴ Jeong et al have reported a 22.7% incidence of the development of keratopathy. More than half of these patients had severe enough keratopathy to stop the injections.⁶ The toxic effect of methotrexate is dose-dependent so frequent injections may cause increased severity of keratopathy. Methotrexate also increases inflammatory mediator release from corneal epithelial cells adding to the keratopathy caused by its cytotoxic effects.⁶

The management of methotrexate-induced keratopathy includes oral folic acid supplementation, topical folinic acid and lubricating eye-drops. There is no evidence-based information on the optimal dose and the administration route of folic acid, which can ameliorate the toxic effects of methotrexate without compromising its therapeutic effect. Topical administration of folic acid can be an alternative option.⁶ Folinic acid has been successfully used in severe cases with success.^{2 4} Folinic acid has a very short half-life. Also, a commercial preparation of folinic acid and folic acid for topical use is not readily available. So, managing the keratopathic effect of methotrexate is fraught with many challenges. Zhou et al have proposed a reduced frequency regimen to reduce the keratopathic effects of methotrexate. The safety and efficacy of this modified regimen need to be established beyond doubt.¹ In severe cases of keratopathy, cessation of intravitreal methotrexate has become necessary in many studies.^{2 6}

Reflux and spillage of drugs can occur during any intravitreal injection procedure.⁷ This exposes the corneal epithelium and the limbal stem cells to methotrexate and its toxic effects. We could manage to prevent this complication by a simple method of using a large amount of BSS to wash off any inadvertently spilled methotrexate on the ocular surface. A cotton bud was kept on the injection site during the saline wash to prevent any drug reflux due to the patient squeezing the eyes. We could not achieve significant remission in symptoms with oral folic acid supplementation. But with the above-described procedure, we could ameliorate the symptoms significantly, and the patient tolerated the drug.

Learning points.

• Keratopathy is a common complication of intravitreal methotrexate injection, which may lead to cessation of the treatment.

• Prevention of reflux of the drug onto the ocular surface during and after the procedure and washing off any inadvertently spilled drug can help prevent or minimise keratopathy.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).