The Discovery That Saved a Baby’s Life

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In December of 2016, Cornelius Crystal* was 6 weeks old—and both of his eyes were red and tearing. His parents took him to a local pediatric ophthalmologist, who diagnosed him with adenoviral conjunctivitis and prescribed a short course of TobraDex. At this time, the ophthalmologist noted that Cornelius also had a membrane under both upper and lower eyelids, and peeling was performed.

However, the membranes recurred despite repeated attempts at peeling over several months. After the fourth membrane peel, Cornelius’ parents brought him to us at the Duke Eye Center.

We Get a Look

When Cornelius presented to our eye clinic at 6 months of age, his mother reported that he had no apparent vision issues but noted that he was experiencing significant tearing and eye irritation. He had no other past medical or ocular history and had been born full-term at 39 weeks. During this consultation, Cornelius’ parents expressed concern that the membranes recurred each time they were peeled. Based on the his­tory of chronicity and recurrence, we were concerned about a chronic toxic or foreign body reaction, sarcoidosis, amyloidosis, herpes simplex, or severe vernal or atopic keratoconjunctivitis.

The exam. Cornelius’ vision was fix-and-follow in both eyes, as expected for his age. His IOP readings were normal, and he had no relative afferent pupillary defect. His visual fields and extraocular movements were full to clinic testing. The cycloplegic refraction showed a mild myopic astigmatism in both eyes.

The exam showed bilateral (left larger than right) large lesions under the up­per and lower eyelids, with conjunctival injection and increased tear meniscus (Figs. 1A, 1B). There were no corneal or eyelid lesions, and the rest of the exam was unremarkable.

We decided to remove the mem­branes again in the operating room and send a specimen to pathology for evaluation. We everted both the right and left upper and lower eyelids and slowly peeled away the membranes with occasional use of a Tooke blade and micro-Westcott scissors. At the site of each excision, amniotic membrane attached with fibrin glue was placed to facilitate healing. Because of the con­stant tearing, we also took this opportu­nity to evaluate the nasolacrimal ducts. Fluorescein-dyed saline was instilled into each cannula and retrieved in the nose via nasal suction, ruling out a concurrent obstruction.

The pathology report. The patholo­gy report revealed brightly eosinophilic amorphous and fibrillar material that stained brown with the fibrin immunohistochemical stain. With Masson trichrome, the specimen stained mostly blue and light red, typical of fresh and aging fibrin. There was no sign of amy­loid using Congo red stain.

The pathologist’s impression: these findings were consistent with ligneous conjunctivitis.

WHAT’S YOUR DIAGNOSIS? The patient experienced multiple recurrences of chronic conjunctivitis and membrane.

A Rare Condition

Ligneous conjunctivitis is a rare chronic conjunctivitis characterized by fibrin-rich membranes or pseudo­membranes. It is typically associated with plasminogen deficiency, which can result from a mutation of the PLG gene on chromosome 6.¹ This gene is respon­sible for the production of plasmino­gen, the precursor protein of plasmin, which degrades fibrin and other matrix proteins into their byproducts.²

When microtrauma of the ocular surface induces the wound healing cascade, the lack of plasmin can cause extensive fibrin matrix deposition. As this fibrin matrix cannot be replaced with granulation tissue and is unable to be remodeled, wound healing is impaired.

Typical presentation. Patients typ­ically present with fibrinous pseudo­membranes or true membranes on the palpebral conjunctiva.¹ These mem­branes are often described as thick and “woody,” can be sessile or pedun­culated, and range in color from white to yellow or even red. They can lead to chronic tearing, pain, corneal abrasions, and photophobia. Long-term complica­tions include corneal scarring, corneal neovascularization, and symblepharon. A viral infection can trigger the devel­opment of these membranes, causing possible confusion with the pseudo­membranes that may occur with viral conjunctivitis.

Ligneous conjunctivitis is a very rare condition, estimated at about 1.6 patients per million (though this condition is likely underdiagnosed).¹ In addition to ocular findings, patients can have sys­temic associations, including ligneous lesions in the respiratory tract, oral cavity, brain, and genital tract.³ It is important to coordinate with other specialties—particularly hematology—when managing patients.

Diagnosis. The differential diagno­sis for a chronic recurrent membrane in the pediatric population includes chronic toxic or foreign body reaction, sarcoidosis, amyloidosis, herpes sim­plex, or severe vernal or atopic kera­toconjunctivitis. Definitive diagnosis is made with analysis of a biopsy by pathology.

The patient’s systemic level of plas­minogen activity can be tested with an assay. In our patient, the plasminogen activity level was 14% of expected (nor­mal range is 85%-120% of expected). Patients are considered to have Type 1 plasminogen deficiency, also known as hypoplasminogenemia, when they have both decreased levels of plas­minogen and decreased plasminogen activity.³ Patients with normal levels of plasminogen but reduced levels of activity are described as having Type 2 plasminogen deficiency, also known as dysplasminogenemia, which is usually asymptomatic. Genetic testing also can be performed for mutations in the PLG gene in the patient and family.

A thorough multidisciplinary eval­uation of the full extent of symptoms from plasminogen deficiency should also be performed. It is important not to stop at control of ocular symptoms when a diagnosis of plasminogen deficiency is made after presenting with ligneous conjunctivitis.

Management/treatment. The cur­rent literature includes many reports of successfully treating the lesions with top­ical hyaluronidase or alpha chymotryp­sin, both of which dissolve the fibrin matrix. After dissolution, anti-inflam­matory treatment with topical steroids, topical cyclosporine, or systemic aza­thioprine has been shown to decrease the rate of recurrence.¹ More recently, reports have trended toward supple­mentation of natural plasminogen with fresh frozen plasma to directly treat the underlying deficiency.⁴

It is important not to surgically re­move these lesions without adjunctive therapy, as that would simply restart the wound healing cascade and cause recurrence of these membranes. In a series of 17 cases, surgical excision fol­lowed by aggressive topical heparin and steroids led to success in 76.4% (13/17) of patients.⁵ The mechanism of treat­ment with heparin is to inhibit throm­bin formation, which then inhibits the production of fibrin—and, thus, fibrin matrix formation.

Treatment of this condition should involve a multidisciplinary team. This should include a hematologist to coor­dinate laboratory and genetic workup. Referrals to other specialists should be made based on internal findings, due to possible lesions in the respiratory tract, oral cavity, brain, and genital tract.

BEYOND THE EYES. Bronchoscopy image of an irregular mass (arrow) in his airway near his vocal cords.

Our Patient

We referred Cornelius to a clinical trial in which he received topical plasminogen drops.⁶ Shortly after therapy was initiated, his membranous lesions resolved. However, 3.5 years later, he developed voice hoarseness. A bronchoscopy was performed; this showed an irregular mass in his airway near his vocal cords (Fig. 2). Had the earlier diagnosis not been made, the new mass might have been excised and then recurred, possibly growing larger. Instead, Cornelius was switched to weekly IV plasminogen and the mass disappeared.

He is now 6 years old. In his most recent follow-up, his BCVA was 20/20 in both eyes, and there were no signs of membranes in any part of his body. His case is a reminder that if plasminogen deficiency is caught early enough, its detection can potentially save a life.

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* Patient name is fictitious.

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1 Schuster V, Seregard S. Surv Ophthalmol. 2003;48(4):369-388.

2 Castellino FJ, Ploplis VA. Thromb Haemost. 2005;93(4):647-654.

3 Schuster V et al. J Thromb Haemost. 2007;5(12):2315-2322.

4 Shapiro AD et al. Haematologica. 2020;105(3):554-561.

5 De Cock R et al. Ophthalmology. 1995;102(11):1654-1659.

6 Caputo R et al. Ophthalmology. 2022;129(8):955-957.

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Drs. Tian and Peralta Chacon are ophthalmology residents; Dr. Daluvoy is associate professor of ophthalmology in the Cornea, External Disease, and Refractive Surgery Department; and Dr. Freedman is chief of the Pediatric Ophthalmology and Strabismus Division. All are affiliated with the Duke Eye Center in Durham, N.C. Relevant financial disclosures: None.

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