Ligneous conjunctivitis is a rare form of conjunctivitis with recurrent pseudomembrane formation that occurs in patients with plasminogen deficiency. We present a case of an 8-week-old female infant with ligneous conjunctivitis.
An 8-week-old female infant presented to the general ophthalmology clinic with bilateral eyelid swelling, injection, and mucoid drainage. Her birth was uncomplicated, and she was breastfeeding normally. The parents reported no family history of eye conditions. The symptoms were noted in the second week of life and had gradually worsened. Membrane formation was found on the upper tarsal conjunctiva of both eyes. One month prior to presentation, the patient was taken to the emergency department and had the membranes removed (Figures 1–2). She was administered topical steroid therapy for presumed conjunctivitis and instructed to follow up with a cornea specialist.
Right eye demonstrating membranes before excision in the emergency department. Left eye and membrane specimen (resting on cheek) after removal. Bilateral periorbital erythema and thickening of the skin.
Resolution of conjunctival membranes after excision in the operating room.
On presentation to our clinic, her visual acuity was light perception and intraocular pressure was normal. On slit-lamp examination, dense membranes were present on the tarsal conjunctiva bilaterally. The membranes were removed with a cotton swab and sent to pathology. Cyclosporine 1% drops were started four times daily, but failed to prevent recurrence of membrane formation over a 2-month period. Results of pathologic examination of the membranes were positive for a fibrovascular membrane with scattered acute and chronic inflammation, which is consistent with ligneous conjunctivitis. The membranes were excised and an amniotic membrane was placed. The patient was then given heparin drops 1,000 units/mL four times daily.
The patient and her parents were referred to the hematology department for a systemic work-up. She was found to have severe plasminogen deficiency (12%; reference range: 65% to 176%). Her mother had a mild plasminogen deficiency (59%), whereas her father had a normal serum plasminogen level (74%). The patient began weekly transfusions of fresh frozen plasma, coordinated with membrane removal by an ophthalmologist under general anesthesia. Three months later, she began fresh frozen plasma ophthalmic drops (0.5 mL in each eye, four to six times per day). The patient obtained 3-mL aliquots of fresh frozen plasma from Texas Children's Hospital Blood Bank in Houston, Texas. The fresh frozen plasma was dispensed with instructions to store the drops at a temperature of 1°C to 10°C, with any unused drops expiring at midnight of the fifth day. Unfortunately, the membranes continued to recur. The patient was subsequently enrolled in a compassionate-use study for plasminogen eye drops at the Indiana Hemophilia and Thrombosis Center. After 3 months of treatment with plasminogen eye drops, there was no recurrence of membrane formation. The patient's family then moved to another state and her care was transferred to a local pediatric ophthalmologist and cornea specialist, but the topical plasminogen therapy was maintained. Six months later, the patient developed an upper respiratory tract infection, and was found to have lesions in her respiratory mucosa. The patient was admitted to the hospital, where she received fresh frozen plasma infusions and intravenous plasminogen through a ProMetic BioTherapeutics study at the Indiana Hemophilia and Thrombosis Center. Topical plasminogen was discontinued at this time. The patient's pulmonary symptoms resolved within 3 days of therapy. Respiratory mucosal lesions were not found on bronchoscopy or laryngoscopy examination 2 weeks after intravenous plasminogen therapy. She continues to receive home intravenous plasminogen therapy every 4 days. At her most recent visit, 27 months after initial presentation, she did not have any recurrence of her ocular membranes.
Ligneous conjunctivitis is a rare, autosomal recessive, membranous conjunctivitis characterized by recurrent formation of a pseudomembrane described as having a “woody” induration. The pathogenesis of ligneous conjunctivitis involves a deficiency in plasminogen type 1. Plasminogen is a precursor molecule of plasmin, which is responsible for degradation of fibrin. The absence of plasminogen leads to fibrin-rich pseudomembrane formation. Ligneous conjunctivitis presents with chronic tearing and conjunctival injection, followed by formation of pseudomembranes, most commonly on the upper tarsal conjunctiva, but the lower eyelid and bulbar conjunctiva may also be involved. The disease is bilateral approximately 50% of the time and the cornea can also be involved, potentially leading to blindness. Membranes have been documented to form in response to ocular irritants such as dust or foreign bodies. There have also been reports of infections or previous surgeries initiating an attack. In our case, presumed conjunctivitis triggered the first episode of ligneous conjunctivitis. Systemic associations include lesions of the mouth, ear, nasopharynx, trachea and respiratory tract, gastrointestinal tract, or female genital tract.1 Our patient exhibited lesions in her respiratory tract, which caused stridor and worsening respiratory symptoms until intravenous plasminogen therapy was initiated, resulting in a week-long hospitalization.
Treatment of ligneous conjunctivitis is not standardized. Surgical excision of the pseudomembranes with subsequent medical therapy leads to short-lived improvement followed by recurrence, and often worsening, of pseudomembrane formation. Some therapeutic options that have not yielded effective long-term results include topical administration of hyaluronidase, corticosteroids, cyclosporine, cromolyn, and antiviral agents. Other therapies include immunosuppressive therapy, such as cyclosporine A and azathioprine, which can be locally or systemically administered. A combination of heparin with topical corticosteroids or alpha-chymotrypsin and fresh frozen plasma eye drops are other therapeutic options.1,2
Repeated plasminogen infusions were shown to be effective in resolving ligneous pseudomembranes in 1998.3 Effective treatment with plasminogen topically was first reported in 2002.4 To our knowledge, the effectiveness of topical plasminogen therapy was assessed in one human study,5 one case series,4 and four case reports6–9 in which the effectiveness of topical plasminogen therapy was assessed. Our study adds to this literature by describing the youngest patient with the longest follow-up duration who was treated effectively with both topical and systemic plasminogen.
A study with 11 patients from three sites (1 United States, 2 Italy) sought to determine the clinical safety and efficacy of plasminogen ophthalmic drops in patients with ligneous conjunctivitis.5 Four males and seven females were enrolled. Seven had unilateral lesions, whereas four had lesions present bilaterally. Patients were treated for 4 weeks followed by surgical excision if required (8 of 11 patients). Therapy with plasminogen was continued and follow-up was conducted at 3 months. In all compliant patients, full regression was seen at the 3-month follow-up visit. One male patient with bilateral involvement was removed from the study due to non-compliance after excision and demonstrated recurrence of lesions. The findings from the remaining five case reports, as well as our case, are summarized in Table 1.
Literature Review of Patients With Ligneous Conjunctivitis
Our patient presented as an 8-week-old female infant with membranous conjunctivitis in both eyes. She failed topical therapy including cyclosporine, topical steroids, heparin, and fresh frozen plasma drops. Surgical management also failed to resolve her symptoms. The diagnosis of plasminogen deficiency helped guide therapy and the patient was eventually enrolled in a topical plasminogen study, where her ocular symptoms resolved and no ocular recurrence was noted. Topical plasminogen therapy is not yet approved by the U.S. Food and Drug Administration but seems promising as a therapeutic option for patients with confirmed ligneous conjunctivitis, whereas intravenous plasminogen is a good option for systemic disease.
- Mocanu CL, Manescu MR, Deca AG, Craitoiu S, Jurja S. Clinical and histopathological aspects in two cases of ligneous conjunctivitis. Rom J Morphol Embryol. 2016;57:601–605.
- Schuster V, Seregard S. Ligneous conjunctivitis. Surv Ophthalmol. 2003;48:369–388. doi:10.1016/S0039-6257(03)00056-0 [CrossRef]
- Schott D, Dempfle C, Beck P, et al. Therapy with purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. N Engl J Med. 1998;339:1679–1686. doi:10.1056/NEJM199812033392305 [CrossRef]
- Watts P, Suresh P, Mezer E, et al. Effective treatment of ligneous conjunctivitis with topical plasminogen. Am J Ophthalmol. 2002;133:451–455. doi:10.1016/S0002-9394(01)01433-7 [CrossRef]
- Nakar CT, Caputo R, Price FW Jr., et al. Safety and efficacy of human plasma derived plasminogen ophthalmic drops for treatment of ligneous conjunctivitis: report of phase 2/3 clinical trial. Blood. 2015;126:2288.
- Heidemann DG, Williams GA, Hartzer M, Ohanian A, Citron ME. Treatment of ligneous conjunctivitis with topical plasmin and topical plasminogen. Cornea. 2003;22:760–762. doi:10.1097/00003226-200311000-00009 [CrossRef]
- Caputo R, Pucci N, Mori F, Secci J, Novembre E, Frosini R. Long-term efficacy of surgical removal of pseudomembranes in a child with ligneous conjunctivitis treated with plasminogen eye-drops. Thromb Haemost. 2008;100:1196–1198. doi:10.1160/TH08-04-0233 [CrossRef]
- Conforti FM, Di Felice G, Bernaschi P, et al. Novel plasminogen and hyaluronate sodium eye drop formulation for a patient with ligneous conjunctivitis. Am J Health Syst Pharm. 2016;73:556–561. doi:10.2146/ajhp150395 [CrossRef]
- Ang MJ, Papageorgiou KI, Chang SH, Kohn J, Chokron Garneau H, Goldberg RA. Topical plasminogen as adjunctive treatment in recurrent ligneous conjunctivitis. Ophthal Plast Reconstr Surg. 2017;33:37–39. doi:10.1097/IOP.0000000000000694 [CrossRef]
Literature Review of Patients With Ligneous Conjunctivitis
|Study||Age (y)||Sex||Localization||Follow-up Duration (Mo)||Outcome|
|Watts et al.4 (2002)||5||F||Bilateral||12||Recurrence|
|Watts et al.4 (2002)||5||F||Unilateral (right)||12||Remission|
|Watts et al.4 (2002)||1||M||Bilateral||12||Remission|
|Heidemann et al.6 (2003)||7||M||Unilateral (right)||3||Remission|
|Caputo et al.7 (2008)||2||M||Bilateral||12||Remission|
|Conforti et al.8 (2016)||9||F||Bilateral||1||Remission|
|Ang et al.9 (2017)||32||F||Bilateral||5||Remission|
|Current case||8 wks||F||Bilateral||27||Remission|