Eur J Pediatr (2011) 170:1333–1336 DOI 10.1007/s00431-011-1483-9
SHORT REPORT
Management of ligneous conjunctivitis in a child with plasminogen deficiency Helen Pergantou & Dimitra Likaki & Maria Fotopoulou & Olga Katsarou & Panagiota Xafaki & Helen Platokouki
Received: 16 March 2011 / Accepted: 3 May 2011 / Published online: 31 May 2011 # Springer-Verlag 2011
Abstract Plasminogen deficiency, a rare autosomal recessive disorder, is classified as type I (hypoplasminogenemia) or type II (dysplasminogenemia). Hypoplasminogenemia is characterized by impaired wound healing while ligneous conjunctivitis (LC) is its main manifestation presenting with redness of the conjunctivae and progression to pseudomembranes' formation on the palpebral surfaces. A 4-year-old girl with LC in her left eye and impaired vision was referred to our unit. The conjunctival membranes had been already excised twice, followed by recurrences. Soon after the third recurrence, a probable diagnosis of LC was suggested, confirmed by a reduced plasminogen activity at 20% (normal values 80–120%). Both of her parents have slightly reduced plasminogen levels (50–60%) without any relevant symptom. Fresh frozen plasma (FFP) was administered systemically and topically, initiating 2 days before surgical removal of pseudomembranes with electrocautery under general anaesthesia. Systemic FFP was administered for 12 days postoperatively, along with topical use; the later was continued thereafter for 3 months. No recurrence was H. Pergantou (*) : P. Xafaki : H. Platokouki Haemophilia Centre/Haemostasis Unit, Aghia Sophia Children’s Hospital, Athens GR11527, Greece e-mail:
[email protected] D. Likaki Service d’ Ophthalmologie, Lille, France M. Fotopoulou Ophthalmologic Department, Aghia Sophia Children’s Hospital, Athens, Greece O. Katsarou Blood Transfusion Centre—Haemophilia Centre, Laikon Hospital, Athens, Greece
noticed. The vision was improved. Two weeks after cessation of the topical treatment, pseudomembranes reappeared. Topical application of FFP was reinitiated soon thereafter, and the girl underwent a second operation to have the conjunctival pseudomembranes removed. The perioperative therapeutic management was as previously described. Systemic treatment was stopped at the end of the tenth day while topical application of FFP was being continued until now, 10 months postoperatively. No recurrence has been observed and the vision remains at 9/ 10. Conclusion: Since surgical excision of the conjunctival pseudomembranes alone in patients with LC does not protect from recurrences, the perioperative administration of FFP, both systemically and topically improves the outcome. Furthermore, the long-term application of topical FFP preparations seems to prevent recurrences and has a protective effect on the vision of these patients. Keywords Ligneous conjunctivitis . Plasminogen deficiency . Fibrinolysis
Introduction Plasminogen deficiency, a rare autosomal recessive disorder affecting 1.6 out of 1,000,000 individuals, is classified as type I (hypoplasminogenemia) or type II (dysplasminogenemia) [10]. In patients with plasminogen deficiency, wound healing capability is severely reduced and is often obvious in mucous membranes (e.g. conjunctivae) where plasminogen plays a crucial role in intravascular and extravascular fibrinolysis [6]. Ligneous conjunctivitis (LC) is the main manifestation (80% of the cases) of hypoplasminogenemia (type I). It firstly appears with erythema of the conjunctivae and chronic tearing followed by the
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formation of pseudomembranes (yellow-white or thick red masses with a wood-like consistency) on the palpebral surfaces. Pseudomembranes' development is often the result of mechanical injury to the conjunctival mucosa relating to infection, trauma or surgery [9]. The mucosa of mouth, ears, gastrointestinal, respiratory and female genital tract may also be involved, leading to local complications. Management of these patients is problematic, both due to lack of therapeutic recommendations and product availability for appropriate substitution therapy. Several therapeutic approaches have been reported to treat LC, most of them with disappointing results. Surgical removal of pseudomembranes seems to be initially helpful and relieving, but it always results in their recurrence. Topical use of heparin, corticosteroids, cyclosporine, azathioprine, hyaluronidase and α-chymothrypsin has been used with limited success [3, 8, 9]. Although the topical and systemic administration of plasminogen concentrates in clinical trials has been proved effective in treating these lesions [3, 8], they are not available on the international market while the use of fresh frozen plasma (FFP) systemically and topically was chosen in some cases with different results [4, 11].
Materials and methods In this article, the case of a child with plasminogen deficiency and LC is presented in whom the combination of topical and systemic administration of FFP proved to be effective. FFP had not been prepared with a specific formulation to be used as a collyrium. FFP was filled in empty sterilized drop bottles stored at −70°C. One bottle every other day was used for eye drop application and was kept in refrigerator at 4°C for 2 days.
Case report A 4-year-old girl was referred to our unit with severe unilateral thick yellow pseudomembranes originating from the conjunctivae of her left eye (Fig. 1a, b). Her vision was Fig. 1 Patient's left eye prior to therapeutic intervention. a External palpebral appearance. b Formation of pseudomembranes on internal palpebral surface
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severely impaired ipsilaterally to 2/10. The child was suffering from conjunctivitis of the left eye since the age of 12 months. Initially presenting as redness and thin white membrane formation, the conjunctivitis progressively worsened in the following years. The girl was born at full term with a weight of 2,850 g. She had a brother and a sister, twins of 6 years old, with no history of conjunctivitis. The mother complained of recurrences of mild “redness” in both eyes but no severe impairment of conjunctivae was detected, while the father had no complaints. Both parents were born in the same village, on a small island, but no consanguinity was reported. At referral, the child had already undergone surgical excision of pseudomembranes twice, during a period of 6 months, followed by a quick recurrence within 2–3 days after excision. Soon after the third recurrence, a possible diagnosis of LC was suggested. Reduced plasminogen activity at 20% (normal values 80– 120%, method of chromogenic substrates) confirmed the diagnosis of hypoplasminogenemia. Mother's plasminogen activity was 63%, father's 55%, while plasminogen activity of her brother and sister was 72% and 105%, respectively. The patient was hospitalized in order to receive appropriate management. Since plasminogen concentrates either for intravenous use or as eye drops preparation are not yet commercially available, FFP was chosen to be administered systemically (20 ml/kg of body weight, every 8 h) and topically (one drop every 3 h) 2 days prior to surgical removal of pseudomembranes by electrocautery under general anaesthesia. In order to keep patient's plasminogen activity around 60% until healing, systemic FFP was administered for 12 days, along with topical use, postoperatively. Yet, plasminogen activity was only 40% on the second day of intravenous administration to rise to 60% at the end of the week. Topical use of FFP was applied every 3 h for the first 3 days after surgical removal and every 4 h for a week thereafter. The patient continued to receive topical FFP, every 6 h for 3 months postoperatively. No recurrence was noticed during this therapeutic period. Systemic or topical side effects relating to the FFP administration were also not observed. At the end of the first month, vision had already significantly improved (8/
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10). Two weeks after cessation of the topical treatment, pseudomembranes reappeared on the conjunctivae, thus indicating a recurrence of LC. Topical application of FFP was reinitiated soon thereafter, at a frequency of six times daily, resulting in a slight regression of pseudomembranes while the patient's vision did not further deteriorate. Subsequently, the girl underwent a second operation with electrocautery under general anaesthesia to have the conjunctival pseudomembranes removed. The patient was managed perioperatively as previously described. Systemic treatment was stopped at the end of the tenth day postoperatively. Topical application of FFP every 6 h was being continued until now, 10 months after the second surgical procedure. No recurrence has been observed and the vision remains at 9/10 (Fig. 2a, b).
Discussion Although LC was firstly reported in 1847 [2] and its detailed histological description was published in 1924 by Lijό Pavia [5], the term “conjunctivitis lignosa” or “ligneous conjunctivitis” was introduced by Borel [1] in 1933 and the link of this clinical entity to plasminogen deficiency was established in 1997 [10]. Since then a large number of management strategies for treating these lesions have been tried with minimal success. Dr Volker Schuster and his laboratory have been strongly involved in the study of the disease and have the largest experience regarding genetic analysis of the mutations and polymorphisms related to the disorder [6, 9, 10]. As it is known, fibrin deposits of all body fluids are cleared by the fibrinolytic system. In the tear fluid plasminogen activators released by the cornea convert plasminogen into plasmin, which quickly clears the cornea of fibrinogen deposits. The absence of plasmin activity results in the formation of fibrin-rich membranous material which is typically observed in patients with LC [7, 10]. The wood-like appearance of the conjunctival lesions is due to Fig. 2 Patient's left eye after treatment. a External and b internal palpebral surface
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the activation of inflammatory cells and fibroblasts and the drying out of the fibrin in the affected eye. Interestingly, pseudomebranes' formation is often the result of different stimuli such as infection and trauma. Corneal involvement from these lesions occurs in 20–30% of cases and may result in sight loss [6]. Our patient had severe impairment of her vision at 2/10, at referral, due to the pushing effect of pseudomembranes on the cornea. Her vision was significantly improved after the successful management of LC and remains at 9/10 10 months postoperatively. Surgical removal of these lesions without systemic and/or topical substitution treatment with plasminogen-containing products, such as FFP or plasminogen concentrates, is a potent trigger for recurrence of ligneous pseudomembranes which usually reappear in a few days. Many forms of local treatment have been tried such as heparin, corticosteroids, cyclosporine, azathioprine, hyaluronidase and αchymotrypsin with no consistent or complete success [6, 9, 10]. Recently some authors reported the successful management of LC with topical and/or systemic plasminogen concentrates prepared from FFP [3, 8]. Unfortunately, plasminogen ophthalmologic solution and a systemic purified plasminogen concentrate are not currently commercially available. Thrombolytic agents that contain plasminogen are a possible treatment modality that has been utilized for treatment of LC (Amy Shapiro, Chistoph von Buch, personal communication) [6]. FFP as a topical treatment alone or along with systemic FFP intravenous administration has shown encouraging results in controlling pseudomembrane recurrences [4, 11]. In our patient, surgical removal of pseudomembranes was combined with administration of FFP systemically and topically which was introduced 2 days prior to the operation. Due to the short half-life of plasminogen in the FFP preparation, systemic and local treatments were applied in short intervals, preand postoperatively, until the complete healing of the surgical trauma, succeeded 2 weeks after the operation. Then, the systemic administration of FFP was stopped and the patient continued to receive topical FFP every 6 h for
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3 months postoperatively. Pseudomembranes' reappearance soon after cessation of the topical treatment underscores the hypothesis that surgical removal of these lesions can be effective in the long term, only if it is associated with the long-term topical administration of a solution containing plasminogen (e.g. FFP). The second management of our patient and the successful long-term application of FFP topically confirm this theory. Finally, the optimal outcome of our patient's vision seems to be hopeful.
Disclosures The authors stated that they have no interests which might be perceived as posing a conflict or bias.
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Eur J Pediatr (2011) 170:1333–1336 3. Caputo R, Pucci N, Mori F, Secci J, Novembre E, Frosini R (2008) Long-term efficacy of surgical removal of pseudomembranes in a child with ligneous conjunctivitis treated with plasminogen eyedrops. Thromb Haemost 100:1196–1198 4. Gürlü VP, Demir M, Alimgil ML, Erda S (2008) Systemic and topical fresh-frozen plasma treatment in a newborn with ligneous conjunctivitis. Cornea 27(4):501–503 5. Lijό Pavia J (1924) Tumor inflammatorio fungoso recidivante de la conjunctiva palpebral. Semana Med 31:326–331 6. Mehta R, Shapiro AD (2008) Plasminogen deficiency. Haemophilia 14:1261–1268 7. Mirshahi S, Soria J, Nelles I et al (1996) Plasminogen activators in human corneal fibroblasts: secretion, cellular localization and regulation. Fibrinolysis Proteolysis 10:255–262 8. Schott D, Dempfle C-E, Beck P, Liermann A, Mohr-Pennert A, Goldner M et al (1998) Therapy with purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. N Engl J Med 339 (23):1679–1686 9. Schuster V, Hügle B, Tefts K (2007) Plasminogen deficieny. J Thromb Haemost 5:2315–2322 10. Schuster V, Seregard S (2003) Ligneous conjunctivitis. Surv Ophthalmol 48:369–388 11. Tabbara KF (2004) Prevention of ligneous conjunctivitis by topical and subconjunctival fresh frozen plasma. Am J Ophthalmol 138 (2):299–300
