Authors refer about detailed analysis of ten years follow up of a child patient with ligneous conjunctivitis. They document presence of all typical eye findings (especially recurrent formation of granulomatous pseudotumors in affected mucous membrane) related to this rare pseudomembranous conjunctivitis. The clinical picture of the disease includes plasminogen deficiency, a factor newly considered as primary cause of the disease. The diagnosis was confirmed histologicaly by repeated probatory excisions. Pseudomembranous inflammation with mixed inflammatory infiltrate containing large amount of elements of chronical as well as acute inflammatory reaction is typical. Granuloma with the accumulation of the PAS-positive amorphous matrix with high content of the fibrin and with the network of newly formed vessels is the component of the inflammatory picture. The treatment was based on successively discovered knowledge of the possible etiopathogenesis of the disease. Only the ninth, last surgical procedure induced longer-term remission, which lasts sixteen months until now. The granuloma excision was combined with the mitomicin application on the wound surface and a conjunctivoplasty. During the postoperative period, the ointment with heparin, corticosteroid and antibiotic was applied. The purpose of the mitomicin use is to slow down the fibroproliferative reparative reaction. Covering of the wound surface decreases the number of microtraumas on the uneven postoperative scleral surface. Heparin in the interstitial tissue of the wound surface blocks the conversion of fibrinogen to fibrin.

Otolaryngological manifestations of ligneous conjunctivitis.Int J Pediatr Otorhinolaryngol. 2003 Feb;67(2):189-94.

Ligneous conjunctivitis is a rare condition that can involve the mucous membranes of the upper and lower airways and temporal bone extensively. This can lead to life threatening airway obstruction. Involvement of the middle ear and mastoid may cause significant conductive hearing loss. This is the first reported case with temporal bone sections of ligneous conjunctivitis, and awareness of the associated obstructive hydrocephalus may prevent death in this condition. Evidence suggests that plasminogen deficiency may be a causative factor in ligneous conjunctivitis, and this finding may offer new prospects for management.

Ligneous conjunctivitis in a patient with plasminogen type I deficiency--case report with review of literature.Klin Monatsbl Augenheilkd. 2002 Mar;219(3):156-8.

BACKGROUND: Ligneous conjunctivitis is a rare chronic pseudomembranous conjunctivitis. It forms nodular masses on the palpebral conjunctiva. Beside the conjunctival affection pseudomembranes can also be found on other mucosal tissues. PATIENT: We report on a male baby who had a ventriculoperitoneal shunt due to hydrocephalus internus on his fourth day after birth. Recurrent pseudomebranous conjunctivitis started in the first week of life. This was refractory to drug therapy and reoccurred soon after surgical procedure. The analysis of clotting parameters revealed homozygous plasminogen deficiency. CONCLUSION: Recently type I plasminogen deficiency seems to be a major reason for developing conjunctivitis lignosa. Homozygous and heterozygous mutations in the plasminogen gene are found. At the moment no satisfactory therapy is available. Cases with mild ophthalmological symptoms seem to be positively influenced by a therapy of topical steroids combined with heparin. In severe cases with generalised symptoms systemic therapy with lys-plasminogen is necessary. High costs and poor bioavailability complicate systemic therapy. Improved plasminogen variants for treatment of severe type I plasminogen deficiency would be of great clinical importance.

Ligneous conjunctivitis: a case report.Jpn J Ophthalmol. 2001 Jul-Aug;45(4):375-7.

BACKGROUND: Ligneous conjunctivitis is a rare condition characterized by chronic, recurrent conjunctivitis associated with pseudomembrane, and it may involve other mucous membranes in the mouth, nasopharynx, trachea, and vagina. We examined and treated a case of presumed ligneous conjunctivitis. CASE: The patient was a 10-year-old boy. His chief complaints were visual impairment, discomfort, and discharge, but no itching in his eyes. His upper eyelids appeared thick without swelling. He had a past history of surgery for lid entropion. His two siblings had similar follicular conjunctivitis. OBSERVATIONS: This case exhibited several characteristics of ligneous conjunctivitis, such as large follicles, recurrent pseudomembrane and normal level IgE in the serum. Indispensable characteristics of vernal keratoconjunctivitis, strong itching, and extensive papillary formation, were not found. In spite of the lack of woody hardness of the conjunctiva, other clinical findings led to the diagnosis of ligneous conjunctivitis. Definite histological diagnosis was not obtained, because of the lack of common histological characteristics among previously reported cases with ligneous conjunctivitis. The boy had developed corticosteroid glaucoma after instillation of dexamethasone 0.1% for 7 months at a previous time. We successfully treated this case with combined instillation of fluorometholon and cyclosporin after trabeculotomy. CONCLUSIONS: Ligneous conjunctivitis must be considered as one type of differential diagnosis of vernal keratoconjunctivitis. Cyclosporin is an effective alternative for the treatment of ligneous conjunctivitis, especially in a case with a possible history of corticosteroid glaucoma.

Pulmonary involvement in a child with ligneous conjunctivitis and homozygous type I plasminogen deficiency.Pediatr Pulmonol. 2001 Aug;32(2):179-83.

Ligneous conjunctivitis (LC) is a rare disorder characterized by a chronic course of recurrent membranous lesions at conjunctivae. Pseudomembranes of other mucous membranes have been reported in patients with LC, but to the best of our knowledge, no case with alveolar involvement has been described. Here, we report a 2.5-year-old girl with LC who had tracheoaveolar involvement and homozygous type I plasminogen deficiency. Tracheal involvement was diagnosed by bronchoscopic biopsy and alveolar involvement with postmortem biopsy. She was shown to be homozygous for frameshift mutation in plasminogen exon 14 (Gly565ins-G) with molecular genetic examination of DNA which was obtained from parafin embedded postmortem lung tissue. Ligneous inflammation of the upper and lower respiratory tract must be considered in children with LC and recurrent respiratory tract problems.

Ligneous conjunctivitis in a girl with severe type I plasminogen deficiency.Graefes Arch Clin Exp Ophthalmol. 2000 Sep;238(9):797-800.

BACKGROUND: Ligneous conjunctivitis is a rare form of chronic recurrent pseudomembranous disease and may be associated with systemic membranous pathological changes. Recently ligneous conjunctivitis has been linked to severe type I plasminogen deficiency. We report on a patient with plasminogen deficiency and severe bilateral ligneous conjunctivitis. A new treatment approach and its outcome in this patient are described. CASE REPORT: We present the case of a 9-month-old Turkish girl with massive swelling of the eyelids and hard white pseudomembranes on both lids. The conjunctival smear was positive for Streptococcus pneumoniae. The clinical diagnosis was: ligneous conjunctivitis with superinfection. Histological investigation showed fibrin as major component of the pseudomembranes. The coagulation analyses revealed decreased plasminogen activity (<5%; normal 80-120%) and decreased plasminogen antigen (<0.4 mg/dl; normal 6-25 mg/dl). The failure of surgical therapy led to the attempt at treatment with intravenous lys-plasminogen. A significant improvement of the ocular symptoms occurred; stabilization with no recurrent pseudomembranes could be achieved for 6 months after treatment. DISCUSSION: The initial amelioration of symptoms in our patient after systemic replacement therapy confirms the etiological importance of plasminogen deficiency in the development of ligneous conjunctivitis. Curative treatment of ligneous conjunctivitis is still not available. However, intravenous application of plasminogen offers new possibilities in therapy, although long-term treatment seems necessary.

Ligneous conjunctivitis: a local manifestation of a systemic disorder? J AAPOS. 2000 Oct;4(5):313-5.

Ligneous conjunctivitis is a descriptive term. It refers to the "woody" consistency of the pseudomembrane that usually forms on the palpebral conjunctiva of those affected. It is rare and probably only one manifestation of a multiorgan, pseudomembranous disease. (1-4) We report a case of ligneous conjunctivitis in which investigation revealed a plasminogen deficiency in the heterozygous range (previously reported only in association with a homozygous plasminogen deficiency). We suggest a strategy for investigating known and new cases of ligneous conjunctivitis and/or pseudomembranous disease.

Ligneous conjunctivitis: biochemical evidence for hypofibrinolysis. Inflammation. 2000 Feb;24(1):45-71.

Ligneous conjunctivitis (LC) is a rare disease of unknown etiology characterized by the growth of "woody" plaques on ocular and extraocular mucosa. These lesions are comprised of fibrin and both direct and indirect evidence implicates hypofibrinolysis as the primary defect in LC. To further elucidate the pathophysiology of LC we investigated the biochemical aspects of ligneous lesions with respect to the fibrinolytic system. Ligneous lesions were obtained from the right eye of a 15 year-old female patient with longstanding LC since age 2.5 year. Ligneous conjunctivitis in this patient has exhibited a chronic recurrent coarse and has involved multiple muscosal sites. Samples analyzed included an abundant mucoid thread from the conjunctival fornix and the ligneous plaque attached to the inferior tarsus. Samples were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to characterize protein profiles and by a variety of zymographic methods to visualize fibrinolytic enzymes. We found that mucoid and ligneous samples were distinct entities. Specifically, ligneous samples contained polypeptides with electrophoretic profiles characteristic of intact fibrin, and were replete in fibrin-bound tissue plasminogen activator (t-PA). Despite the presence of ample t-PA, ligneous samples were essentially devoid of fibrinolytic activity. In contrast, neither proteins nor t-PA could be detected in mucoid samples when fractionated by 7.5-15% SDS-PAGE or analyzed by fibrin zymography, respectively. Despite the absence of t-PA, mucoid samples were replete in fibrinolytic activity. This activity was plasminogen independent, heterogenous and inhibited by PMSF. Degradation profiles suggested that this activity represented in part alpha-chymotrypsin, consistent with this patient's treatment regime, as well as plasmin, elastase and an unidentified neutrophil-derived activity. Interestingly, ligneous samples contained both latent and activated forms of matrix metalloproteinase-9 (MMP-9), whereas mucoid samples contained predominantly activated forms of MMP-9. LC is characterized by defective fibrinolysis, despite the presence of ample t-PA and intact fibrin, and by an abundant mucoid thread which binds both endogenous and exogenous enzymes including serine protease(s) and collagenase(s). The implications of these results with respect to a role for exuberant mucus production or abnormal mucins in the development of a relative mucosal-site specific plasmin(ogen) deficiency is discussed.

Ligneous conjunctivitis: a clinicopathologic study of 3 cases.: Int Ophthalmol. 1998-1999;22(4):201-6.

The clinical, histopathologic features, and treatment outcomes in 3 patients with ligneous conjunctivitis are described. Bilateral, idiopathic membranes occurred in the palpebral conjunctiva in 2 patients. In 1 patient, unilateral conjunctival changes occurred in the bulbar conjunctiva, at the site of pterygium excision. Treatment included topical hyaluronidase, chymotrypsin, heparin, and cyclosporine and surgical excision with limited or no success. In one patient, conjunctival autografting from the normal fellow eye resulted in pseudomembrane formation at the donor site in the previously unaffected eye. Histopathological evaluation of excised membranes revealed the presence of amorphous eosinophilic hyaline material and chronic inflammatory cells. Immunohistochemical study revealed a predominance of T-lymphocytes. This case series confirms the recalcitrant clinical course of ligneous conjunctivitis. Conventional treatment modalities described in literature were not useful in the management of this condition. Surgical manipulation of the unaffected fellow eye in patients with unilateral disease can result in pathologic conjunctival changes, and is best avoided.
 
Polymorphonuclear elastase in patients with homozygous type I plasminogen deficiency and ligneous conjunctivitis.Semin Thromb Hemost. 1998;24(6):605-12.

Laboratory studies were performed on six female patients (ranging in age from 1 to 31 years) with ligneous conjunctivitis, which we regard as a systemic condition consisting of ligneous conjunctivitis and other pseudomembranous lesions. Plasminogen levels were severely reduced in all six patients; five patients were homozygous, and one patient was double heterozygous for type I plasminogen deficiency. Of family members tested, 11 of 12 parents and two of six siblings tested were diagnosed as heterozygous. No thrombotic episodes had occurred in any of the patients. Polymorphonuclear (PMN) elastase protein levels were markedly elevated in all, significantly more so in the homozygous patients (range 88 to 335 ng/mL; normal range, 20+/-10 ng/mL) than in the heterozygous patient (58 ng/mL). Of 11 parents examined, only 1 mother had normal PMN elastase (27 ng/mL, with plasminogen antigen 60% and plasminogen functional activity 86%), whereas values were moderately elevated (range 42 to 110 ng/mL) in the other 10 parents examined. After plasminogen substitution, PMN elastase levels consistently decreased but did not reach normal values. We interpret our findings as indicating that non-plasmin-induced fibrinolytic processes, possibly mediated via elastase, may be intensified in patients with plasminogen deficiency.

Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis.  Blood. 1997 Aug 1;90(3):958-66.

Ligneous conjunctivitis is a rare and unusual form of chronic pseudomembranous conjunctivitis that usually starts in early infancy. The disease may be associated with pseudomembranous lesions of other mucous membranes in the mouth, nasopharynx, trachea, and female genital tract. We examined two unrelated Turkish girls both suffering from ligneous conjunctivitis and occlusive hydrocephalus. Both children exhibited a severe plasminogen deficiency. Genomic DNA from both patients as well as from clinically healthy family members were screened for mutations in the plasminogen gene by polymerase chain reaction, single-strand conformation polymorphism (SSCP) analysis, and DNA sequencing. In the first girl with ligneous conjunctivitis a homozygous G-->A point mutation was identified in plasminogen exon 7 at position 780 leading to an amino acid exchange (Arg216-->His). Her healthy sister and her healthy parents were heterozygous for this mutation. The second patient revealed a homozygous G-->A point mutation in plasminogen exon 15 at position 1924 which leads to a stop-codon (Trp597-->Stop). The healthy parents were shown to be heterozygous for this mutation. In addition, the father's second allele revealed another mutation in the same codon (Trp597-->Cys) (compound heterozygosity). In conclusion, certain homozygous mutations in the plasminogen gene may cause ligneous conjunctivitis.

Homozygous type I plasminogen deficiency. Semin Thromb Hemost. 1997;23(3):259-69.

Homozygous type I plasminogen (Plg) deficiency has not been described in human subjects so far. Ligneous conjunctivitis is a rare and unusual form of chronic pseudomembranous conjunctivitis of unknown etiology. Here we report for the first time on homozygous type I Plg deficiency in three unrelated female patients who suffered from ligneous conjunctivitis and additional pseudomembranous lesions of other mucous membranes. The disease is caused by massive fibrin depositions within the "extravascular space" of mucous membranes because of absent clearance by plasmin. Infusions of albumin, fresh frozen plasma, or Lys-plasminogen (Lys-Plg) into two of the three patients revealed normal Plg activation capacity in these patients. The absence of fibrinolytic activity could therefore be shown to be due to Plg deficiency. Similar studies in the third patient have not been completed. In the two patients studied so far, infusions of Lys-Plg resulted in prompt and adequate Plg recovery with a short half-life and high amounts of plasmin-antiplasmin complexes and D-dimer. One patient additionally revealed an inherited partial factor XII deficiency. Functionally, this factor XII deficiency did not interfere with Plg activation. However, there may be a pathway of Plg activation in this patient via the prekallikrein C1-INH system.

Ligneous conjunctivitis: an ophthalmic disease with potentially fatal tracheobronchial obstruction. Laryngeal and tracheobronchial features. Ann Otol Rhinol Laryngol. 1990 Jul;99(7 Pt 1):509-12.

Ligneous conjunctivitis is a rare disease of unknown cause characterized by pseudomembranous, fibrous, woody, plaquelike deposits on the conjunctiva. The disease appears to be hereditary and/or familial. Deposits similar to those found in the eye occur in the larynx, tracheobronchial tree, nose and nasopharynx, and vagina. When these lesions occur in the larynx and tracheobronchial tree, voice change and potentially life-threatening obstruction and pulmonary disease may occur. This paper reports the findings in a child with ligneous conjunctivitis who was followed for 1 1/2 years and who had laryngeal and tracheobronchial involvement with voice change and airway obstruction. The literature is reviewed and the histopathologic findings and endoscopic findings and management of the patient are documented. Because the patient had multiple papillomata of both hands, a possible association with human papillomavirus was suspected but never confirmed.

Ligneous conjunctivitis. A clinicopathologic study of 17 cases. Ophthalmology.1987 Aug;94(8):949-59.

Seventeen cases of ligneous conjunctivitis were studied. Most of the patients were children; however, two elderly individuals were involved (range, birth to 85 years). The most common site was the tarsal conjunctiva, where firm sessile or pedunculated membranous lesions were seen. However, corneal involvement, as well as similar and recurrent lesions, were also present in the larynx, vocal cords, trachea, nose, vagina, cervix, and gingiva. Many recurrences (up to 10 times) rapidly followed simple surgical excision in all patients. Histopathologically, the lesions were characterized by subepithelial, eosinophilic, amorphous material admixed with acute and chronic inflammatory cells. The finding of amorphous material containing fibrin, immunoglobulins, and albumin suggested leakage from hyperpermeable blood vessels. Electron microscopic studies of the lesions disclosed few abnormal blood vessels with wide gaps between endothelial cells that were surrounded by a thick multilaminar basement membrane. The duration of the disease ranged from 4 months to 44 years. After several recurrences, spontaneous resolution occurred in six patients.

Morphologic studies of the pathogenesis of ligneous conjunctivitis.Klin Monatsbl Augenheilkd. 1987 Jan;190(1):40-5.

The cases of ligneous conjunctivitis published since 1964 are presented in a review of the literature. A total of 84 cases have been described. The predominance of this disease in women is lower than was previously thought. Ligneous conjunctivitis tends to occur more frequently in children. However, it is not a "disease of little girls". Two cases are described in the present paper, including pathomorphological studies. In both cases, neutrophilic granulocytes were studied by electron microscopy. The results are compared with a control case and with corresponding reports in the literature. The number of granules in the neutrophilic granulocytes was significantly reduced in both cases. In one of the cases studied the granules were increased in size. These findings support the hypothesis that ligneous conjunctivitis could be the result of a lowered resistance associated with a disturbance of wound healing.