Elsevier

Survey of Ophthalmology

Volume 48, Issue 4, July–August 2003, Pages 369-388
Survey of Ophthalmology

Major review
Ligneous conjunctivitis☆

https://doi.org/10.1016/S0039-6257(03)00056-0Get rights and content

Abstract

Ligneous conjunctivitis (McKusick 217090) is a rare form of chronic conjunctivitis characterized by the development of firm fibrin-rich, woody-like pseudomembraneous lesions mainly on the tarsal conjunctivae. Less frequently, similar lesions may occur on other mucous membranes of the body indicating that these manifestations are part of a systemic disease. Histopathological findings from affected humans and (plasminogen-deficient) mice indicate that wound healing, mainly of injured mucosal tissue, is impaired due to markedly decreased (plasmin-mediated) extracellular fibrinolysis. Pseudomembraneous lesions of the eyes and other mucosal tissue mainly contain clotted fibrin(ogen). Actually, systemic plasminogen deficiency has been linked to ligneous conjunctivitis in humans and mice. In one case, ligneous conjunctivitis has been induced by antifibrinolytic treatment with tranexamic acid. Further rare associated disorders of ligneous conjunctivitis are congenital occlusive hydrocephalus and juvenile colloid milium. This review outlines the historical background, clinical characteristics of ligneous conjunctivitis and its associated complications, histological abnormalities of pseudomembraneous lesions, inheritance, hemostasiologic and molecular genetic findings in affected patients, current treatment approaches, and the plasminogen-deficient mouse as an animal model.

Section snippets

Historical review

Ligneous conjunctivitis (McKusick 217090) was first reported in a 46-year-old man with bilateral pseudomembraneous conjunctivitis as early as 1847.14 A few years later, in 1854, Von Graefe also referred to ligneous conjunctivitis though he did not introduce its distinctive name.70., 105., 138. In 1924, the first detailed histologic description of pseudomembraneous conjunctivitis was reported.75 LijóPav3/4(c)a reported also the characteristics of pseudomembranes that may develop—mainly

Clinical features of ligneous conjunctivitis

Ligneous conjunctivitis is an unusual and rare form of chronic “idiopathic membraneous” conjunctivitis characterized by initial chronic tearing and redness of the conjunctivae and the subsequent formation of pseudomembranes mostly on the palpebral surfaces that progress to white, yellow-white, or red thick masses with a woody-like consistency that replace the normal mucosa.43., 61., 99., 103. Although the term ligneous pseudomembraneous lesion is emphasized in the international ophthalmologic

Epidemiology of Ligneous conjunctivitis

The prevalence and incidence of ligneous conjunctivitis and its associated complications is not known at present. Ligneous conjunctivitis occurs worldwide and has been reported from Japan,93., 124. India,105., 126. Brazil,1 former Czechoslovakia,92 Romania,20 Russia,95 USA,5., 22., 36., 61., 66., 79., 118., 120., 128. Switzerland,54., 69. Canada,28., 80. Germany,48., 78., 85., 86., 87., 89., 90., 96., 99., 115., 116., 117., 118., 119., 132., 142. UK,23., 29., 82. Belgium,31., 45., 83. France,14.

Ligneous peridontitis (ligneous gingivitis)

In at least 16 patients with ligneous conjunctivitis additional pseudomembraneous lesions affecting the gingiva have been reported and described as “amyloidaceous ulcerated gingival hyperplasia” or “destructive membranous peridontal disease” (ligneous peridontitis).6., 32., 47., 53., 56., 61., 116., 118., 121. In 8 patients, ligneous peridontitis occurred without involvement of the eyes (Fig. 7a).53., 56., 121.

Taken together, these findings suggest that both clinical manifestations are causally

Ligneous Conjunctivitis in Animals

Ligneous conjunctivitis has been described not only in humans but also in different animal species such as Doberman pinschers104 (Fig. 7b) and canines (DT Ramsey; personal communication, April 1997). The clinical and histological findings are quite similar to that observed in humans. In 3 of 4 dogs with ligneous conjunctivitis, reported so far,104 concomitant signs of multisystemic disease (ulcers and plaque lesions of buccal and gingival mucosa, free pleural and peritoneal fluid, renal

Ligneous Conjunctivitis Is a Genetic Disorder with an Autosomal-Recessive Inheritance Pattern

Although most cases of ligneous conjunctivitis are sporadic, familial cases have been reported. Borel was the first who described three affected siblings.11., 12. In 1937, Oguchi described a Japanese family with two affected children, a boy and a girl.93 Later, three papers each reported two sisters with ligneous conjunctivitis.18., 72., 112. In each of four other unrelated families ligneous conjunctivitis was observed in brothers.7., 22., 49., 141. In 1954, five cases of ligneous

The plasminogen activator (PA)-plasmin(ogen) system and the matrix metalloprotease (MMP) family play an important role in wound healing

Wound healing is a highly regulated tissue-remodeling process involving inflammation, cell proliferation and migration, angiogenesis, and extracellular matrix (ECM) production, in which the injured tissue is removed and substituted with normal tissue. Mechanical injury of tissues (skin, mucosa, and others) is followed by exudation of plasma proteins and immediate coagulation of fibrin(ogen), the main constituent of pseudomembranes in patients with ligneous conjunctivitis.36., 61., 115.

This

Diagnosis of Ligneous Conjunctivitis

The diagnosis of ligneous conjunctivitis is mainly based on the clinical picture (pseudomembraneous lesions on conjunctivae and/or other mucosal sites of the body, eventually in association with colloid milium or congenital occlusive hydrocephalus), the typical histological findings, and eventually on a positive family history (affected siblings).

In very rare cases, true amyloidosis of the eye and/or the gingiva may resemble ligneous conjunctivitis and/or gingivitis.64 Amyloidosis can be

Primary surgical and/or topical treatment

In predisposed subjects, ligneous conjunctivitis may follow surgical procedures such as excision of a pterygium140 or pinguecula,51 cataract extraction, ptosis or strabismus surgery,29 conjunctival transplantation9., 120. and keratoplasty.132 Surgery without sufficient prophylactic measures (such as topical heparin) is by itself a potent trigger for recurrence of ligneous pseudomembranes, which usually reappear within a few days.29., 44., 84. Therefore, the number of excisions of

Perspectives for the Future

Unfortunately, no lys-plasminogen preparations for therapeutic use are currently available worldwide. Furthermore, long-term treatment with lys-plasminogen seems to be impractible for the following reasons: short half-life of normal lys-plasminogen, high costs, and the need for a central venous catheter for daily lys-plasminogen infusions.

Therefore, it seems necessary, to develop “retarded” plasminogen preparations (i.e., pegylated plasminogen) with a markedly increased half-life.

Summary

Ligneous conjunctivitis is a rare uncommon form of chronic conjunctivitis that usually affects children, girls more often than boys, but may occur at any age. A characteristic of this disease is the development of firm “woody-like” pseudomembraneous lesions on the tarsal and bulbar conjunctivae. Ligneous conjunctivitis appears to be the ocular manifestation of a systemic disease, which might be accompanied by formation of pseudomembranes on the mucosa of the mouth (ligneous gingivitis or

Method of Literature Search

The literature review was based on comprehensive PubMed and Medline searches generating references on ligneous conjunctivitis or conjunctivitis lignosa, plasminogen deficiency, and plasminogen-deficient mice published from 1966 through 2002. This primary search was followed by checking the references and the references of the references in normal and review articles. The search included papers in foreign languages (French, German, Russian, Spanish, Turkish, and others).

References (142)

  • A.A. Hidayat et al.

    Ligneous conjunctivitis. A clinicopathologic study of 17 cases

    Ophthalmology

    (1987)
  • E.J. Holland et al.

    Immunohistologic findings and results of treatment with cyclosporine in ligneous conjunctivitis

    Am J Ophthalmol

    (1989)
  • J. Hornova et al.

    Primary amyloidosis of gingiva and conjunctiva and mental disorder in a brother and sister

    Oral Surg Oral Med Oral Pathol

    (1968)
  • A. Kanai et al.

    Histologic and electron microscope studies of ligneous conjunctivitis

    Am J Ophthalmol

    (1971)
  • H.R. Lijnen et al.

    Restoration of thrombolytic potential in plasminogen-deficient mice by bolus administration of plasminogen

    Blood

    (1996)
  • E. Martinovic et al.

    Ligneous conjunctivitis related to a defect in the fibrinolytic system

    Can J Ophthalmol

    (2001)
  • T.E. Petersen et al.

    Characterization of the gene for human plasminogen, a key proenzyme in the fibrinolytic system

    J Biol Chem

    (1990)
  • G.B. Abreu et al.

    Conjuntivite lenhosa: apresentção de um caso

    ArqIPB

    (1992)
  • N. Aoki et al.

    Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis

    J Clin Invest

    (1978)
  • M.F. Babcock et al.

    Ligneous tracheobronchitis: an unusual cause of airway obstruction

    Anesthesiology

    (1987)
  • J.B. Bateman et al.

    Ligneous conjunctivitis: an autosomal recessive disorder

    J Pediatr Ophthalmol Strabismus

    (1986)
  • M. Baykara et al.

    Oral findings in a ligneous conjunctivitis case

    HÜ Dis Hek Fak Dergisi

    (1995)
  • A.J. Berlin et al.

    Scleral grafting in the management of ligneous conjunctivitis

    Ophthalmic Surg

    (1982)
  • A. Berta et al.

    Determination of plasminogen activator activities in normal and pathological human tears. The significance of tear plasminogen activators in the inflammatory and traumatic lesions of the cornea and the conjunctiva

    Acta Ophthalmol (Copenh)

    (1990)
  • J.R. Bierly et al.

    Ligneous conjunctivitis as a complication following strabismus surgery

    J Pediatr Ophthalmol Strabismus

    (1994)
  • G. Bietti et al.

    [Clinical contribution to current therapeutic orientations in conjunctivitis lignosa]

    Doc Ophthalmol

    (1969)
  • M.G. Borel

    Un nouveau syndrome oculo-palpébral

    Ann Oculistique

    (1934)
  • M.G. Borel

    Un nouveau syndrome palpébral

    Bull Soc Fr Ophthalmol

    (1933)
  • P.L. Bosselini

    Sur deux cas de pseudo-milium colloide familial

    Ann Dermatol Syph Paris

    (1906)
  • M. Bouisson

    Ophthalmie sur-aigue avec formation de pseudomembranes àla surface de la conjonctive

    Ann Oculist

    (1847)
  • D.C. Buck et al.

    Ligneous conjunctivitis involving the cervix. Case report

    Br J Obstet Gynaecol

    (1990)
  • T.H. Bugge et al.

    Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction

    Genes Dev

    (1995)
  • A. Bujadoux

    Les conjonctivites ligneuses

    Soc Ophthal Midi France

    (1942)
  • P. Carmeliet et al.

    Physiological consequences of loss of plasminogen activator gene function in mice

    Nature

    (1994)
  • P. Cernea et al.

    [The etiopathogenetic aspects in ligneous conjunctivitis]

    Oftalmologia

    (1991)
  • J.D. Chambers et al.

    Ligneous conjunctivitis

    Trans Am Acad Ophthalmol Otolaryngol

    (1969)
  • M.M. Chowdhury et al.

    Juvenile colloid milium associated with ligneous conjunctivitis: report of a case and review of the literature

    Clin Exp Dermatol

    (2000)
  • S.R. Cohen

    Ligneous conjunctivitis: an ophthalmic disease with potentially fatal tracheobronchial obstruction. Laryngeal and tracheobronchial features

    Ann Otol Rhinol Laryngol

    (1990)
  • D. Cohen Tervaert et al.

    Ligneous conjunctivitis

    Doc Ophthalmol

    (1986)
  • T.J. Cooper et al.

    Lingeous conjunctivitis with tracheal obstruction. A case report, with light and electron microscopy findings

    Can J Ophthalmol

    (1979)
  • F. Demarmels Biasiutti et al.

    Is plasminogen deficiency a thrombotic risk factor? A study on 23 thrombophilic patients and their family members

    Thromb Haemost

    (1998)
  • C. Demeulemeester et al.

    A puzzling case: conjunctivitis lignosa?

    Bull Soc Belge Ophtalmol

    (1998)
  • J.P. Diamond et al.

    Tranexamic acid-associated ligneous conjunctivitis with gingival and peritoneal lesions

    Br J Ophthalmol

    (1991)
  • G. Dolan et al.

    Thrombovascular disease and familial plasminogen deficiency: a report of three kindreds

    Br J Haematol

    (1988)
  • S. Duke-Elder

    Diseases of the outer eye

  • H. Ebner et al.

    Colloid milium: light and electron microscopic investigations

    Clin Exp Dermatol

    (1977)
  • E. Ergin Ciftci et al.

    Ligneous conjunctivitis, hydrocephalus, hydrocele, and pulmonary involvement in a child with homozygous type I plasminogen deficiency

    Eur J Pediatr

    (2003)
  • T. Firat

    A new method for the treatment of ligneous conjunctivitis

    Turk J Pediatr

    (1969)
  • T. Firat et al.

    Histochemical investigations on ligneous conjunctivitis and a new method of treatment

    Acta Ophthalmol (Copenh)

    (1970)
  • J. Francois

    Considerations on the importance of genetics in ophthalmology

    Ophthalmologica

    (1979)

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    This study was supported by the Deutsche Forschungsgemeinschaft (grant Schu 560/4-3). The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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