Ligneous Conjunctivitis : Symptoms, Causes, Diagnosis, Management, Complications and Prevention

Ligneous Conjunctivitis : Symptoms, Causes, Diagnosis, Management, Complications and Prevention

Ligneous conjunctivitis (LC) is a rare, potentially sight and even life-threatening (e.g. by airway obstruction) disorder characterised by recurrent, often bilateral fibrin-rich pseudo-membranous lesions of wood-like consistency that develop mainly on the tarsal conjunctiva. It is the main clinical manifestation of systemic plasminogen deficiency and typically presents in childhood. There appears to be a higher incidence in females as compared to males. With plasminogen deficiency, wound-healing capability is diminished and is most pronounced in mucous membranes, such as conjunctiva.  Plasminogen is converted to plasmin by plasminogen activators in the blood. Plasmin is a serine protease and is the predominant fibrinolytic enzyme in the human circulation, and is also found in the extracellular matrix. Plasmin plays an important role in haemostasis, as well as, is an integral component of wound healing (acts by degrading fibrin). Due to plasminogen deficiency, fibrin rich membranes or mucous strands accumulate, which on desiccation of the fibrin leads to the ligneous consistency of the conjunctival lesions. Episodes may be triggered by relatively minor trauma, surgery (done particularly for pterygium or pinguecula) or by systemic events such as fever and anti-fibrinolytic therapy. Similar mechanisms occur in extra-ocular manifestations of plasminogen deficiency.

LC is rare, and the prevalence of this disorder has not been firmly established. LC can occur in older individuals, despite it being classically associated with infants and children.

Less frequently, LC may lead to similar membrane formation in mucous membranes of other organs, such as:

  • Oral cavity (ligneous gingivitis).
  • Gastrointestinal tracts.
  • Upper and lower respiratory tracts (sinus, larynx, trachea, bronchi, and lungs).
  • Ears.
  • Female genital tracts.
  • Renal collecting system.

Rarely, it may also cause:

  • Juvenile colloid milium of the skin.
  • Occlusive hydrocephalus.

Several studies have shown extra-ocular manifestations of severe plasminogen deficiency even without ocular involvement.

Histopathological findings indicate that impaired wound healing, mainly of injured mucosal tissue, is due to markedly decreased, plasmin-mediated extracellular fibrinolysis.

LC is characterised by multiple recurrences after local excision, and management involves the adjunctive use of topical and systemic replacement of plasminogen.

Symptoms

 

Patients typically present with chronic conjunctivitis and LC is bilateral in about half of the cases. Duration of disease varies from few months to many years.

According to the severity, ocular (eye) symptoms may be:

Early cases show:

  • Redness.
  • Chronic watering.
  • Mild discomfort.
  • Pain.
  • Photophobia (sensitivity to light).
  • White or red masses on conjunctiva.

Severe cases may have:

  • Constant discomfort which affect daily activities.
  • Lesions may extend beyond the lid margin.
  • Membranes.

 A conjunctival lesion is commonly noted by parents.

Systemic symptoms:

Oro-pharynx:

After conjunctival involvement, the second most frequently affected site is mouth. There may be:

  • Loss of dental integrity.
  • Painless nodular ulcers.
  • Hyperplasia of gums.

Ears:

  • Fluctuating hearing loss.
  • Chronic infection of tympanic membrane and middle ear.

Respiratory Tract:

  • Dysphonia (change in voice).
  • Chest infections or recurrent pneumonia.
  • Potentially life-threatening airway obstruction.

Genitourinary Tract:

Ligneous lesions occurring in the female genital tract, most commonly affects cervix, causing ligneous cervicitis. Lesions may also involve vagina, fallopian tubes, ovary and endometrium of uterus. This may cause:

  • Dysmenorrhoea – the most common presenting symptom.
  • Infertility.

Juvenile Colloid Milium of the skin:

This is a rare skin condition characterised by the development of small, yellow-brown, translucent papules.

Congenital Occlusive Hydrocephalus:

LC patients may rarely have congenital occlusive hydrocephalus.

Causes

 

There is evidence to support that ligneous conjunctivitis is the result of plasminogen deficiency.

There are two types of plasminogen deficiency:

  • Type I (hypo-plasminogenaemia) is a quantitative deficiency.
  • Type II (dys-plasminogenaemia) is a qualitative deficiency.

Type I deficiency is the type most associated with LC.

With plasminogen deficiency, wound-healing capability is diminished and is most pronounced in mucous membranes, such as the conjunctiva. The impaired wound healing capacity causes an arrest of granulation tissue formation and excessive fibrin deposition. Thus, fibrin rich membranes or mucous strands accumulate, stimulating inflammatory cells and fibroblasts, while desiccation of the fibrin leads to the ligneous consistency of the conjunctival lesions. Similar patho-physiologic mechanisms occur in extra-ocular manifestations of plasminogen deficiency.

While in extra-vascular spaces, fibrinolysis, with low to non-existent levels of plasminogen activity, is impaired. However, in vessels this is not the case, as can be inferred from the fact that thrombotic phenomena is absent in patients with LC and plasminogen deficiency. It has been suggested that non-plasmin induced fibrinolysis is intensified in patients with plasminogen deficiency and ligneous conjunctivitis.

 Genetics of disease:

Genetics of the disease allows for prenatal diagnosis in known carrier families, which may be crucial in cases of obstructive congenital hydrocephalous.

Development of ligneous lesions is caused by:

  • Sporadic mutations in plasminogen gene. This is the most common cause. The gene for plasminogen is located on chromosome 6, and is produced predominantly by the liver.
  • Compound-heterozygous mutations.
  • Homozygous mutations.Tissue injury:Due to the appearance, histopathology, clinical course, and response to treatment, it is also believed that LC results from an exaggerated inflammatory response to tissue injury. This injury may arise from infection or physical trauma, including surgery. These factors may incite a genetic predisposition, such as plasminogen deficiency, to develop this response.Many cases of antecedent viral or bacterial infections have been described, including staphylococcal, streptococcal, and haemophilus conjunctivitis. In these cases, it appears that LC, in genetically susceptible individuals, develops as an abnormal response to the conjunctival trauma elicited by the infecting organisms.Trauma, especially from surgery, is also thought to be a cause of LC. LC appears to develop as an abnormal response of the immune system to the conjunctival trauma.

Diagnosis

 

The diagnosis of LC is based on the clinical picture (ocular and/or extra-ocular membranous lesions), the typical histological findings, and a possible positive family history. In most patients with LC, hypo-plasminogenaemia may be found.

If the responsible mutation has been identified in an affected family, then prenatal diagnosis of children at risk is possible.

Ocular Features:

Examination of eyes should be carried out under slit-lamp (bio-microscopy) by an eye-specialist.

Patients typically present with chronic conjunctivitis. Discharge or membranes are not seen in the early stages.

Conjunctival ligneous lesions: The earliest true ligneous lesion appears as a highly vascularised, raised, friable lesion. It may be covered by a thick yellow-white mucoid discharge. This lesion can be removed easily with forceps, although it tends to bleed on removal. With continued inflammation, a white, thickened, avascular mass appears above the neo-vascular membrane. Attempts at removal of this lesion often results in recurrence of the lesion to its original size within days. These lesions are most often seen on the palpebral conjunctiva of the upper and lower eyelids but may also be found on the bulbar conjunctiva, including the limbus. Bulbar conjunctival involvement may occur either de novo or from extension of a palpebral lesion. Despite appropriate therapy, inflammation may continue, and the chronic lesions become thickened, vascularised, and firm, giving rise to the name ‘ligneous’ meaning woody.

Corneal lesions: Limbal lesions may extend over the surface of the cornea and may lead to corneal:

  • Neovascularisation.
  • Scarring.
  • Infection.
  • Melting.

 Systemic Features:

Fever or infections of the upper respiratory tract, urinary tract, or female genital tract, may either precede or concomitantly occur with LC, or might even act as a trigger for the development of membranes.

Oro-pharynx:

Membranous lesions may cause:

  • Loss of dental integrity.
  • Painless nodular ulcers.
  • Gingival hyperplasia.

Ears:

Membranous lesions may occur on:

  • Tympanic membrane.
  • Middle ear causing otitis media.

Respiratory Tract:

Ligneous lesions may involve:

  • Larynx.
  • Vocal cords.
  • Trachea.
  • Bronchial tree.

Genitourinary Tract:

Ligneous lesions in female genital tract may involve:

  • Cervix causing ligneous cervicitis.
  • Vagina.
  • Fallopian tubes.
  • Ovary.
  • Endometrium.

Juvenile Colloid Milium:

This is a rare skin condition characterised by the development of small, yellow-brown, translucent papules, typically in sun-exposed areas of the skin. It tends to occur prior to puberty.

Congenital Occlusive Hydrocephalus:

LC patients are also reported to suffer from congenital occlusive hydrocephalus.

Laboratory diagnosis:

  • Abnormality of plasminogen activity and/or antigen: Laboratory analysis confirms disorder with an abnormality of plasminogen activity and/or antigen. Since ligneous lesions are most commonly seen in type I plasminogen deficiency, the antigen test alone is insufficient to rule out this disease.
  • Prenatal testing: Prenatal testing to identify genetic mutations may be conducted to identify this disease.

Histopathological/ Immuno-histochemical evaluation:

Histological examination of ligneous membranes shows superficial or sub-epithelial deposits of eosinophilic amorphous hyaline, amyloid-like material with a variable proportion of granulation tissue with accompanying inflammatory cells (lymphocytes, plasma cells and granulocytes). This amorphous hyaline material contains mainly fibrin and other plasma proteins, such as albumin and immune-globulins (mainly IgG). Ligneous lesions may also contain variable amounts of muco-polysaccharides in adjacent granulation tissue. Abnormal vascular permeability has also been suggested as the source of various components of the ligneous lesions.

Immuno-histochemical evaluation of LC lesions showed a cellular infiltrate that was composed mainly of T lymphocytes. Immuno-fluorescent techniques demonstrated that the major components of the hyaline material in the substantia propria were immune-globulins (mainly IgG).

Topical cyclosporine A has been reported to be more effective than other topical agents (short of plasminogen preparations) in the treatment of this disorder. Cyclosporine A prevents the activation and recruitment of the T-cell response. Finally, a decrease in the number of B lymphocytes and plasma cells occur. These results indicate the local effect of cyclosporine A on the immune-response. The clinical response and histopathological confirmation of the effect of Cyclosporine A further support the inflammatory nature of this disease.

Ligneous conjunctivitis should be differentiated from:

Any inflammatory or infectious disease which can cause a chronic pseudo-membranous conjunctivitis, such as:

  • Viral conjunctivitis:
  • Herpes simplex infection.
  • Epidemic keratoconjunctivitis.
  • Molluscum contagiosum.
  • Bacterial conjunctivitis:
  • Staphylococcus aureus.
  • Streptococcus haemolyticus.
  • Neisseria gonorrhoeae.
  • Chlamydia trachomatis.
  • Corynebacterium diphtheriae.
  • Allergic conjunctivitis:
  • Vernal keratoconjunctivitis.
  • Toxic conjunctivitis:
  • Chemical conjunctivitis:
  • Acid.
  • Alkali.
  • Stevens-Johnson syndrome.
  • Amyloidosis.

Management

 

Management should be carried out under medical supervision.

Management of LC tends to be unsatisfactory and spontaneous resolution is rare.

It is important to discontinue any anti-fibrinolytic therapy.

Medical therapy:

  • Plasminogen substitution: Systemic and topical plasminogen substitution or Fresh Frogen Plasma (FFP) is presently being investigated as the primary treatment for ligneous conjunctivitis. Topical plasminogen preparations, extracted from fresh frozen plasma, have successfully been used in the treatment of LC. Using FFP bypasses, the need for plasminogen concentrate alone, which has a very short half-life and is difficult to have it readily available.
  • Cyclosporine A: Cyclosporine A had been the most promising element in the therapeutic management before plasminogen.
  • Other measures: Based on the early observations of the presence of granulation tissue and inflammatory cells in ligneous tissue, topical medical regimens toward these non-specific findings were developed. Topical therapy including, topical hyaluronidase, heparin, azathioprine, alpha-chymotrypsin, sodium cromoglycate, antibiotics, corticosteroids, and fibrinolysin have shown limited success.

Surgical therapy:

Because trauma to the conjunctiva is likely to be an aetiological factor in LC, conjunctival surgery must be performed with utmost care.

  • Excision of ligneous lesions: Systemic and topical plasminogen or FFP treatment is started to help soften the pseudo-membrane and facilitate removal. Complete excision with diathermy of the base of all ocular ligneous lesions is done. General anaesthesia may be used in adults with significant disease, and in all children. Failure to completely remove the lesion results in rapid recurrence, because the retained lesion acts as physical barrier to topical medical treatment.

Immediately after surgery, the patient is continued on systemic and topical FFP, and started on a corticosteroid, broad-spectrum antibiotic and topical cyclosporine A. These medications are given after surgery, as early recurrence is the hallmark of this disorder.

A small but significant amount of recurrence will be seen daily in every patient, and every recurrent lesion must be debrided daily. If abnormal tissue is allowed to collect for even 1 to 2 days, it will act as a barrier and prevent the topical medications from reaching the basal tissue, which is the origin of ligneous membranes.

Repeat excision is conducted for the recurrent lesions.

  • Amniotic membrane transplantation: Barbino and Rolando performed amniotic membrane transplantation for conjunctival reconstruction of LC.

Surgical intervention may be needed to relieve obstruction in patients with congenital occlusive hydrocephalus.

Prognosis:

The prognosis for ligneous conjunctivitis is variable and is based upon the extent, length and the affected site producing symptoms. It depends on the ability to control inflammation and recurrence of pseudo-membranes. Patients with corneal involvement have poorer visual prognosis.

Many patients have lived into adulthood. Many patients experienced significant morbidity, including loss of function of an affected organ, such as loss of sight or loss of dentition.

Systemic involvement of respiratory tract (tracheo-bronchial lesions) with pseudo-membranes may be life threatening due to respiratory failure. This group of patients are in need of specific therapy that treat and prevent these lesions and the sequelae thereof.

The quality of life of untreated patients with significant disease is not optimal.

Complications

 

Ligneous conjunctivitis may lead to complications like:

  • Recurrence of disease on withdrawal of the topical medicine.
  • Recurrence of disease after surgical excision.
  • Neovascularisation of cornea.
  • Scarring of cornea.
  • Corneal perforation.
  • Corneal infections.
  • Loss of vision.
  • Amblyopia in children.

Prevention

There is no primary preventive measure for this disease as it is often inherited.

References:

http://ijbamr.com/pdf/December%202014%20392-396.pdf.pdf

http://europepmc.org/articles/PMC4463565

http://www.joponline.org/doi/abs/10.1902/cap.2012.110060?journalCode=cap

http://eyewiki.aao.org/Ligneous_Conjunctivitis

http://www.ncbi.nlm.nih.gov/pubmed/12850227

http://bjo.bmj.com/content/53/6/373.full.pdf