Introduction
Anatomy
The conjunctiva is a transparent mucous membrane that lines the inner surface of the eyelids and the anterior surface of the globe, terminating at the corneoscleral limbus. It is richly vascular, supplied by the anterior ciliary and palpebral arteries. There is a dense lymphatic network, with drainage to the preauricular and submandibular nodes corresponding to that of the eyelids. It has a key protective role, mediating both passive and active immunity. Anatomically, it is divided into the following:
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The palpebral conjunctiva starts at the mucocutaneous junction of the lid margins and is firmly attached to the posterior tarsal plates. The tarsal blood vessels are vertically orientated.
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The forniceal conjunctiva is loose and redundant.
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The bulbar conjunctiva covers the anterior sclera and is continuous with the corneal epithelium at the limbus. Radial ridges at the limbus form the palisades of Vogt, the likely reservoir of corneal stem cells. The stroma is loosely attached to the underlying Tenon capsule, except at the limbus, where the two layers fuse. The plica semilunaris (semilunar fold) is present nasally, medial to which lies a fleshy nodule (caruncle) consisting of modified cutaneous tissue.
Histology
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The epithelium is non-keratinizing and around five cell layers deep ( Fig. 5.1 ). Basal cuboidal cells evolve into flattened polyhedral cells, subsequently being shed from the surface. Mucus-secreting goblet cells are located within the epithelium, being most dense inferonasally and in the fornices.
Fig. 5.1
Histology of the conjunctiva
(Courtesy of J Harry)
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The stroma (substantia propria) consists of richly vascularized loose connective tissue. The accessory lacrimal glands of Krause and Wolfring are located deep within the stroma. Secretions from the accessory lacrimal glands are essential components of the tear film.
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Conjunctiva-associated lymphoid tissue (CALT) is critical in the initiation and regulation of ocular surface immune responses. It consists of lymphocytes within the epithelial layers, lymphatics and associated blood vessels, with a stromal component of lymphocytes and plasma cells, including follicular aggregates.
Clinical features of conjunctival inflammation
Symptoms
Non-specific symptoms include lacrimation, grittiness, stinging and burning. Itching is the hallmark of allergic disease, although it may also occur to a lesser extent in blepharitis and dry eye. Significant pain, photophobia or a marked foreign body sensation suggest corneal involvement.
Discharge
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Watery discharge is composed of a serous exudate and tears, and occurs in acute viral or acute allergic conjunctivitis.
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Mucoid discharge is typical of chronic allergic conjunctivitis and dry eye.
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Mucopurulent discharge typically occurs in chlamydial or acute bacterial infection.
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Moderately purulent discharge occurs in acute bacterial conjunctivitis.
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Severe purulent discharge is suggestive of gonococcal infection.
Conjunctival reaction
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Hyperaemia that is diffuse, beefy-red and more intense away from the limbus is usual in bacterial infection ( Fig. 5.2A ). This ‘conjunctival injection’ should be distinguished from the ciliary injection of iridocyclitis (see Ch. 11 ).
Fig. 5.2
Signs of conjunctival inflammation. (A) Hyperaemia (conjunctival injection); (B) petechial haemorrhages; (C) chemosis; (D) pseudomembrane; (E) infiltration; (F) scarring
(Courtesy of P Saine –fig. A; S Tuft – fig. B; C Barry – fig. F)
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Haemorrhages may occur in viral conjunctivitis, when they are often multiple, small and discrete (‘petechial’ – Fig. 5.2B ), and severe bacterial conjunctivitis, when they are larger and diffuse.
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Chemosis (conjunctival oedema) is seen as a translucent swelling ( Fig. 5.2C ), which when severe may protrude through the eyelids. Acute chemosis usually indicates a hypersensitivity response (e.g. pollen), but can also occur in severe infective conjunctivitis. Subacute or chronic chemosis has numerous causes:
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Local, e.g. thyroid eye disease, chronic allergic conjunctivitis, ocular or eyelid surgery, trauma.
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Increased systemic vascular permeability, e.g. allergic conditions, infections including meningitis, vasculitis.
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Increased venous pressure, e.g. superior vena cava syndrome, right-sided heart failure.
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Decreased plasma oncotic pressure, e.g. nephrotic syndrome.
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Membranes
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Pseudomembranes ( Fig. 5.2D ) consist of coagulated exudate adherent to the inflamed conjunctival epithelium. They can be peeled away leaving the underlying epithelium intact.
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True membranes involve the superficial layers of the conjunctival epithelium so that attempted removal leads to tearing. The distinction between a true membrane and a pseudomembrane is rarely clinically helpful and both can leave scarring following resolution.
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Causes include severe adenoviral conjunctivitis, gonococcal and some other bacterial conjunctivitides ( Streptococcus spp., Corynebacterium diphtheriae ), ligneous conjunctivitis and Stevens–Johnson syndrome.
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Infiltration represents cellular recruitment to the site of chronic inflammation and typically accompanies a papillary response. It is recognized by loss of detail of the normal tarsal conjunctival vessels, especially on the upper lid ( Fig. 5.2E ).
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Subconjunctival cicatrization (scarring) may occur in trachoma and other severe conjunctivitides ( Fig. 5.2F ). Severe scarring is associated with loss of goblet cells and accessory lacrimal glands, and can lead to cicatricial entropion.
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Follicles
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Signs. Multiple, discrete, slightly elevated lesions resembling translucent grains of rice, most prominent in the fornices ( Fig. 5.3A ). Blood vessels run around or across rather than within the lesions.
Fig. 5.3
(A) Conjunctival follicles; (B) histology of a follicle showing two subepithelial germinal centres with immature lymphocytes centrally and mature cells peripherally; (C) conjunctival macropapillae; (D) histology of a papilla showing folds of hyperplastic conjunctival epithelium with a fibrovascular core and subepithelial stromal infiltration with inflammatory cells
(Courtesy of J Harry – figs B and D)
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Histology shows a subepithelial lymphoid germinal centre with central immature lymphocytes and mature cells peripherally ( Fig. 5.3B ).
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Causes include viral and chlamydial conjunctivitis, Parinaud oculoglandular syndrome and hypersensitivity to topical medications. Small follicles are a normal finding in childhood (folliculosis), as are follicles in the fornices and at the margin of the upper tarsal plate in adults.
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Papillae can develop only in the palpebral conjunctiva and in the limbal bulbar conjunctiva where it is attached to the deeper fibrous layer.
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Signs. In contrast to follicles, a vascular core is present. Micropapillae form a mosaic-like pattern of elevated red dots as a result of the central vascular channel, macropapillae (<1 mm – Fig. 5.3C ) and giant papillae (>1 mm) develop with prolonged inflammation. Apical infiltrate or staining with fluorescein or the presence of mucus can be present with marked activity. Limbal papillae have a gelatinous appearance.
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Histology shows folds of hyperplastic conjunctival epithelium with a fibrovascular core and subepithelial stromal infiltration with inflammatory cells ( Fig. 5.3D ). Late changes include superficial stromal hyalinization, scarring and the formation of crypts containing goblet cells.
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Causes include bacterial conjunctivitis, allergic conjunctivitis, chronic blepharitis, contact lens wear, superior limbic keratoconjunctivitis and floppy eyelid syndrome.
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Lymphadenopathy
The most common cause of lymphadenopathy associated with conjunctivitis is viral infection. It may also occur in chlamydial and severe bacterial conjunctivitis (especially gonococcal), and Parinaud oculoglandular syndrome. The preauricular site is typically affected.
Bacterial Conjunctivitis
Acute bacterial conjunctivitis
Acute bacterial conjunctivitis is a common and usually self-limiting condition caused by direct contact with infected secretions. The most common isolates are Streptococcus pneumoniae , Staphylococcus aureus , Haemophilus influenzae and Moraxella catarrhalis . A minority of cases, usually severe, are caused by the sexually transmitted organism Neisseria gonorrhoeae , which can readily invade the intact corneal epithelium. Meningococcal ( Neisseria meningitidis ) conjunctivitis is rare, and usually affects children.
Diagnosis
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Symptoms
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Acute onset of redness, grittiness, burning and discharge.
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Involvement is usually bilateral although one eye may become affected 1–2 days before the other.
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On waking, the eyelids are frequently stuck together and may be difficult to open.
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Systemic symptoms may occur in patients with severe conjunctivitis associated with gonococcus, meningococcus, Chlamydia and H. influenzae. In children, the possibility of progression to systemic involvement should always be borne in mind.
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Signs are variable and depend on the severity of infection.
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Eyelid oedema and erythema ( Fig. 5.4A ) may occur in severe infection, particularly gonococcal.
Fig. 5.4
Bacterial conjunctivitis. (A) Eyelid oedema and erythema in severe infection; (B) diffuse tarsal and forniceal conjunctival hyperaemia (injection); (C) mucopurulent discharge; (D) profuse purulent discharge
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Conjunctival injection as previously described ( Fig. 5.4B and see Fig. 5.2A ).
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The discharge can initially be watery, mimicking viral conjunctivitis, but rapidly becomes mucopurulent ( Fig. 5.4C ).
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Hyperacute purulent discharge ( Fig. 5.4D ) may signify gonococcal or meningococcal conjunctivitis.
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Superficial corneal punctate epithelial erosions are common.
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Peripheral corneal ulceration may occur in gonococcal and meningococcal infection, and may rapidly progress to perforation.
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Lymphadenopathy is usually absent except in severe gonococcal and meningococcal infection.
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Investigations are not performed routinely but may be indicated in the following situations:
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In severe cases, binocular conjunctival swabs and scrapings should be taken for urgent Gram staining, particularly to exclude gonococcal and meningococcal infection (Gram-negative kidney-shaped intracellular diplococci).
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Culture should include enriched media such as chocolate agar or Thayer–Martin for N. gonorrhoeae .
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Polymerase chain reaction (PCR) may be required for less severe cases that fail to respond to treatment, particularly to rule out the possibility of chlamydial and viral infection.
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Treatment
About 60% resolve within 5 days without treatment.
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Topical antibiotics , usually four times daily for up to a week but sometimes more intensively, are frequently administered to speed recovery and prevent re-infection and transmission. There is no evidence that any particular antibiotic is more effective. Ointments and gels provide a higher concentration for longer periods than drops but daytime use is limited because of blurred vision. The following antibiotics are available:
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Chloramphenicol, aminoglycosides (gentamicin, neomycin, tobramycin), quinolones (ciprofloxacin, ofloxacin, levofloxacin, lomefloxacin, gatifloxacin, moxifloxacin, besifloxacin), macrolides (erythromycin, azithromycin) polymyxin B, fusidic acid and bacitracin.
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Some practitioners, particularly in the United States, believe that chloramphenicol should not be used for routine treatment because of a possible link with aplastic anaemia.
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Gonococcal and meningococcal conjunctivitis should be treated with a quinolone, gentamicin, chloramphenicol or bacitracin 1–2 hourly as well as systemic therapy (see below).
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Systemic antibiotics are required in the following circumstances:
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Gonococcal infection is usually treated with a third-generation cephalosporin such as ceftriaxone; quinolones and some macrolides are alternatives. It is essential to seek advice from a microbiologist and/or genitourinary specialist.
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H. influenzae infection, particularly in children, is treated with oral amoxicillin with clavulanic acid; there is a 25% risk of developing otitis and other systemic problems.
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Meningococcal conjunctivitis, also particularly in children, in whom early systemic prophylaxis may be life-saving as up to 30% develop invasive systemic disease. The advice of paediatric and infectious disease specialists must be sought but if in doubt treatment with intramuscular benzylpenicillin, ceftriaxone or cefotaxime, or oral ciprofloxacin should not be delayed.
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Preseptal or orbital cellulitis (see Ch. 3 ).
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Topical steroids may reduce scarring in membranous and pseudomembranous conjunctivitis, although evidence for their use is unclear.
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Irrigation to remove excessive discharge may be useful in hyperpurulent cases.
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Contact lens wear should be discontinued until at least 48 hours after complete resolution of symptoms. Contact lenses should not be worn whilst topical antibiotic treatment continues.
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Risk of transmission should be reduced by hand-washing and the avoidance of towel sharing.
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Review is unnecessary for most mild/moderate adult cases, although patients should be cautioned to seek further advice in the event of deterioration.
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Statutory notification of public health authorities may be required locally for some causes.
Giant fornix syndrome
Giant fornix syndrome is an uncommon entity causing chronic relapsing pseudomembranous purulent conjunctivitis. It is believed to be due to retained debris in a voluminous upper fornix acting as a focus for persistent bacterial colonization (usually S. aureus ) in an elderly patient with levator disinsertion. Large protein aggregations may be visualized in the upper fornix, though double eversion with a retractor may be necessary to identify these. Secondary corneal vascularization and lacrimal obstruction are common. It is frequently unilateral. Treatment involves repeated sweeping of the fornix with a cotton-tipped applicator and topical and systemic antibiotics; intensive topical steroid may be helpful. Surgical forniceal reconstruction may be necessary in recalcitrant cases.
Adult chlamydial conjunctivitis
Pathogenesis
Chlamydia trachomatis ( Fig. 5.5 ) is a species of Chlamydiae, a phylum of bacteria that cannot replicate extracellularly and hence depends on host cells. They exist in two principal forms: (a) a robust infective extracellular ‘elementary body’ and (b) a fragile intracellular replicating ‘reticular body’. Adult chlamydial (inclusion) conjunctivitis is an oculogenital infection usually caused by serovars (serological variants) D–K of C. trachomatis , and affects 5–20% of sexually active young adults in Western countries . Transmission is by autoinoculation from genital secretions, although eye-to-eye spread probably accounts for about 10%. The incubation period is about a week.
Urogenital infection
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In males chlamydial infection is the most common cause of non-gonococcal urethritis (NGU), also termed non-specific urethritis (NSU). It should be noted that the latter term is also sometimes used to mean urethritis in which both gonococcal and chlamydial infection have been ruled out. Chlamydial urethritis is frequently asymptomatic in men. C. trachomatis may also cause epididymitis, and can act as a trigger for Reiter syndrome.
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In females chlamydial urethritis typically causes dysuria and discharge. It may progress to pelvic inflammatory disease (PID), carrying a risk of infertility; 5–10% of women with PID develop perihepatitis (Fitz-Hugh–Curtis syndrome).
Diagnosis
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Symptoms consist of the subacute onset of unilateral or bilateral redness, watering and discharge. Untreated, the conjunctivitis becomes chronic, and though self-limiting may persist for several months. It is important to enquire about sexual exposure if chlamydial conjunctivitis is suspected.
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Signs
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Watery or mucopurulent discharge.
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Tender preauricular lymphadenopathy.
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Large follicles are often most prominent in the inferior fornix ( Fig. 5.6A ) and may also involve the upper tarsal conjunctiva ( Fig. 5.6B ).
Fig. 5.6
Adult chlamydial conjunctivitis. (A) Large forniceal follicles; (B) superior tarsal follicles; (C) peripheral corneal infiltrates; (D) superior pannus
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Superficial punctate keratitis is common.
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Perilimbal subepithelial corneal infiltrates ( Fig. 5.6C ) may appear after 2–3 weeks.
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Chronic cases have less prominent follicles and commonly develop papillae.
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Mild conjunctival scarring and superior corneal pannus ( Fig. 5.6D ) are not uncommon.
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Investigations. Tarsal conjunctival scrapings are obtained using a spatula or the blunt side of a scalpel blade.
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Nucleic acid amplification tests such as PCR are likely to be the investigation of choice in time but validation for ocular specimens is limited at present.
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Giemsa staining for basophilic intracytoplasmic bodies is performed by applying scrapings onto a glass slide.
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Direct immunofluorescence detects free elementary bodies with about 90% sensitivity and specificity.
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Enzyme immunoassay for direct antigen detection is also useful.
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McCoy cell culture is highly specific.
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Swabs can be taken for bacterial culture, and serology may be helpful in selected cases.
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Treatment
Empirical treatment may be given if the clinical picture is convincing pending investigation results, or if investigations are negative.
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Referral to a genitourinary specialist is mandatory in confirmed cases, particularly for the exclusion of other sexually transmitted infections, contact tracing and pregnancy testing.
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Systemic therapy involves one of the following:
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Azithromycin 1 g repeated after 1 week is generally the treatment of choice, although a second or a third course is required in up to 30% of cases. Some guidelines advocate only a single 1 g dose.
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Doxycycline 100 mg twice daily for 10 days (tetracyclines are relatively contraindicated in pregnancy/breastfeeding and in children under 12 years of age).
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Erythromycin, amoxicillin and ciprofloxacin are alternatives.
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Topical antibiotics such as erythromycin or tetracycline ointment are sometimes used to achieve rapid relief of ocular symptoms, but are insufficient alone.
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Reduction of transmission risk involves abstinence from sexual contact until completion of treatment (1 week after azithromycin), together with other precautions as for any infectious conjunctivitis.
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Re-testing for persistent infection should take place 6–12 weeks after treatment.
Trachoma
Pathogenesis
Trachoma is the leading cause of preventable irreversible blindness in the world. It is related to poverty, overcrowding and poor hygiene, the morbidity being a consequence of the establishment of re-infection cycles within communities. Whereas an isolated episode of trachomatous conjunctivitis may be relatively innocuous, recurrent infection elicits a chronic immune response consisting of a cell-mediated delayed hypersensitivity (Type IV) reaction to the intermittent presence of chlamydial antigen and can lead to loss of sight. Prior contact with the organism confers short-term partial immunity but also leads to a heightened inflammatory reaction upon reinfection. Vaccination has an effect similar to primary infection in sensitizing the individual, and so is not helpful. The family childcare group is the most important re-infection reservoir, and consequently young children are particularly vulnerable. The fly is an important vector, but there may be direct transmission from eye or nasal discharge. Trachoma is associated principally with infection by serovars A, B, Ba and C of Chlamydia trachomatis , but the serovars D–K conventionally associated with adult inclusion conjunctivitis, and other species of the Chlamydiaceae family such as Chlamydophila psittaci and Chlamydophila pneumoniae have also been implicated.
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