Hyperacute conjunctivitis presents with the explosive onset (<24 hours) of severe purulent discharge, marked conjunctival hyperemia, chemosis, and papillary reaction. The most common etiology is N. gonorrhoeae. Gonococcal conjunctivitis has a high association with keratitis and ulceration, which may rapidly progress to perforation. Up to one third of the patients may have concurrent chlamydial venereal disease. Conjunctival gram-stained smears and cultures help establish the diagnosis. Although topical antibiotics and copious irrigation are part of the treatment, systemic treatment for gonorrhea and chlamydia is imperative.¹⁰

Acute purulent conjunctivitis presents with an acute onset (hours to days) of purulent discharge, conjunctival hyperemia, and papillary reaction which are less dramatic as compared to hyperacute conjunctivitis. The most common pathogens include Streptococcus pneumoniae, Staphylococcus aureus, Hemophilis influenzae, and Moraxella catarrhalis. The infection is usually self-limited, and is often treated with empiric antibiotics. The treatment is controversial, however, since some studies have found no increased benefit of topical antibiotics as compared to supportive care, unless the treatment was implemented early at the onset of culture-positive bacterial conjunctivitis. Conjunctival cultures are not always indicated for acute purulent conjunctivitis, however. The decision to culture may be influenced by lack of resolution of symptoms despite empiric antibiotics, by severe presentation that may be difficult to distinguish from hyperacute conjunctivitis, and by an immunocompromised state of a host.(10,11)

Chlamydia trachomatis is the microorganism that causes trachoma (serotypes A-C), neonatal and adult inclusion conjunctivitis (serotypes D-K), and lymphogranuloma venereum (serotypes L1-L3).^12,13,14,15 The agent is an atypical microorganism that resembles bacteria in the sense of sensitivity to antibiotics but, like a virus, is an obligate intracellular organism. The intracellular reproduction of chlamydia produces the elementary bodies and initial bodies. The cytoplasmic inclusion body, known as an elementary body, is a small particle, 200 to 350 nm in diameter. The elementary body, after enlargement (up to 1 μm), is known as an initial body. The initial bodies divide by binary fission, multiply, and reorganize into numerous small highly infectious elementary bodies that are released from the cell. Histologically, large basophilic initial bodies can be seen to cap the nucleus of infected cells, and the accumulation of numerous initial bodies is identified intracytoplasmically by Giemsa-stained cells scraped from the surface of the infected epithelium (Fig. 14).¹⁶ Cell culture isolation and PCR are widely used methods for diagnosis of Chlamydia trachomatis infection.

Acute allergic conjunctivitis is one of the more common etiologies of a noninfectious conjunctivitis, which occurs due to the direct exposure of the ocular mucosal surfaces to environmental allergens. Seasonal allergic conjunctivitis (SAC) is a type I, IgE and mast cell-mediated hypersensitivity reaction to pollens from grasses and trees, whereas perennial allergic conjunctivitis (PAC) is a type I hypersensitivity reaction to common household allergens, such as dust mites and animal dander. Itching, mucous discharge, milky or pale pink edematous conjunctiva with papillary reaction, and eventually cicatricial changes (supepithelial fibrosis) are observed clinically. Additionally, venous congestion can cause the appearance of dark circles around the eyes called “allergic shiner,” and patients often experience rhinitis. Clinical history or family history of atopy may be present.^20,21

The diagnosis is made easier by detailed clinical history. Serological tests may reveal elevated serum IgE in over 70% of the patients, whereas tear fluid IgE is present in almost all tear fluid samples. However, these findings are not specific.²¹ Skin testing by an allergist can pinpoint the offending allergen(s).

Histopathologically, mast cells are increased in number in the bulbar and tarsal substantia propria, and occasionally in the epithelium. In some patients, eosinophils may also be demonstrated within the epithelium and substantia propria, but their absence does not preclude the diagnosis.^2,22,23

Vernal keratoconjunctivitis (VKC) is a bilateral chronic mast cell-lymphocyte-mediated allergic disorder, which involves both type I and type IV hypersensitivity reactions. VKC affects predominantly prepubescent boys. Sex distribution equalizes after puberty. Strong personal and/or family history of atopy can be elicited in many patients. Seasonal peak incidence in spring is characteristic, but the condition can persist all year round, particularly in hotter tropical climates. Characteristic symptoms are intense pruritus, photophobia, blepharospasm, and copious ropy mucoid discharge.^21,24

Clinical examination reveals diffuse papillary hypertrophy, typically in the upper tarsal region. Giant cobblestone-like papillae may develop in severe cases (palpebral VKC). Bulbar conjunctival hyperemia and chemosis, and formation of gelatinous-white limbal nodules (Horner-Trantas dots) are observed in limbal form of VKC (Fig. 15A), which can occur in isolation or in conjunction with palpebral VKC. Corneal changes (corneal VKC) may also be observed and include punctate epithelial erosions in the superior and central cornea and superficial shield-like ulcers, which can lead to stromal opacification and vascularization. An association with keratoconus has been reported.^2,21,24

Conjunctival scrapings of the superior tarsal conjunctiva will demonstrate the presence of eosinophils and free eosinophilic granules, suggestive of degranulation. Histopathology of the superior tarsal conjunctiva shows epithelial hyperplasia and proliferation of fibrovascular connective tissue along with the infiltrate of mast cells, eosinophils, lymphocytes, plasma cells, and monocytes. Horner-Trantas dots histopathologically appear as microaggregates of degenerated eosinophils and epithelial cells (Fig. 15B).^2,25

Atopic keratoconjunctivitis (AKC) is a more serious, potentially sight threatening condition, associated with atopy. Unlike VKC, AKC is a perennial, T cell-mediated type IV immune hypersensitivity reaction, although seasonal exacerbations reflecting a compounding type I hypersensitivity response also occur. AKC can present in youth, albeit usually at an older age then VKC, and exhibits a progressive course as the patient matures. Presenting signs include bilateral atopic dermatitis of the eyelids, blepharitis, conjunctivitis, cataracts, and corneal punctate epithelial erosions, ulceration, and vascularization. Keratoconus has been also associated with AKC. In contrast to VKC, papillae in AKC are small- to medium-sized, are equally distributed on tarsal and palpebral conjunctiva, and may even show lower tarsal conjunctiva predilection. Conjunctival scarring with symblepharon formation may occur in advanced stages of the disease.^21,25

Tear fluid may show increase in IgE concentration. Conjunctival cytology may reveal eosinophils, although they are not as numerous as in VKC, and are less often degranulated. Conjunctival epithelium may show an infiltrate of mast cells and eosinophils, epithelial pseudogland formation, and increased goblet cell density. Mast cells and mononuclear cell infiltration are prominent in the substantia propria. Fibroblast proliferation and fibrosis can also be observed, reflecting cicatrizing changes in late disease.^21,25,26

Giant papillary conjunctivitis (GPC) has been originally described in eyes with foreign bodies (ocular prosthesis, extruded scleral buckle, and corneal foreign bodies), but has become increasingly more common with the advent of soft contact lenses.²¹ The etiology of GPC is not fully understood, and may involve an immune-mediated response to repeated mechanical trauma or to a type IV hypersensitivity to contact lens-related material.²⁷

Symptoms are similar to VKC, and include itching with a mucoid ropy discharge. Foreign body sensation and intolerance to contact lens wear are also common. Clinical examination will reveal giant papillae on superior tarsal conjunctiva. Although giant papillae have been originally defined as being greater then 1 mm in diameter, it is now believed that papillae 0.3 mm or larger, in association with the other signs and symptoms of contact lens-induced conjunctivitis, are diagnostic of GPC.

Histopathology of the conjunctiva in the region of giant papillae demonstrates thickened and irregular epithelium, with prominent pseudoglands of Henle. Goblet cells may be decreased in density in the epithelium at the apices of the papillae and increased in number in interpapillary crypts. Mast cells, eosinophils, and basophils are observed both within the epithelium and in the substantia propria (Fig. 16). Abnormally elevated concentrations of immunoglobulins (IgE, IgG, and IgM, and complement components) have been found in tears of affected patients. These findings suggest a combined mechanical and immune-mediated pathophysiology of GPC.^28,29

The management of patients with allergic conjunctivitis is directed towards a specific entity, and includes allergen avoidance, climatotherapy, topical medications (antihistamines, masts cell stabilizers, steroids, cyclosporine drops), systemic medications (cyclosporine), and, occasionally, cryoablation or surgical removal of giant papillae.

Erythema multiforme major is a complex immunological syndrome, which manifests in a vesiculobullous reaction of the skin and mucous membranes. Toxic epidermal necrolysis (TEN) is the most severe form of erythema multiforme, characterized by extensive sloughing of the epidermis and mucous membranes. Autoimmune response triggered by drugs (antibiotics, anticonvulsans, salicylates) or infectious organisms has been implicated in the pathogenesis of erythema multiforme.^30,31,32

The initial ocular manifestations of SJS/TEN include eyelid edema, erythema, crusting, and conjunctival hyperemia. Severe conjunctival chemosis, membrane, and pseudomembrane formation are observed less commonly. In later stages of the disease, severe dry eye and conjunctival scarring with symblepharon formation can occur. Some patients may also develop recurrent conjunctival inflammation unrelated to mechanical irritation or dryness, possibly linked to immune-complex vasculitis.^30,31,32,33

Histopathology of the conjunctiva in the acute stage of SJS shows vacuolar interface mucositis, necrotizing epithelial cells, and perivascular lymphocytic infiltration. More superficial conjunctival involvement is observed in TEN, characterized by intraepithelial inflammation and bullae and extensive epithelial sloughing. In chronic disease, fibrosis and loss of goblet cells may be observed, and mononuclear inflammatory cell infiltration is present in the substantia propria (Fig. 17A). Conjunctival biopsy in patients with recurrent conjunctivitis after SJS occasionally reveals vasculitis or perivasculitis, immunoreactant deposition in vessel walls, vascular basement membrane disruption, thickening, and reduplication, and a preponderance of helper T lymphocytes, macrophages, and Langerhans’ cells. Rarely, cicatricial pemphigoid with its representative pathologic findings is observed as a sequela of SJS (see the subsequent text).^{30,31,32,33,34}

Management of SJS/TEN is mainly supportive with ocular lubrication and surveillance for infection. Oral and topical corticosteroids are sometimes used, but their role is controversial. Symblephara can be treated by lysis and use of rings, but this is also a controversial treatment modality. Surgical correction of eyelid malposition and trichiasis, forniceal reconstruction, and keratoprosthesis for corneal complications can be attempted in the later stages of SJS/TEN (Fig. 17B).³⁰

Ocular cicatricial pemphigoid (OCP) is a type II immune-mediated hypersensitivity disorder, characterized by deposition of autoantibodies to the basement membrane zone (BMZ) at the epithelial-subepithelial junction of mucous membranes (oral cavity, eye, nose, pharynx, larynx, trachea, esophagus, genitalia, and anus) and occasionally at the dermo-epidermal junction of the skin. Some of these autoantibodies are directed against the ß4 integrin subunit and laminin 5/epiligrin (IgG), whereas others are reacting with as yet uncharacterized 45 kd antigen (IgA). Binding of the antibodies to the target antigens at BMZ leads to complement activation, deposition, and inflammatory cell infiltration, manifesting clinically by subepithelial bullae formation and eventual cicatrization. Rarely, patients with OCP demonstrate circulating IgG and IgA autoantibodies and display serologic activity against classical bullous pemphigoid antigens. Environmental triggers, such as topical medications, have been occasionally implicated in pathogenesis of OCP in genetically predisposed individuals.^30,35,36,37

The disease most commonly begins in the fifth or sixth decade of life and has a female predominance. The conjunctiva is involved in approximately 80% of patients with mucous membrane pemphigoid. The conjunctival lesions begin in one eye, but bilateral involvement eventually occurs. The clinical course of OCP is characterized by slow relapsing-remitting progression from chronic conjunctivitis to subepithelial fibrosis, fornix foreshortening, symblepharon and ankyloblepharon formation, corneal ulceration and opacification, and ocular surface keratinization.^30,35

Histopathology of the conjunctiva in acute stage of OCP shows subepithelial bullae with predominantly subepithelial inflammatory infiltrate, composed mostly of T lymphocytes, and to a lesser extent of macrophages, dendritic cells, and neutrophils. Later in the course of disease, squamous metaplasia and loss of goblet cells are observed within the epithelium. Activation of fibroblasts leads to abnormal deposition of extracellular matrix and collagen in the substantia propria in the cicatrizing stages of OCP. Direct immunofluorescence, immunoperoxidase technique, and immunoelectron microscopy may demonstrate deposition of IgA, IgG, IgM, and C3 along the BMZ, but negative conjunctival biopsy does not exclude the diagnosis of OCP (Fig. 18).^36,37,38,39

Medical therapy for OCP includes systemic methotrexate, cyclophosphamide, dapsone, and, possibly, intravenous immunoglobulin (IVIg). Topical corticosteroids may suppress the inflammatory response during acute exacerbations. Topical Vitamin A has been shown to reverse, to some extent, keratinization. Surgical therapies include correction of eyelid deformities, mucosal grafting for fornix reconstruction, cultivated corneal/limbal epithelial cell transplantation with amniotic membrane grafting, and keratoprosthesis.^30,35

Linear IgA bullous disease (LABD) is an autoimmune subepithelial and subepidermal blistering disorder, which typically affects middle age adults, but has also been reported in children. Purely ocular form can occur, which is difficult do distinguish clinically and pathologically from OCP.

Histopathology is similar to OCP. Immunofluorescence demonstrates linear deposition of IgA along BMZ. Deposits of IgG/C3 may also be present. Circulating IgA antibodies to BMZ, epidermal (epithelial), and dermal (stromal) sites can occur in some patients and are helpful in establishing the diagnosis of LABD. Treatment is similar to OCP.

Phlyctenulosis is a local conjunctival and/or corneal inflammation that is believed to be caused by a type IV, cell-mediated, delayed immune hypersensitivity reaction induced by microbial antigens, such as the cell wall components of staphylococcus in developed countries or to Mycobacterium tuberculosis protein in the populations with endemic tuberculosis.^40,41

Phlyctenulosis is typically a disease of the first two decades of life with a strong female predominance. Phlyctenules typically present unilaterally at or near the limbus as one or more small rounded, elevated hyperemic inflammatory nodules, accompanied by engorged vessels. They typically ulcerate centrally and spontaneously involute over a period of several weeks.⁴⁰

Cultures of the eyelids and conjunctiva may be performed in cases when the clinical diagnosis is in doubt, or when phlyctenulosis does not respond to treatment. Heavy growth of S. aureus is characteristic, but negative culture does not rule out the diagnosis.

Histopathology of the phlyctenule shows an initial accumulation of plasma cells, T lymphocytes, and histiocytes in the absence of epithelial ulceration. In later stages, an infiltrate of neutrophils with secondary necrosis and ulceration occur. Organisms are usually not demonstrated within phlyctenules.^40,41

Treatment consists of antibacterial/antimycobacterial and anti-inflammatory measures. Lid hygeine for staphylococcal blepharitis is also advocated to decrease the bacterial burden.

Ligneous conjunctivitis is a rare, usually bilateral, chronic membranous and pseudomembranous disorder, which typically presents in childhood, although rarely adults can be affected as well. The hallmark of ligneous conjunctivitis is the formation of firm, wood-like, yellowish membranes usually on the superior tarsal conjunctiva, and less frequently on bulbar and inferior tarsal conjunctiva (Fig. 19A). Other mucous membranes can be involved, including oral cavity, respiratory tract, middle ear, and genital tract. Although many reports describe spontaneous onset of disease, ligneous-like conjunctival changes may also occur after ocular surgery. Recently, patients with ligneous inflammation were found to have homozygous mutations in the type-1 plasminogen gene. Plasminogen deficiency results in defective fibrinolysis, thus manifesting in extensive fibrin deposition in inflamed or injured tissues.^46,47

Histopathology of the ligneous membrane shows three components (Fig. 19B):^45,48,49

The surface of the ligneous membrane may lack normal epithelium, and contain instead a collection of fibrin and inflammatory cells. This superficial layer may be scraped without bleeding, thus imparting a “pseudomembrane” characteristics to the superficial layer of the ligneous membrane.

Occasionally, foreign material and bacteria have been demonstrated in the ligneous membranes, but they are not believed to be responsible for the etiology of ligneous inflammation.

Ligneous conjunctivitis is usually a self-limited disorder. Serious ocular complications can result, however, including secondary infection and corneal ulceration with perforation. Treatment modalities include surgical excision of the membranes with or without adjunctive cryotherapy and amnionic membrane grafting, although recurrences are frequent. Anecdotal successes with topical corticosteroids, cyclosporine, heparin, purified plasminogen, and with intravenously administered purified plasminogen concentrate have been described.^46,50,51

Conjunctival sarcoidosis typically presents as discrete, yellowish, translucent nodules less then 2 mm in diameter, typically located on the inferior tarsal conjunctiva and in the inferior fornix, and less frequently on the bulbar conjunctiva.⁵² Occasionally, discrete, white, breadcrumb-like deposits scattered over the bulbar conjunctiva are observed in the patients with sarcoidosis.⁵³

Histopathology of a conjunctival sarcoid nodule reveals discrete noncaseating granulomas, with central collection of epithelioid histiocytes, Langhans-type giant cells, and foreign body giant cells, surrounded by a rim of chronic mononulcear inflammatory cells (lymphocytes and plasma cells) (Fig. 20A). Proteinaceous, star-shaped (asteroid) bodies can be found in the cytoplasm of epithelioid histiocytes or foreign body giant cells (Fig. 20B). Basophilic, calcific, lamellated, birefringent Schaumann bodies are also found either within the cytoplasm of epithelioid histiocytes/giant cells or extracellularly. These bodies are not pathognomonic of sarcoidosis. White, breadcrumb-like conjunctival deposits in patients with sarcoidosis were found to consist of a collection of Schaumann bodies, surrounded by epithelioid histiocytes and giant cells.^2,53

Blind biopsy of conjunctival fornix without clinically visible lesions in a patient with high clinical suspicion of sarcoidosis may demonstrate small granulomas, although the yield is low. Evaluation of serial sections from several levels may maximize the yield of biopsy.²

The term ophthalmia nodosa has been originally used to describe a granulomatous, nodular reaction of the conjunctiva and iris to caterpillar hairs. Later, the term has been expanded to describe ocular reactions to vegetable or insect hairs, such as tarantula hairs.⁵⁴ (54)

Five types of ocular reaction to caterpillar hair have been described:⁵⁴

Histopathology of the conjunctival nodule in type 3 reaction reveals foreign material (hairs), surrounded by foreign body granulomatous reaction.

Treatment depends on the level of involvement, and includes irrigation and removal of hairs in type 1 and 2 reactions, excision of granulomatous nodules in type 3 reaction, surgical removal or laser photocoagulation of intraocular hairs, topical/ intraocular steroids, and prophylactic antibiotics.⁵⁴

Conjunctival granulomas, associated with Splendore-Hoeppli phenomenon Conjunctival granulomas may occasionally display deposition of amorphous eosinophilic material, surrounded by epithelioid histiocytes, multinucleated giant cells, lymphocytes, and eosinophils. The nature of the material has been reported as either antigen-antibody complexes, rich in immunoglobulins (IgG, IgM, IgA) and complement (C3), or as the major basic protein of eosinophils. It is hypothesized that temporal relationship between the formation of immune complexes, compliment fixation, chemotaxis, and eventual influx of eosinophils are responsible for varying composition of Splendore-Hoeppli material.^55,56,57

The Splendore-Hoeppli phenomenon has been initially described in a context of reaction to fungal spores, but since then a variety of other infectious (parasitic, bacterial, viral, insect) and noninfectious (synthetic fiber [see below]) processes have been implicated.^55,56,57

Synthetic fiber granuloma (“teddy bear granuloma”) of the conjunctiva results from an inflammatory reaction to synthetic fibers that become implanted in the conjunctival fornices. The lesion classically presents unilaterally in the inferior fornix of a child, who sleeps with a stuffed animal or a blanket made of synthetic material.^58,59

Histopathology is diagnostic, and reveals numerous acellular synthetic fibers that are fairly uniform in diameter, ranging from 17 to 29 μm. The fibers lack central hollow core, do not display PAS-positivity, show parallel chatter marks from microtome blade, demonstrate dark granules on their surface (de-lustering agent), and exhibit a markedly pronounced birefringence with polarized light due to their highly organized chemical composition. These findings are helpful to distinguish the synthetic fibers from human hairs, ophthalmia nodosa, and other inorganic material. The synthetic fibers may be surrounded by Splendore-Hoeppli phenomenon. Foreign body granulomatous reaction to the synthetic material is prominent in the lesion (Fig. 21).^58,59

The treatment involves surgical removal of foreign material and associated inflammatory reaction.

It is hypothesized that actinic granuloma of the conjunctiva represents a cell-mediated immune response to actinically altered elastotic fibers within the substantia propria. The patients present with relatively rapid onset of a painless, vascularized, nasal or temporal bulbar conjunctival nodule, which can be misinterpreted as a vascularized pinguecula, nevus, squamous carcinoma, or metastasis.

Histopathologic evaluation demonstrates prominent actinic elastosis surrounded by granulomatous response.⁶⁰

Parinaud Oculoglandular syndrome is a rare condition, characterized by granulomatous conjunctivitis with regional lymphadenopathy. This syndrome may be caused by a variety of infectious and noninfectious agents, but the most common culprit is Bartonella henselae (cat-scratch disease).⁶¹

Cat-scratch disease is the most frequently recognized form of systemic Bartonela henselae infection, which presents with flu-like illness associated with regional lymphadenopathy. Most cases are believed to be transmitted by a scratch or bite from a flea-infested kitten, but direct inoculation with infected flea feces is also possible. Although Parinaud Oculoglandular syndrome is the most common ocular manifestation of cat-scratch disease, other ocular complications include optic neuritis, neuroretinitis, retinochoroiditis, and orbital infiltrates.^2,61,62

Serologic testing (indirect immunofluorescence, enzyme-linked immunoassays) is the most cost-effective means for diagnosing cat-scratch disease. A cat-scratch disease antigen skin test can be used also to identify infected patients. Isolation of Bartonella from biopsy specimens is extremely difficult and requires special culture techniques.^2,61

Histopathologic evaluation of conjunctival nodules reveals discrete granulomas (which later may become necrotizing) and reactive follicular hyperplasia. The Warthin-Starry silver stain is helpful in demonstrating bacilli within granulomas. Electron microscopy can also demonstrate bacilli in challenging cases (Fig. 22).^2,61

The disease is self limited in immunocompetent patients, one of the reasons why the optimal treatment is debatable. Immunocompromised patients can demonstrate dramatic response to antibiotics, however, such as erythromycin, azithromycin, or doxycycline. Rifampin is often used as adjuvant.^61,62

Other etiologies of Parinaud Oculoglandular syndrome include: ^{62,63,64,65,66,67,68}

The primary lysosomal disorders of complex lipids (gangliosides and sphingomyelin) affect the central nervous system, causing psychomotor retardation. All are autosomal recessive, except for Fabry’s disease, which is X-linked recessive. In addition to psychomotor retardation, Fabry’s disease can also affect the skin, renal, and cardiovascular systems. Ocular manifestations of Fabry’s disease include: corneal clouding, retinal opacification, and optic atrophy. Fabry’s disease manifests in conjunctival and retinal vascular tortuosity, whorl-like corneal opacities (cornea verticillata), periorbital edema, and cortical cataracts. Of note, conjunctival changes in Fabry’s disease may precede corneal deposits and cataracts.⁷⁷

Conjunctival biopsies show ultrastructural evidence of complex lipid storage, manifesting in concentrically arranged membranous lamellae within Schwann cells, histiocytes, fibroblasts, and endothelial cells. Mucopolysaccharide-like fibrinogranular material may be occasionally demonstrated as well (multiple sulfatase deficiency). In Fabry’s disease, abnormal lipid material accumulates within the adventitial, smooth muscle, and endothelial cells of conjunctival blood vessels.⁷⁷

The neuronal ceroid lipofuscinoses are a large group of an autosomal recessive, lysosomal storage disorders of childhood, characterized by accumulation of autofluorescent lipopigment granules in most tissues, including brain and retinal neurons. Although the exact pathogenesis and precise characterization of the deposit in Batten disease are unknown, several genes have been identified, some encoding lysosomal enzymes involved in protein metabolism.^78,79

The affected patients display progressive psychomotor retardation and visual loss. Ocular findings include “bull’s eye” maculopathy, retinitis pigmentosa fundus, and nonrecordable electroretinogram.^78,79

Immunofluorescence studies of the conjunctiva may demonstrate autofluorescent lipopigment granules within the epithelium. Electron microscopy can demonstrate lysosomal inclusions (granular deposits, fingerprint profiles, and curvilinear profiles) within the histiocytes and Schwann cells of peripheral nerves.^78,79,80

Cystinosis is an autosomal recessive disorder manifested by the accumulation of the amino acid cystine within lysosomes of various tissues, due to a defect in transport across the lysosomal membrane.

Three forms have been described:

Eye exam is remarkable for fine, scintillating conjunctival and corneal crystals throughout the corneal stroma and conjunctival substantia propria in all three forms of cystinosis (Fig. 25A). In addition, crystals can occasionally be observed in the trabecular meshwork, iris, ciliary body, choroid, retina, and optic nerve. Photophobia and salt-and-pepper pigmentary retinopathy are also observed in infantile cystinosis.^77,81,82

Conjunctival biopsy reveals rectangular, square, and hexagonal birefringent crystals, measuring between 0.2 to 2.0 μm in diameter. The crystals accumulate within the epithelial cells and in fibroblasts and histiocytes of subsantia propria (Fig. 25B). The crystals are water-soluble and dissolve during fixation. Therefore, the tissue must be fixed in absolute ethanol and processed rapidly to minimize the aqueous dilution.^77,82

Alkaptonuria is an autosomal recessive metabolic disorder of tyrosine metabolism, caused by the deficiency of homogentisic acid 1,2-dioxygenase enzyme, which results in an increased level of homogentisic acid in serum. Oxidized homogentisic acid gives a characteristic bluish-black color to urine. Oxidized and polymerized homogentisic acid accumulates within the connective tissues (cartilage, skin, nails, and in the interpalpebral sclera, conjunctiva, and cornea), causing bluish-brown discoloration, referred to as ochronosis.^83,84