PATHOGENESIS

A defect in transport across the lysosomal membrane leads to intracellular accumulation of cystine.

CLINICAL PRESENTATION

Cystinosis is categorized on the basis of the patient’s age at diagnosis and the severity of symptoms. Nephropathic cystinosis is divided into infantile (classic) and intermediate (juvenile or adolescent) forms. Dwarfism and progressive renal dysfunction are prominent in infantile cystinosis and less severe in the juvenile disease. Life expectancy is normal in nonnephropathic cystinosis (formerly called adult cystinosis). All 3 types are characterized by the deposition of fine iridescent and polychromatic cystine crystals in the conjunctiva, cornea, iris, and other parts of the eye. The crystals are densest in the peripheral cornea but are present throughout the anterior stroma, even within the central cornea (Fig 8-4), and can be seen in the trabecular meshwork with gonioscopy. Patients with cystinosis often have photophobia, and the crystals can recur following PK. Table 8-2 lists other causes of corneal crystals; Table 8-3 summarizes the ocular and systemic findings in disorders of amino acid metabolism.

Figure 8-4 Nonnephropathic cystinosis. Slit-lamp photograph showing diffuse stromal refractile crystals.

(Courtesy of Stephen E. Orlin, MD.)

Liang H, Baudouin C, Tahiri JHR, Brignole-Baudouin F, Labbe A. Photophobia and corneal crystal density in nephropathic cystinosis: an in vivo confocal microscopy and anterior segment optical coherence tomography study. Invest Ophthalmol Vis Sci. 2015;56(5): 3218–3225.

LABORATORY EVALUATION

Cystine crystals may be seen in conjunctiva, blood leukocytes, or bone marrow.

MANAGEMENT

Topical cysteamine 0.44% is a commercially available agent used to reduce the density of the crystals and diminish corneal pain, possibly by reducing the frequency of corneal erosions. Cysteamine is thought to react with intracellular cystine, forming a cysteine–cysteamine disulfide that resembles lysine and is transported through the lysosome by the normal lysine transport system. Posterior segment manifestations such as pigmentary retinopathy and optic nerve involvement may be treated with oral cysteamine, which may also prevent or delay other manifestations of the disease, including death.

Table 8-2 Differential Diagnosis of Corneal Crystals

Table 8-3 Disorders of Amino Acid Metabolism

PATHOGENESIS

Tyrosinemia type II is an autosomal recessive disorder resulting from defective tyrosine aminotransferase, which leads to excess tyrosine in the blood and urine. The elevated tyrosine level likely has a direct effect on lysosomal membranes, leading to enzyme release. The gene defect is located at 16q22.1–22.3.

CLINICAL PRESENTATION

Ocular changes include marked photophobia, tearing, conjunctival injection, and tarsal papillary hypertrophy. Affected patients experience recurrent episodes of corneal erosions and pseudodendrites (Fig 8-5), which usually do not stain well with fluorescein or rose bengal. Continued episodes of epithelial breakdown can result in corneal vascularization and scarring. It is important to consider this disorder in young children who may carry a diagnosis of recurrent herpes simplex virus keratitis.

LABORATORY EVALUATION

Hypertyrosinemia and tyrosinuria with normal phenylalanine levels and conjunctival biopsy showing soluble tyrosine aminotransferase deficiency are diagnostic.

Figure 8-5 Slit-lamp photograph showing a pseudodendrite in a patient with tyrosinemia.

(Courtesy of Robert W. Weisenthal, MD.)

MANAGEMENT

Restriction of dietary intake of tyrosine and phenylalanine can reduce the severity of both the corneal and systemic changes, including cognitive impairment. The institution of appropriate dietary restrictions, even later in life, can improve mental status.

PATHOGENESIS

Homogentisate 1,2-dioxygenase, the enzyme necessary to degrade tyrosine and phenylalanine, is deficient in patients with this disorder. Phenylalanine and tyrosine cannot be metabolized beyond homogentisic acid, which is oxidized and polymerized into alkapton, a brown-black material similar to melanin. Alkapton binds to collagen and is then deposited in connective tissues as a dark pigment; this process is known as ochronosis.

CLINICAL PRESENTATION

Systemic findings include arthropathy; renal calculi; and pigmentation of cartilaginous structures, including earlobes, trachea, nose, tendons, dura mater, heart valves, and prostate. Eventually, medial and lateral rectus muscle tendons and the sclera adjacent to the tendon insertions develop a smudgelike bluish-black pigmentation (Fig 8-6). Darkly pigmented, dotlike opacities, similar to those seen in spheroidal degeneration, may appear in the corneal epithelium or in the Bowman layer, near the limbus.

LABORATORY EVALUATION

The urine of affected patients turns dark on standing. Alkaptonuria is diagnosed by finding elevated levels of homogentisic acid in the urine.

Figure 8-6 Slit-lamp photograph from a female patient with alkaptonuria, showing ochronosis (scleral pigmentation) at the insertion of the lateral rectus muscle.

(Courtesy of Irving M. Raber, MD.)

MANAGEMENT

No specific therapy is available, but high-dose ascorbic acid may reduce arthropathy in young patients. Gene therapy may be a future treatment.

Srinivasan S, Shehadeh-Mashor R, Slomovic AR. Corneal manifestations of metabolic diseases. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Philadelphia: Elsevier; 2017:620–644.

CLASSIFICATION AND CLINICAL PRESENTATION

Ocular amyloidosis is classified as either primary (idiopathic) or secondary (to a chronic disease) and as either localized or systemic. A useful classification of amyloidosis considers these 4 types. Each type is summarized in Table 8-4.

Primary localized amyloidosis is the most common form of ocular amyloidosis. Conjunctival amyloid plaques occur in the absence of systemic involvement (Fig 8-7). Gelatinous droplike corneal dystrophy (formerly primary familial amyloidosis), classic lattice corneal dystrophy (LCD1), and lattice variants are special forms of primary localized amyloidosis and are discussed in Chapter 7. Polymorphic amyloid degeneration is discussed in Chapter 6.

Table 8-4 Amyloid in the Eye

Figure 8-7 Clinical photograph of the inferior palpebral conjunctiva, showing moderate thickening with yellowish amyloid deposition.

(Courtesy of Stephen E. Orlin, MD.)

Primary systemic amyloidosis is a heterogeneous group of diseases in which waxy, ecchymotic eyelid papules occur in association with vitreous veils and opacities as well as with pupillary anomalies such as light–near dissociation. Orbital involvement, extraocular muscle involvement with ophthalmoplegia, and scleral infiltration with uveal effusion have been reported. The most common form of primary systemic amyloidosis is an autosomal dominant group of diseases linked to mutations in the transthyretin gene (TTR, prealbumin) on chromosome 18 (18q11.2–q12.1); more than 40 mutations in this gene have been described.

Familial amyloidosis, Finnish type, or gelsolin type (Meretoja syndrome) is an example of primary systemic amyloidosis. This condition was initially described in persons of Finnish descent but was later reported in individuals of other ethnicities. Previously called lattice corneal dystrophy type 2, it has been excluded as a corneal dystrophy by the International Committee for the Classification of Corneal Dystrophies (IC3D) because of its systemic associations.

Familial amyloidosis presents in the third to fourth decade of life. Because the ocular symptoms are the first to arise, the ophthalmologist is often the first physician to see patients with this condition, who typically present with corneal findings. Affected patients have a characteristic facial mask; dermatochalasis; lagophthalmos; pendulous ears; cranial and peripheral nerve palsies; and dry, lax skin with amyloid deposition (Fig 8-8). The classic corneal lattice lines are less numerous and more peripheral, and they spread centripetally from the limbus. The central cornea is relatively spared; corneal sensation is reduced. The risk of open-angle glaucoma may be increased, and dry eye and recurrent erosions may occur late in life.

PATHOLOGY OF FAMILIAL AMYLOIDOSIS

Light microscopy shows amyloid in the lattice lines as a discontinuous band under the Bowman layer and within the sclera. The amyloid in this condition is related to gelsolin and does not stain for type AA or AP. The mutated gelsolin is observed to be deposited in the conjunctiva, sclera, and ciliary body; along the choriocapillaris; in the ciliary nerves and vessels; and in the optic nerve. Extraocularly, amyloid is detected in arterial walls, peripheral nerves, and glomeruli. On confocal microscopy, deposits are observed along the basal epithelial cells and stromal nerves.

Figure 8-8 A, Diffuse lattice lines in Meretoja syndrome. B, Typical facies.

(Reproduced with permission from Weiss JS, Møller H, Lisch W, et al. The ICD3 classification of the corneal dystrophies. Cornea. 2008; 27(10 Suppl 2):S16.)

Reidy JJ. Corneal and conjunctival degenerations. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Philadelphia: Elsevier; 2017:856–874.

Srinivasan S, Shehadeh-Mashor R, Slomovic AR. Corneal manifestations of metabolic diseases. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Philadelphia: Elsevier; 2017: 620–644.

PATHOGENESIS

Hyperuricemia may be familial, arising from an enzyme deficiency (eg, hypoxanthine phosphoribosyltransferase in Lesch-Nyhan syndrome). More commonly, gout is polygenic or secondary to obesity, cytotoxic chemotherapy, myeloproliferative disease, diuretic therapy, or excessive alcohol consumption.

CLINICAL PRESENTATION

Acute inflammation of the sclera, episclera, or conjunctiva can occur. Fine corneal epithelial and stromal deposits may appear in the absence of inflammation. Either an orange-brown band keratopathy or a typical whitish band keratopathy is seen in rare cases.

LABORATORY EVALUATION

Serum uric acid level is typically elevated. However, in urate keratopathy, the uric acid level may be normal in the presence of keratopathy if there is no concurrent inflammation.

MANAGEMENT

Indomethacin, colchicine, or phenylbutazone is used for acute treatment; long-term reduction in uric acid levels should be pursued with medications such as allopurinol. Superficial corneal deposits can be removed mechanically with scraping or keratectomy.

PATHOGENESIS

Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder caused by multiple allelic substitutions or deletions in a Cu²⁺-ATPase-transporting β-polypeptide, linked to mutations in the ATP7B gene on chromosome 13 (13q14.3–q21). Copper is deposited first in the liver, then in the kidneys, and eventually in the brain and the cornea at the Descemet membrane (Fig 8-9).

CLINICAL PRESENTATION

Muscular rigidity increases, and tremor and involuntary movement gradually occur in a fluctuating course resembling parkinsonism. Unintelligible speech and mild dementia usually occur concomitantly. Equal numbers of patients (40%) present with hepatic or nervous system symptoms. In the cornea, a golden-brown, ruby-red, or green pigment ring (Kayser-Fleischer ring) consisting of copper deposits appears in peripheral Descemet membrane (see Fig 8-9), although not all patients with Wilson disease manifest this ring. Copper deposition occurs in the posterior Descemet membrane, first superiorly, then gradually spreading to meet inferior deposits. Gonioscopy may assist in visualizing the ring. A “sunflower” cataract may be present.

The differential diagnosis includes primary biliary cirrhosis, chronic active hepatitis, exogenous chalcosis, and progressive intrahepatic cholestasis of childhood. These and other non-Wilsonian hepatic disorders can also be associated with Kayser-Fleischer rings, but only Wilson disease is characterized by decreased serum ceruloplasmin levels and neurologic symptoms.

LABORATORY EVALUATION

Patients with Wilson disease can be differentiated from patients with other diseases that show Kayser-Fleischer rings by their inability to incorporate radioactive copper into ceruloplasmin. Low serum ceruloplasmin, high non-ceruloplasmin-bound serum copper, and high urinary copper suggest the diagnosis, which can be confirmed with liver biopsy. Nonspecific findings of proteinuria, aminoaciduria, glycosuria, uricaciduria, hyperphosphaturia, and hypercalciuria are seen.

MANAGEMENT

Wilson disease can be treated with penicillamine. Liver transplantation is reserved for patients with fulminant liver failure. The Kayser-Fleischer ring disappears gradually with therapy, including liver transplant, and the disappearance of the rings can be used to help monitor therapy. Electrophysiologic abnormalities from retinal dysfunction have been shown to reverse after treatment of the disease.

Figure 8-9 Wilson hepatolenticular degeneration. Deposits of copper in the Descemet membrane (Kayser-Fleischer ring).

(Reproduced with permission from Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 3rd ed. Vol 1. Philadelphia: Elsevier/Mosby; 2011:299.)

PATHOGENESIS

Porphyria cutanea tarda, the form most commonly associated with ocular surface disease, is either sporadic or inherited in an autosomal dominant pattern (band 1p34). The enzyme uroporphyrinogen decarboxylase is deficient, resulting in an accumulation of porphyrins in the liver and in the circulation. Typically, a second insult to the liver, such as alcoholism or drug metabolism, triggers the condition in late middle age.

A severe form of porphyria, called hepatoerythropoietic porphyria (HEP), is a homozygous presentation of the same enzymatic defect, but onset of the disease is in infancy.

CLINICAL PRESENTATION

Hyperpigmentation, erythema, scleroderma-like changes, increased fragility, and vesicular and ulcerative lesions occur on sun-exposed surfaces of the body. There is interpalpebral injection, and the conjunctiva may develop vesicles, scarring, and symblepharon mimicking bullous pemphigoid; conjunctival necrosis may also occur. Necrotizing scleritis has been reported. The cornea may be affected by exposure or by thinning and perforation at the limbus. Skin and ocular lesions may fluoresce.

LABORATORY EVALUATION

Urine turns dark on standing. Reduced liver and red cell uroporphyrinogen decarboxylase activity confirms the diagnosis. Hepatic biopsy shows liver parenchymal cells filled with porphyrins that fluoresce bright red in ultraviolet light.

MANAGEMENT

Protection from ultraviolet light and reduction of iron by phlebotomy or subcutaneous deferoxamine are the principal treatments. No specific ocular treatment is available, although artificial tears may help wash away porphyrins. Corneal thinning and perforation are treated in standard ways.

Srinivasan S, Shehadeh-Mashor R, Slomovic AR. Corneal manifestations of metabolic diseases. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Philadelphia: Elsevier; 2017:620–644.

Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.