Noninflammatory diseases of the sclera are encountered infrequently in ophthalmic practice. Their detection is easily overlooked by the ophthalmologist because of this and because of the absence of inflammation. Furthermore, major textbooks of ophthalmology usually do not include discussions of the differential diagnosis of noninflammatory diseases of the sclera, and so ophthalmologists are generally unaware that distinguishing features, such as deposits, thinning, thickening, and masses of the sclera can be diagnostically valuable (Table 8.1).

Like scleritis and episcleritis, noninflammatory diseases of the sclera cannot be properly understood as isolated entities but must be seen in relation to the larger picture of a patient’s general health. Noninflammatory diseases of the sclera may be signs of systemic diseases, such as metabolic disorders, connective tissue abnormalities, or hematologic disturbances. Noninflammatory diseases of the sclera also may be signs of ocular diseases, such as inherited or congenital connective tissue abnormalities, degenerations, or tumors. In many instances, the attributes of the scleral abnormalities are sufficiently distinctive that the diagnosis of the associated illness is first suspected by the ocular presentation.

This chapter reviews the clinical features and pathophysiology of the diseases associated with noninflammatory diseases of the sclera. The aim is to stimulate the readers to search for them and

to pursue the appropriate course of action should such abnormalities be discovered.

8.1Scleral Deposits

Scleral depositions of abnormal substances are due to either systemic inherited or acquired metabolic abnormalities, or ocular degenerative processes. For organizational purposes, these disorders are discussed in groups based on the biochemical substance accumulated (Table 8.1). Scleral changes characteristics of the different metabolic diseases are shown in Table 8.2.

8.1.1Scleral Protein Deposition

8.1.1.1 Porphyria

The porphyrias are characterized by the excessive excretion of one or more fluorescent pigments known as porphyrins. The porphyrias are inherited disorders which can be divided into two major types: erythropoietic, in which porphyrins accumulate in red blood cells, and hepatic porphyria, in which porphyrins accumulate in the liver. The former may be subdivided into erythropoietic uroporphyria (congenital porphyria) and erythropoietic protoporphyria; the latter may be subdivided into acute intermittent porphyria, porphyria cutanea tarda, porphyria variegata, and hereditary coproporphyria. Exposure to sunlight,

Table 8.1 Classification of noninflammatory affections of the sclera

1.Scleral Deposits

1.1Protein Porphyrias Cystinosis Alkaptonuria Amyloidosis

1.2Lipid

Familial Hypercholesterolemia Histiocytosis X

Age-related Degeneration

1.3Carbohydrate Mucopolysaccharidosis

1.4Mineral (Calcium) Hyperparathyroidism Hypervitaminosis D

Idiopathic Hypercalcemia of Infancy Sarcoidosis

Hypophosphatasia Age-related Degeneration Senile Hyaline Plaques

1.5Pigment (Bilirubin) Jaundice

2. Scleral Thinning (Blue Scleras)

2.1Inherited or Congenital Diseases Systemic

Marfan’s Syndrome Osteogenesis Imperfecta Pseudoxanthoma Elasticum Ehlers-Danlos Syndrome

Ocular Keratoconus Buphthalmos Colobomas Myopia

2.2Adquired Diseases Systemic

Iron-deficiency Anemia Myasthenia Gravis

Ocular

Paralimbal Scleromalacia

3.Scleral Thickening Nanophthalmos Scleropachynsis Phthisis Bulbi

4.Scleral Masses

4.1Dermoid Choristomas

4.2Epithelial Tumors Papillomas

Intraepithelial Epitheliomas Squamous cell carcinoma

4.3Dense Connective Tissue Tumors Nodular Fasciitis

Fibromas

Fibrous Histiocytoma Sarcoma

(continued)

Table 8.1 (continued)

4.4Vascular Tumors Hemangioma Lymphangioma

4.5Blood Cell Tumors Leukemia Lymphoma Lymphosarcoma

4.6Nervous Tumours Neurofibroma

Neurilemmoma (Schwannoma)

4.7Pigmented Tumors Nevus Melanocytoma

4.8Secondary Tumors

Table 8.2 Scleral deposits and metabolic diseases

certain drugs, hormones, or nutritional alterations are essential in determining the clinical expression of the porphyrias.

Scleral involvement may be a complication (though rare) of congenital porphyria, porphyria cutanea tarda, and porphyria variegata [1–7]. Acute intermittent porphyria, erythropoietic protoporphyria, and hereditary coproporphyria do not produce scleral lesions at all.

Congenital porphyria becomes manifest within a few days of birth as blisters on skin surfaces exposed to light, eventually leading to scarring and mutilation. The disease is due to excessive deposition of porphyrins in the tissues, leadingtoseverephotosensitization.Uroporphyrin I, derived from bone marrow normoblasts, is excreted in the urine. Progression of the disease leads to early death usually as a result of infection or hemolytic anemia.

Porphyria cutanea tarda, the most common form of porphyria seen in Europe and in the USA, is characterized by cutaneous photosensitivity, formation of bullae, ulcers, and scars on areas exposed to light, hyperpigmentation of the skin, liver disease, and hypertrichosis [8]. The disease is due to a partial deficiency of the enzyme uroporphyrinogen decarboxylase. Uroporphyrin I, derived from excessive synthesis in the liver, is excreted in the urine. Although the disease may be inherited in an autosomal-dominant manner, a positive family history is usually not obtained. Porphyria cutanea tarda may be latent for many years but may be precipitated by excessive alcohol consumption.

Porphyria variegata, is characterized by cutaneous photosensitivity, jaundice, colic, and psychosis during acute attacks. It may be asymptomatic between attacks. Coproporphyrins and protoporphyrins are excreted in the feces.

Scleral involvement in congenital porphyria, porphyria cutanea tarda, and porphyria variegata is often described as painless, bilateral, symmetric areas of scleral thinning without surrounding inflammation, with a bluish color in the base and calcareous degeneration in the adjacent area [1, 2, 9–11]. These areas of scleromalacia perforans are usually localized to the sun-exposed interpalpebral fissures. The adjacent cornea may become secondarily involved with corneal opacification, thinning, or perforation [10]. Areas of active scleral inflammation, either acute diffuse anterior scleritis or posterior scleritis, also may occur [4, 10]. The pathogenesis of the scleral involvement is unknown, but presumably it is the result of oxidative or fluorochemical reactions. Uroporphyrin and 7-carboxylporphyrin has been found by thinlayer chromatographic analysis in conjunctiva and sclera [2]. Treatment of patients with porphyria should include general treatment of porphyria and specific treatment of acute scleritis.

The diagnosis of scleral involvement due to porphyria is based on the presence of bilateral scleral thinning, sometimes with acute scleritis, associated with characteristic cutaneous lesions and with excessive urine or feces excretion of pigments.

8.1.1.2 Cystinosis

Cystinosis is a presumably genetically determined defect of amino acid metabolism which gives rise to intracellular deposition of crystalline cystine in the reticuloendothelial cells of the bone marrow, lymphatics, liver, spleen, and kidney. The eye also can be affected. There are three clinical forms: the infantile form, the benign adult form, and the intermediate adolescent form [12–14]. The infantile form or Fanconi’s disease, or Toni-Fanconi-Lignac disease begins in infancy and is characterized by growth retardation, rickets, secondary hyperparathyroidism, polyruria, glucosuria, urinary loss of potassium and amino acids, and progressive renal failure leading to death usually by the age of 10 [15]. The benign adult form is asymptomatic, with normal renal function and normal life expectancy [16]. The adolescent form appears in the second decade of life with rickets or renal failure; life expectancy depends on the degree of renal dysfunction [17].

All three forms of cystinosis may present with ocular findings, including the deposition of glistening, polychromatic, and needlelike or fusiform cystine crystals in cornea, conjunctiva, iris, episclera, and superficial scleral tissues; crystals have also been observed in ciliary body, choroid, and retinal pigment epithelium [18, 19]. The deposition of crystals progresses with the disease, but never seems to cause any inflammatory reaction within the episclera or sclera. Peripheral retinal abnormalities may be present in the infantile form consisting of generalized depigmentation; they occasionally may precede the corneal, conjunctival, iris, episcleral, and scleral findings [20]. Corneal deposits are diagnostic; they appear as a layer of homogeneously distributed iridescent crystals which are dispersed through the entire stroma. Crystals are evident in greatest density peripherally near the limbus, while centrally only the anterior half to two thirds is involved [21]. In the infantile form, corneal crystals appear as early as 6 months of age, can cause intense photophobia, and do not impair vision. In the adult form or adolescent form, corneal crystals may be the only manifestation of cystinosis.

The presence of episcleral or scleral polychromatic crystals associated with the characteristic corneal involvement is very suggestive of cystinosis. The diagnosis of cystinosis can be confirmed by conjunctival biopsy and analysis of cystine by column chromatography [22]. Longterm oral administration of cysteamine is effective in improving renal function and growth in young patients [23], but it does not prevent corneal crystal deposition. Frequent instillation of topical cysteamine (0.1%) may reverse the deposition of crystals in the central cornea [24, 25].

8.1.1.3 Alkaptonuria

Alkaptonuria (ochronosis) is a rare autosomal recessive disorder characterized by the absence of the enzyme homogentisic acid oxidase, normally present in liver and kidney [26, 27]. As a result of this error of metabolism, homogentisic acid, a normal intermediary in the metabolism of phenylalanine and tyrosine, accumulates in tissues, including the episclera and sclera, and is excreted in the urine.

Alkaptonuria is usually diagnosed on the basis of the urine containing homogentisic acid that darkens slowly if left to stand, or rapidly with the addition of strong alkali (alkapton), pigmentation of cartilage of the ear, trachea, nose, tendons, heart valves, and prostate (ochronosis), and, in later years, arthritis. In the infant, a first sign of alkaptonuria may be the presence of dark urine in a wet diaper. Ocular findings are helpful in suspecting the diagnosis of alkaptonuria. They include scleral pigmentation, seen as triangular patches in the interpalpebral area at the insertion of the horizontal recti muscles (areas exposed to light), and episcleral pigmentation, seen as pinguecular-like masses between the limbus and the insertion of horizontal recti muscles [28–31]. Occasionally, pigmentation may involve the whole sclera. The pigment is gray or bluish black (although microscopically it appears ochre), and it increases with age. More diffuse pigmentation, seen as oil drop-like globules when examined by retroillumination, may be found in the subepithelium and in Bowman’s membrane of the periph-

eral cornea [30, 31]. Conjunctiva and lid pigmentation also may be seen.

Any patient who develops scleral or episcleral pigmentation should be questioned and examined for urine and cartilage abnormalities.

8.1.1.4 Amyloidosis

Amyloid is an eosinophylic hyaline extracellular material made up of sheets of fibrous protein that may be deposited in various tissues of the body, including the sclera [32]. Although foreign-body cell reactions occasionally may be seen, amyloid does not produce any inflammatory response by its presence in tissues. Several classifications of the amyloidoses by various criteria have been only partially successful because of the overlapping of the different categories. One of the classifications differentiates amyloidosis into primary and secondary amyloidosis, depending on the absence or the presence of a preexisting disease, respectively. Both categories are further classified into familial and nonfamilial types. Primary amyloidosis, particularly the familial type, is the form most commonly associated with deposition of amyloid in the lid, cornea (lattice corneal dystrophy), conjunctiva, iris, choroid, retina, vitreous, ciliary nerves, extraocular muscles, orbit, and sclera [33–36]. Scleral amyloidosis is asymptomatic and does not show any specific lesion. Amyloidosis is suspected clinically, and confirmed by biopsy of appropriate tissues.

Although there are no detectable clinical changes, histologic studies show that amyloid deposition in sclera occurs more often as age increases [37]. Amyloid deposition in sclera also may occur following severe scleral inflammation at any age [38, 39].

Amyloid stains brown with Congo red and exhibits dichroism and birefringence with polarized light. It also shows metachromasia with crystal violet, fluorescence with thioflavine T, and positive staining with hematoxylineosin, periodic acid Schiff (PAS), iodine, and Sirius red.