Orbit

Normal Anatomy

I. The orbital volume is approximately 30 ml, and the orbital depth (anterior to posterior) is approximately 4.5 cm (Figs. 14.1–14.5).

A. The medial orbital wall is quite thin (<0.5 mm) and transparent.

B. The roof of the orbit, composed mainly of the orbital plate of the frontal bone, is thinnest anteriorly, where it is adjacent to the frontal sinus, and separates the orbit from the frontal lobes of the brain.

C. The orbital floor is composed of the orbital plates of the maxilla and zygomatic bones and a small contribution from the palatine bone posteriorly. The floor is also thin, 0.5–1 mm, and thus is easily fractured, especially medial to the infraorbital canal.

D. The lateral orbital wall is thick, composed anteriorly by the zygomatic bone and posteriorly by the greater wing of the sphenoid.

Fig. 14.1 Normal orbit. Composite illustration of the seven bones of the orbit. (From Levine MR, Larson DW: Orbital tumors. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 4, New York, Gower Medical, 1993:10.4–10.13. © Elsevier 1993; adapted from Zide B, Jelks G: Surgical Anatomy of the Orbit. New York, Raven Press, 1985.)

Fig. 14.3 Normal orbit. Right orbital structures and their basic relationships as seen from above. (From Levine MR, Larson DW: Orbital tumors. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 4. New York, Gower Medical, 1993:10.4–10.13. © Elsevier 1993.)

Fig. 14.4 Normal orbit—side view. Retrobulbar contents of orbit. (From Levine MR, Larson DW: Orbital tumors. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 4. New York, Gower Medical, 1993:10.4–10.13. © Elsevier 1993.)

Fig. 14.5 Normal orbit—front view. Lacrimal gland and surrounding structures. (From Buffam FV: Lacrimal disease. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 4. New York, Gower Medical, 1993:7.1–7.6. © Elsevier 1993.)

II. In addition to the bony walls, the eye, and the optic nerve, the orbit contains many soft-tissue structures such as fat, muscle (striated and nonstriated), cartilage, bone, fibrous tissue, nerves, and blood vessels.

A. Other than the epithelia within the eyeball, the lacrimal gland is the only epithelial structure in the orbit.

B. All orbital structures may be involved in disease processes.

C. Orbital disease, whatever its cause, tends to increase the bulk of the orbit, so the main presenting sign is exophthalmos.

Exophthalmos

I. The main clinical manifestation of orbital disease is exophthalmos (ocular proptosis), the extent and direction of which depend on a number of factors ¹: (1) size of lesion, (2) character of lesion (expansile vs. infiltrative growth, rapid vs. slow growth), (3) location of the lesion in the orbit (small lesion in muscle cone causes more exophthalmos than lesion of same size outside the muscle cone; lesions anterior to septum orbitale do not produce exophthalmos unless they also grow posteriorly), and (4) lesion’s effect on the extraocular muscles (complete paralysis of all muscles by itself can cause 2 mm of exophthalmos).

II. Exophthalmos may be simulated by many conditions: lid retraction due to any cause (most commonly Graves’ disease), unilateral enlargement of the globe, high myopia, buphthalmos, sagging lower lid, relaxation of the rectus muscle(s), enophthalmos or microphthalmos of the opposite eye, asymmetry of the bony orbits, and shallow orbits.

III. The most common causes of exophthalmos are thyroid disease (most common for both unilateral and bilateral exophthalmos), hemangioma, inflammatory pseudotumors, and benign and malignant lymphoid tumors (all others are relatively rare).

Although dermoids are one of the most common orbital tumors, if not the most common, they rarely cause exophthalmos because of their position, which is usually anterior to the septum orbitale.

Developmental Abnormalities

Developmental Abnormalities of Bony Orbit

Developmental abnormalities are usually associated with abnormalities of the cranial and facial bones such as tower skull or hypertelorism.

Microphthalmos with Cyst

I. Microphthalmos with cyst (see Fig. 2.10) is usually a unilateral condition, but it may be bilateral.

II. The cyst may be so large as to obscure the microphthalmic eye.

III. Proliferated neuroectodermal tissue (i.e., pseudogliomatous hyperplasia) may simulate an orbital neoplasm.

IV. The condition is caused by incomplete closure of the fetal cleft.

Although microphthalmos with cyst usually has no known cause, it may be associated with the 13q deletion or chromosome 18 deletion defect (partial 18 monosomy). A congenital cystic eye may also be associated with contralateral persistent hyperplastic vitreous and cerebrocutaneous abnormalities, called cranial ectodermopathy.

V. Histologically, the eye may range from relative normality to complete disorder, and it may contain structures such as ectopic smooth muscle and cartilage. The cyst may be lined by gliotic retina, or it may be filled with proliferated glial tissue that can reach massive amounts (massive gliosis) and simulate a glial neoplasm.

Cephaloceles

I. Cephaloceles are caused by a developmental malformation in which brain tissue or meninges or both are present in the orbit.

A. Meningocele—only meninges are present.

B. Encephalocele—only brain tissue is present; hydroencephalocele—considerable fluid is present in the cyst.

C. Meningoencephalocele—meninges and brain tissue are present.

D. All of the preceding may communicate with the brain. Although the initial communication usually closes, it may rarely remain open.

II. Most cephaloceles are developmental displacements of brain tissue and are generally referred to as ectopic brain tissue.

III. Histologically, most cephaloceles show a structure similar to that of the optic nerve (i.e., white matter separated by pial septa).

Congenital Alacrima

I. Hereditary congenital alacrima is part of a systemic disturbance such as the Riley–Day syndrome or anhidrotic ectodermal dysplasia.

II. An isolated case of congenital alacrima, presumably caused by hypoplasia of the lacrimal gland, has been reported.

Orbital Inflammation

Acute

I. Nonsuppurative (see section Nonsuppurative, Chronic Nongranulomatous Uveitis and Endophthalmitis in Chapter 3)—orbital cellulitis is most commonly caused by extension of an inflammation from the paranasal sinuses (Fig. 14.6).

II. Suppurative (see section Suppurative Endophthalmitis and Panophthalmitis in Chapter 3)

A. Purulent infection (e.g., with Staphylococcus) occurs commonly after trauma.

B. Phycomycosis (mucormycosis) is a devastating cause of suppurative orbital inflammation (Fig. 14.7; see Chapter 4).

Fig. 14.7 Orbital phycomycosis. A, Diabetic man had phycomycosis of left orbit, causing B, left central retinal artery occlusion. Systemic antifungal therapy arrested condition. C, Orbital tissue obtained from another patient who died from phycomycosis shows two large thrombosed orbital vessels surrounded by acute suppurative inflammation. Even under this low magnification, large, hematoxylinophilic, nonseptate fungal hyphae (round bodies) can be seen in the wall of the smaller vessel (artery) on the right. D, Increased magnification of another case stained with periodic acid–Schiff clearly shows the organisms. (A and B, Courtesy of Dr. LA Karp; C, courtesy of Dr. H Ring.)

Chronic

I. Nongranulomatous

A. Chronic nongranulomatous inflammation is the most common inflammatory lesion of the orbit and is of unknown cause (see later in this chapter).

B. A rare cause is the benign lymphoepithelial lesion of Godwin ² (Fig. 14.8).

1. It is characterized by painless unilateral or bilateral enlargement of the salivary or, rarely, the lacrimal glands.

2. It may be part of Sjögren’s syndrome (see later).

3. Rarely, it may become malignant.

4. Histologically, two features characterize benign lymphoepithelial lesion: (1) replacement of the glandular parenchyma by a benign lymphoid infiltrate and general preservation of the lobular architecture of the lacrimal gland, and (2) epimyoepithelial islands of proliferation in the glandular ducts.

Fig. 14.8 Benign lymphoepithelial lesion (of Godwin) and Sjögren’s syndrome. Benign lymphoepithelial lesion is characterized by (1) the glandular parenchyma being replaced by benign lymphoid infiltrate (A); (2) general preservation of the glandular lobular architecture (A); and (3) epimyoepithelial islands of proliferation within glandular ducts (B). Note thickened ductal basement membrane. C, Patient who has Sjögren’s syndrome shows bilateral lacrimal gland enlargement caused by Godwin’s lesion and also rheumatoid arthritis (D). (A and B, From Font RL, Yanoff M, Zimmerman LE: Benign lymphoepithelial lesion of the lacrimal gland and its relationship to Sjögren’s syndrome. Am J Clin Pathol 48:365, 1967, with permission; C and D, modified from Meyer D, Yanoff M, Hanno H: Differential diagnosis in Mikulicz’s syndrome, Mikulicz’s disease and similar disease entities. Am J Ophthalmol 71:516. © Elsevier 1971.)

C. Sjögren’s syndrome (see Fig. 14.8)

1. Sjögren’s syndrome is defined as a chronic autoimmune disorder characterized by lymphoid inflammatory infiltration of the lacrimal and salivary glands, destroying acinar tissue.

Autoantibodies to the ribonucleoprotein (RNP) particles SS-A (also called Ro RNA particle) and SS-B (also called La snRNA) are produced systemically. The immune response to 120-kDa α-fodrin may be important in the initial development of Sjögren’s syndrome.

2. The tissue destruction results in the symptoms of keratoconjunctivitis sicca and xerostomia.

3. Indirect support exists for a putative role of the Epstein–Barr virus (see Chapter 3) in the pathogenesis of the disease.

D. Inflammatory pseudotumor (see later in this chapter)

II. Granulomatous

A. Granulomatous inflammations rarely involve the orbit.

B. Causes include tuberculosis, sarcoidosis, syphilis, fungi, parasites (trichinosis, schistosomiasis, etc.), Crohn’s disease, cat-scratch disease, midline lethal granuloma syndrome (polymorphic reticulosis), and giant cell polymyositis (giant cell granulomatous necrotizing myositis).

C. Tolosa–Hunt syndrome is a benign granulomatous orbital inflammation of unknown cause that presents as a painful ophthalmoplegia. Symptoms usually disappear after steroid therapy.

D. Cholesterol granuloma

1. Cholesterol granuloma has also been called cholesteatoma, lipid granuloma of the frontal bone, xanthomatosis of the orbit, hematoma, and chronic hematic cyst.

Some authors incorrectly use the term cholesteatoma interchangeably with epidermoid cyst. The term epidermoid cyst should not be used, or should it be restricted to postinflammatory tumors that contain squamous epithelium and keratin debris; cholesterol granuloma is never associated with any epithelial elements.

2. Cholesterol granuloma of the orbital bones is a rare extraperiosteal condition that usually involves the frontal bone above the lacrimal fossa.

3. The cause seems to be a hemorrhage into the diploë of the bone, probably secondary to trauma but perhaps secondary to an anomaly in the diploë that could initiate a hemorrhage.

4. Histologically, a granulomatous reaction surrounds cholesterol crystals and altered blood.

E. Inflammatory pseudotumor (see later in this chapter)

Injuries

Penetrating Wounds

I. Direct effect on whatever tissue may be wounded by the injury

II. Complications (indirect effect)

A. Infection

1. Organisms may be introduced at the time of injury.

a. Bacteria cause an acute purulent inflammation.

b. Fungi cause a delayed, chronic, granulomatous inflammation.

B. Inflammation

1. The inflammation may be secondary to toxic products of tissue destruction.

2. Orbital thrombophlebitis may result.

3. A retained intraorbital foreign body may induce inflammation.

a. Frequently, cilia and pieces of skin, bone, wood, and so forth may be introduced into the orbit at the time of injury and cause a foreign-body granulomatous inflammatory reaction.

b. Fungi may enter as a coincidental saprophyte along with the penetrating foreign body, which usually causes a granulomatous inflammatory reaction or even superimposed infection if the organism proliferates.

C. Orbital inflammation may lead to other complications, such as cavernous sinus thrombosis, central retinal vein thrombosis, glaucoma, and proptosis.

Nonpenetrating Wounds

The effects of nonpenetrating wounds are those secondary to contusion and concussion, mainly hemorrhage, secondary muscle palsies, and infraorbital nerve involvement.

Vascular Disease

Primary

I. Primary orbital vascular disease is rare.

II. Causes include varices, arteriovenular aneurysm, thrombophlebitis, and cavernous sinus thrombosis.

Orbital varix, also called distensible venous malformation (Fig. 14.9), may occur anterior to the septum orbitale and not cause exophthalmos, or it may occur posterior to the septum orbitale, causing exophthalmos. The exophthalmos may be acute if the varix undergoes thrombosis.

Fig. 14.9 Orbital varix. A, Clinical appearance of varix before removal. Gross appearance of skin (B) and internal (C) side of removed varix. D, Trichrome stains show microscopic appearance of clotted vein.

Part of Systemic Disease

I. Collagen diseases (see Chapter 6 and later in this chapter)

II. Midline lethal granuloma syndrome (natural killer (NK)/T-cell lymphoma, polymorphic or malignant reticulosis; see later this chapter and see Chapter 6)

III. Allergic granulomatosis (vasculitis; see Chapter 6)

IV. Temporal (cranial) arteritis (see Chapter 13)

Ocular Muscle Involvement in Systemic Disease

Graves’ Disease (Fig. 14.10)

I. Classification of eye changes of Graves’ disease (Box 14.1)

II. Mild form (“thyrotoxic” exophthalmos)

A. The mild form of Graves’ ophthalmopathy has its onset in early adult life, with women predominantly affected (approximately 2 : 1).

Smokers have an increased risk for development of both Graves’ disease and thyroid ophthalmopathy. Temporally, the diagnosis of Graves’ ophthalmopathy tends to follow the diagnosis of hyperthyroidism. Treatment of hyperthyroidism with iodine-131 does not seem to alter the course of Graves’ ophthalmopathy.

B. It may present initially with unilateral involvement but usually becomes bilateral.

C. Clinically and chemically, the patient is hyperthyroid.

D. Lid retraction, the most common clinical sign, may simulate exophthalmos.

E. Occasionally exophthalmos is present.

F. Prognosis for vision is good.

III. Severe form (“thyrotropic” or “malignant” exophthalmos; thyroid ophthalmopathy; thyroid orbitopathy)

A. The severe form is an autoimmune disease that affects people in middle age (average age, 50 years).

1. The disease is characterized by an increased percentage of suppressor/cytotoxic T lymphocytes.

2. Circulating T cells are directed against thyroid follicular cell antigens.

B. It is most common in men, especially those older than 50 years of age, is usually bilateral, and is asymmetric.

C. Clinically and chemically, the patient may be hyperthyroid, hypothyroid, or euthyroid.

The term euthyroid Graves’ disease describes ocular manifestations of Graves’ disease in patients who are “euthyroid” and have no past history suggesting hyperthyroidism. The eye signs are frequently asymmetric. The patients may have a family history of thyroid disease or pernicious anemia. All of the euthyroid patients, however, do show some mild thyroid abnormality (e.g., thyroid autoantibodies, negative thyrotropin-releasing hormone test, negative triiodothyronine suppression test, and goiter).

D. Exophthalmos is severe and frequently associated with pretibial myxedema. Chemosis, dilated vessels (especially over the rectus muscles), and limitation of ocular motility often accompany the exophthalmos.

Orbital accumulation of glycosaminoglycans and increased adipogenesis may play an important role in the development of Graves’ ophthalmopathy.

E. Prognosis for vision is poor.

F. Histologically, the orbital tissue is characterized predominantly by extraocular and periorbital muscle involvement by edema, lymphocytic infiltration (mainly CD4⁺ and CD8⁺ T cells along with some focal aggregates of B cells, plasma cells, and mast cells), endomysial fibrosis, and mucopolysaccharide deposition.

1. Positive staining occurs in extraocular and periorbital muscle for immunoglobulin A1 (IgA1) and IgE antibodies and also C3bi (the terminal attack complex) complement component.

2. The inferior rectus muscle is most prone to fibrosis. If the patient is looking up during tonometry, abnormally high readings may be obtained. Therefore, it is important that the patient be looking straight ahead during applanation tonometry.

Fig. 14.10 Graves’ disease. A, In Graves’ disease, exophthalmos often looks more pronounced than it actually is because of the extreme lid retraction that may occur. This patient, for instance, had minimal proptosis of the left eye but marked lid retraction. B, The orbital contents obtained postmortem from a patient with Graves’ disease. Note the enormously thickened extraocular muscle. C, A histologic section shows both fluid and inflammatory cells separating the muscle bundles. The inflammatory cells are predominantly lymphocytes, plus plasma cells. (A, Courtesy of Dr. HG Scheie; B and C, courtesy of Dr. RC Eagle, Jr.; case in B and C reported in Hufnagel TJ, Hickey WF, Cobbs WH et al.: Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with Graves’ disease. Ophthalmology 91:1411. © Elsevier 1984.)

Box 14.1

Eye Changes in Graves’ Disease

CLASS	OCULAR SYMPTOMS AND SIGNS
0	No signs or symptoms
1	Only signs, no symptoms
2	Soft-tissue involvement with symptoms and signs
3	Proptosis of the eyes
4	Extraocular muscle involvement
5	Corneal involvement
6	Sight loss with optic nerve involvement

(Modified from Werner SC: Classification of the eye changes of Graves’ disease. Am J Ophthalmol 68:646, 1969.)

Myasthenia Gravis

I. Myasthenia gravis is an autoimmune disorder (defect on chromosome 19q13.3) that involves the extraocular muscles, especially the levator palpebrae superioris. A reduction in available acetylcholine receptors occurs at the neuromuscular junctions of skeletal muscles.

II. The most common clinical manifestation is ptosis of the eyelid.

As a rough test, the ptosis can often be aggravated by having the patient raise and lower the eyes 10–30 times in rapid succession. The normal patient can do this easily with no ptosis afterward.

III. Histologically, the ocular muscles are edematous and infiltrated by lymphocytes.

Myotonic Dystrophy (Myotonia Dystrophica; Steinert’s Disease)

I. Myotonic dystrophy, an autosomal-dominant condition, is characterized by myotonia (i.e., failure to relax a contracted muscle voluntarily).

Myotonic dystrophy, like Huntington’s disease, is caused by an expansion of a repeated sequence of three nucleotides. In myotonic dystrophy, the expansion occurs in the 3′ untranslated region of the DM gene. Perhaps disrupted activity of a CUG-binding protein induced by repeats in RNA prevents the protein from doing its normal job of splicing a certain family of genes.

A. Its onset is between 20 and 30 years of age, with patients rarely living beyond 40 or 50 years.

B. Frontal baldness and endocrinopathy, especially testicular atrophy, are common.

II. Ocular findings

A. Cataracts showing iridescent dots in the anterior and posterior cortex, and a stellate grouping of opacities at the posterior pole of the lens along the posterior suture lines

B. Foveal dystrophy that hardly affects vision and pigmentary retinopathy

C. Ocular hypotension

III. Histologically, selective atrophy of muscle fibers is seen.

Myotonia Congenita (Thomsen’s Disease)

I. Myotonia congenita, an autosomal-dominant or -recessive condition, is characterized by myotonia.

A. Its onset is early in life and may involve muscles of the face and eyelids.

B. It does not cause death and rarely causes severe disability.

II. Histologically, the muscles are not atrophic; individual muscle fibers may be larger than normal with an increase in sarcolemmal nuclei.

Mitochondrial Myopathies

I. Mitochondrial myopathies (cytopathies) are rare multisystem diseases that mainly affect the central nervous and musculoskeletal systems. Abnormal mitochondria are found in the periphery of skeletal muscle fibers, which have a characteristic “ragged-red” appearance when stained with the modified trichrome stain.

II. Four of these entities are of major ophthalmic importance: Leber’s hereditary optic atrophy; chronic progressive external ophthalmoplegia (CPEO); Kearns–Sayre syndrome (KSS); and the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS).

The inheritance of these point mutations of mitochondrial DNA is from mothers alone because the mitochondrial contribution to the embryo comes only from the maternal ovum.

A. Leber’s hereditary optic atrophy (see Chapter 13)

B. CPEO

1. CPEO is a slowly progressive, bilaterally symmetric, ocular muscle dystrophy that starts in late childhood or adulthood. It is inherited through the maternal transmission of one or more mitochondrial large-deletion DNA mutations.

2. Ptosis, external ophthalmoplegia, and often a pigmentary retinopathy can be seen.

3. Histology of muscle fibers includes atrophy, large variation in diameter, and granular and vacuolar degeneration; absence of glycogen, cross-striations, myofibrillar structure, and succinic dehydrogenase; fibrous and fatty replacement of tissue; and preservation of myelinated nerve fibers and myoneural junctions.

Mitochondria of selective muscle fibers appear abnormal in size, shape, number, and internal structure, whereas others seem normal, resembling the changes found in Leber’s hereditary optic atrophy. Because the modified trichrome stain colors the abnormal muscle fibers red, the fibers have been called ragged-red fibers.

C. KSS

1. KSS consists of the triad of external ophthalmoplegia, pigmentary retinopathy, and heart block. Other findings include mental retardation, hearing loss, endocrinopathy, and cerebellar ataxia.

2. KSS is inherited through the maternal transmission of one or more mitochondrial large-deletion DNA mutations.

3. Histologically, along with the characteristic ragged-red appearance seen under light microscopy with the modified trichrome stain, electron microscopy shows well-preserved, swollen mitochondria containing circular cristae or granular deposits.

D. MELAS (Fig. 14.11)

1. MELAS usually has an abrupt onset before the age of 15 years with symptoms of visual loss, hemiparesis or hemianopia, strokelike episodes, headaches, and convulsions.

2. Patients have short stature and increased serum and cerebrospinal fluid lactate levels.

3. MELAS is inherited through the maternal transmission of one or more mitochondrial point DNA mutations (nucleotide positions 3243 and 3271).

4. Ocular findings include external ophthalmoplegia, atypical pigmentary retinopathy, and nuclear cataract.

5. Histologically, along with the characteristic ragged-red appearance seen under light microscopy with the modified trichrome stain, electron microscopy shows an increased number of mitochondria containing abnormal cristae.

a. The eyes show abnormalities of the macular photoreceptor–retinal pigment epithelium (RPE)–choriocapillaris complex, namely absent or degenerated outer segments and hyperpigmented and hypopigmented RPE.

1) The cytoplasm of RPE cells show ballooned, structurally abnormal (“giant”) mitochondria.

2) The photoreceptor inner segments demonstrate markedly altered mitochondria (increased number, loss of cristae, circular cristae, ballooned mitochondria, and paracrystalline inclusions).

b. Abnormal mitochondria are also found in choriocapillaris endothelial cells and smooth muscle cells of choroidal and retinal blood vessel walls.

Fig. 14.11 Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome. A, Complete external ophthalmoplegia present in 20-year-old woman. B, Fundus shows a fine, dustlike, “salt-and-pepper” appearance. C, Microscopic section of degenerated extraocular muscles stained with trichrome shows “ragged-red” fibers. D, Cytoplasm of retinal pigment epithelial cells packed with many ballooned, structurally abnormal (“giant”) mitochondria. (Case presented by Dr. R Folberg to the meeting of the Verhoeff Society, 1993, and reported in Rummelt V, Folberg R, Ionasescu V et al.: Ocular pathology of MELAS syndrome with mitochondrial DNA nucleotide 3243 point mutation. Ophthalmology 100:1757. © Elsevier 1993.)

Dermatomyositis

I. Dermatomyositis is a collagen disease of unknown cause with a poor prognosis; death is a frequent outcome.

II. Men predominate and may acquire the disease in childhood.

III. Conjunctivitis, iritis, ptosis, paralysis of external ocular muscles, horizontal nystagmus, and exophthalmos may be present.

Erythematous, edematous patches of skin are frequently seen. A predilection for the face and periorbital region exists, where a violaceous heliotrope may occur around the eyes, on the lids, and on the cheeks.