The orbital bones begin to develop during the first 2 months of embryogenesis.¹ Toward the end of the fifth week, the axes of the two orbits begin to move forward as a result of the growth of the maxillary processes.² Most of the orbital bones are formed during the third month of gestation, but their complete ossification and fusing takes a longer time to complete, at approximately the seventh month of gestation. At term, the orbit is almost spherical in configuration. The periorbital sinuses begin to develop at approximately the second month of gestation and continue to grow after birth. Although the eye reaches adult size (approximately 7 mL) at approximately age of 2.5 years, the adult form and dimensions of the orbit (approximately 30 mL) are not finalized until puberty. Therefore, between the second month of embryogenesis and the age of puberty, numerous factors may affect the development of the orbit. For example, if the globe fails to develop or it is microphthalmic, the orbit does not attain its normal volume. However, if a congenital cyst or tumor develops within the orbit and expands its volume, the socket reaches a very large size unless the cyst is removed

Orbitocraniofacial deformities can be categorized in two large groups as craniosynostosis and clefting disorders.

This developmental pathology of the orbit is dependent on the fusional abnormalities between the bones and it is divided into primary and secondary forms. Primary craniosynostosis refers to premature fusion of cranial sutures caused by embryologic error. Secondary synostosis is the premature closure of sutures because of other causes such as intrauterine trauma or effects of teratogenic drugs.^3,4 Approximately 15% of craniosynostosis cases are associated with systemic abnormalities and are known as syndromic craniosynostosis; the remaining 85% represent nonsyndromic forms.⁵ Syndromic craniosynostosis represent a variety of inherited syndromes with abnormal development of the skull and orbit including: Apert syndrome with syndactyly of hands and feet, Crouzon syndrome with shallow orbits and proptosis, maxillary hypoplasia and cleft palates, and Pfeiffer syndrome with malformation of thumb and great toe and soft tissue syndactyly.⁶

These malformations involve more extensive soft tissue abnormalities and depending on the location and the extent of the cleft, may be associated with bone malformations as well. The mapping system that is used to describe the location of a cleft is known as the Tessier clock face. In this scheme, the clefts are numbered from 0 to 14 beginning at the inferonasal area and moving clockwise to the superior nasal area. Commonly encountered clefting syndromes are: Goldenhar syndrome, Treacher-Collins syndrome, and the facial microsomias^7,8 (Table 1).

Orbital injuries result from the absorption of kinetic energy that occurs whenever the orbital tissues contact an object moving at a different speed.²⁵ The orbital rim is capable of absorbing a considerable amount of kinetic energy without being fractured. Yet, a variety of impact forces striking the orbit may result in fractures in different areas.²⁶ The absorption of the kinetic energy by an orbital bone may lead to contusion and/or laceration of the skin and superficial soft tissues, local deformation of the adjacent structures, globe, orbital soft tissues and bones and increases pressure in the orbital cavity. A common end result of an orbital impact is the fracture of the floor and/or the medial wall (lamina papyracea)²⁷ (Fig. 3). Fractures of other orbital bones occur less often. Foreign bodies may be introduced into the orbit at the time of injury and may cause secondary problems depending on the nature and the location of the foreign body.²⁸ Some foreign bodies such as copper may cause tissue necrosis and degeneration (chalcosis), and others particularly organic matter, may carry organisms such as bacteria and fungi into the orbital tissues and cause secondary infections²⁹ (Fig. 3). Once the fracture of an orbital bone occurs, it may produce sharp edges to lacerate adjacent soft tissue structures including the globe, optic nerve, other nerves, muscles, and vessels.³⁰ Depending on the damage of the particular tissue, functional deficit results.

Another issue to deal with in an injured orbit is the development of hematoma, hematic cyst, and cholesteotoma. Hemorrhage in the orbit may occur spontaneously without any physical exertion in healthy individuals. Although terminology is not very strict, hematoma usually refers to a localized collection of blood within orbital soft tissues that develops secondary to trauma. When the blood collection within the orbit becomes organized and surrounded by a thin pseudocapsule, it is known as a hematic cyst³¹ (Fig. 4). If the hemorrhage develops within an existing lymphatic or vascular tumor, these lesions are known as blood cysts or “chocolate” cysts.³²

Hematic cyst consists of a localized collection of blood surrounded by a nonepithelium-lined thin fibrous capsule.³³ These lesions usually develop within 1 to 2 weeks of orbital trauma but chronic cases may occur up to 20 years after orbital injury.^34,35 They may reach to a size causing proptosis, extraocular motility disturbance, compression on the globe and optic nerve, that can easily be detected with ultrasonography, CT, or MRI. Hematic cysts may develop within the muscle cone or in the extraconal orbital locations.^33,34,35,36 These cysts are lined by fibrovascular tissue at the periphery and contain degenerated erythrocytes, protein debris, and cholesterol crystals. In many instances the thin nonepithelial lining is adherent to the adjacent structures with fibrous tissue.

Cholesteatoma is another cystic lesion that is confined within a “pseudowall” without an epithelial lining.³⁷ Cholesteotomas are usually located in the superior lateral orbit within the lacrimal gland fossa. Imaging studies may show a cystic, semi-cystic, or a solid lesion within the diploe of the bone or within the orbital soft tissues, with or without erosion of the adjacent bone.³⁸ Histopathologically the lesion is composed of cholesterol clefts, hemosiderin, and hematoidin granules, other blood breakdown products and fibrin surrounded by a mixed lymphohistiocytic infiltrate and multinucleated foreign body giant cells.³⁹

On imaging studies these lesions appear as unilocular rounded masses with destruction of the adjacent frontal and zygomatic bones. Although bone involvement in general implies malignancy, the sclerosing character of the bony destruction in choleosteoma, which is best seen in bone window images, favors a benign lesion. Although bone destruction also makes one think along the lines of metastatic tumors, one should also consider benign lesions such as brown tumor, aneurysmal bone cyst, and ruptured dermoid. Multiple cuts of the frontal bone should be examined to rule out the possibility of intracranial extension.

Osteomyelitis of the orbital bones evolving as a complication of paranasal sinusitis is another entity that should be considered in the differential diagnosis of cholesteotoma. In osteomyelitis the bone infection extends into the periosteal space and beyond. Precise delineation of the lesion can be performed with CT and MRI particularly in combination with bone SPECT, a sensitive technique used to detect osteomyelitis within cranial and orbital bones.⁴⁰

Although a commonly encountered space occupying lesion in the orbit, mucocele is technically not a neoplasm. It is a cystic cavity lined by pseudostratified respiratory epithelium prolapsing into the orbit from a paranasal sinus, most commonly the frontal followed by the ethmoidal sinus (Fig. 5). Primary mucoceles develop as a result of an inflammatory obstruction of the ostium of the paranasal sinuses. Secondary mucoceles, however, are most commonly seen after orbital trauma and surgery; they may also develop secondary to neoplasms of paranasal sinuses and nasopharynx. If there is a superimposed infection, the lesion is referred to as pyocele. The mucocele develops as a well delineated cystic structure originating from a paranasal sinus. Depending on the location, it may compress orbital structures including extraocular muscles, optic nerve, and the globe.⁴¹ Clinical presentation of the mucocele is usually with globe displacement and/or proptosis, extraocular motility deficiency, particularly in the direction of the sinus extension into the orbit, and other compressive symptoms.⁴² The crepitant or calcified hard wall of the mucocele may be palpated underneath the superior or medial orbital rim. Mucoceles in general, are rare in children, however, a unique variant, ethmoidal mucopyocele, is known to occur in the medial canthal area, with lateral displacement of the globe.

On CT, mucoceles present as hypointense, expanding masses originating from the paranasal sinuses. Early in their development these lesions are small, mucous-containing cysts. Later they are characterized by crescent-shaped and thinned remodeling of the bony walls of the orbit and sinuses.⁴³ On MRI, mucocele presents with different appearances depending on the amount of free water within its luminal contents. When the intraluminal mucous becomes inspissated, the signal intensity in both T1 and T2 images decrease, getting closer to normal air content of the sinus.⁴⁴ Treatment of mucocele is surgical excision.

Other injuries with toxic chemicals and radiation are known to damage orbital tissues.^45,46,47

Orbital arteriovenous (AV) fistulas are established as a result of abnormal flow between the arteries and veins. These lesions can be divided into three basic types: carotid cavernous, dural and orbital AV fistulas. Carotid cavernous fistula is usually traumatic but may also develop secondary to a rupture of an aneurysm particularly in elderly atherosclerotic patients. These fistulas commonly develop between an intracavernous segment of internal carotid artery and cavernous sinus and shunt arterial blood into superior ophthalmic vein.⁴⁸ Dural cavernous fistulas, however, develop between small meningeal branches of internal/external carotid artery and the cavernous sinus. These small vessels that have thin walls that may rupture spontaneously particularly in hypertensive individuals, secondary to minor trauma and maintain a low blood flow.

Orbital AV fistulas usually develop secondary to traumatic rupture of the ethmoidal artery into the orbital venous system. This type of fistula maintains a low blood flow. Clinical findings of AV fistulas include rapidly developing proptosis, edema of the conjunctiva and eyelids, dilatation and tortuosity of the conjunctival and episcleral vessels, and secondary glaucoma.

Most of these cases are diagnosed with imaging procedures including CT, MRI, angiography, color Doppler ultrasonography, and catheterized angiography.⁴⁹ Current treatment of these lesions is embolization via catherization.⁵⁰ Morphologic data are limited to autopsy material because most patients with AV fistulas do not undergo biopsy procedure. These lesions show irregular, malformed arteries and veins with abnormal elastic and muscular layers and secondary endothelial cell proliferation. Approximately half of the low shunt fistulas close spontaneously;⁵¹ therefore, it is best to follow-up some of these patients conservatively if they do not have severe symptoms.

Orbital varix is a rare vascular lesion with questionable histopathogenesis. The absence of valves in the orbital venous system and the weakening of venous wall may lead to pooling and stasis of blood resulting in distention of the venous channel with thrombosis. In gross appearance, the varix is a distended vein containing a canalized or uncanalized thrombus.^52,53 Histopathologically varix consist of irregular vascular channels lined by endothelial cells. In chronic lesions, the blood vessel walls irregularly thicken with fibrosis and deposits of chronic inflammatory cells mixed with deposits of calcium and hemosiderin pigment are seen. Orbital varices are divided into primary and secondary types. The primary orbital varix is confined to the orbit as an isolated lesion without any connection to other A-V malformations. The secondary orbital varix, however, develops as an extension of an intracranial AV malformation that shunts blood to the orbital venous system causing the venous channels to distend secondarily.⁵⁴ Management of orbital varix consists of total surgical excision when possible and/or endovascular embolization.

Thyroid-associated orbitopathy, better known as Graves disease (Gd), is an idiopathic orbital inflammation that primarily involves the muscles and soft tissues of the orbit and the eyelids. The commonly involved muscles include inferior, medial, superior and lateral recti that cause swelling of the tissue leading to proptosis and eyelid retraction (Fig. 9). Gd is the most common cause of unilateral and bilateral proptosis in adults; although uncommonly it may be seen in children as well.

The pathogenesis of Gd is not completely understood; therefore, it is labeled as an “autoimmune” process.^82,98 It has been suggested that individuals with HLA-B8 major histocompatility antigen Haplotype are genetically susceptible to Gd.⁹⁹ The hypothesis is that circulating T-cells directed against an antigen in thyroid follicular cells recognize a similar antigen in extraocular muscles and orbital soft tissues.¹⁰⁰ Experimental studies suggest that thyrotropin receptor (TSH-R) is one of the possible entities to stimulate the autoantibodies that lead to the inflammatory changes within orbital soft tissues. In Gd there is a predominance of T-cells with Th1 profile, although Th2 profile of cytokine production has also been reported.¹⁰⁰ The cytokines stimulate fibroblasts to produce glycosaminoglycans that in turn lead to deposition of this substance within the muscle tissue leading to anatomic and functional deficiencies (Fig. 9). Although cell mediated immune reaction predominate in early Gd, humoral immunity plays a greater role in later phases.¹⁰¹

Some of the immune changes are reflected in the histopathology of Gd, which can basically be divided in two stages. The active inflammatory stage consists of perivascular edema and clustering of lymphocytes and plasma cells; lymphoid follicles are not frequent in Gd. In the chronic stage the volume of the involved orbital tissues are increased because of the deposition of glycoproteins and mucopolysaccharides and secondary to the infiltration of fibroblasts producing collagen. Later in chronic stages of the disease, the edema decreases and the muscles are primarily infiltrated with interstitial fibroblasts and chronic inflammatory cells leading to fibrosis.

Although 80% of patients with Gd present with a history of hyperthyroidism, approximately 10% suffer hypothyroidism or autoimmune thyroiditis; occasionally, an euthyhroid individual may also develop the signs and symptoms of Gd.¹⁰² Upper lid retraction is the most frequent clinical sign in early Gd (75%) followed by asymmetrical bilateral proptosis (60%) and restriction of extraocular muscles (40%). Compressive optic neuropathy may result secondary to the enlargement of the extraocular muscles in the apex. Optic nerve malfunction is manifested by afferent pupillary defects and color vision and visual field deficiencies in approximately 5% of Gd patients.

The best means of evaluation of extraocular muscles is imaging with CT and/or MRI.¹¹ Axial CT scan is very valuable to depict the enlargement of the extraocular muscles and determine whether there is any infiltration into other orbital soft tissues. Coronal sections are also very useful to evaluate the enlargement of the muscles and their relationship to the optic nerve in the orbital apex.¹⁰³ In differential diagnosis of Gd, one should keep in mind that it is not only the most frequent cause of bilateral proptosis but unilateral proptosis as well. Therefore, the slowly progressive unilateral presentation may be confused with orbital pseudotumors, neoplasia, and solitary vascular lesions such as orbital varix.^104,105 Orbital metastatic neoplasms may also be confusing if they are limited to the extraocular muscles. Imaging usually reveals nodular enlargement of the muscle and the diagnosis of a metastatic disease may be confirmed with fine needle aspiration biopsy (FNAB). The treatment of Gd includes oral and intravenous steroids, radiation and surgery.

Orbital pseudotumor is a nonspecific chronic inflammatory condition of unknown etiology. Although an underlying immune process is suspected, no conclusive mechanism has been established for the development of this curious entity.⁸⁷ IOI may develop with sudden onset of painful proptosis associated with motility disturbances, eyelid swelling, redness and chemosis. It may develop as a diffuse or localized lesion and its histopathology varies accordingly from case to case; the histopathology is also variable at different stages of the disease. The extraocular muscles may be involved with the inflammatory process but the main target is the orbital fibroadipose tissue. The inflammatory process may be grouped into two main categories: (1) diffuse and (2) localized nonspecific orbital inflammation. The localized nonspecific inflammation is further divided according to specific sites, i.e., myositis, dacryoadenitis, periscleritis and perineuritis. Each of these subgroups may present as an acute, subacute or chronic process in a given patient.

The histopathology of the IOI usually consists of a mixed polymorphonuclear and lymphocytic infiltrate during the early phases; as the disease advances, lymphoid follicle formation and fibrous tissue proliferation dominates the picture¹⁰⁶ (Fig. 10). Patchy aggregates of lymphocytes and/or lymphoid follicles are frequently seen, but these lymphoid aggregates are not confluent as in lymphoid neoplasia and hyperplasia. Because of the diffuse fibrous reaction and the nonspecific nature of the mixed inflammatory infiltrate, the biopsy diagnosis of pseudotumor is not pathognomonic, but it should be correlated with clinical and radiologic findings in each case. Histopathologic patterns may vary in different regions of the specimen, therefore, it is advisable that these biopsies are processed totally. Hard granulomas, perivascular lymphocytic infiltrates, and occasionally true vasculitis may be identified within the orbital tissues of clinically typical IOI. Although polymorphonuclear leukocytes and eosinophils are occasionally seen, prominent acute inflammatory infiltrates should lead the pathologist to consider a vasculitis, such as polyarthritis nodosa or Wegener granulomatosis.

Tolusa-Hunt syndrome, otherwise known as painful external ophthalmoplegia, is another inflammatory process of the orbit of unknown etiology. It is conceivable to think that it represents a localized form of idiopathic orbital inflammation (IOI) and presents with typical clinical manifestations because of its presentation in the orbital apex. The clinical symptoms include a severe, constant deep orbital pain associated with functional deficiencies of third, fourth, fifth and sixth cranial nerves.¹⁰⁷ Typically, the orbital pain that presents abruptly also responds to systemic corticosteroid treatment with the same abruptness. Other symptoms of the disease including third, fourth, and sixth cranial nerves palsies and the hypesthesia of the periorbital skin also respond well to corticosteroid treatment. Although bilateral cases do occur; a great majority of patients with Tolosa-Hunt syndrome present unilaterally and therefore, should be differentiated from the tumors, which may involve the orbital apex including meningioma, pituitary adenoma, neurofibroma, paraganglioma, nasopharyngeal squamous cell carcinoma and metastatic tumors.^108,109

Tumors of the apex, however, usually cause a gradual development of motility dysfunction depending on the location of the tumor that may be accompanied with dull pain but usually not with an abrupt onset of panophthalmoloplegia and explosive pain.

Sarcoidosis is a multisystem disease of an idiopathic nature that commonly involves the orbit and the eye. Systemically it involves the lungs and the upper respiratory tract, liver, spleen, lymphatic and hematopoetic tissues, central nervous system and the skin. Although there is considerable evidence in favor of sarcoidosis being infectious in nature, no causative agent has been established so far. The etiopathogenesis of sarcoidosis is still unknown.¹¹⁰ The typical noncaseating granulomas are made of T-lymphocytes of helper and suppressor types and dendritic Langerhans cells with human leukocyte antigen (HLA)-DR expression. Perivascular inflammatory reaction is characteristic of a delayed type hypersensitivity response. Some investigators think that noncaseating epithelioid granulomatous reaction, which is determined as the hallmark feature of the disease may be the host’s immune response to presently unknown causative agent(s). Although the exact significance of granuloma formation in sarcoidosis is not clearly known, it appears that this tissue reaction is a secondary event as a result of exaggerated cellular immune response to a class of unknown antigens. It is hypothesized that the suppressor aspect of cell mediated response in sarcoidosis is abnormal and therefore reduces the function of helper T-lymphocytes. The initial step in granuloma formation of sarcoidosis is considered to be triggered by a cytokine (interleukin-1) that increases the proliferation of helper T-lymphocytes and activate these cells. Activated helper T-cells in turn secrete interleukin-2; a mitogen, which stimulates the proliferation of helper T-cells even further.¹¹¹ As a consequence these cells aggregrate at the site of the causative insult and secrete monocyte chemotactic factors that lead to the gathering of epitheloid macrophages and multinucleated giant cells to form granulomas. Sarcoidosis is also associated with increased B-cell activity manifested by polyclonal hyperglobulinemia.^112,113,114

Sarcoid granulomas are made of epithelioid cells and multinucleated giant cells, surrounded by lymphocytes and occasional plasma cells (Fig. 11). Many inclusion bodies have been described in the giant cells of sarcoidosis but none of these is pathognomonic. The granulomatous response of sarcoidosis is rather typical but not unique for this entity; fungal diseases, tuberculosis, Crohn disease and leprosy may produce similar granulomas¹¹⁵ (Table 2).

Approximately one-fourth of sarcoidosis patients develop ocular and orbital manifestations including anterior and posterior uveitis, chorioretinitis, conjunctival and eyelid granulomas and orbital mass lesions (Fig. 11). Lacrimal gland is a common site of involvement; autopsy studies show a high percentage of microscopic disease; however, only 15% to 20% of the patients show clinical symptoms. Although virtually any part of the orbit may be involved with sarcoidosis, the most common site is the lacrimal fossa and the disease in this location may be confused with chronic dacryoadenitis, Sjögren syndrome, or space-occupying lesion. Sarcoid granulomas may also extend into the orbit from adjacent sinus mucosa.¹¹⁶ If other manifestations of the disease are absent, these cases may mimic secondary orbital tumors and they can only be differentiated by biopsy.

Patients with distinctive systemic manifestations with bilateral hilar lympadenopathy, skin lesions, uveitis, etc., usually show increased angiotensin-converting enzyme (ACE) levels.¹¹⁷ Serum lysozyme and calcium levels may also be increased in sarcoidosis but neither one of these tests is specific for the disease. The ultimate diagnosis is by biopsy. Some advocate to perform biopsy only on the sarcoid-suspect lesions such as skin and conjunctival nodules in which the yield is usually rewarding. Others support random “blind” biopsy of the conjunctiva in sarcoid suspects. The yield of random biopsy without a distinct lesion is rather low (approximately 25% positive), but the conjunctival biopsy carries low morbidity and can be inexpensively and quickly performed in the clinic, as opposed to more invasive biopsies of transbroncheal lymph nodes, liver, and orbit. It is advisable, from the practical standpoint, to biopsy the conjunctiva randomly early in the workup of a sarcoidosis-suspect patient.¹¹⁸ If the biopsy result reveals granulomatous inflammation, more invasive procedures with high morbidity and cost can be avoided.

The involvement of the optic nerve with sarcoidosis is usually an anterior process and associated with typical retinal vasculitis, however, the optic nerve involvement may rarely extend posteriorly and form a mass lesion.¹¹⁹

The treatment of sarcoidosis is directed to the systemic disease. Surgery may be necessary to biopsy or debulk orbital lesions if there is a need for histopathologic evaluation in patients with no other easily accessible biopsy sites. In few instances, the orbital disease presents with no history or detectable symptoms of systemic sarcoidosis (Fig. 11). In these patients, sarcoidosis is usually a surprising diagnosis obtained from an orbital “tumor.” The mainstay of treatment is the use of systemic corticosteroids and antimetabolites such as methotrexate.

Sjögren syndrome (SS) consists of a triad of symptoms including dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and “dry joints” (arthritis).¹²⁰ Primary SS is not associated with other connective tissue diseases; however, secondary SS symptoms overlap with the manifestations of systemic lupus erythematosis, polymyositis, polyarteritis nodosa, scleroderma, and rheumatoid arthritis.¹²¹ Like many other autoimmune diseases, SS does not have a clear cut etiology, however, primary SS is considered a mononuclear inflammatory vasculopathy closely linked to HLA-DR3 and HLA-DRw52; secondary SS associated with rheumatoid arthritis is linked to HLA-DR4.¹²² Many viruses, including Epstein-Barr, CMV, HIV, and hepatitis-C, have been reported to have an etiologic role in SS. Immune complex formation and deposition are considered to be the physiopathology of cutaneous and ocular vasculitis.¹²³

Histopathology of the conjunctiva as well as the lacrimal gland is nonspecific consisting of lymphocytic and plasma cell infiltrates surrounded by eosinophilic basement membrane like material (Table 2). These units are called epimyoepithelial islands and are considered to be diagnostic of SS.¹²⁴ Lacrimal gland also reveals acinar atrophy and increased fibrosis surrounding the ductules¹²⁵ (Fig. 12). Diagnosis of SS is based on minor salivary gland biopsy rather than the biopsy of the lacrimal gland, because the latter procedure is more invasive and carries a higher morbidity.¹²⁶

Keratoconjunctivitis sicca is the most common presentation of SS in the eye occurring in approximately 90% of patients. Diminished tear meniscus and decreased tear break up time (BUT) with diminished tear production documented with Schirmer strips are common findings. Less commonly, patients develop episcleritis/scleritis in primary type of SS.¹²⁷ Because of peripheral and central nervous system involvement, optic neuritis and internuclear ophthalmoplegia may be seen in these patients. From the orbital standpoint, the asymmetrical presentation of the disease may be confused with an orbital lymphoma or sarcoidosis. In most cases, however, the disease presents with bilateral enlargement of the lacrimal glands and with the presence of other symptomatology SS is easy to diagnose (Fig. 12). It should be kept in mind, however, that SS patients have an increased risk of developing B-cell lymphomas in the salivary glands and cervical lymph nodes. This association was not found to be true for the lacrimal gland. However, orbital lymphoma that may mimic the presentation of SS should always be considered in the differential diagnosis.

Wegener granulomatosis (WG) is an idiopathic systemic vasculitis that also causes necrotizing granulomatous inflammation.¹²⁸ The classical triad of the disease includes necrotizing granulomatous vasculitis of upper and lower respiratory tracts, and necrotizing glomerulonephritis. Small vessel disease also affects the eye and orbit leading to conjunctivitis, scleritis, uveitis and thromboembolic phenomenon of the choroidal vessels and central retinal artery.^94,95,129

Orbital involvement also results from necrotizing vasculitis with or without granulomatous inflammation leading to painful proptosis, eyelid and conjunctival edema, and extraocular motility disturbance. Optic nerve disease may result from the combination of vasculitis of the optic nerve and meningeal vessels and/or the compression caused by an orbital space occupying lesion.⁹⁵ This on occasion may lead to occlusion of the central retinal artery.¹³⁰

Although the specific pathogenesis of WG is unknown, there is consensus that the disease develops as a result of an autoimmune mechanism, however, it does not appear to be caused by immune complex deposition like other forms of vasculitis.¹³¹ It has been speculated that the vasculitis of WG is triggered by an infectious process.^132,133 As a rule, the respiratory tract involvement in WG precedes renal or systemic disease, however, many atypical cases with lack of involvement of one organ system or another are well recognized.¹³⁴

It is well known that anti-neutrophil cytoplasmic antibodies (ANCA) function to contain the inflammatory responses by proteolysis, primarily by collagenases and elastases.¹³⁵ C-ANCA is a very sensitive and specific serologic marker for WG with a sensitivity increasing up to 96% for active disease.^136,137 Others hypothesize that C-ANCA is not merely a marker for the disease but in itself is pathogenic.¹³⁸ High and low C-ANCA titers are known to correlate well with disease activity and remission respectively.^139,140 Biopsy-proven head and neck particularly orbit cases are known to occur without elevated titers of C-ANCA.¹⁴¹

The classical histopathologic picture includes necrotizing vasculitis with necrosis and granulomatous inflammation (Table 2). However, a considerable variability is observed in the biopsies obtained from different organs and the classical appearance is not always demonstrable.^142,143 Upper respiratory tract and orbit biopsies usually show vasculitis and necrosis but rare granulomas.^144,145 Lung biopsy results usually present with diffuse necrotizing vasculitis of small blood vessels resembling an infectious process. Polymorphonuclear cells and eosinophils may form cuffs around blood vessels but granulomas are rare.¹⁴⁶ Kidney biopsies show necrotizing glomerulonephritis without well-formed granulomas.¹⁴⁷

Orbital biopsy samples also fail to depict the typical combination of vasculitis and granulomatous inflammation (Fig. 13). Kalina and co-workers reported the presence of complete triad of vasculitis, necrosis and granulomatous inflammation in only 54% of the biopsies.¹⁴² Granulomas also present some variability; in certain instances they are seen as typical hard granulomas made of aggregates of epitheloid cells, and giant cells surrounded by lymphocytes and occasional plasma cells. Granulomas that present within necrotic areas, however, may present as palisading lesions containing numerous polymorphonuclear leukocytes and eosinophils.

Ophthalmic involvement of WG is best categorized in two types: (i) focal disease that is the result of vasculitis and primarily affects the anterior and posterior segments of the eye and (ii) contiguous disease that is primarily seen in the orbit as a result of WG extending from the nasal cavity and perinasal sinuses. Orbital disease that develops acutely with painful proptosis, eyelid and conjunctival edema and ocular motility disturbance is the most common ocular manifestation in WG ^95,148 (Fig. 13). This presentation of WG may mimic orbital pseudotumor and infectious cellulitis as well as lymphoma and metastatic carcinoma.