Clinicopathologic Correlates in Orbital Disease
Zeynel A. Karcioglu
Maria Kirzhner
Of all essential human senses, vision is the most important. The eyes, organ of vision, should be well protected and supported functionally and structurally. This protection and support is provided by the orbit, which is a coneshaped bony structure with a volume of 30 mL in which the 7-mL globe is positioned centrally and anteriorly. All the support systems of the globe, including the optic nerve, lacrimal gland, extraocular muscles, fibroadipose tissue, peripheral nerves, ganglionic tissue, and blood vessels, are designed to be confined within approximately 25 mL of space surrounding the eyeball. Many tissues are crowded in this limited space and give origin to a variety of congenital, structural, inflammatory, degenerative and neoplastic diseases. Furthermore, orbital pathologies are not limited to primary disorders; many systemic diseases and disorders of the globe may affect the orbit secondarily. The orbit is also secondarily affected by the diseases of the cranium, eyelids, conjunctiva, and the nasal cavity and paranasal sinuses. This chapter attempts to give an overview of the clinicopathologic correlation of orbital diseases. Because of limited space, entities that are encountered more often are detailed and some other less frequently seen pathologies are only mentioned with citations of pertinent references.
STRUCTURAL DISORDERS
Congenital Anomalies
Orbitocraniofacial Deformities
The orbital bones begin to develop during the first 2 months of embryogenesis.1 Toward the end of the fifth week, the axis 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 ossification and fusion take a longer time to complete, around the seventh month of gestation. At term, the orbit is almost spherical in configuration. The periorbital sinuses begin to develop around the second month of gestation and continue to grow after birth.3 Although the eye reaches adult size (approximately 7 mL) around the age of 2½ 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. On the other hand, if a congenital cyst or tumor develops within the orbit, to expand 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.
Craniosynostosis
This developmental pathology of the orbit is dependent on the fusional abnormalities between the orbital and the nasomaxillary bones. Particularly the lacrimal bones provide a suture system that monitors the remodeling adjustments in the complex growth of orbit.4 Craniosynostosis is divided into primary and secondary forms. Primary craniosynostosis refers to premature fusion of cranial sutures due to embryologic error. Secondary synostosis is the premature closure of sutures due to other causes such as intrauterine trauma or effects of teratogenic drugs.5 Approximately 15% of craniosynostosis cases are associated with systemic abnormalities and are known as syndromic craniosynostosis; the remaining 85% represent nonsyndromic forms.6 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, narrow optic canals, and proptosis; maxillary hypoplasia and cleft palates; and Pfeiffer syndrome with malformation of thumb and great toe and soft-tissue syndactyly.7
Clefting disorders
These malformations predominantly involve 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 utilized 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 microsomias8,9 (Table 17.1).
TABLE 17-1. Summary of Orbitocraniofacial Dysmorphic Syndromes | ||||||||||||||||||||||||||||||||||||||||||
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Anophthalmos/Microphthalmos
When the globe is abnormally developed, microphthalmos, congenital cystic eye and rarely, anophthalmos occur. Microphthalmos usually occurs as a unilateral condition, and in about 10% of cases, it is associated with other craniofacial malformations including agenesis of the corpus callosum, polymicrogyria, and midline arachnoidal cysts. Microphthalmos may be seen as part of several genetically determined neuronal migration disorders such as Walker-Warburg syndrome, Aicardi syndrome, and Fukuyama congenital muscular dystrophy.10,11
In cases of microphthalmos and anophthalmos, the orbit may be well formed but does not develop to a full adult volume. The mechanism by which the presence of the globe effects the growth of the orbit is not well understood. Microphthalmos may be associated with a colobomatous cyst as a result of the abnormal closure of the embryonic optic fissure leading to the prolapse of neuroectodermal tissues into the orbit (Fig. 17.1). This cystic structure may increase rapidly in size to overshadow the abnormal globe and may be confused with a neoplasm. When cystic lesions in the orbit are suspected, imaging studies should be performed not only to look for other intracranial abnormalities but also to establish a possible connection of the cyst to the colobomatous globe or to abnormally formed meninges.12 Macrophthalmos (buphthalmos) may also rarely develop as a congenital anomaly in patients with Sturge-Weber syndrome and rarely in neurofibromatosis type I (NF-I).
 FIG. 17.1 Congenital lesions—A very large cystic teratoma of a 1-month-old child (A). Frame (B) depicts histology of this lesion that contains a variety of tissues, endodermal, ectodermal, and mesenchymal. An orbital cyst (C) in an orbit-containing micro-ophthalmic globe. C, D: The protrusion of the cyst inferiorly creates a mechanical lower lid ptosis that narrows the right maldeveloped conjunctival sac even further. Axial and sagittal CT scan showing a ME occupying the entire orbit (E). The histopathologic examination of the lesion revealed both meningeal (M) and brain (B) tissues (F). The high-power histopathology reveals ciliated ependymal cells lining some of the cystic spaces (arrowhead) (G). |
Orbitocranial Maldevelopments
Cephalocele results from the extension of maldeveloped CNS tissues including meninges (meningocele), brain parenchyma (encephalocele), and the combination of the two (meningoencephalocele [ME]) into the orbital cavity.13,14
Intraorbital cephaloceles may develop anteriorly at the suture lines of orbital bones or posteriorly extending into the orbit from orbital fissures and the optic canal. Depending on the combination of these herniations they may contain brain and/or meningeal tissues (Fig. 17.1). Aberrant fibroglial tissue has also been described in the orbit.15
Hamartoma is a tumor-like proliferation of tissues that normally exist at a given body location. The best examples of orbital hamartomas are the vascular hamartomatous lesions, which are composed of vascular elements including capillary endothelial cells, distended or collapsed cavernous blood and lymph vessels, and tortuous arterial and venous channels with or without anastomoses. Other examples of hamartomatous orbital tumors include neurofibroma and lipomatous hamartoma.16
Choristoma, on the other hand, is a tumor-like proliferation of tissues that are not normally present at a given body location. The most commonly encountered example of orbital choristoma is a dermoid.17,18 Dermoids, which present with many varieties, result from the entrapment of epithelial structures at the site of closure of fetal fissures. Superficial dermoid cysts occur primarily subcutaneously anterior to orbital septum or within the anterior orbit. If the cyst wall is made of epidermis without dermal tissues, it is classified as an epidermoid cyst. These lesions are occasionally lined by conjunctival or pseudostratified respiratory epithelium.17 The superficial lesions must be distinguished from deep orbital dermoids that are usually rounded, encapsulated tumors filled with fatty materials, keratin, and dermal structures such as hair particles. Histopathologically, the dermoid wall is lined by keratizing squamous epithelium with dermal appendices including hair follicles, sebaceous, and eccrine glands.18
Most of the dermoids are well outlined by ultrasonography because of their anterior location, thus making CT or MRI rarely necessary.19 If the dermoid is unusually large or located at the frontal zygomatic suture, CT is necessary to document the relationship of the lesion to the bone prior to surgical intervention. Rarely, dermoids at the frontozygomatic suture may develop dumbbell shaped lesions partially within the orbit and partially extending into the temporal fossa.20 Unusually, large superior orbital dermoids particularly those which leak and create granulomatous reaction within adjacent soft tissues may erode the bone and extend into the frontal sinus or the cranium (Fig. 17.2). Another rare presentation of dermoid and epidermoid is the intradiploic type, which develops within the diploid space of orbital bones and presents at birth.21
Orbital Teratoma
Teratoma is a germ cell tumor that contains tissues derived from endoderm, ectoderm, and mesoderm22 (Fig. 17.1). Therefore, these lesions may contain skin, bowel, lung, brain, thyroid, cartilage, and bone tissues. Most teratomas develop unilaterally and in girls. A great majority of these congenital tumors are benign. Occasional reports have documented malignant transformation within orbitocranial teratomas.23,24 However, these benign tumors continue to grow after birth because of the collection of secretions from different tissues into the partially cystic spaces of the tumor. Some teratomas create massive proptosis, and most can only be treated by exenteration. However, some of these masses have been reported to be removed surgically with preservation of the globe and other vital orbital structures.24
Trauma
Mechanical Injury
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 of different areas.26,27 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). An increase in orbital volume as measured by 3D reconstructions of CT series has been reported in most isolated orbital floor injuries; many claim that this increased orbital volume is the main cause of posttraumatic enophthalmos and, therefore, recommend surgical repair of the floor27 (Fig. 17.3). 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. 17.3). 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.27,30 Depending on the damage of the particular tissue, functional deficit results. Ocular and orbital injuries secondary to radiant energy and chemical burns are true emergencies and require urgent and precise evaluation and treatment. The sequelae of these injuries can be severe and particularly difficult to manage.31
 FIG. 17.2 Dermoid—Different presentations of dermoid (d): superior medial, semi-solid mass pushing the globe down and out (A); a ruptured dermoid causing an inflammatory reaction within adjacent soft tissues (B); a large superior lateral dermoid eroding through the roof of the orbit to extend into the brain (C); extraorbital dermoid within the subcutaneous tissues of the eyebrow (D); gross appearance of the cystic dermoid containing whitish yellow cheesy keratin material intermixed with hair (E); dumbbell dermoid that is present on both sides of the frontozygomatic fissure (F); histopathology of dermoid wall (dw) containing skin appendages, the lumen of the dermoid is lined with stratified squamous epithelium producing keratin (K) (G). |
 FIG. 17.3 Orbital trauma—Axial CT scan (A) and T1-weighted MRI (B) show multiple organic foreign bodies (fb) within the left medial rectus muscle and posterior orbit. The round tissue depicted in the inset was removed at the time of surgery; histopathologically, it proved to be a foreign body granuloma (fbg). A coronal CT scan (C) and the intraoperative photograph (D) depict a large, inferior orbital rim (ior) fracture. The right inferior rectus muscl, which was prolapsed into the maxillary sinus, is highlighted with an arrowhead (C). |
Other issues to deal within an injured orbit are the development of a hematoma, hematic cyst, cholesterol granuloma, or cholesteatoma. 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 cyst (Fig. 17.4). 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 cysts 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, and compression on the globe and optic nerve, which 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.
Cholesterol granuloma is another type of cystic lesion, which is confined within a “pseudowall” without an epithelial lining. These lesions are usually located in the superior lateral orbit within the lacrimal gland fossa.37 Imaging studies may show a cystic, semicystic, 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. Cholesterol granuloma should also be differentiated from another rare orbital lesion, cholesteatoma. Clinically and histopathologically, these mass lesions share many similarities with one significant distinction: cholesteatoma results from proliferation of epithelial tissue extending into the orbit from conjunctiva or paranasal sinuses. Furthermore, about one-fourth of orbital cholesteatomas have been reported to recur with the possibility of malignant transformation.39
 FIG. 17.4 Hematic cyst—Axial CT scan (A) showing a large superiorly located, well-circumscribed hematic cyst (hc) presenting as a homogeneous low-density image. Intraoperative photograph of the same case shows dark brown hematic cyst. B: Frames (C, D) show the gross and histopathologic appearance of the hematic cyst, respectively. It is surrounded by a fibrous pseudocapsule (arrows) containing a mixture of cholesterol crystals, (cc), hematoidin crystals (hc), and other proteinaceous debris. |
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, sclerosing character of the bony destruction in cholesterol granuloma, 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.37,38,39
Osteomyelitis of the orbital bones evolving as a complication of paranasal sinusitis is another entity that should be considered in the differential diagnosis of cholesteatoma. In osteomyelitis, the bone infection extends into the periosteal space and beyond. Precise delineation of the lesion can be done with CT and MRI particularly in combination with bone single-photon emission computed tomography (SPECT), a sensitive technique used to detect osteomyelitis within cranial and orbital bones.40
Mucocele
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 sinues41 (Fig. 17.5). The primary mucoceles develop as a result of an inflammatory obstruction of the ostium of the paranasal sinuses. Secondary mucoceles, on the other hand, 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.40,42 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.
 FIG. 17.5 Mucocele—Moderate proptosis and slight lateral displacement of the left eye secondary to a large medially located mucocele originating from the ethmoid sinus (m). A, B: Note the compression of the calcified wall of the lesion onto the globe and the optic nerve (B). The large cystic nature of the mucocele with low internal reflectivity and segmentally calcified wall is demonstrated by ultrasonography (C). Gross specimen of the stripped mucosal lining of the mucocele from the same case (D). |
On CT, mucoceles present as hypointense, expanding masses originating from the paranasal sinuses. Early in their development, these lesions are small, mucouscontaining cysts. Later they are characterized by crescentshaped and thinned remodeling of the bony walls of the orbit and sinuses.42
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 decreases, getting closer to normal air content of the sinus.43 Treatment of mucocele is surgical excision.44
Other injuries and burns with toxic chemicals and radiation are known to damage orbital tissues.45,46,47 Ocular and orbital injuries secondary to radiant energy and chemical burns are true emergencies and require urgent and precise evaluation and treatment. The sequelae of these injuries can be severe and particularly difficult to manage.31
Vascular Malformations
Arteriovenous (AV) Fistula
Orbital AV fistulas are established as a result of abnormal flow between the arteries and the 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.48,49 Dural cavernous fistulas, on the other hand, develop between small meningeal branches of internal/external carotid artery and the cavernous sinus.50 These small vessels have thin walls, which 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.51
Most of these patients are diagnosed with imaging procedures including CT, MRI, angiography, color Doppler ultrasonography as well as catheterized angiography.52,53 Current treatment of these lesions is embolization via catherization.54 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;50 therefore, it is best to follow some of these patients conservatively if they do not have severe symptoms.
Orbital Varix
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.53,55 Histopathologically, varixes 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 AV malformations. The secondary orbital varix, on the other hand, develops as an extension of an intracranial AV malformation that shunts blood to the orbital venous system causing the venous channels to distend secondarily.56 Management of orbital varix consists of total surgical excision when possible and/or endovascular embolization.
ORBITAL INFLAMMATION
Microbial Inflammation
Microbial infections of the orbit develop due to a variety of organisms, which are introduced to the orbit by different routes. Bacterial orbital infections are the most common, which primarily originate from the paranasal sinuses, and to a lesser degree secondary to penetrating injuries with or without foreign bodies, and rarely, secondary to endophthalmitis or systemic infectious process such as bacterial septicemia and tuberculosis. The most common cause of bacterial orbital cellulitis is Staphylococci and Streptococci species. Although Haemophilus influenza was a common causative organism in children younger than 4 years, recent vaccination efforts have decreased the incidence of H. influenza cellulitis significantly.57 On the other hand, community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been increasingly reported as a vision-threatening pathogen to afflict immunocompetent children and adults.58
Anatomically speaking, if the infection is limited to anterior of the orbital septum, involving the eyelids, it manifests itself primarily with lid and conjunctival edema and some venous congestion but not with proptosis.59 This process, which is known as preseptal cellulitis, is usually initiated with skin injuries or an upper respiratory tract infections in children. On the other hand, if the infectious process involves orbital soft tissues beyond the septum, it is called orbital cellulitis (Fig. 17.6). Cellulitis usually develops secondary to a paranasal sinus disease, clinically associated with axial proptosis, marked chemosis, congestion of retinal veins, limitation of extraocular motility, and swelling and pain around the eye. Depending on the severity of the condition, vital structures within the orbit such as the globe and the optic nerve may be compressed or infiltrated by the infection. Generally in children, the orbital cellulitis originates from the ethmoid sinus and may limit itself to the subperiosteal site for a while and later spread into orbital soft tissues.
Acute bacterial orbital cellulitis presents a nonspecific histopathology associated with diffuse polymorphonuclear infiltrate, which may on occasion lead to abscess formation60 (Table 17.2). Subperiosteal and soft-tissue abscesses may present with decreased vision, disc edema, and increased intraorbital and intraocular pressures. Orbital abscess is best demonstrated with MRI. Emergent orbital exploration and the drainage of the abscess are indicated.
Orbital cellulitis may also be caused by different types of foreign bodies including organic and nonorganic matter and nonautogenous surgical implants.28 Inorganic foreign materials, such as metal and glass, are usually well tolerated and do not cause infection unless they significantly distort the orbital anatomy with exposure to periorbital sinuses and nasal cavity. Organic foreign bodies such as wood and vegetable fibers, on the other hand, trigger significant foreign body reaction and sometimes suppurative inflammation. These should be documented by CT and/or MRI and surgically removed29 (Fig. 17.3). Today many nonautogenous materials are used in ocular and orbital reconstruction, including porous implants, mesh materials, polymeric silicone plates, sponges for scleral buckling procedures, and reservoirs of drainage valves for glaucoma. Implants and repair blocks made of porous materials may lead to acute infection when they erode through a sinus or conjunctival epithelium. Whenever there is a foreign body, noncaseating granulomatous reaction with multinucleated giant cells is identified, adjacent to the foreign material; secondary acute inflammation may be superimposed. In penetrating injuries, the nature of the foreign body is an important factor.
 FIG. 17.6 Orbital cellulitis—Frames (A) and (B) show the appearance of right orbital cellulitis secondary to Staphylococcus infection from right ethmoidal sinus. The proptosis, chemosis, and visual loss in this patient worsened after the ethmoidectomy and the medial orbit had to be explored with additional drainage of pus. Note the stretch of the right optic nerve and pear-shaped right globe secondary to marked proptosis on an axial CT scan (B). Frame (C) shows another case with severe ethmoiditis causing cellulitis of the right orbit, with the extension of the infection preseptally toward the left globe. The patient responded well to ethmoidectomy and drainage of the abscess from the right medial orbit. Frame (D) shows the appearance of a preseptal and anterior orbital cellulitis secondary to a longstanding foreign body caused in a motor vehicle accident. The patient depicted in frame (E) developed Streptococcal orbital cellulitis with secondary brain abscess as depicted in the sagittal T1-weighted MRI (F). |
TABLE 17-2. Correlation of Cellular Pathology to Clinic Diagnosis in Orbital Inflammatory Lesions | ||||||||||||||||||
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An exception to suppurative soft-tissue reaction caused by bacteria is chronic caseating granulomatous inflammation, which is caused by mycobacteria and certain types of fungi (Table 17.2). Ocular and adnexal tuberculosis is usually seen with manifestations of systemic mycobacterium infection.61,62,63 Owing to the recent increase in the numbers of immunologically suppressed individuals secondary to viral epidemics and wider use of immunosuppressant antimetabolites in longer surviving cancer and transplant patients, the incidence of tuberculosis has been rising steadily during the last two decades and the clinical picture of the disease has been changing, with many cases developing due to atypical mycobacteria that are resistant to traditional multidrug treatment.64 It has been reported that the individuals with HIV/AIDS have an incidence of tuberculosis 500-fold more than that is seen in the general population.65
The orbital disease is more often seen in children and nonwhite patients. History of antecedent penetrating injury is a common presentation of tuberculosis, due to atypical mycobacteria. Histopathology of tuberculosis consists of zonal granulomatous inflammation with numerous epithelioid histiocytes surrounding a necrotic (caseating) center. Tissue diagnosis is pathognomonic only with the documentation of positive acid-fast organisms; however, in many cases, tissue may fail to demonstrate the mycobacteria, but the cultures grow Mycubacterium tuberculosis or atypical Mycobacteria. Orbital tuberculosis is usually associated with systemic disease (Fig. 17.7).
In most instances, fungi infect the orbit as an extension of the paranasal sinus disease or following penetrating injury associated with the introduction of organic matter. Most of the fungal infections, particularly mucormycosis, often develop in immunocompromised patients.66 Orbital mucormycosis is an emergency situation because it causes rapidly progressing necrotizing inflammation secondary to vascular involvement (Fig. 17.8). Orbital exploration should be done immediately to establish the diagnosis by identifying the broad, nonseptated hyphae and for surgical debridement as well as irrigation with antifungal agents. The prognosis of mucormycosis is very poor. Aspergillosis, unlike mucormycosis, presents a low-grade, smoldering chronic granulomatous inflammation, which may be confused with primary orbital tumor.67 The identification of the organism in fungal and parasitic diseases is crucial at the time of surgery; fungi may also be identified with smears and frozen section.68 In any kind of orbital exploration secondary to cellulitis, tissue samples should be obtained for gram, fungal, and acid-fast bacillus (AFB) stains and aerobic, anaerobic, and fungal cultures.
As a rule, no matter how rarely, any microbial inflammation, including bacteria, fungi, viruses, and others, may infect the orbit and cause acute, chronic, or granulomatous inflammation leading to tissue damage and fibrosis. These rare diseases include syphilis,69 leprosy,70,71 Lyme disease,72,73 Parinaud syndrome,74,75 and actinomycosis.76,77 Examples of parasitic orbital infections include echinococcosis, cysticercosis, myiasis, and trichinosis of extraocular muscles.78,79,80,81,82,83,84
 FIG. 17.7 Orbital tuberculosis—A 2-year-old boy with left orbital tuberculosis. A: Mother and the child had systemic disease. A case of bilateral orbital and perinasal sinus tuberculosis is shown in the coronal CT of a 28-year-old man. B: Note the irregular involvement of the bony tissues of the orbits and the sinuses. Frames (C) and (D) show a caseating granuloma (c) and AFB-positive tuberculous bacilli in necrotic inflammation (arrowheads), respectively. |
Nonmicrobial Inflammation
Many forms of inflammatory processes may trigger orbital inflammation, which simulates neoplasms by producing proptosis and associated orbital findings.85,86,87 These include Graves disease (Gd),88,89,90,91 idiopathic orbital inflammation (IOI; orbital pseudotumor),92,93,94,95 Tolosa-Hunt syndrome,96,97 sarcoidosis,85,98 Sjögren syndrome (SS),99,100 and Wegener granulomatosis.101,102
Graves Disease
Thyroid-associated orbitopathy, better known as Gd, is an IOI 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. 17.9). Gd is the most common cause of unilateral and bilateral proptosis in adults, although uncommonly it may be seen in children91 as well.
The pathogenesis of Gd is yet to be completely delineated. The current leading hypothesis favors an “autoimmune” process.87,91,103 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.103,104 Experimental studies suggest thyrotropin receptor (thyroid stimulating hormone receptor [TSH-R]) as the most likely entity to stimulate the autoantibodies initiating inflammatory changes within orbital soft tissues. More recently, insulin-like growth factor-1 receptor has been implicated as a another strong candidate in the autoimmune process.103,104
In Gd there is a predominance of T-cells with Th1 profile although Th2 profile of cytokine production has also been reported. The cytokines stimulate fibroblasts to produce glycosaminoglycans (GAG), which in turn lead to deposition of this substance within the muscle tissue leading to anatomic and functional deficiencies (Fig. 17.9). Although cell-mediated immune reaction predominates in early Gd, humoral immunity plays a greater role in later phases.103 Orbital fibroblasts are the main target of the autoimmune cascade, thus the main mediator of the chain of events that occurs in Gd. T-cell-mediated inflammatory response is responsible for the swelling and inflammation. A subpopulation of fibroblasts can undergo adipocyte differentiation, leading to increased orbital fat. T-cell mediators induce effector cell proliferation and synthesis of GAG responsible for increased thickness of extraocular muscles and increased edema. Some of the immune changes are reflected in the histopathology of Gd, which can basically be divided into 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 is 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.
 FIG. 17.8 Mucormycosis—The appearance of mucormycosis in the right orbit, periorbital skin, and maxillary sinuses of a 60-yearold man with diabetic ketoacidosis (A). Frame (B) shows the funduscopic appearance of a central retinal artery thromboembolism with resultant “cherry-red spot” from another case of orbital mucormycosis. Frame (C) shows the extensively necrotic, bloodless cut surface of the exenteration specimen from the patient shown in frame (A). Histopathologic examination of this specimen revealed numerous nonseptated mucormycosis hyphae with 90° branching (D) in Gomori methenamine silver stain. |
Although 80% of patients with Gd present with a history of hyperthyroidism, approximately 10% suffer with hypothyroidism or autoimmune thyroiditis; occasionally, a euthyroid individual may also develop the signs and symptoms of Gd.105 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%). Restriction of extraocular muscles may lead to increased intraocular pressure.106 Compressive optic neuropathy may result secondary to the enlargement of the extraocular muscles in the apex. Optic nerve malfunction is manifested by decreased visual acuity and color vision, afferent pupillary defect, and visual field deficiencies in about 5% of Gd patients.
The best means of evaluating extraocular muscles is imaging with CT and/or MRI.107 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.107 In differential diagnosis of Gd, one should keep in mind that it is not only the most frequent cause of bilateral proptosis but also unilateral proptosis. Therefore, the slowly progressive unilateral presentation may be confused with orbital pseudotumors, neoplasia, and solitary vascular lesions such as orbital varix.108,109 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.
 FIG. 17.9 Gd—All the clinical findings of Gd are depicted in Figure (A) including bilateral proptosis and lid lag with extraocular motility disturbance, chemosis, and congestion of conjunctival blood vessels. Axial CT scan reveals marked swelling of all recti muscles with compression optic neuropathy with visual field defects (C). Frame (D) reveals extensive mucopolysaccharide deposition with total loss of normal skeletal muscle architecture. |
Idiopathic Orbital Inflammation
Orbital Pseudotumor
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.92,93 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: (i) diffuse and (ii) localized nonspecific orbital inflammation. The localized nonspecific inflammation is further divided according to specific sites, that is, 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 dominate the picture110 (Fig. 17.10). 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 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 (WG).
 FIG. 17.10 Orbital pseudotumor—A patient with subacute orbital pseudotumor showing mild proptosis with hyperemia and edema of the eyelids and limited extraocular motility of the left eye (A) and (B). The left medial rectus muscle is severely involved with the disease, which is also present to a lesser degree within the left inferior rectus muscle. Frames (C) and (D) reveal a mixture of lymphocytes, plasma cells, and eosinophils within fibroadipose tissues of the orbit. |
A recently reported variant of orbital pseudotumor is in the group of IgG4-related systemic inflammatory diseases.111 This group of disorders of unknown etiology has been reported to effect pancreas, submandibular and parotid glands, biliary tree, thyroid, retroperitoneum, kidneys, and lungs.95 The histopathologic findings in all the different organs are identical and include a lymphoplasmacytic inflammatory infiltrate, phlebitis, and varying degrees of fibrosis.112 The plasma cells with immunoglobulin G4 on their surface stain in increasing numbers (Fig. 17.11). As this variant of IOI has a more sclerosing nature and responds better to immunomodulatory treatments, a biopsy with special stains for IgG4 is warranted to improve diagnosis and treatment.
Tolosa-Hunt Syndrome
Tolosa-Hunt syndrome, otherwise known as painful external ophthalmoplegia, is another inflammatory process of the orbit with unknown etiology. It is conceivable to think that it represents a localized form of 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.96,97 Typically, the orbital pain, which presents abruptly, responds to systemic corticosteroid treatment with the same abruptness. Other symptoms of the disease including third, fourth, and sixth cranial nerves palsies and 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 that may involve the orbital apex including meningioma, pituitary adenoma, neurofibroma, paraganglioma, nasopharyngeal squamous cell carcinoma,andmetastatic tumors.113,114
 FIG. 17.11 IgG4-related systemic inflammatory disease— fibrosis in orbital soft tissues mixed with relatively mild inflammation of lymphocytes and plasma cells (A). Immunostaining for IgG4 depicts numerous positive plasma cells (B). (Courtesy of Dr. David Bourne of Charlottesville, Virginia). |
Tumors of the apex, however, usually cause a gradual development of motility dysfunction depending on the location of the tumor, which may be accompanied with dull pain but usually not with an abrupt onset of panophthalmoloplegia and explosive pain.
Nonspecific Granulomatous Inflammation
Sarcoidosis
Sarcoidosis is a multisystem disease of an idiopathic nature, which commonly involves the orbit and the eye. Systemically, it involves the lungs and the upper respiratory tract, liver, spleen, lymphatic and hematopoietic tissues, CNS, 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.115,116
The typical noncaseating granulomas are made of T-lymphocytes of helper and suppressor types and dendritic Langerhans (L) 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 activates these cells. Activated helper T-cells in turn secrete interleukin-2; a mitogen, which stimulates the proliferation of helper T-cells even further.117 As a consequence, these cells aggregate at the site of the causative insult and secrete monocyte chemotactic factors, which lead to the gathering of epithelioid macrophages and multinucleated giant cells to form granulomas. Sarcoidosis is also associated with increased B-cell activity manifested by polyclonal hyperglobulinemia.116
Sarcoid granulomas are made of epithelioid cells and multinucleated giant cells, surrounded by lymphocytes and occasional plasma cells (Fig. 17.12). 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 granulomas116,118 (Table 17.2).
Approximately one-fourth of sarcoidosis patients develop ocular and orbital manifestations including anterior and posterior uveitis, chorioretinitis, conjunctival and eyelid granulomas, and orbital mass lesions119 (Fig. 17.12). 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, SS, or a space-occupying lesion. Sarcoid granulomas may also extend into the orbit from adjacent sinus mucosa.120 If other manifestations of the disease are absent, these cases may mimic secondary orbital tumors and they can only be differentiated by biopsy.
 FIG. 17.12 Sarcoidosis—The appearance of a large sarcoidosis granuloma involving the anterior orbit and periorbital skin (g). The central dome-like lesion is due to secondary to a Staphylococcus infection. In addition, plaquoid skin lesions of sarcoidosis are seen above the left eyebrow, on the left upper eyelid, and on the periorbital skin. A: The T2-weighted axial MRI with contrast reveals bilateral enlargement of lacrimal glands (g) in another case. Frames (C) and (D) show T1-weighted sagittal MRIs with localized granulomatous masses of sarcoidosis within the posterior orbit involving the apex and extending into the cavernous sinus. C, D: A well delineated but not encapsulated mass of a sarcoid granuloma (E). The histopathology of sarcoidosis consists of multiple granulomas composed of histiocytic cells, chronic inflammatory cells, and multinucleated giant cells (g) (F). |
Patients with distinctive systemic manifestations of bilateral hilar lymphadenopathy, skin lesions, uveitis, and so on usually show increased angiotensin-converting enzyme (ACE) levels.121 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 biopsy only 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.122 The yield of a random biopsy without a distinct lesion is rather low (around 25% positive), but the conjunctival biopsy carries low morbidity and can be inexpensively and quickly done in the clinic, as opposed to more invasive biopsies of transbronchial 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.122,123 If the biopsy 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.124 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. 17.12). In these patients, sarcoidosis is usually a surprising diagnosis obtained from an orbital “tumor.” The main stay of treatment is the use of systemic corticosteroids and steroid-sparing medications such as methotrexate.
Sjögren Syndrome
SS consists of a triad of symptoms including dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and “dry joints” (arthritis).99,125 Primary SS is not associated with other connective tissue diseases; however, secondary SS symptoms overlap with the manifestations of systemic lupus erythematosus, polymyositis, polyarteritis nodosa, scleroderma, and rheumatoid arthritis.126 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-DR4.127 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.128
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 17.2). These units are called epimyoepithelial islands and are considered to be diagnostic of SS.129 Lacrimal gland also reveals acinar atrophy and increased fibrosis surrounding the ductules130 (Fig. 17.13). Diagnosis of SS is based on minor salivary gland biopsy rather than the biopsy of the lacrimal gland, as the latter procedure is more invasive and carries a higher morbidity.130
Keratoconjunctivitis sicca is the most common presentation of SS in the eye occurring in about 90% of patients. Diminished tear meniscus and decreased tear breakup time (BUT) with diminished tear production documented with Schirmer strips are common findings. Because of peripheral and CNS 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. 17.13). 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, which 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.131 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.101,102
 FIG. 17.13 Sjögren disease—A patient with bilateral enlargement of lacrimal glands, which was involving the left side more than the right (A, B). Minor salivary gland biopsy from the lower lip revealed infiltration of eosinophils, lymphocytes, and plasma cells. The biopsy was sufficient to make the diagnosis combined with the clinical picture. The same patient developed orbital lymphoma, which is depicted in frame (B), 3 years after the diagnosis of Sjögren disease. |
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.101 This on occasion may lead to occlusion of the central retinal artery.132
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.133 It has been speculated that the vasculitis of WG is triggered by an infectious process.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 antineutrophil 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 Others hypothesize that C-ANCA is not merely a marker for the disease but in itself is pathogenic.137 High and low C-ANCA titers are known to correlate well with disease activity and remission, respectively.138 Biopsy-proven head and neck particularly orbit cases are known to occur without elevated titers of C-ANCA.139
The classical histopathologic picture includes necrotizing vasculitis with necrosis and granulomatous inflammation (Table 17.2). However, a considerable variability is observed in the biopsies obtained from different organs and the classical appearance is not always demonstrable.140,141 Upper respiratory tract and orbit biopsies usually show vasculitis and necrosis but rare granulomas.142,143 Lung biopsies usually present with diffuse necrotizing vasculitis of small blood vessels resembling an infectious process.144 Kidney biopsies show necrotizing glomerulonephritis without well-formed granulomas.144
Orbital biopsies also fail to depict the typical combination of vasculitis and granulomatous inflammation (Fig. 17.14). Kalina and coworkers reported the presence of complete triad of vasculitis, necrosis, and granulomatous inflammation in only 54% of the biopsies.140 Granulomas also present some variability; in certain instances, they are seen as typical hard granulomas made of aggregates of epithelioid cells, and giant cells surrounded by lymphocytes and occasional plasma cells. Granulomas, which present within necrotic areas, on the other hand, may present as palisading lesions containing numerous polymorphonuclear leukocytes and eosinophils.
Ophthalmic involvement of WG is best categorized into two types: (i) focal disease, which is the result of vasculitis and primarily affects the anterior and posterior segments of the eye, and (ii) contiguous disease, which is primarily seen in the orbit as a result of WG extending from the nasal cavity and perinasal sinuses. Orbital disease, which develops acutely with painful proptosis, eyelid and conjunctival edema, and ocular motility disturbance, is the most common ocular manifestation in WG.101,145 (Fig. 17.14). This presentation of WG may mimic orbital pseudotumor and infectious cellulitis as well as lymphoma and metastatic carcinoma.145
 FIG. 17.14 WG—Mild proptosis combined with conjunctival chemosis and hyperemia adjacent to congested tortuous blood vessels of a WG patient. The right optic nerve disc shows optic nerve pallor (inset). The excisional biopsy from the conjunctival lesion reveals granulomatous vasculitis with focal necrosis (arrow) (B). |
Advances in the management of WG over the last 30 years have improved survival with this disease, which in its classical form is rapidly fatal, if not treated.144 It is extremely important to establish the diagnosis of WG as early as possible because the early treatment may prevent renal failure, which is usually the cause of death. The mainstay of treatment is systemic immunosuppression with cytotoxic therapy, usually a combination of corticosteroids and cyclophosphamide.144 Although definitive treatment of any ophthalmic involvement is systemic immunosuppression, orbital inflammation may respond poorly to systemic cytotoxic therapy and may remain active in spite of the remission of the systemic disease.145,146 There is recent evidence that rituximab may also be an effective alternative for patients with WG in whom the usual immunosuppressive medicines have failed.146
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