Nonspecific orbital inflammation

Nonspecific orbital inflammation (NSOI) refers to a space-occupying inflammatory disorder that simulates a neoplasm (it is sometimes known as orbital pseudotumor or idiopathic orbital inflammatory syndrome) but has no recognizable cause. This disorder accounts for approximately 5% of orbital lesions and can affect children and adults. Clinically, the onset is often abrupt, and patients usually report pain. The inflammatory response may be diffuse or compartmentalized. When localized to an extraocular muscle, the condition is called orbital myositis (Fig 14-2); when localized to the lacrimal gland, it is called dacryoadenitis.

In the early stages of NSOI, inflammation predominates, with a mixed inflammatory response (eosinophils, neutrophils, plasma cells, lymphocytes, and histiocytes [macrophages]) that is often perivascular and frequently infiltrates muscle and fat, causing fat necrosis. In later stages, fibrosis is the predominant feature, often with interspersed lymphoid follicles with germinal centers. The fibrosis may replace orbital fat and encase extraocular muscles and the optic nerve, restricting their function (Fig 14-3). Some cases that demonstrate significant fibrosis and deposition of collagen as the dominant histologic feature early on seem to lack the inflammatory clinical signs usually associated with NSOI. Whether this “sclerosing” variant is a separate entity or a variant of NSOI remains controversial.

Figure 14-2 Nonspecific orbital inflammation (NSOI). NSOI can affect any orbital structure. In myositis, the skeletal muscle fibers (arrows) are surrounded by a dense infiltrate of chronic inflammatory cells. Unlike in thyroid eye disease, in myositis the muscle tendons are involved.

Figure 14-3 Nonspecific orbital inflammation. A, Note the mixture of inflammatory cells, mostly lymphocytes (small, blue) and plasma cells (larger, with pink cytoplasm), and the bundle of collagen (asterisk) running through the orbital fat. B, Diffuse fibrosis dominates the histologic picture of this fibrosing orbititis, representing a later stage of the condition in part A.

Often included in the differential diagnosis of NSOI is a lymphoproliferative process such as lymphoma. Immunophenotypic and molecular genetic analyses can differentiate NSOI from lymphoid tumors based on whether the infiltrate of lymphocytes is polyclonal (NSOI) or monoclonal (lymphoma). CD20 and CD25 receptors have been found in cases of NSOI and may provide the basis for treatment selection. Immunoglobulin (Ig) G4–positive lymphoplasmacytic infiltrates have recently become a marker for IgG4-related sclerosing disease (see “Immunoglobulin G4–related disease” later in the chapter). The nature of the pathologic findings dictates the recommended treatment. See BCSC Section 7, Oculofacial Plastic and Orbital Surgery, for further discussion.

• Wallace ZS, Khosroshahi A, Jakobiec FA, et al. IgG4-related systemic disease as a cause of “idiopathic” orbital inflammation, including orbital myositis, and trigeminal nerve involvement. Surv Ophthalmol. 2012;57(1):26–33.

Thyroid eye disease

Thyroid eye disease (TED) (also known as Graves disease, thyroid ophthalmopathy, thyroid-associated orbitopathy, and Basedow disease) is related to thyroid dysfunction and is the most common cause of unilateral or bilateral proptosis (exophthalmos) in adults. The signs and symptoms of TED are related to inflammation of the orbital connective tissue, alterations in the extracellular matrix of the extraocular muscles, inflammation and fibrosis of the extraocular muscles, and adipogenesis. The muscles appear firm and white, and the tendons are usually not involved. Early in the disease, a cellular infiltrate of mononuclear inflammatory cells (eg, lymphocytes, plasma cells, mast cells) and fibroblasts permeates the interstitial tissues of the extraocular muscles, most commonly the inferior and medial rectus muscles (Fig 14-4). The fibroblasts synthesize hyaluronic acid (hyaluronan) and other glycosaminoglycans, resulting in enlargement of the muscles.

Because orbital fibrocytes (considered precursor cells of fibroblasts) are derived from the neural crest and are pluripotent, the enhanced cell signaling that occurs in TED promotes adipocyte differentiation and adipogenesis. These cellular changes lead to the characteristic features of TED.

Figure 14-4 Thyroid eye disease (TED). A, Clinical photograph shows asymmetric proptosis and eyelid retraction, most prominent on the right. B, Computed tomography (CT) scan (axial view) shows fusiform enlargement of the extraocular muscles (asterisks) with sparing of the muscle tendons.C, The muscle bundles of the extraocular muscle are separated by fluid accompanied by an infiltrate of mononuclear inflammatory cells.

(Parts A and B courtesy of Sander Dubovy, MD.)

As a result of the increased bulk within the orbit, the optic nerve may be compromised at the orbital apex, and optic nerve head swelling may result. The late stages of TED are associated with progressive fibrosis that results in restriction of ocular movement and severe eyelid retraction with resultant exposure keratitis.

See BCSC Section 7, Oculofacial Plastic and Orbital Surgery, for more detailed discussion of TED, including pathogenesis, clinical features, and treatment.

• Shan SJ, Douglas RS. The pathophysiology of thyroid eye disease. J Neuroophthalmol. 2014; 34(2):177–185.

Immunoglobulin G4–related disease

Immunoglobulin G4–related disease (IgG4-RD) is an inflammatory condition that has characteristic features of tumefactive lesions in one or more organs; a lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells; variable degrees of fibrosis, often in a storiform pattern (whorls of cells); obliterative phlebitis; and elevated serum IgG4 levels (Fig 14-5). Orbital and ocular adnexal involvement in IgG4-RD, also known as IgG4-related ophthalmic disease, was initially described as bilateral and symmetric, with persistent swelling of the lacrimal glands and infiltration of IgG4 plasma cells. However, IgG4-RD can manifest not only in the lacrimal glands, but also in the extraocular muscles, orbital nerves, sclerae, and eyelids. The proposed criteria for IgG4-related ophthalmic disease include

• imaging studies showing lacrimal gland enlargement or a mass lesion involving the lacrimal gland, trigeminal nerve, or various other ophthalmic tissues

• histologic examination showing lymphoplasmacytic infiltration with associated fibrosis, and with a ratio of IgG4-positive to IgG-positive plasma cells ≥40% or >50 IgG4-positive plasma cells per high-power field (40× objective)

• serum IgG4 level ≥135 mg/dL

The diagnostic criteria for IgG4-RD and its clinical implications continue to evolve.

• Goto H, Takahira M, Azumi A; Japanese Study Group for IgG4-Related Ophthalmic Disease. Diagnostic criteria for IgG4-related ophthalmic disease. Jpn J Ophthalmol. 2015;59(1):1–7.

Excerpted from BCSC 2020-2021 series: Section 4 - Ophthalmic Pathology and Intraocular Tumors. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.