Amyloidosis encompasses a spectrum of disorders characterized by the abnormal deposition of insoluble protein aggregates. Amyloidosis can affect any organ and may be a localized or systemic disease. The disease may be primary, ie, idiopathic, as in
primary systemic amyloidosis, or secondary, as in reactive amyloidosis in a patient with chronic rheumatoid arthritis or tuberculosis. Ophthalmologic involvement in amyloidosis may have important diagnostic and therapeutic ramifications. This review is meant to serve as an overview of the ophthalmological manifestations of amyloidosis with an emphasis on clinical findings.
Historically, physicians categorized amyloidosis based solely on clinical features. Modern classification systems employ biochemical subtyping, utilizing a capital A followed by an abbreviation for the amyloidogenic protein, eg, ATTR for transport protein transthyretin (TTR) amyloidosis. One useful classification scheme integrates the biochemical subtyping, hereditary pattern and extent of disease, resulting in three broad categories: local amyloidosis, hereditary systemic amyloidosis and acquired systemic amyloidosis. As an example, systemic AL amyloidosis, previously known as "primary systemic amyloidosis," is classified as a subtype of acquired systemic amyloidosis.
Cutaneous amyloidosis can be localized or secondary to systemic disease. Localized amyloid deposition can be found microscopically in the presence of a variety of cutaneous tumors, actinic keratosis and seborrheic dermatosis. This type of amyloidosis is
nearly always subclinical and an incidental pathological finding.
In acquired systemic amyloidosis, most commonly systemic AL amyloidosis and myeloma-associated amyloidosis, cutaneous manifestations are frequently present and may have diagnostic utility. Spontaneous hemorrhagic purpura of the eyelids, considered virtually pathognomonic of systemic amyloidosis, occurs in up to 15% of patients with acquired disease. Waxy eyelid deposits and periocular cutaneous nodules may also be encountered.
Orbital amyloidosis, although microscopically present in most patients with systemic amyloidosis, rarely produces clinically evident disease. Either local or systemic amyloidosis may infiltrate any orbital structure, most commonly the orbital fat, extraocular muscles and lacrimal gland. Associated signs and symptoms include ptosis, keratoconjunctivitis sicca, proptosis, ocular motility disturbances, palpable mass lesions and pupillary abnormalities. Pain uncommonly accompanies orbital amyloidosis, and its presence should prompt the examiner to consider alternative diagnoses. The radiographic appearance of orbital amyloidosis is generally nonspecific, although the presence of scattered intralesional calcifications may be suggestive.
The clinical appearance of corneal amyloidosis varies with the etiology but commonly features grayish subepithelial or intrastromal deposits in a filamentous or nodular pattern. Symptoms vary with the size, number and location of deposits. Patients range from asymptomatic to severely disabled secondary to corneal opacification and painful recurrent erosions.
|Slit lamp retroillumination demonstrating fine, glassy stromal opacities in a patient with Type I Lattice Corneal Dystrophy.
Image: submitted by Dr. Goshe
The most common type of corneal amyloidosis is lattice corneal dystrophy (LCD), a genetically heterogeneous group of conditions with at least four subtypes. Type I presents early in life with fine, glassy, centrally located branching lines in the stroma
producing visual symptoms and recurrent erosions. LCD type II (Meretoja syndrome) is a systemic disease presenting in young adulthood with cutaneous, nervous and corneal manifestations. Frequent recurrent erosions and impaired corneal sensation are often
present by age 40 years. Types III and IV are mildly symptomatic and present later in life. Avellino, or granular-lattice, dystrophy demonstrates features of both granular corneal dystrophy and LCD. The granular deposits typically appear first, and severe vision loss is rare.
Gelatinous droplike dystrophy presents in the first decade of life with vision loss and photophobia due to progressive subepithelial amyloid deposition. Although the deposits may be initially mistaken for band keratopathy, progressive accumulation over time produces larger nodules and the characteristic "mulberry-like" appearance. Polymorphic amyloid degeneration is an idiopathic bilateral condition characterized by amyloid deposition in the central cornea with a punctate or filamentous pattern. Patients are typically middle-aged at the time of diagnosis and minimally symptomatic.
Corneal amyloid deposition may be present incidentally in a variety of other corneal diseases, including keratoconus, trauma, retrolental fibroplasia, infectious and immune-related keratitis, and chronic bullous keratopathy. The appearance of these deposits is nonspecific, and the amyloid is generally only identified during histopathological examination. The nature and significance of these deposits remain unclear.
The classic description of conjunctival amyloidosis is that of middle-aged adult with a painless, yellow-pink, rubbery lesion that may be diffuse or well-circumscribed. Ptosis, a visible or palpable mass, and recurrent subconjunctival hemorrhage are commonly reported symptoms. Any area of the conjunctiva may be affected, including the caruncle and semilunar fold. Adjacent cutaneous or orbital involvement occasionally is present and may be detected clinically or radiographically. Conjunctival amyloidosis, although once considered a benign, localized disease without systemic implications, is now known to be associated with systemic amyloidosis in up to 6% of patients.
In patients with hereditary systemic amyloidosis, iris and anterior chamber involvement may present in association with vitreoretinal involvement. A "scalloped" configuration of the iris margin may signify amyloid deposition in the iris stroma or, alternatively, disruption of the parasympathetic innervation of the iris sphincter. Anterior chamber involvement appears as whitish, flocculent debris in the aqueous, on the lens capsule or on the iris surface. Secondary glaucoma often ensues and clinically appears similar to pseudoexfoliation syndrome.
Although direct involvement of the lens fibers in patients with amyloidosis has not been described, amyloid may deposit on the lens capsule with resultant clinical manifestations. Pseudopodia lentis, punctate dots on the posterior capsule resembling ameboid foot processes, are considered pathognomonic of vitreoretinal amyloidosis in patients with heredofamilial disease.
Despite the high prevalence of choroidal amyloid deposition microscopically in patients with systemic AL amyloidosis and heredofamilial amyloidosis, clinical manifestations are essentially nonexistent, owing to the diffuse nature of the deposition.
|Fundus photograph demonstrating vitreous veils in a patient with hereditary systemic amyloidosis.
Image: submitted by Dr. Goshe
Vitreoretinal amyloidosis manifests as "lacy," "cobweb-like," "sheet-like" or "stringy" veils of gray or yellowish-white material in the vitreous. Deposits may arise perivascularly, although the retinal vessels usually appear normal clinically and angiographically. Bilateral disease is typical, but unilateral or highly asymmetric presentations exist. Symptoms include floaters, blurry vision or glare, or patients may be asymptomatic. Displacement of a vitreous veil into the visual axis may manifest an acute decrease in visual acuity. Vitreoretinal amyloidosis frequently arises in the setting of neuropathic heredofamilial systemic disease and is often accompanied by multiple organ involvement. Mutations in TTR, also known as prealbumin, are responsible for the majority of cases.
Congo red staining demonstrating apple-green birefringence when viewed through crossed polarimetric filters remains the gold standard for establishing the diagnosis of amyloidosis. In patients with orbital or conjunctival disease, tissue biopsy may be necessary to exclude lymphoproliferative disorders. When orbital or conjunctival amyloidosis is diagnosed, a medical evaluation is always warranted to exclude systemic disease.
Patients with corneal amyloidosis are often diagnosed presumptively based on clinical features and family history, although histopathologic confirmation can be attained at the time of surgical intervention. Genetic testing, although not yet widely used for diagnostic purposes, may be used to confirm the presence of a pathologic mutation in a research setting or to verify the diagnosis in questionable cases.
When intraocular amyloidosis is present, the disorder is frequently systemic and often associated with a positive family history. In these patients, other organs are usually sampled to confirm or exclude the diagnosis while minimizing morbidity. Subcutaneous fat or bone marrow biopsy is adequately sensitive and specific and relatively well-tolerated by most patients. Coordination with an internist well-versed in evaluating patients with suspected amyloidosis is advisable.
In asymptomatic or mildly symptomatic patients with localized conjunctival or orbital amyloidosis, observation may be indicated, provided an adequate systemic evaluation has been completed. Surgical excision or debulking remains the treatment of choice for most symptomatic cases, including ocular motility disturbances, compressive optic neuropathy, and unacceptable cosmetic appearance. Long-term success after surgery is variable. In one retrospective series, five of 11 patients with conjunctival or orbital amyloidosis showed significant progression after surgical debulking. Radiotherapy, either alone in or conjunction with surgical debulking, may be useful in patients with extensive infiltrative disease or patients not amenable to surgery due to a medical contraindication.
Surgical treatment for visually significant corneal amyloidosis typically employs penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK). Although technically more challenging and limited to patients with preserved endothelial function, DALK offers distinct advantages over traditional PK with regard to intraoperative safety and postoperative risk of rejection. Care must be taken bare Descemet's membrane completely during DALK, as late recurrence may be attributable to incomplete excision of abnormal stroma. Phototherapeutic keratectomy has also been advocated by some ophthalmologists, although problems with incomplete excision, irregular astigmatism, and early recurrence may affect visual outcomes.
In patients with visually significant vitreal amyloidosis, vitrectomy has been used with satisfactory results. Recurrence is common in the presence of systemic disease. Glaucoma may develop concurrently with vitreal amyloidosis or follow an independent time course. Filtering surgery may be indicated at the time of vitrectomy or at any time postoperatively. Direct seeding of the trabecular meshwork during surgery has been theorized as a possible mechanism based on histopathologic examination of one such patient.
Therapy for systemic amyloidosis is typically managed by a rheumatologist or a subspecialist well-versed in the use of chemotherapeutic agents. Conventional treatment includes prednisone and melphalan, a DNA alkylating agent. Other agents include dexamethasone, thalidomide, etanercept, glycosaminoglycan analogues, and various types of targeted immunotherapy. Autologous stem cell transplantation, an increasingly popular procedure in some institutions, may be curative in some patients. This treatment carries a significant mortality risk and is contraindicated in patients with advanced hepatic, renal or cardiac failure. Reactive secondary amyloidosis, deposition of amyloid in the setting of chronic inflammatory disease, uncommonly has significant ocular sequelae, and treatment is geared toward the underlying disease.
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- Jeff Goshe, MD, can be reached at 1400 8th Ave., Fort Worth, TX 76104; 216-444-2020.
- Disclosure: No products or companies are mentioned that would require financial disclosure.