Eyelid Manifestations of Systemic Disease
Catherine Wang, MD · Mark Levine, MD
The eyelid may be a common site for the manifestation of several systemic diseases. Because several structures of the eyelid share a common ectodermal origin with the skin, many diseases may exhibit both dermatologic and ophthalmic pathology at this location.1 A variety of systemic diseases may manifest signs and symptomatology in the eyelids. These diseases are:
Graves disease is an autoimmune inflammatory disorder with an unclear etiology. It has a female predominance and often occurs between the third and fourth decades. There is commonly a familial predisposition to Graves disease. It is often associated with other autoimmune disorders such as pernicious anemia, myasthenia gravis, and diabetes mellitus.2
Pathogenesis involves the formation of autoantibodies that bind to thyroid stimulating hormone (TSH) receptors in thyroid cell membranes and cause the gland to overfunction.2 As a result of hyperactivity of the thyroid gland, Graves disease typically displays three major manifestations. One, two or all three may be present. These include hyperthyroidism with diffuse goiter, ophthalmopathy, and dermathopathy.3 Goiter may occur when the thyroid gland is enlarged diffusely due to lymphoid hyperplasia and infiltration. Thyrotoxicosis can be variable in its presentation. Common signs and symptoms include heat intolerance, restlessness, sweating, anxiety, palpitations, muscle cramps, weight changes especially weight loss, and menstrual irregularities.3 Dermatopathy, referred to as "myxedema," is characterized by the thickening of the dermis due to infiltration with lymphocytes and mucopolysaccharides.3 This occurs in approximately 3% of patients, and typically, it affects the pretibial region.2
Graves ophthalmopathy, also known as thyroid orbitopathy, thyroid eye disease, or thyrotoxic exophthalmos, occurs due to infiltration of T-lymphocytes and macrophages and increased production of glycosaminoglycans. This results in an increased volume of the extraocular muscles, adipose tissues, and orbital connective tissues.4 It may manifest unilaterally or bilaterally. Although Graves ophthalmopathy is usually associated with hyperthyroidism, it may also occur in cases of hypothyroidism, Hashimotos thyroiditis, and euthyroid Graves disease.
One characteristic eyelid finding is lid retraction. This is the most common ophthalmic feature, and it occurs in approximately 75% of Graves patients. Lid retraction is responsible for both functional and cosmetic problems. This lid retraction in primary gaze is referred to as the Dalrymple sign. Lid lag, referred to as the Von Graefe sign, can develop in up to 50% of patients. It is the retarded descent of the lid in downgaze.5 These lid manifestations can lead to exposure keratitis and dry eye symptoms.
Other clinically significant ocular manifestations include proptosis, periorbital swelling, chemosis, optic neuropathy, and restrictive extraocular myopathy, which most commonly affects the inferior and medial recti muscles. The most common ocular symptoms include pain or discomfort, lacrimation, photophobia, blurred or decreased vision, and diplopia secondary to ophthalmoplegia.3,4 Graves disease is the most common cause of unilateral or bilateral proptosis in adults.4
Diagnosis may be made through laboratory evaluation, imaging, or both. Typically, lab testing reveals increased serum T3, T4, thyroid resin uptake, and free thyroxine with undetectable TSH levels due to suppression. In rare cases of pituitary hypofunction, TSH is elevated. TSH receptor antibody levels may be elevated in up to 80% of cases, but is not required for diagnosis.2 Furthermore, antithyroglobulin and antimicrosomal antibodies, and anti-nuclear antibody may be elevated in patients with Graves disease.
Imaging modalities such as ultrasound, computerized tomography, or magnetic resonance imaging may be useful in detecting extraocular muscle involvement and optic nerve compression.
Treatment of systemic disease varies depending on the cause and severity of disease. Adrenergic antagonists, such as propanalol, may be used for symptomatic relief of acute hyperthyroidism, while thioureas may be used for long-term antithyroid therapy. Other options include radioactive iodine for destroying overactive thyroid tissue, and surgical thyroidectomy.3,2, 10
In terms of Graves orbitopathy, most patients require only supportive care such as topical lubrication. In fact, approximately 50% of cases resolve spontaneously.5 However, in cases of severe inflammation, intervention may be required to prevent exposure keratopathy, strabismus, and optic neuropathy. In conjunction with systemic treatment for hyperthyroidism, corticosteroids may be used to reduce edema and cellular infiltration. Orbital radiation therapy may be helpful in severe orbital congestion threatening optic nerve compression, especially when used concomitantly with steroids.3,5
Indications warranting surgical intervention include exposure keratopathy, optic nerve compression, and poor cosmesis. If surgery is required, the proper sequence of surgical procedures performed for Graves disease is orbital decompression, followed by strabismus surgery, and finally, eyelid surgery. Rationale for this sequence is based on the possibility of orbital decompression affecting ocular motility and lid position, while strabismus surgery may also influence eyelid position.10,11 Common surgical procedures for correction of lower lid retraction include inferior rectus resection, mullerectomy, recession of lower lid retractors, and lateral tarsorrhaphy for exposure keratopathy.12 Common surgical procedures for correction of upper lid retraction are mullerectomy alone or levator-Muller muscle recession.
Wegeners granulomatosis is a multisystem inflammatory disorder typically described as a necrotizing granulomatous vasculitis of the upper and lower respiratory tract, small-vessel vasculitis, and glomerulonephritis.6,7,8 Tissues most commonly affected in descending order include:
In fact, 8% to 16% of patients present with ophthalmic disease and up to 77% of total cases may show orbital involvement.2,4
Ocular manifestations may be variable involving the orbit, lacrimal system, periocular tissues, or the anterior and posterior segments of the eye. Ocular involvement in Wegeners mainly results from focal vasculitis of small vessels, thrombosis, hemorrhage and granulomatous inflammation.8
The orbit is typically the site most frequently involved; proptosis is the most common finding occurring in 20% of patients.7,8 Orbital granulomatous disease may present as an inflammatory "pseudotumor" picture with orbital pain, proptosis, edema of the eyelids, ophthalmoplegia, diplopia, and decreased vision secondary to optic nerve compression.6
Other ocular manifestations of Wegeners granulomatosis include scleritis, episcleritis, conjunctivitis, keratitis, nasolacrimal duct obstruction, dry eyes, and less commonly, retinal vasculitis.
Diagnosis may be made based on tissue biopsy from sites including the lung, paranasal sinuses, orbit, and kidney yielding the classic triad of vasculitis, necrosis, and granulomatous inflammation. Lab tests for the detection of cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) show presence in more than 90% of patients with active classic Wegeners granulomatosis and 67% to 86% of limited Wegeners granulomatosis.7
The extent of disease and treatment determine the clinical course of Wegeners granulomatosis. Systemic corticosteroids and cytotoxic agents have proven effective in improving prognosis, despite serious side effects. Oral steroids alone showed little benefit for treatment of severe ocular inflammation, while the addition of cyclophosphamides reduced morbidity and increased survival.8
Sarcoidosis is a systemic, idiopathic, granulomatous inflammatory disease. It most commonly manifests in the pulmonary, lymphatic, renal, neurological, and musculoskeletal systems, as well as in the eye and orbit. It is a progressive disorder that begins typically between 20 to 40 years of age and is characterized by remissions and exacerbations.9
Ophthalmic manifestations may occur in 33% to 55% of patients with sarcoid. Patients may also report mild symptoms consistent with interference of reflex and emotional tearing secondary to lacrimal gland infiltration.9 Eyelid involvement resembles cutaneous sarcoid involvement elsewhere. These lesions consist of firm, brownish-red or purple papules and plaques that may be pruritic. Associated atrophy and hyper- or hypopigmentation of the surrounding epidermis may occur. Miliary sarcoid often presents with small elevated papules with a waxy translucency that have a predilection for the face, eyelids, neck, and shoulders.1 These lesions occur commonly in black patients and resemble syringoma, lichen planus, and trichoepithelioma.1
With regard to the orbit, the lacrimal gland is the most commonly involved orbital tissue.9 Patients with lacrimal gland involvement present with unilateral or bilateral nodular palpebral swelling that is painless.1,9 Less than 1% of patients with ocular sarcoid exhibit an orbital inflammatory syndrome characterized by pain, proptosis, ophthalmoplegia, diplopia, and decreased vision.9
Ocular sarcoidosis may present in a variety of ways including gradual decreasing vision, pain, redness, and photophobia. Anterior uveitis with mutton-fat keratic precipitates, and possibly koeppe's and busacca's iris nodules, are the most frequent ocular manifestations of sarcoid.1 Other common presentations include episcleral, scleral, and conjunctival nodules, band keratopathy, keratoconjunctivitis sicca, cataract, secondary glaucoma, vitritis, chorioretinal granulomas, periphlebitis, and neovascularization.1,9
Several diagnostic tests are available for the diagnosis of sarcoidosis including elevated serum angiotensin-converting enzyme (ACE) and lysozyme levels. ACE, an enzyme synthesized by monocytic cells that have transformed from phagocytic into storage or secretory cells in sarcoidosis, is elevated in 60% to 90% of patients with active sarcoidosis.9 Lysozyme, although less specific, is another enzyme produced by granuloma cells in sarcoidosis. Other diagnostic measures include chest x-ray to examine for hilar adenopathy, gallium scan, which targets areas of active T-cell and macrophage infiltration, and tissue diagnosis showing noncaseating epithelioid cell granulomas histopathologically.9
Although topical and intralesional steroid injections may be useful for treatment of cutaneous lesions, systemic corticosteroids are used for the treatment of systemic sarcoidosis.1
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder that involves a widespread vasculitis. It affects multiple organ systems including the integumentary, cardiac, pulmonary, renal, central nervous system, gastrointestinal, and rheumatic systems. Onset occurs usually between the ages of 20 and 40. White people are more commonly affected than blacks, and approximately 85% of patients are women.3 A genetic predisposition has been recognized, and certain HLA haplotypes such as DR2 and DR3 have been linked to the disorder. As several pharmacologic agents have been implicated as causing a lupus-like syndrome, this possibility must be ruled out before making a diagnosis of SLE.
Systemic features include fever, anorexia, malaise, and weight loss. In addition, cutaneous manifestations are common. Well-defined, erythematous to violaceous elevated scaling patches occur in a "butterfly pattern" over the nasal bridge, malar cheek area and lower eyelids. These areas heal with varying degrees of atrophy, scarring, and hypo- or hyperpigmentation.1 Other cutaneous findings include periungual erythema, nail fold infarcts, alopecia, and Raynauds phenomenon. Multisystem involvement may present with arthritis, pleurisy, pleural effusions, pneumonia, pneumonitis, pericarditis, arrhythmias, abdominal pain, peritonitis, glomerulonephritis, seizures, and psychoses.3
In terms of eyelid manifestations, periorbital cutaneous involvement may result in a blepharitis-like picture, madarosis, and a chronic violaceous periorbital edema with telangiectasias.1 Other ocular manifestations are more common. Typical anterior segment findings include:
Posterior segment findings, secondary to vasculitis, include:
Since several different autoantibodies are produced in SLE, many laboratory findings including antinuclear, antidouble-stranded DNA, anti-Smith, anticardiolipin, and antiphospholipid antibodies are useful in diagnosis. Other laboratory findings such as anemia, proteinuria, hypocomplimentemia, and false-positive serologic testing for syphilis are seen.2
Systemic treatment often requires the use of corticosteroids for control of serious complications. Severe cases resistant to steroid treatment may be treated with immunosuppressive agents such as cyclophosphamide, chlorambucil, and azathioprine. Cutaneous lesions respond well to topical or intralesional steroid therapy. Severe skin involvement may require the use of systemic steroids or antimalarial therapy. Avoidance of sunlight and sunscreen usage is also encouraged.1
Erythema multiforme is a self-limiting cutaneous syndrome caused by a variety of precipitating factors. The most common etiological agents include infectious, such as mycoplasma pneumonia, herpes simplex, and Epstein barr virus infections, and pharmacologic.1 Antibiotics, especially sulfonamides, are most often implicated as the offending agent, followed by seizure medications, nonsteroidal anti-inflammatory drugs, diuretics, analgesics, and various others.10
Although the syndrome is characterized by macular, papular, urticarial, or bullous lesions, it is best known for its target-like lesions that are often found on the palms and ankles.1,10 The bullous condition is referred to as Stevens-Johnson syndrome, which affects cutaneous and mucosal surfaces. Toxic epidermal necrolysis is recognized as a severe form of Stevens-Johnson syndrome, in which extensive epidermal necrosis occurs.
Ocular involvement occurs commonly. During the acute phase of both Stevens-Johnson disease and toxic epidermal necrolysis, swelling, crusting and erythema of the eyelids occur. The conjunctiva may become injected and bullae may form. This is followed by conjunctivitis, or in severe cases, pseudomembranous or membranous conjunctivitis. Inflammation may result in scar tissue in the form of symblepharon or ankyloblepharon. Late complications resulting from cicatricial changes include entropion, trichiasis, lagophthalmos, and severe dry eye syndrome.10
Topical antibiotics and steroids, lubrication, symblepharon lysis, tarsorrhaphy, and bandage soft contact lenses are recommended for ocular complications. Besides general supportive measures and discontinuation of the offending agent, no specific treatment for Stevens-Johnson disease or toxic epidermal necrolysis exists. In fact, recent data suggest that systemic corticosteroid use in appropriate burn intensive care treatment centers offered no improvement in overall survival.10
Neurofibromatosis, also referred to as Von Recklinghausens Disease, is a neurocutaneous phakomatosis that is inherited in an autosomal dominant manner. Alterations in neural crest cells account for disease manifestations systemically. It is characterized by development of neurofibromas within the:
Systemically, the disease may manifest with neural tumors that may develop in the brain, spinal cord, and cranial, peripheral and sympathetic nerves. Skeletal defects also occur. They vary from scoliosis, dysplasia of the sphenoid bone, facial hemiatrophy, and short stature, to mild macrocephaly. Embryonal tumors or neurofibrosarcomas may develop in 5% of patients.9
Cutaneous findings include the characteristic neurofibroma. Neurofibromas are superficial dermal tumors that vary from pea-sized to large pedunculated masses.1 Lesions vary in number and may occur anywhere. Often, they spare the palms, soles, and genitalia. Plexiform neuromas, which are subcutaneous tumors of peripheral nerves composed of diffuse proliferations of Schwann cells within nerve sheaths, also occur. Other common cutaneous manifestations include axillary freckling, pigmented hairy nevi, and café-au-lait spots, which are areas of increased epidermal melanin due to giant melanosomes.3
Neurofibromatosis is the most common phakomatous disorder involving the orbit. Although eyelid changes are uncommon, neurofibromas may affect the eyelids, which can result in pedunculated or plexiform neuromas. Typically, these present at birth or early in life and result in an S-shaped mechanical ptosis of the upper eyelid.1
Orbital involvement may occur as the result of optic nerve gliomas that develop in approximately 15% of patients.4 These may be unilateral or bilateral and have a tendency to extend posteriorly involving the chiasm and hypothalamus. Spheno-orbital encephalocele may also occur due to congenital dysplasia of the sphenoid bone. Patients characteristically present with a pulsating proptosis.
Intraocular manifestations include Lisch nodules, iris hamartomas that develop during the teenage years and typically affect 95% of patients.4 Other findings include ectropion uveae, prominent corneal nerves, congenital glaucoma, choroidal nevi, and retinal astrocytomas. Neurofibromas may involve the conjunctiva, retina, optic nerve, and orbit.
Surgical treatment for intracranial or intraspinal tumors may be necessary if symptoms occur. Otherwise, plastic surgery may be an option for correction of disfiguring lesions. Plexiform neurofibromas of the eyelid should be corrected surgically to prevent amblyopia.
Tumors metastatic to the orbit are uncommon and occur less often than intraocular metastases. In fact, metastatic disease accounts for approximately 1% to 13% of all orbital masses.11 It is uncertain whether the prevalence of orbital metastasis is increasing or if this is actually the result of increased survival of cancer patients, changes in metastatic patterns, or both.12
Metastasis to the orbit differs among adults and children in a variety of manners:
A retrospective study performed by the Wills Eye Hospital revealed that the primary tumor site in adult orbital metastases in 35 cases between 1974 and 1986 was 51% breast, 17% prostate, 6% lung and gastrointestinal tract, 3% kidney, melanoma and choroidal melanoma, and 11% unknown.11
While most patients present with a history of cancer, between 30% to 61% of patients with orbital metastases exhibit ocular clinical findings prior to diagnosis of the primary malignancy.12 Patients present with more than one ocular symptom. The most frequently encountered early signs and symptoms include:
Patients presenting with findings suspicious of metastastic disease should be questioned about past medical history and undergo a complete physical exam that includes a breast examination and chest x-ray at the least.11 Serum carcinoembryonic antigen (CEA) levels may also be valuable in certain cases. Orbital CT is useful for evaluation of extraocular muscle involvement, identification of a mass, and possibly ruling out another etiology for orbital inflammation. After localization by CT, tissue diagnosis may be made via fine needle aspiration biopsy or open biopsy. Histopathology, electron microscopy and immunohistochemistry may be necessary for diagnosis.
Treatment of metastatic tumors of the orbit is typically palliative and may consist of local radiation therapy plus or minus chemotherapy. Surgical excision is not recommended except in cases of small, well-circumscribed or easily accessible tumors, or those causing excessive pain and proptosis.11 Furthermore, some advocate wide excision of orbital lesions in tumors such as carcinoid and renal cell carcinoma, in which survival is longer.
Granuloma annulare (GA) is a benign, chronic, granulomatous inflammatory dermatosis that affects children and young adults. It occurs two times more often in women than men. Etiology remains unclear, but an immune-complex vasculitis has been postulated.1,13 Other causes that have been reported include:
GA has also been found in association with systemic diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus, and sarcoid.15
Patients often present with flesh-colored or violaceous papules, plaques, or nodules arranged in an annular configuration.16,14 Lesions are typically asymptomatic, often lacking pruritus, scaling, and ulceration.1 The rings tend to enlarge over several months to years and eventually resolve spontaneously. Eruptions occur on the extremities, and especially on the dorsal surfaces of the hands, feet, and extensor surfaces. The approximate distribution of GA lesions is:
Although lesions are not commonly found on the face, periorbital involvement may occur.
Several forms of the disease exist. The most common form of GA is the localized form, which manifests as a limited number of asymptomatic papules ranging from 1 mm to 5 mm in diameter. These resolve spontaneously in 50% of patients. This may take as long as 2 years.16 Other forms include the disseminated form that involves hundreds to thousands of small 1-mm to 2-mm papules, and is referred to as generalized GA. Finally, deep dermal or subcutaneous GA presents as larger, superficial or deep skin-colored lesions.13 These may be fixed to underlying bone or soft tissue. Like the other forms, this form has a predilection for the extremities and rarely involves the periorbital area. Rare cases that do manifest with periorbital nodules often involve the upper lid at the superotemporal region near the lateral canthus.14
In terms of diagnosis, tissue biopsy is recommended especially when lesions display a nondistinctive presentation. Histopathology is characterized by focal degeneration of collagen, reactive inflammation, and fibrosis.14 A central zone of degenerating collagen or "necrobiosis" is surrounded by palisading inflammatory cells consisting of histiocytes and fibroblasts. Increased mucin within the necrobiotic area is characteristic of GA.15
Despite the fact that 50% to 75% of cases resolve spontaneously within two years, up to 40% of cases recur at the original site.15,14 Though not all cases require treatment, various treatment methods have been advocated. The most widely accepted form of treatment involves the use of topical or intralesional steroids. Other proposed mechanisms include cryotherapy, surgical excision, laser destruction, radiation therapy, and a number of systemic drugs such as chloroquine, potassium iodide, thyroxine, dapsone, and isotretinoin.13,14
The Melkersson-Rosenthal syndrome (MRS) consists of a triad of symptoms that includes recurrent orofacial swelling, relapsing facial nerve palsy, and a fissured tongue. This is an uncommon disease that lacks racial predilection and displays almost equal gender distribution.17 The etiology is unknown, but autosomal dominance has been shown in certain cases. The disease usually manifests in adolescence or early adulthood, but lacks prodromal symptoms.1
The classic triad is rarely seen in its complete form. Often, monosymptomatic or oligosymptomatic forms occur. In fact, the complete triad of symptoms only occurs in 25% of cases, in which patients typically present with facial nerve palsy.18 However, orofacial edema is the most important and consistent manifestation of MRS, and is the presenting sign in 42% of patients.18 It is described as painless, nonpruritic, firm, non-pitting edema that is often asymmetrical. Swelling may affect the chin, lip, forehead, cheeks, and periorbital tissue. The spectrum of swelling changes ranges from swelling of the lower lip to bilateral facial edema. Swelling often undergoes remissions and exacerbations for months to years, eventually resulting in permanent edema. In addition to the oral manifestations of labial swelling, mucosal swelling, paresthesias, erythema, and abnormal salivation may occur. Swelling may cause cosmetic deformities, as well as difficulties with eating and speech.17,18
Facial palsy is the presenting complaint in 39% of cases, and occurs in approximately 20% to 47% of patients during the course of the disease.18 This recurrent facial paralysis is unilateral, indistinguishable from Bells palsy, and has a sudden onset.18 A minority of patients may also report taste deficits along the anterior two thirds of the tongue.
Lingula plicata, fissured tongue, is the least constant and least common of the triad of symptoms. Incidence is estimated to be one-third to one-half of all patients affected. It is characterized by deep grooves on the dorsal surface of the tongue that tend to radiate from the main trunk that runs anteroposteriorly. Other characteristics may include swelling and diminished taste. Moreover, secondary bacterial or fungal infections may occur.17,18 Extracutaneous manifestations such as hyperhidrosis, hypogeusia, glossodynia, and epiphora may occur. Ophthalmic findings encountered include lagophthalmos, exposure keratitis, retrobulbar optic neuritis, paralysis of the medial rectus, and symptoms of diplopia.17,18 Chronic disease may result in blepharochalasis.
Diagnosis often proves difficult since the classic features typically are not present at the same time. Tissue diagnosis is often required, and most biopsies are obtained from the lip, gingiva, and oral mucosa. Histopathology demonstrates dilated lymphatics and perivascular aggregates of lymphocytes, histiocytes, and plasma cells in early lesions, while noncaseating epitheliod granulomas with Langhans giant cells are typical of advanced stages.17,18
Despite the fact that prognosis for overall survival remains good, complete remission is unlikely. Treatment is mainly aimed at symptomatic relief. While intralesional steroid injections may be beneficial, cold packs, ointments, and prevention of infection are often recommended to the patient. Facial nerve paralysis may rarely be treated with surgical decompression of the facial nerve, and surgical reduction cheiloplasty may be beneficial in relieving lip or eyelid swelling.17,18
Juvenile xanthogranuloma (JXG) is a cutaneous disorder commonly affecting infants and young children. It is characterized by solitary or multiple yellow, brown, or red papules or nodules that consist of benign proliferations of histiocytes.1,19 Lesions typically appear on the head, neck, trunk, and limbs. Systemic JXG involving internal organs is rare.5 However, lesions may be found on the eyelid, most often occurring as single nodules, or in epibulbar tissues and the orbit.1
Other relevant ocular complications include uveal involvement, which may result in spontaneous hyphema and secondary glaucoma.1,19 Since 92% of patients with ocular manifestations of JXG are 2 years of age or younger, these sight-threatening lesions must be diagnosed and treated promptly. Once diagnosis has been determined histopathologically, ophthalmic screening is recommended. Screening is recommended particularly for patients with multiple skin lesions and patients younger than 2 years old.19 Eyelid lesions should be treated surgically to prevent deprivational amblyopia.
Necrobiotic xanthogranuloma is a cutaneous disorder of lymphohistiocytic proliferation that results in inflammatory, necrobiotic, and xanthomatous changes. It is typically seen in association with systemic diseases involving paraproteinemia and plasma proliferative disorders such as multiple myeloma, leukemia, and Hodgkins disease.20
Ophthalmic manifestations may occur in the form of bilateral xanthelasma-like eyelid lesions that may undergo necrosis. Biopsy of these lesions shows palisading granulomatous inflammation with necrobiotic foci and, frequently, xanthoma cells and touton giant cells.20
Treatment relies on identification and management of the underlying systemic disease.