Sarcoidosis

Sarcoidosis is a systemic inflammatory disease characterized by the development of non-caseating epithelioid cell granulomas in tissues and organs throughout the body, it may take an acute or chronic course and is often a benign self-limited disorder. Its clinical manifestations are protean and depend upon the specific site(s) of inflammation in any given patient. Intrathoracic involvement occurs in close to 90 per cent of cases, with granulomas in the lungs and/or intrathoracic lymphoid tissue. Ocular involvement occurs in about 25 per cent of cases and produces some of the most serious complications of this disorder.

Although its aetiology is unknown, sarcoidosis is associated with a number of immunologic abnormalities. There is a depression of the cell-mediated immune system, manifested by a decreased total number of circulating T-lymphocytes and an impaired responsiveness of T-cells to antigenic stimulation. An increased number of activated T-cells has also been found in sarcoid patients. Abnormalities of the humoral immune system include a polyclonal increase in circulating immunoglobulins and the presence of a variety of autoantibodies.

THERAPY

Ocular:    Most of the ophthalmologic complications of sarcoidosis are secondary to inflammatory involvement of ocular or periocular structures and respond quite well to steroid therapy. Topical steroids may suffice in the treatment of anterior uveitis. While awake, 1% prednisolone eyedrops are used every 1 to 2 hours, with gradual tapering of the dose as the inflammation subsides. This must be combined with mydriatic/cycloplegic drops to avoid development of posterior synechiae with a small, bound-down pupil. Long-acting drugs, such as 1 per cent atropine twice daily or 2 to 5 per cent homatropine 4 times daily, are preferred in acute or severe uveitis, while shorter acting mydriatics (1% tropicamide) can be used once daily to keep the pupil moving in patients with low-grade, chronic inflammatory disease. A combination of mydriatic agents, including 2.5 or 10 per cent phenylephrine, may be used in an attempt to break preexistent posterior synechiae.

When anterior segment inflammation is very severe or does not respond quickly to topical medication, this treatment should be supplemented by anterior subtenon steroid injection; 40 mg of triamcinolone, 40 mg of methylprednisolone, or 24 mg of dexamethasone may be used. Triamcinolone has the greatest anti-inflammatory activity, is well absorbed, produces little discomfort when injected, and lasts 2 to 3 weeks. The periocular injection may be repeated in 3 to 4 weeks, if needed.

Glaucoma may develop as a result of the underlying disease or may occur as a response to the topical steroid therapy. If the patient is a steroid responder, fluorometholone drops may produce a sufficient anti-inflammatory response without as much pressure-elevating effect as topical prednisolone. Regardless of its aetiology, the glaucoma may be treated with topical 0.25 or 0.5 per cent timolol every 12 hours and/or carbonic anhydrase inhibitors, such as 250 mg of acetazolamide 4 times daily or long-acting 500 mg Sequels 3 to 4 times a day.

Systemic:    Systemic steroid therapy is indicated for control of posterior segment inflammation, orbital disease, the neuro-ophthalmologic complications of sarcoidosis, or anterior segment inflammatory disease not responsive to topical or periocular steroids. Treatment should begin with 60 to 80 mg of prednisone daily (or equivalent doses of prednisolone or dexamethasone). The drugs may be given as a single daily dose before breakfast or in divided doses 4 times daily. The dosage should be slowly tapered as the inflammation subsides. Alternate-day therapy with twice the usual daily dose may avoid some of the complications of prolonged systemic steroid therapy. It may be useful in patients requiring long-term treatment for chronic inflammatory disease but should not be employed in the initial stages of treatment when rapid control of significant inflammation is desired.

There are no other drugs which can approach the effectiveness of systemic steroids in the treatment of sarcoidosis. In patients requiring treatment and in whom strong contraindications to the use of systemic steroids are present, drugs such as chlorambucil, azathioprine, or methotrexate may be of value. The drugs are given orally in daily doses. They should be considered only under unusual circumstances and given in consultation with physicians thoroughly familiar with their use. A dosage of 100 mg of oxyphenbutazone 4 times daily has been reported to be effective in the treatment of some patients with systemic sarcoidosis.

Surgical:    Since the initial ocular complications of sarcoidosis are inflammatory in nature, surgery plays little role in their management. However, surgery may be required in the management of late complications, such as cataract formation which occurs secondary to the chronic uveitis and/or steroid therapy. Surgical or laser iridectomy may be needed to relieve pupillary block with iris bombs if the synechiae cannot be broken with mydriatic therapy. Filtering surgery is a last resort in uncontrolled glaucoma secondary to chronic angle closure with peripheral anterior synechiae, though the inflammatory nature of the underlying disease decreases the chance of a successful outcome.

Argon laser photocoagulation is of value in treating the retinal neovascularization seen in sarcoid patients. Focal treatment of the neovascular fronds with 50-micron spots at 0.1 second produces closure and regression of the vessels. Disc neovascularization, without extensive areas of peripheral retinal vascular nonperfusion, may regress promptly with systemic steroid therapy. A 4- to 6-week trial of systemic steroids is appropriate before attempting laser photocoagulation.

Ocular or Periocular Manifestations:

PRECAUTIONS

The major complications of the treatment of sarcoidosis are related to the adverse effects of steroid therapy. Systemic steroids produce a host of potentially serious side effects and should be used in consultation with the patient's internist. Salt and water retention may cause problems in patients with cardiac disease or hypertension. Potential aggravation or unmasking of diabetes mellitus, peptic ulcer, gastritis, esophagitis, or chronic infections (especially tuberculosis) requires particular attention. Other serious side effects include steroid-induced myopathy, osteoporosis with vertebral collapse, psychiatric problems, aseptic necrosis of the hip and adrenal insufficiency secondary to rapid withdrawal of the drugs after prolonged treatment. Ocular complications of both systemic and topical therapy include the development of posterior subcapsular cataracts and elevated intraocular pressure.

Sarcoid inflammatory disease tends to be recurrent, especially as therapy is decreased or withdrawn. Both the patient and the treating physician must be aware of this, and careful follow-up evaluations are essential. Synechiae and their complications may develop fairly rapidly; if significant inflammation is present, weak mydriatics, such as tropicamide, are not strong enough to prevent their development or to break them once they occur. Patients should be encouraged to seek attention at the first sign of a change in their ocular status. At the same time, the physician must not "overtreat" the disease. Many uveitis patients develop a chronic "breakdown" in their bloodocular barrier, with mild flare and an occasional cell in the anterior chamber. Distinguishing this situation from a chronic, active, on-going inflammatory process may be difficult. The absence of new synechiae, keratic precipitates, and increasing anterior chamber reaction allows the ophthalmologist to observe the patient without reinstituting or increasing the therapy.

Every patient with anterior segment sarcoidosis should be carefully evaluated for posterior segment disease. Care must be taken to avoid a situation in which topical therapy is producing a satisfactory regression of anterior uveitis, while leaving a serious, progressive, posterior inflammatory process untouched. Although most patients have bilateral ocular disease, the extent of involvement and degree of inflammation may be quite asymmetric. Both eyes must be carefully evaluated.

COMMENTS

The ocular complications of sarcoidosis are usually part of a generalised disorder, and a coordination of effort between the ophthalmologist and other physicians caring for the patient is essential. Almost all patients with ocular sarcoidosis have evidence of active disease elsewhere in the body. Although there has been widespread debate in the medical literature as to when sarcoidosis should be treated, the presence of ocular inflammatory disease is almost universally accepted as an absolute indication for initiating therapy.

The diagnosis of sarcoidosis is made with greatest confidence by histopathologic demonstration of noncaseating epithelioid granulomas in affected tissues. Conjunctival biopsy may reveal typical granulomas, but the incidence of positive biopsies is low unless a granulomatous lesion is seen clinically. Other important diagnostic aids include typical findings on chest x-rays, elevated levels of serum angiotensin-converting enzyme, and positive gallium uptake scans. While not absolutely diagnostic, a positive scan in the presence of elevated angiotensin-converting enzyme levels is very strongly suggestive of the presence of sarcoidosis. While anterior uveitis is the most common clinically observed manifestation of ocular sarcoidosis, conjunctival biopsy studies and lacrimal gland gallium uptake studies suggest that asymptomatic lacrimal gland and conjunctival granulomas are actually the most common forms of ocular involvement. Ocular changes are more likely to occur in patients with sarcoidosis of the skin, peripheral lymphadenopathy, hypercalcemia, neurologic involvement, parotid enlargement, and joint disease. Band keratopathy is strongly associated with an underlying hypercalcemia. Other reported associations include posterior segment inflammation (especially optic nerve involvement) with central nervous system sarcoidosis, and upper respiratory involvement with sarcoidosis of the lacrimal sac.

There are, within the broader clinical spectrum of sarcoid disease, several widely recognized syndromes having ocular components. These include Heerfordt's syndrome (uveitis, parotid enlargement, a chronic febrile course, and cranial nerve palsies-especially VII) and Lofgren's syndrome (erythema nodosum, bilateral hilar adenopathy, acute iritis, and parotitis). Lofgren's syndrome is generally considered to have a relatively benign, self-limiting course. Another sarcoid "syndrome" includes chronic uveitis, cutaneous sarcoidosis, bone cysts, and pulmonary fibrosis and is considered a more persistent and troublesome clinical complex.

Treatment of ocular sarcoidosis requires both diligence and patience. Therapy in this condition is seldom a quick, "one-shot" proposition. The patient's clinical response is the ultimate determinant in making decisions as to the type, route, and duration of therapy. Recurrences may develop after long periods of quiescence, and these patients must be followed indefinitely.

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