Woman presents with decreased vision, panuveitis and pulmonary symptoms
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A 54-year-old woman presented urgently to the comprehensive ophthalmology service for bilateral discharge for 4 months, intermittent floaters/flashes in the right eye for 6 months and gradually decreasing right eye vision for years.
She had been seen by an optometrist who recommended frequent use of artificial tears, with resulting improvement in her discharge. The patient noted that in the past she had had multiple self-limited episodes of extreme blurry vision and that she had many pairs of glasses over the years but none of them had significantly improved her vision. She denied any history of amblyopia and felt that her vision in the right eye was previously normal. She had occasional episodes of pain in the right eye greater than the left eye.
Source: Angell Shi, MD, and Lana Rifkin, MD
Her medical history included hypertension, latent tuberculosis that had been treated with a full course of rifampin, gastroesophageal reflux disease, vitamin D deficiency, liver hemangioma, gallstones, and a thyroid nodule that was biopsied and found to be a benign follicular nodule. She had no other surgical history. She denied any smoking, alcohol or drug use. She had no allergies and was on losartan.
A review of systems was completed and corroborated with previous medical records. She reported breathing problems and dyspnea with exertion, specifically becoming short of breath with stairs. She noted that she had been evaluated in the past for emphysema but did not have this diagnosis. A calcified mediastinal lymph node was noted on a CT scan 9 years ago. She also endorsed bilateral knee pain and morning stiffness in her hands and fingers. She reported dizziness in the morning but denied any headaches or paresthesias. She had no gastrointestinal issues, history of unusual rashes, or personal or family history of any autoimmune diseases. She denied any tick bites, recent travel or illnesses, or trauma. She had been born in China and immigrated to the U.S. about 25 years ago.
Review of the patient’s relevant laboratory results that had been completed in the past showed a positive ANA with highly elevated titer (1:2560 in a homogenous pattern).
Examination
Best corrected visual acuity was 20/30 in the right eye and 20/25 in the left eye. Pupils were equal, round and briskly reactive to light bilaterally with no relative afferent pupillary defect. Extraocular motility, visual fields to confrontation and IOP were normal.
Slit lamp exam demonstrated findings consistent with dry eyes (mild meibomian gland dysfunction, 3+ diffuse patchy punctate epithelial erosions and decreased tear breakup time) as well as trace injection. A subtle conjunctival lesion in the inferior fornix of the right eye was noted. The anterior chambers were deep bilaterally with 2+ cell and trace flare. She had early cortical cataracts in both eyes. There were no keratic precipitates, and the irides appeared normal without nodules. There were no anterior or posterior synechiae. Posteriorly, she had vitreous syneresis with several snowballs inferiorly, which were more prominent in the right eye than the left. She had 1+ vitreous cell and trace vitreous haze in both eyes. Optic nerves were normal with a cup-to-disc ratio of 0.4 and no disc edema. There was macular edema of the right eye, and the left macula appeared normal. Vessels were normal with no evidence of vasculitis. The retinal periphery of the right eye demonstrated inferior scattered punctate hypopigmented chorioretinal spots and a single intraretinal hemorrhage superiorly (Figure 1a). There were nasal retinal pigment epithelial changes in both eyes.
OCT (Figure 2) and fluorescein angiography (Figure 3) showed the presence of macular edema in the right eye. There was no other evidence of disc or vessel leakage in either eye.
What is your diagnosis?
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Bilateral panuveitis
This patient’s symptoms and findings of bilateral panuveitis (particularly the presence of snowballs and chorioretinal lesions) in the setting of known pulmonary disease are consistent with possible ocular sarcoidosis. The differential diagnoses for other types of panuveitides include syphilis, tuberculosis, Vogt-Koyanagi-Harada syndrome (VKH), Behçet’s disease, toxoplasmosis and toxocariasis. However, the clinical presentation and characteristic retinal findings may help differentiate these (for example, the distinct chorioretinal scarring typically present in toxoplasmosis). Several of these diagnoses also present with specific systemic findings not present in this patient. VKH may present with neurologic symptoms (neck stiffness, tinnitus), skin findings and choroidal depigmentation in the chronic stage. Behçet’s disease typically presents with oral and genital ulcers, an obliterative vasculitis and skin lesions. In the absence of these features, these diagnoses are less likely.
Sarcoidosis is a granulomatous systemic inflammatory disease that commonly affects the eyes, skin, lungs and lymph nodes. The prevalence of systemic sarcoidosis in the United States has been reported around 49.8 per 100,000 white people and 141.4 per 100,000 Black people. Ocular involvement in the disease is variable but may be the first manifestation, ranging from 13% to 79% in various studies. Ocular manifestations most commonly present as uveitis and conjunctival nodules. The age distribution is bimodal, with peaks at 20 to 30 years and 50 to 60 years.
The International Workshop on Ocular Sarcoidosis established criteria for diagnosis, including clinical signs and systemic investigations (eg, laboratory tests and imaging). The most recently revised criteria in 2017 include the following seven intraocular signs: mutton-fat keratic precipitates, iris nodules at pupillary margin (Koeppe) or in stroma (Busacca) or both; trabecular meshwork nodules, tent-shaped peripheral anterior synechiae or both; snowballs or “string of pearls” vitreous opacities; multiple chorioretinal peripheral lesions; nodular or segmental periphlebitis, macroaneurysm or both; optic disc nodule(s) or granuloma(s), solitary choroidal nodule or both; and bilaterality. Systemic investigations in suspected ocular sarcoidosis include bilateral hilar lymphadenopathy; negative tuberculin test or interferon-gamma release assays; elevated serum ACE; elevated serum lysozyme; elevated CD4/CD8 ratio greater than 3.5 in bronchoalveolar lavage fluid; abnormal accumulation of gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging; lymphopenia; and parenchymal lung changes consistent with sarcoidosis.
The diagnosis of ocular sarcoidosis can be classified as definite, presumed or probable. In definite ocular sarcoidosis, there is a positive biopsy with compatible uveitis. In presumed ocular sarcoidosis, the diagnosis is not supported by biopsy, but bilateral hilar lymphadenopathy is present with two intraocular signs. In probable ocular sarcoidosis, the diagnosis is not supported by biopsy and bilateral hilar lymphadenopathy is absent, but three intraocular signs and two systemic investigations are present. Importantly, other causes of granulomatous uveitis, such as tuberculosis and syphilis, must be ruled out before a diagnosis of ocular sarcoidosis can be made.
Workup and management
Serum ACE levels are a well-established biomarker for granulomatous inflammation and are frequently elevated in patients with sarcoidosis. Up to 80% of patients with sarcoidosis have elevated serum ACE levels, with a sensitivity of 22% to 86% and a specificity of 54% to 95%. Lysozyme levels may also be elevated in sarcoidosis, although typically more so at the onset of disease. Serum soluble interleukin-2 receptor (IL-2R) has recently been shown to have high sensitivity (88%) and specificity (85%) for sarcoidosis and may be superior to ACE in establishing the diagnosis. A number of other serum and imaging biomarkers are the subject of ongoing research. Serum testing for tuberculosis and syphilis may also be indicated to rule out these diagnoses.
Chest imaging (X-ray and/or CT) are highly recommended for screening given the high likelihood of pulmonary involvement. Less frequently, whole-body FDG-PET imaging can be performed, which can help identify areas of active inflammation and potential biopsy sites.
The standard initial treatment of sarcoidosis is steroids. Topical, periocular/intraocular and oral steroids have utility in treating inflammation, with topical treatment usually being first line. Periocular injections of steroids are frequently given for patients who do not respond to topical treatment or who have posterior segment involvement; intravitreal injections or steroid implants are another option. Topical cycloplegics can be used to reduce ciliary spasm and pain from inflammation and to prevent the development of posterior synechiae. Systemic steroid treatment is useful for patients with chronic bilateral disease and/or in those who have systemic involvement, particularly neurosarcoidosis. Steroid-sparing immunosuppressives such as methotrexate and mycophenolate mofetil are used for long-term treatment and for those with disease refractory to steroids. Cyclosporine and azathioprine are also occasionally used, and more novel biologic agents such as TNF-alpha inhibitors are becoming increasingly popular.
Discussion
Ocular sarcoidosis may present with a variety of intraocular and extraocular findings, and the diagnostic criteria provided by the International Workshop on Ocular Sarcoidosis are not an exclusive list of ocular signs. Patients may have conjunctival nodules, acute follicular conjunctivitis or chronic cicatricial conjunctivitis; scleritis and corneal involvement are rare. Anterior uveitis is common and, as discussed above, typically presents with granulomatous keratic precipitates, iris nodules, and anterior and/or posterior synechiae. In the posterior segment, characteristic findings include vitreous opacities, snowballs and snowbanks (accumulation of white exudates over the pars plana and ora). Periphlebitis or perivascular sheathing are common and may be described as “candle wax drippings” due to the appearance of the perivascular exudates. Choroidal granulomas, chorioretinal lesions, and optic disc nodules or granulomas may be seen.
Neuro-ophthalmic findings (neurosarcoidosis) most commonly present as optic or facial nerve involvement; granulomatous inflammation leading to infiltration or compression of the optic nerve and optic nerve sheath can cause optic disc edema, neuritis and perineuritis. Papilledema can occur from increased intracranial pressure, and encephalopathy, peripheral neuropathy and other neurologic symptoms can also occur. In the adnexae and orbit, lacrimal gland inflammation can occur and produce features of dry eye. Granulomatous inflammation and lesions of the eyelid, extraocular muscles and orbital fat can be present and potentially cause ptosis, proptosis, pain and eyelid edema. As with other types of uveitis, cataract formation, glaucoma and macular edema may occur as sequelae.
Clinical course continued
Our patient’s ACE was elevated at 120 U/L (normal range, 9 to 67). Lysozyme and IL-2R levels were normal. A chest X-ray revealed diffuse bilateral pulmonary nodules, with innumerable bilateral spiculated pulmonary nodules, predominantly in the apices and in a bronchovascular distribution, noted on follow-up CT scan. Numerous enlarged mediastinal lymph nodes were also present. She was evaluated by a pulmonologist and proceeded with endobronchial ultrasound bronchoscopy and transbronchial biopsy. Pathology results were negative for acid-fast bacilli and demonstrated non-necrotizing granulomatous inflammation with positive immunohistochemistry for CD68 (highlighting histiocytes), confirming the diagnosis of sarcoidosis.
Summary
Sarcoidosis is a systemic condition with frequent ocular involvement; it may present with a wide variety of ocular findings and should be on the differential for any patient with uveitis. Ocular sarcoidosis can occur in any anatomic location of the eye, and it may be chronic with an insidious presentation. Clinical suspicion should prompt further workup, including laboratory testing and chest imaging, particularly in the setting of any respiratory symptoms. Tissue biopsy is the gold standard for confirming a definite diagnosis, but even without a positive biopsy, the diagnosis may still be presumed or probable. Given its vision- and potentially life-threatening complications, the appropriate diagnosis and treatment of ocular and systemic sarcoidosis are essential for practicing ophthalmologists.
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- For more information:
- Angell Shi, MD, and Lana Rifkin, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Yi Ling Dai, MD, and Teresa P. Horan, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.