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Man presents with unilateral intermediate uveitis
The patient experienced 10 days of blurred vision in the right eye without associated pain or redness.
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A 55-year-old man with a medical history of hypertension and benign prostatic hypertrophy presented with 10 days of blurred vision in the right eye without associated pain or redness.
Examination
On initial examination, the patient’s best corrected visual acuity was 20/25 in the right eye and 20/20 in the left eye. IOPs were 14 mm Hg and 15 mm Hg in the right and left eyes, respectively. Anterior segment examination was significant for rare anterior chamber cell and pigment with 3+ anterior vitreous cell in the right eye. The view to the posterior pole was hazy due to vitritis, although the retina appeared normal and there was no evidence of snowballs or snowbanks (Figure 1). Examination of the left eye was normal.
Fundus fluorescein angiography demonstrated a normal transit time without evidence of vasculitis or hyperfluorescent lesions. Spectral-domain optical coherence tomography was likewise unremarkable (Figure 1). An extensive review of systems for uveitis was significant only for drinking from a fountain in Italy and a self-limited rash on the patient’s leg while on a cruise.
Figure 1. Color fundus photograph of the right eye demonstrating hazy media (a). Color fundus photograph of the left eye (b). Unremarkable
SD-OCT of the right macula (c).
Images: Branchini L, Barouch F
What is your diagnosis?
Intermediate uveitis
Intermediate uveitis may be infectious, inflammatory or neoplastic. The differential diagnosis includes multiple sclerosis, tuberculosis, sarcoidosis, human T-cell lymphoma virus infection, syphilis, Lyme disease, primary intraocular lymphoma, intraocular tumors with vitreous dissemination, Fuchs’ heterochromic iridocyclitis and idiopathic pars planitis.
Complete blood count, metabolic panel, plasma level of angiotensin-converting enzyme and Quantiferon gold were all within normal limits. Chest X-ray and serologies for Lyme, syphilis and HIV were also negative.
Diagnosis and management
The patient was started on treatment for presumed idiopathic uveitis. Over the following year, he was treated with several trials of topical steroids, transseptal Kenalog (triamcinolone acetonide, Bristol-Myers Squibb) and ultimately methotrexate, with variable but limited success. One year after presentation, the patient developed left leg weakness with a foot drop. MRI of the brain with and without gadolinium demonstrated multifocal areas of homogenous mass-like enhancement of the genu and splenium of the corpus callosum with surrounding edema. Lesions subependymal to the lateral ventricles were also found (Figures 2 and 3). Stereotactic brain biopsy revealed diffuse large B-cell lymphoma. The patient subsequently underwent a diagnostic pars plana vitrectomy for a vitreous biopsy, which confirmed the presence of intraocular large monoclonal B lymphocytes on flow cytometry.
Primary intraocular lymphoma (PIOL), typically a B-cell lymphoma, is a notoriously difficult diagnosis to make. Maintaining a high index of suspicion in patients with persistent uveitis despite treatment with steroids and anti-infectious agents is important. Clinical presentation along with ophthalmic imaging modalities can be suggestive of this disease. Subretinal homogenous semi-opaque lesions can be seen on SD-OCT. Tissue diagnosis may be achieved with vitreous biopsy, anterior chamber paracentesis, lumbar puncture or brain biopsy in cases in which PIOL has progressed to primary central nervous system lymphoma (PCNSL).
Immunosuppressants, including corticosteroids, must be discontinued before any diagnostic procedure to increase the chances of obtaining a representative sample. Even when this is done, there is still a high false negative rate. Flow cytometry and immunohistochemistry can detect monoclonality and are useful in making the diagnosis.
Vitreous levels of the cytokines interleukin-10 and interleukin-6 are helpful diagnostically. IL-10 levels are elevated in samples with malignant B-cells whereas IL-6 is elevated in inflammatory processes. An IL-10:IL-6 ratio of greater than 1 is suggestive of lymphoma.
Discussion
PIOL was first described by Cooper in 1951 as malignant lymphoma of the uveal tract and historically has also been called ocular reticulum cell sarcoma. Because this malignancy is so rare, it is difficult to know the exact incidence. PIOL is considered a subset of PCNSL, which has a quoted incidence of 0.44 per 100,000 person-years (2006 to 2010) as recorded by the Central Brain Tumor Registry of the United States.
Figure 2. Axial MRI with gadolinium T2 weighted demonstrating homogenous mass-like enhancement of the genu and splenium of the corpus callosum (arrows) with surrounding edema.
Figure 3. Coronal MRI with gadolinium T1 weighted demonstrating enhancing lesions subependymal to the lateral ventricles (arrow).
Known as a “masquerade syndrome,” PIOL can present in a number of ways. It often mimics intermediate or posterior uveitis and can rarely present with anterior chamber inflammation and keratic precipitates. Typical findings of inflammatory uveitis such as ocular injection and posterior synechiae are usually absent. Patients tend to have relatively preserved visual acuity. Creamy subretinal or sub-pigment epithelium lesions with orange-yellow infiltrates and overlying “leopard skin” pigmentary changes have also been described. Progression to PCNSL may be detected by MRI. Of patients with PIOL, 56% to 90% develop PCNSL. Conversely, only 15% of patients with PCNSL develop ocular manifestations. Central nervous system (CNS) lesions tend to be homogenous and periventricular and may be either unifocal or multifocal.
A nuanced treatment approach based upon patient presentation is important. Because of the rarity of this condition, there are no double-blinded placebo-controlled clinical trials. For disease localized to the vitreous, intravitreal methotrexate or rituximab has been shown to be efficacious. Some experts advocate intravitreal treatment alone with close follow-up for localized disease.
It is generally accepted that systemic therapy is needed when there is CNS involvement — typically radiation and/or systemic chemotherapy. In an attempt to compare the efficacy of radiotherapy to chemotherapy, Berenbom et al compared the results of 12 patients who received radiation alone, chemotherapy alone or a combination of the two. None of the patients who received radiotherapy had an ocular recurrence at 19 months.
Orbital radiation can be used in conjunction with total brain radiation. Generally speaking, it is not advisable to treat with orbital radiation alone for isolated ocular disease due to the increased risk of radiation-related morbidity if the patient subsequently requires whole brain radiation for CNS involvement.
Conclusion
This was a 55-year-old man with chronic, unilateral, intermediate uveitis that was minimally responsive to treatment with steroids and oral methotrexate. After developing neurologic symptoms, he was found to have intracranial lesions and was diagnosed with PCNSL after undergoing a brain biopsy. He subsequently underwent a diagnostic vitrectomy that was consistent with primary intraocular lymphoma. A PET scan showed uptake in the known CNS lesions without evidence of distant metastasis. Due to the CNS component of the malignancy, a combination of chemotherapy and radiation is currently being pursued. Treatment consists of rituximab vincristine, high-dose methotrexate, procarbazine and dexamethasone along with whole brain (including orbital) radiation.
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For more information:
Lauren Branchini, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; website: www.neec.com. Fina C. Barouch, MD, is affiliated with Tufts Medical Center and Lahey Clinic and can be reached at Lahey Clinic, 1 Essex Center Drive, Peabody, MA 01960; 978-538-4400; Web site: www.lahey.org.
Edited by Gregory D. Lee, MD, and Nora W. Muakkassa, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; website: www.neec.com.