Man presents with 2-month history of declining vision
Exam findings include vitritis, white retinal infiltrates and inferior retinal detachment.
A 74-year-old man was referred to the retina service at Lahey Hospital and Medical Center by an outside ophthalmologist with progressive decreased vision in the left eye for 2 months. Cataract surgery was performed 2 days before presentation.
The patient was compliant with post-cataract surgery medications, consisting of Ilevro (nepafenac ophthalmic suspension 0.3%, Alcon), Durezol (difluprednate ophthalmic emulsion 0.05%, Alcon) and Vigamox (moxifloxacin hydrochloride ophthalmic solution 0.5%, Alcon). He denied any eye pain, flashes, floaters, discharge, redness or eye trauma.
The patient had a history of primary central nervous system (CNS) lymphoma diagnosed 19 months earlier, treated with high-dose methotrexate, rituximab, vincristine and whole-brain radiation, with a brain MRI 5 months before presentation showing no evidence of recurrence.
Best corrected visual acuity was 20/20 in the right eye and hand motion in the left. The pupil was briskly reactive to light in the right but sluggish in the left with an afferent pupillary defect. IOP was 16 mm Hg in the right eye and 10 mm Hg in the left. Extraocular muscle movements were intact. The patient had a full confrontational visual field on the right eye and extinguished field on the left.
Anterior segment exam revealed a moderate nuclear sclerotic cataract with cortical changes in the right eye. On the left, there was an inferior subconjunctival hemorrhage, temporal corneal suture with an otherwise clear cornea, trace anterior chamber cell and flare, a posterior chamber IOL well-centered in the bag, and 3+ anterior vitreous cell. Posterior segment exam was unremarkable in the right eye, but exam in the left eye revealed dense vitritis and white choroidal infiltrates throughout the posterior pole and macula, with central subretinal fluid and cystoid macular edema (Figure 1a). The exam was also significant for a peripheral inferior serous retinal detachment.
What is your diagnosis?
The differential diagnosis for this patient with subacute unilateral vision loss, vitritis, white retinal infiltrates and retinal detachment includes infectious, inflammatory or neoplastic causes.
Infectious causes to consider are syphilis, tuberculosis, toxoplasmosis, viral retinitis and endophthalmitis. This patient was at increased risk of infection in the postoperative period, and cataract alone could have accounted for the 2 months of pre-existing worsening visual symptoms. Syphilis, tuberculosis, Lyme disease and toxoplasmosis have wide varieties of presentations, including patchy retinal infiltrates and vitritis, and serologic testing aids in making the diagnosis. Acute retinal necrosis would typically progress more rapidly.
Neoplastic causes include primary vitreoretinal lymphoma (PVRL), B- or T-cell lymphoma, HTLV-1 lymphoma, Hodgkin’s disease, Richter’s syndrome, uveal lymphoid proliferations, amelanotic melanoma and metastasis.
Median age of onset of PVRL is in the mid-50s, typically presenting with decreased visual acuity and floaters, associated with vitritis, elevated creamy yellow retinal lesions and sub-retinal pigment epithelium infiltrates. B-cell lymphoma can additionally present with retinal vasculitis, necrotizing retinitis, focal uveal masses and anterior uveitis, typically in patients with a known history of systemic lymphoma. HTLV-1 lymphoma, caused by the retrovirus endemic in southwest Japan, Caribbean islands and central Africa, is generally associated with subretinal infiltrates, as well as retinal vasculitis, cotton-wool spots, retinal hemorrhages, iris nodules and CME in patients with adult T-cell leukemia or lymphoma. Hodgkin’s disease and Reiter’s syndrome rarely have intraocular involvement in patients with known pre-existing systemic disease. Uveal lymphoid proliferations are evident as multifocal creamy choroidal lesions, anterior uveitis, hypopyon, serous retinal detachment, ocular hypertension and epibulbar mass, and may be associated with systemic lymphoma. Retinal detachment and associated vitritis can obscure an underlying malignant melanoma.
Posterior uveitis with multiple chorioretinal lesions may be from multifocal choroiditis, sarcoidosis, Vogt-Koyanagi-Harada disease and Behçet’s disease, frequently with suggestive systemic manifestations.
Spectral-domain OCT on presentation showed central subretinal fluid with intraretinal changes and adjacent sub-RPE hyperreflective infiltrates (Figure 1b). Fluorescein angiography revealed multiple areas of confluent and discrete choroidal hyperfluorescence located throughout the posterior pole with leakage in late frames (Figure 2a). There was no involvement noted in the right eye.
Given his history of CNS lymphoma and the clinical presentation, the patient was suspected to have ocular involvement of primary CNS lymphoma. The Hematology/Oncology and Radiation Oncology departments requested a tissue diagnosis before initiating therapy. A 25-gauge vitrectomy was subsequently performed to obtain an undiluted vitreous biopsy. Flow cytometry was consistent with a lymphomatous process. Subsequently, brain MRI showed a thin subretinal collection in the upper nasal quadrant of the left eye and no new brain lesions (Figure 2b). There was no evidence of metastatic disease on PET scan.
The first description of “primary choroidal lymphoma” was by Triebensteinort in 1920. Multiple decades later, the entity was renamed by Klingele and Hogan as “ocular reticulum sarcoma” and by Vogel as “reticulum cell sarcoma” involving the retina. In the 1980s, with the development of the WHO’s lymphoma classification and the discovery of associations between intraocular lymphoma and primary CNS lymphoma (PCNSL), the nomenclature “primary intraocular lymphoma” (PIOL) was proposed. More recently, “primary vitreoretinal lymphoma (PVRL)” was established in lieu of PIOL, to distinguish it from primary uveal lymphoma.
PVRL, typically as an extranodal non-Hodgkin’s large B-cell lymphoma, has identical cytology features and phenotypic expression as PCNSL, so they are usually considered part of the spectrum of the same disease. Ocular involvement has been reported in up to 25% of PCNSL affecting the brain or spinal cord, while approximately 80% of patients with PVRL develop CNS involvement. Interestingly, neither the CNS nor the intraocular space is known to contain lymphatic tissue. It is proposed that lymphoma cells might arise in a site external to the CNS or eye, yet are able to grow only in these immunologically sequestered locations.
As a challenging masquerade syndrome, autoimmune or infectious etiology may be presumed and the diagnosis missed. Steroids and other immunosuppressive agents may result in improved exam findings, but this response typically does not persist, and the “uveitis” may appear to become resistant to treatment.
The diagnosis is usually made with vitreous humor and, rarely, chorioretinal biopsy. It is laborious to arrive at a diagnosis from tests on the vitreous specimen because of the low cell concentration and propensity of cells to undergo autolysis. Best results are achieved with rapid processing and analysis, including immediate fixation. Flow cytometry, immunohistochemistry, DNA extraction for monoclonality and PCR studies are also performed. Ancillary testing can be helpful in supporting the clinical diagnosis. Patients with suspected PVRL should undergo MRI of the brain and potentially lumbar puncture, given that 25% of patients with CNS lesions have a positive CSF cytology, which would obviate the need for ocular tissue diagnosis.
The mainstay of treatment for unilateral PVRL is in the form of intravitreal methotrexate, intravitreal rituximab or stereotactic external beam radiotherapy, with close follow-up for the development of PCNSL. Frenkel and colleagues reported the largest study over a 10-year period on intravitreal methotrexate for treatment of PVRL, delivered as an intensive induction-consolidation-maintenance regimen of 25 injections during 1 year. Remission was reached after a mean of 6.4 injections, with 95% requiring 13 injections or fewer. In Berenbom’s series of 12 patients receiving either chemotherapy alone, radiotherapy alone or a combination, he reported no ocular relapses in the patients who had received radiotherapy (30 Gy to 35 Gy in 15 fractions) during a mean follow-up of 19 months. However, CNS lesions were detected at a mean time of 8 months in this group, compared with 28 months for those who received chemotherapy. Therefore, chemotherapy combined with ocular irradiation classically results in better control of ocular disease and CNS involvement, which seems to be associated with survival.
Variations in patient sample, diverse treatment regimens and small case series have jeopardized literature estimations on mortality from PVRL, with rates ranging from 9% to 81% in follow-up periods from 12 months to 35 months, overall determined by the presence of CNS lesions.
The patient underwent local radiotherapy, with a total dose of 3060 cGy in 17 fractions over 22 elapsed calendar days, which will be followed by six cycles of systemic temozolomide. At 11-week follow-up, visual acuity improved from hand motion to counting fingers at 6 inches. Examination revealed atrophic RPE changes extending into the macula, with resolved serous retinal detachment and subretinal fluid, also apparent on SD-OCT (Figure 3).
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- For more information:
- Melina I. Morkin, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; website: www.neec.com. Jeffrey L. Marx, MD, and Jeffrey Chang, MD, are affiliated with Tufts Medical Center and Lahey Hospital and Medical Center and can be reached at Lahey Hospital and Medical Center, 31 Mall Road, Burlington, MA 01805; website: www.lahey.org.
- Edited by Kristen E. Dunbar, MD, and Kendra Klein, MD. They can be reached at the New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.