Man presents with unilateral blurry vision
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A 56-year-old white man was referred to the uveitis clinic at the New England Eye Center by an outside ophthalmologist for sudden-onset painless vision loss that started 2 months before presentation.
His chief complaint was blurry vision in the left eye, associated with photosensitivity. He also described “seeing through a black line” in the vision that was intermittent, as well as an “ache” that he treated with over-the-counter analgesics. The symptoms were constant and persistent, without associated flashes, floaters or eye pain.
Source: Erin Lanzo, MD, Lana Rifkin, MD, and Shilpa Desai, MD
He denied any medical or surgical history other than hyperlipidemia. He did not take any regular medications. His family history was significant for nonspecified cancer in his mother and glaucoma and prostate cancer in his father. He worked as a teacher.
His ocular history included glaucoma suspect based on large cup-to-disc ratios in both eyes, visually insignificant cataracts and dry eyes.
Examination
On exam, the patient’s uncorrected visual acuity was 20/20 in the right eye and 20/25 in the left eye, improved from 20/50 in the left eye measured by the referring ophthalmologist. Confrontation visual fields were full in both eyes. IOP measured by Goldmann applanation tonometry was 13 mm Hg and 14 mm Hg in the right and left eyes, respectively. Extraocular movements were full with orthotropic alignment. Both pupils reacted to light without afferent pupillary defect.
On external exam, the lids and lashes were normal in both eyes. The conjunctiva and sclera were normal without evidence of conjunctival lesions or granulomas. The corneas were clear without keratic precipitates. The anterior chamber of both eyes was formed without any white or pigmented cells. The irises were normal without synechiae or transillumination defects. The patient had 1+ nuclear sclerosis in both eyes. The vitreous was clear without cells or haze.
On dilated fundus exam, the optic nerves appeared pink and sharp with 0.8 cup-to-disc ratio in both eyes. Macula and periphery in the right eye were normal. The macula in the left eye showed retinal pigment epithelial (RPE) changes in a leopard spot pattern (Figure 1). Peripheral RPE changes were noted in the left eye as well. The vessels appeared normal in both eyes.
What is your diagnosis?
See answer below.
Unilateral RPE changes
Unilateral RPE changes within the macula and periphery suggest a differential diagnosis that must include consideration of dystrophic processes, degenerative conditions, inflammatory or infectious etiologies, and masquerade syndromes.
The leopard spot pattern of RPE changes is a classic characteristic of ocular lymphoma, which is the primary differential diagnosis to investigate given the patient’s age and clinical exam.
Of the inherited dystrophies that may cause RPE changes, the autosomal dominant pattern dystrophies — specifically the reticular and multifocal varieties — may present with a net-like distribution of RPE changes or flecks. These conditions tend to be bilateral and predominantly macular, however. Our patient had a normal right eye exam, as well as peripheral changes in the left eye. Macular degeneration typically presents with drusenoid deposits unlike the more patterned RPE changes seen here.
Of the infectious etiologies, syphilis and tuberculosis must be ruled out. In the absence of other signs of vitreous inflammation and/or focal retinal whitening, chronic endophthalmitis would be unlikely.
Sarcoidosis is on the differential of any posterior uveitic process. One should consider other causes of posterior uveitis, although here they may be less likely based on the absence of other key distinguishing features on exam: Behçet’s disease (unlikely without signs of vasculitis), birdshot chorioretinopathy (lack of characteristic peripheral lesions) and other multifocal choroidopathies.
Additional workup
To aid in clinical distinction between these entities, further in-office testing to include OCT, autofluorescence and fluorescein angiogram would be helpful.
Fundus autofluorescence was obtained and showed spots of hyperautofluorescence and hypoautofluorescence within the left macula as well as the nasal and temporal periphery (Figure 2). The right eye was normal (Figure 3).
OCT of the macula showed a normal right eye and hyperreflective outer retinal infiltrates in the left eye (Figure 4).
Fluorescein angiogram was obtained and showed absence of disc leakage and vasculitis in both eyes, as well as abnormal hyperfluorescent staining of the left eye (Figure 5).
At the conclusion of the visit, laboratory workup, MRI of the brain, vitreous biopsy and lumbar puncture were coordinated. Angiotensin-converting enzyme and lysozyme, treponemal antibody, HIV and tubercular testing were all negative. Chest X-ray was negative for signs of sarcoidosis. A complete blood count and a complete metabolic panel done within the previous month were normal.
A vitreous biopsy was obtained by an outside retina surgeon closer to the patient’s home. No malignant cells were identified; the sample was IL-6 and IL-10 negative. The sample was insufficient to conduct PCR for immunoglobulin gene rearrangement. PCR for MYD88 was invalid likely due to lack of nucleic acid concentrations.
A lumbar puncture showed colorless fluid with slight leukocytosis (10 cells/mm3; normal range, 0 to 5 cells/mm3) and 13 red cells. Results were 92% lymphocytes (normal range, 63% to 99%), 8% monocytes (normal range, 3% to 37%), 60 mg/dL protein (normal range, 15 mg/dL to 45 mg/dL) and 57 mg/dL glucose (normal range, 40 mg/dL to 80 mg/dL).
The MRI findings of the brain were “nonenhancing nodule within the right lateral ventricle with nonaggressive imaging characteristics. The lack of enhancement or restricted diffusion would not be typical for lymphoma. This most likely represents a subependymoma of no clinical significance.” The radiologist’s recommendation was to plan for follow-up MRI at 3 months given suspicion for intraocular malignancy based on the ophthalmic exam.
Discussion
This patient had suspected vitreoretinal lymphoma.
Intraocular lymphoma can present locally or be a manifestation of systemic disease and may affect the uvea or the vitreoretinal tissue. A rare entity, it represents less than 1% to 2% of intraocular tumors and only 1% to 2% of extranodal sites of non-Hodgkin’s lymphoma, although the incidence has been reportedly increasing with rising numbers of immunocompromised patients, increased life expectancy, and more widespread access to better diagnostic technology.
Primary vitreoretinal lymphoma (PVRL), previously called primary intraocular lymphoma (PIOL), is important to distinguish given its relationship to central nervous system (CNS) disease, which may occur simultaneously or present after the ocular findings. The majority of vitreoretinal lymphomas are diffuse large B-cell lymphomas, although T-cell lymphomas have been reported. The name change from PIOL to PVRL helped distinguish PVRL from other ocular-adnexal lymphomas that may primarily originate from ocular tissue but do not have an association with CNS lymphoma and are most frequently low-grade marginal zone lymphoma. Patients with PVRL will develop simultaneous or subsequent CNS disease 60% to 90% of the time, while patients with primary CNS lymphoma will manifest PVRL 15% to 25% of the time.
PVRL typically presents in patients in the sixth to seventh decade, although it has been reported in patients as young as 15 years old. There is no racial predilection for the disease, and studies differ as to whether men or women are more commonly affected.
Patients may report blurred or reduced vision with floaters and present with any combination of signs of anterior segment inflammation, vitritis and/or subretinal plaque-like lesions, although signs of posterior uveitis are more frequent than anterior. PVRL often masquerades as uveitic conditions; it is a difficult diagnosis, and clinical suspicion is essential. The subretinal lesions are described as small yellow-white “mounds” that may enlarge and eventually coalesce to larger yellow lesions with central darker pigmentation, known as leopard pattern pigmentation. Optic disc edema, vasculitis and retinal hemorrhages may also be seen. In some cases, an isolated retinal lesion may underlie an exudative retinal detachment. More rarely, patients may present with inflammatory glaucoma. Findings are bilateral in 64% to 83% of cases but may initially present unilaterally or asymmetrically.
OCT findings are classically described as subretinal white hyperreflective excrescences of the RPE that correspond to the leopard spot pattern evident on clinical exam, fundus autofluorescence and fluorescein angiogram.
Diagnosis requires a multifaceted and multidisciplinary approach. Histology, along with immunohistochemistry and molecular analysis, is the gold standard for diagnosis, although tissue samples may be difficult to acquire or may be insufficient. Specimens can be obtained with fine needle aspiration of the vitreous or via pars plana vitrectomy, which carries the small but possible risk for extension of the lymphoma to the epibulbar space via the sclerotomy site. Negative vitreous samples are common due to scarcity of cells; this is the most common reason for misdiagnosis. Retinal or chorioretinal biopsy may be required but presents additional risks and challenges depending on the location of the infiltrate. In eyes that have no visual function or conservative measures are not possible, diagnostic enucleation is an option.
Neuroimaging and full systemic evaluation are indicated if there is suspicion for PVRL, given the prevalence of concurrent CNS involvement. This evaluation also helps to differentiate PVRL from secondary metastatic disease to the intraocular tissue.
Treatment for PVRL is not standardized and varies depending on CNS involvement but may include intravitreal chemotherapy with methotrexate, systemic chemotherapy and/or radiation therapy. Comanagement with neuro-oncology, radiation oncology, ophthalmology and pathology optimizes patient care.
Given the rarity of the disease, reports of prognosis are varied and indicate a wide survival range of 9% to 81% at 12 to 35 months. The prognosis depends on CNS involvement (with a trend toward better survival if only ocular tissue is affected), histologic type (with poorer prognosis for T-cell lymphoma), and timing and type of treatment pursued. Disease recurrence after treatment is common and portends a poor prognosis with respect to functional vision and life expectancy.
Case resolution
After the initial workup, the patient was referred to the retina service at the New England Eye Center for further management and second opinion. Given the negative MRI, vitreous biopsy and negative lumbar puncture results, it was thought that the chorioretinal process was low grade although still likely infiltrative and most suggestive of lymphoma. Options were discussed, including observation vs. trial of intravitreal steroid vs. intravitreal methotrexate. Given that there was no large lesion, a chorioretinal biopsy would be high risk and low yield, as the patient had good preserved visual acuity and the biopsy site would be the macula. The patient elected to proceed with intravitreal methotrexate injections with his local retina provider.
Ten weeks after initial presentation and 6 weeks after evaluation with the retina service at NEEC, the patient noted new dizziness accompanied by blurry vision in the left eye. He presented to an outside emergency department and was initially diagnosed with benign paroxysmal positional vertigo after CT imaging of the brain revealed no acute abnormalities. The patient’s symptoms did not subside and were later associated with nausea and vomiting not relieved by prescription antiemetics.
Repeat MRI was coordinated by the patient’s primary care doctor and showed multiple subependymal enhancing masses within the frontal horn of the lateral ventricle, cerebellum, third ventricle, cerebral aqueduct, fourth ventricle, bilateral foramina of Luschka and lateral ventricles (Figure 6). There was no midline shift or hydrocephalus.
He was admitted to an outside hospital where he was evaluated by ocular oncology and neuro-oncology with a leading diagnosis of vitreoretinal lymphoma with CNS lymphoma. He underwent a full evaluation that revealed no other systemic involvement. A brain biopsy was deferred given the small size of the lesions and high-risk location. Likewise, a chorioretinal sample was again deferred given the likely low yield and high-risk macular location.
Empiric chemotherapeutic treatment with systemic methotrexate, rituximab and temozolomide was commenced with subsequent resolution of enhancing disease on repeat brain MRI. The patient’s visual acuity improved to 20/30 from previous interval decline to 20/80 in the left eye. The right eye continued to be disease free. The patient elected to defer intravitreal methotrexate injections while on systemic therapy.
- References:
- Chan CC, et al. Discov Med. 2013;15(81):93-100.
- Ishida T, et al. Retina. 2010;doi:10.1097/IAE.0b013e3181b408a2.
- Jahnke K, et al. Clin Ophthalmol. 2007;1(3):247-258.
- Tang LJ, et al. Int J Ophthalmol. 2017;doi:10.18240/ijo.2017.08.19.
- For more information:
- Edited by Yi Ling Dai, MD, and Teresa P. Horan, MD, of New England Eye Center, Tufts University School of Medicine. They can be reached at ydai@tuftsmedicalcenter.org and thoran@tuftsmedicalcenter.org.