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Woman presents with cloudy declining vision and flashes
Exam findings include nummular peripheral hypopigmented lesions and subretinal plaques.
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A 56-year-old Caucasian woman presented with painless, slowly decreasing “murky” vision in the left eye over a period of 3 weeks, along with flashes. Her ocular history was positive for hemorrhagic posterior vitreous detachment after blunt trauma with a basketball to the same eye 4 months earlier. On that exam, she was also noted to have “fullness of the optic nerve, venous beading and inferior drusen OS.” Despite the physician’s recommendation to return after 4 to 6 weeks, the patient was lost to follow-up until new visual symptoms started. She had also undergone strabismus surgery 30 years earlier and had incipient cataracts, myopia and presbyopia.
Medical history included migraines and osteoarthritis. She was taking eletriptan, magnesium oxide and melatonin. Family history was only positive for coronary artery disease and diabetes in the father. She was working as a sales engineer and denied any history of intravenous drug use or high-risk sexual activity. Review of systems was positive for remote history of genital herpes.
Upon presentation, the patient was diagnosed with multifocal choroiditis with panuveitis and vasculitis and was referred to the Uveitis Service.
Images: Morkin MI, Rifkin LM, Shah CP
Examination
Best corrected visual acuity was 20/25 in the right eye and 20/100 in the left eye. The pupils were briskly reactive to light with no relative afferent pupillary defect in either eye, and IOP was 16 mm Hg in the right eye and 10 mm Hg in the left eye. Slit lamp examination of the right eye was unremarkable, while the left eye showed diffuse active keratic precipitates, trace anterior chamber cell, 2+ anterior vitreous cell, and 1 to 2+ vitreous haze. Fundus exam revealed left optic disc edema, numerous round mid-peripheral hypopigmented choroidal lesions along with focal subretinal plaques in the temporal, inferior and superonasal macula (Figure 1a). Indocyanine green angiography (ICGA) delineated the sharply defined choroidal lesions (Figures 1b and 1c) temporal to the macula in the left eye, while the right eye was unremarkable.
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Subacute unilateral vision loss
The differential diagnosis for this case of subacute unilateral vision loss with panuveitis, keratic precipitates and retinochoroiditis with subretinal infiltrates includes infectious, inflammatory and neoplastic causes.
Infectious causes include syphilis, tuberculosis, toxoplasmosis and viral disease. While these conditions can present with a wide variety of findings on examination, including retinal infiltrates and vitritis, acute retinal necrosis typically progresses more rapidly and manifests as coalescent white patches of necrotizing retinitis. In these scenarios, serologic and aqueous/vitreous testing aids in making the diagnosis.
Inflammatory disorders that can lead to posterior uveitis with chorioretinal lesions include multifocal choroiditis, sarcoidosis, Behçet’s disease and acute posterior multifocal placoid pigment epitheliopathy, among others. In cases of autoimmune disease, systemic manifestations should be carefully assessed.
Neoplastic causes to consider are primary vitreoretinal lymphoma (PVRL), amelanotic melanoma, metastatic cancer and uveal lymphoid proliferations. PVRL is usually associated with vitritis and subretinal pigment epithelial infiltrates, and can sometimes develop an overlying mottled brown pigmentation that gives a “leopard skin” appearance. Retinal vasculitis, focal uveal masses and anterior uveitis can also be present. Keratic precipitates are characteristically dense and white in these patients. Metastatic disease usually presents as pale choroidal lesions with associated subretinal fluid in the absence of vitreoretinal involvement. Uveal lymphoid proliferations can additionally lead to the development of hypopyon, epibulbar masses, serous retinal detachments and ocular hypertension. Vitritis can also obscure an underlying amelanotic melanoma.
Workup and management
Durezol (difluprednate ophthalmic emulsion 0.05%, Alcon) four times a day was started, and workup was obtained, which revealed negative ACE and non-reactive RPR/FTA-ABS test. QuantiFERON Gold was initially indeterminate but negative after repeat testing. Purified protein derivative skin test was negative, and chest X-ray was normal. Once these initial infectious etiologies were ruled out, and given that the presentation did not seem consistent with herpetic disease, 60 mg of oral prednisone daily was started. At 1-week follow-up, vision improved subjectively and keratic precipitates resolved, but measured visual acuity remained the same with persistent 2+ anterior vitreous cell reaction. Although the case was not typical of herpetic disease, given the patient’s remote history of genital herpes and relatively poor response to steroids, Valtrex (valacyclovir, GlaxoSmithKline) 1 g orally three times a day was added empirically. The patient initially improved but then deteriorated by the 8-week follow-up, with worsened clouding of vision back to 20/100 and persistent vitreous inflammation. Fundus autofluorescence (FAF) revealed numerous nummular hypoautofluorescent spots in the mid-periphery (Figures 1d and 1e) that appeared hyperfluorescent in fluorescein angiography (FA; Figures 1f and 1g). No vascular leakage was noted.
The patient was brought back for anterior chamber paracentesis, which yielded negative herpes simplex virus, varicella zoster virus and cytomegalovirus polymerase chain reactions (PCRs). After discussion with the retina team and prednisone taper, diagnostic pars plana vitrectomy was performed. Within a few days, while awaiting the results of the vitrectomy, the patient developed changes in cognition as well as difficulty with balance. The vitrectomy results were diagnostic of large B-cell lymphoma by PCR immunoglobulin gene rearrangement study. The patient was referred to the Neuro-oncology Service. Contrast-enhanced brain MRI revealed the presence of a soft tissue lesion in the right posterior parietal lobe, as well as mass effect and midline shift (Figure 2a), which along with an otherwise negative PET scan, was consistent with primary CNS lymphoma.
Armed with the vitreous biopsy results, the patient was promptly entered into a clinical trial that involved systemic methotrexate/rituximab/temozolomide therapy followed by one consolidation cycle of cytarabine. Repeat brain MRI after 1 month showed significant interval decrease in the tumor’s size and mass effect (Figure 2b) and minimal remaining edema 3 months later, when the patient was deemed to have achieved complete remission. All neurological symptoms have resolved. The patient’s most recent visual acuity was 20/200 in the affected eye due to macular edema, epiretinal membrane and cataract development after vitrectomy. Exam showed no active vitritis, but subretinal infiltrates were still visible (Figures 3a to 3c). She has now been randomized to thiotepa-based stem cell bone marrow transplantation.
Discussion
PVRL is considered a variant of primary central nervous system lymphoma (PCNSL), reflecting the shared embryological origin of these two organs and illustrated by similar patients’ demographics despite the presenting location. Intraocular lymphoma most commonly consists of large B-cell lymphoma and typically occurs in the third to eighth decades of life, with a median age at the time of diagnosis of 63 years. While 16% to 34% of PVRLs have CNS involvement on presentation, up to 90% will develop it during the course of the disease. Conversely, 15% to 25% of PCNSL patients are found to have intraocular disease.
Ocular symptoms are non-specific and often include blurry vision, decreased visual acuity and floaters; 60% to 90% of patients have bilateral ocular disease. Eye findings typically include vitritis, yellow retinal plaques and subretinal pigment epithelial infiltrates, sometimes with an overlying characteristic “leopard spotting” pigmentation. Logically, the posterior uveitis mimicry frequently results in a delayed diagnosis. The mean duration of symptoms before diagnosis has been found to average 6 months (range: 0 months to 36 months) for PVRL alone and 3 months (range: 1 month to 48 months) when CNS lesions are present.
A study from 2009 by Fardeau and colleagues identified 53 cases of vitreous biopsy-proven primary intraocular non-Hodgkin lymphoma and analyzed their angiographic and tomographic findings. Punctate whitish lesions in the fundus that corresponded to hypofluorescent small lesions in fluorescein angiography and ICGA had a positive predictive value of 88.9% and negative predictive value of 85% for the diagnosis of intraocular lymphoma. Similarly, another study from 2014 described the FAF findings of intraocular lymphoma, reporting a pattern of granular hypoautofluorescence with surrounding hyperautofluorescence before treatment and patchy hypoautofluorescence corresponding to retinal pigment epithelial atrophy after treatment. Interestingly, our patient presented with the opposite fluorescence pattern, showing hypoautofluorescent spots that appeared hyperfluorescent on FA. Pathophysiologically, this could point to a predominance of atrophy leading to window defects rather than blockage on imaging or, alternatively, relate to the location of the infiltrates relative to the retinal pigment epithelium.
In regards to the diagnosis, identification of malignant cells by vitrectomy, vitreous aspirate or subretinal biopsy remains the gold standard. Nevertheless, the rate of diagnosis of PVRL using cytology alone is only 30%. Therefore, additional confirmatory methods of monoclonality, such as immunohistochemistry, flow cytometry and PCR, have become widely employed to increase the diagnostic yield. For instance, Chan and colleagues performed PCR studies on 85 primary intraocular lymphoma cases and found that 100% had IgH gene rearrangements as a result of the t(14;18) translocation. Likewise, an IL-10 to IL-6 ratio higher than 1 is highly suggestive of B-cell lymphoma and has been found to identify 74.7% of suspected cases. More recently, the occurrence of MYD88 mutations and more specifically the canonical L265P mutation has been identified in 50% to 70% and 96% of intraocular lymphomas, respectively.
In patients with suspected concomitant cerebral involvement, contrast-enhanced brain MRI is considered the best imaging modality. Lumbar puncture should be considered in cases of PCNSL to obviate the need for intraocular biopsy, although only up to 25% of cases with detectable lesions on MRI will have positive cerebrospinal fluid cytology.
There is no strong supporting evidence and, hence, clear consensus in terms of the preferred treatment modality of intraocular lymphoma because the literature is scant and prospective studies dedicated to PVRL alone are lacking. Some authors believe that newly diagnosed PVRL should be treated with local strategies, therefore avoiding systemic side effects and leaving more extensive treatments for brain relapses. On the other hand, although intravitreal methotrexate is highly successful and improves progression-free survival, 73% of eyes develop side effects and 27% show vision decline. Furthermore, local treatment alone has been found to lead to a 4-year overall survival rate of 32% vs. 85% for those receiving systemic therapy. Therefore, many institutions are treating PVRL without CNS involvement in the same manner as PCNSL. This typically consists of systemic methotrexate-based polychemotherapy followed by consolidative whole-brain radiotherapy or either stem cell transplantation or non-myeloablative cytarabine-etoposide chemotherapy.
The decision to pursue a diagnostic vitrectomy in the present case was crucial because the patient became incapacitated within weeks after surgery and soon after neurological symptoms started, and she was permitted initiation of targeted therapy as soon as she was seen by Neuro-oncology. Although subretinal infiltrates are still visible on exam, given the dramatic response to systemic therapy leading to remission, close multidisciplinary follow-up was warranted, deferring intraocular therapy to relapsing vitreoretinal findings, if found.
- References:
- Arcinue CA, et al. Ophthalmology. 2013;doi:10.1016/j.ophtha.2012.09.053.
- Browning DJ, et al. Eye (Lond). 2007;doi:10.1038/sj.eye.6702756.
- Chan CC. Trans Am Ophthalmol Soc. 2003;101:275-292.
- Egawa M, et al. J Ophthalmic Inflamm Infect. 2014;doi:10.1186/1869-5760-4-7.
- Fardeau C, et al. Am J Ophthalmol. 2009;doi:10.1016/j.ajo.2008.12.025.
- Fend F, et al. Br J Haematol. 2016;doi:10.1111/bjh.14025.
- Grimm SA, et al. Ann Oncol. 2007;doi:10.1093/annonc/mdm340.
- Grimm SA, et al. Neurology. 2008;doi:10.1212/01.wnl.0000327672.04729.8c.
- Sagoo MS, et al. Surv Ophthalmol. 2014;doi:10.1016/j.survophthal.2013.12.001.
- For more information:
- Melina I. Morkin, MD, and Lana M. Rifkin, 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. Chirag P. Shah, MD, MPH, can be reached at Ophthalmic Consultants of Boston, 50 Staniford St., Suite 600, Boston, MA 02114; website: www.eyeboston.com.
- Edited by Jessica Moon, MD, and Emily C. Wright, 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.