Multiple Myeloma Presenting as Recalcitrant Macular Edema

Abstract

Purpose:

This article presents an unusual case of ocular involvement of multiple myeloma masquerading as macular edema associated with diabetic retinopathy.

Methods:

A report of a single case.

Results:

The presence of concomitant type 2 diabetes and scattered retinal hemorrhages presented a diagnostic challenge. Large globular vitreous opacities and significant weight loss were suggestive of a neoplastic process. We demonstrate multimodal imaging findings that can be associated with plasma cell dyscrasias and also describe the purported mechanism by which plasma cell dyscrasias cause macular edema and exudative retinal detachments.

Conclusion:

Although multiple myeloma and related plasma cell dyscrasias are rare causes of ocular disease, they should be considered in the differential diagnosis of recalcitrant macular edema, and there should be a low threshold for systemic evaluation.

Case Presentation

A 78-year-old African American man with a history of type 2 diabetes and a recent hemoglobin A_1c level of 8.2, chronic kidney disease, and prostate cancer in remission after brachytherapy presented with bilateral decreased vision. He had undergone uncomplicated cataract surgery 2 months prior in the right eye and 1 month prior in the left eye. Corrected Snellen visual acuity (VA) was 20/40 in both eyes. Dilated funduscopy showed a few scattered dot hemorrhages, and optical coherence tomography (OCT) demonstrated macular edema in both eyes.

Mild, nonproliferative diabetic retinopathy with associated diabetic macular edema was diagnosed in the patient. Treatment was initiated with nepafenac and difluprednate eye drops without improvement, and 2 months after initial presentation, his VA worsened to 20/100 OD and 20/30 OS. He underwent intravitreous bevacizumab injections in both eyes followed 1 month later by intravitreous triamcinolone acetonide injections in both eyes without response to either agent. At 7 months after cataract surgery, the patient’s VA had declined to 20/400 in both eyes, and he was referred to an academic medical center for further evaluation.

On presentation at our retina clinic, a review of systems revealed a weight loss of 23 kg over the preceding 3 months. Slit-lamp examination of the anterior chamber was unremarkable in both eyes without appreciable cell or flare. Examination of the anterior vitreous demonstrated both fine and large globular vitreous opacities, more so in the right eye than in the left (Figure 1), whereas fundus examination (Figure 2) and OCT (Figure 3) demonstrated an inferior exudative retinal detachment in the right eye, scattered retinal hemorrhages in the midperiphery of both eyes, and cystoid macular edema with subretinal fluid in both eyes. Fluorescein angiography of both eyes (Figure 2) demonstrated areas of blockage from vitreous opacities overlying the macula, scattered midperipheral staining, late leakage at the optic disc, and parafoveal leakage without significant peripheral nonperfusion.

Figure 1.

Slit-lamp photograph of the anterior vitreous in the right eye demonstrates large, globular vitreous opacities.

Figure 2.

Baseline ultra-widefield imaging of both eyes was obtained on presentation at our referral center. (A and B) Fundus images of the right and left eyes demonstrate vitreous opacities, scattered intraretinal hemorrhages, and loss of foveal light reflex in both eyes. (A) The right eye also shows an inferior exudative retinal detachment (superior extent indicated by dotted line). (C and D) Fluorescein angiography demonstrates areas of blockage from vitreous opacities overlying the macula, scattered midperipheral staining, and late leakage at the macula and optic disc.

Figure 3.

Serial optical coherence tomography images of the right and left eyes over 1 year. Initial images were taken on presentation at our referral center 7 months after cataract surgery at an outside facility. Initially both eyes demonstrated cystoid macular edema with small outer plexiform layer cysts, subretinal fluid, scattered hyperreflective foci in the outer retina, and prominent thickening of the outer retina. This persisted at 1 month after an oral steroid trial. In the later images after initiation of chemotherapy, there is initial improvement of the subretinal fluid, with subsequent resolution of intraretinal fluid in the right eye and near complete resolution in the left eye along with persistence of subretinal hyperreflective material in the left eye.

At this point, a broad differential diagnosis—involving infectious, inflammatory, infiltrative, and neoplastic causes including a lymphoproliferative process or plasma cell dyscrasia—was considered to explain this constellation of examination findings. Test results for syphilis and tuberculosis were negative, as were those for angiotensin-converting enzyme levels and findings from a chest x-ray to screen for sarcoidosis. A short therapeutic trial of high-dose oral steroids was initiated without interval improvement of symptoms.

Results

Further laboratory workup was significant because of a low hemoglobin level (9.0 g/dL), an elevated serum creatinine level (1.8 mg/dL), and a low serum albumin-to-globulin ratio (0.11). Serum protein electrophoresis demonstrated an immunoglobulin G monoclonal protein population with kappa light chain specificity and an elevated kappa-to-lambda ratio (2.94). Bence Jones proteins were detected in the urine. Subsequent workup including bone marrow biopsy with fluorescence in situ hybridization testing, skeletal survey, and positron emission tomography scan resulted in the diagnosis of multiple myeloma.

Chemotherapy was initiated with lenalidomide, bortezomib, and dexamethasone. After 13 months of therapy, the patient’s VA improved to 20/64 OD and 20/200 OS with resolution of the vitreous globules, resolution of macular edema and exudative retinal detachment in the right eye, and near-complete resolution of macular edema in the left eye (Figures 3 and 4). His systemic health improved, with an increased hemoglobin level to 10.1 g/dL and a 12 kg weight gain.

Figure 4.

Ultra-widefield fundus images of the right and left eyes obtained 16 months after presentation and after 13 months of systemic chemotherapy. (A and B) There is resolution of the exudative retinal detachment and a significant improvement in the degree of vitreous opacities and amount of intraretinal hemorrhage.

Conclusions

In multiple myeloma, immunoglobulin light chains can be deposited in various tissues throughout the body, resulting in light chain deposition disease (LCDD). Typically demonstrated most prominently in the kidneys, LCDD can result in renal failure. ¹ Light chain deposition has also been reported in a variety of ocular tissues, including the cornea, ^2,3 ciliary body, choroid, ⁴ retina, ⁵ and retinal pigment epithelium (RPE). ⁶ Exudative retinal detachment may be observed in association with LCDD, ^{6 -9} wherein light chain deposition in the outer retina and the subretinal space creates increased oncotic pressure, drawing fluid into the subretinal space. ^6,8 It is thought that, when the photoreceptors are separated from the RPE, waste products from the discarded photoreceptors’ outer segments accumulate, causing thickening and increased reflectivity of the outer retina on OCT ⁶ (Figure 3).

Specifically, previously described characteristic OCT features of LCDD include macular edema, small outer plexiform layer cysts, prominence of the middle limiting membrane, and subretinal hyperreflective deposits. ^9,10 Subretinal deposits can demonstrate a vitelliform appearance and adhere to the anterior surface of the RPE or the posterior surface of the neurosensory retina. ^6,7 The present case supports these OCT findings with prominent subretinal deposits, cysts in the outer plexiform layer, and subretinal fluid at presentation.

Our case also demonstrates that the macular edema may be slow to respond to systemic chemotherapy in LCDD cases. Serial OCT scans (Figure 3) revealed that the subretinal fluid resolved prior to the improvement of the intraretinal fluid. Additionally, Figure 4 demonstrates that retinal hemorrhages and blockage from vitreous opacities can be slow to resolve. Although the late macular hyperfluorescence on angiogram (Figure 2) may also be explained by staining of the subretinal deposits, ⁷ or diffuse intraretinal leakage as reported in some prior cases of multiple myeloma, ⁶ it does not strictly fit the classic LCDD angiographic description of the absence of diffuse leakage around the foveal avascular zone. ^{8 -10} The findings in our case could be confounded by a component of postsurgical inflammation following the patient’s recent cataract surgical procedures as well as diabetic retinopathy.

Although the aforementioned characteristic features are often found in retinal presentations of LCDD, cases of macular edema driven by LCDD can have a presentation similar to diabetic macular edema. ⁹ The presence of diffuse retinal hemorrhages associated with hyperviscosity retinopathy ¹¹ in LCDD can further complicate the diagnosis given their similar appearance to intraretinal hemorrhages associated with diabetic retinopathy.

Intraocular lymphoma may present with a retinal appearance similar to multiple myeloma, but it often is associated with more vitreous inflammation, the presence of yellow subretinal deposits on examination and vitreous hyperreflective foci, subretinal and sub-RPE hyperreflective deposits, and vertical hyperreflective lesions seen on OCT. ^{12 -14} These features may be helpful when attempting to differentiate multiple myeloma from other neoplastic causes, but if the systemic workup is inconclusive, a diagnostic vitreous biopsy should be considered. A biopsy of the subretinal material may also be considered (but can be associated with visual morbidity) given the theoretical potential of the eye to serve as a protected reservoir for myeloma cells ¹⁵ as is known to occur in cases of intraocular lymphoma. ¹² Vitreous opacities seen in this case are not typical of LCDD, and this raised suspicion for intraocular lymphoma. A diagnostic vitrectomy was considered, but it was deferred because the patient’s systemic workup was consistent with multiple myeloma. The vitreous opacities resolved following his systemic treatment.

Systemic therapy for multiple myeloma, including chemotherapy and stem cell transplantation, is the mainstay treatment of retinal manifestations of LCDD associated with multiple myeloma. ^{7 -9} Treatment with systemic immunosuppressive agents or with plasmapharesis ¹⁶ may also decrease light chain burden and improve ocular disease manifestations. There are no consensus guidelines on the role of intravitreal treatment of maculopathy associated with multiple myeloma, and treatment decisions are usually made based on clinical judgments and case reports. Intravitreal treatments including dexamethasone or triamcinolone, antivascular endothelial growth factor injections such as bevacizumab, and rituximab have been tried with varied outcomes. ^{17 -19}

In our case, chemotherapy led to complete resolution of intraretinal and subretinal fluid in the right eye, whereas the left eye had a small amount of residual intraretinal fluid. Vision in the left eye was limited by the subretinal hyperreflective material, loss of the outer retinal bands, and RPE atrophy. ⁶ Our patient had previously received both intravitreal triamcinolone and bevacizumab without response, and he opted against adjunctive intravitreal treatment of the persistent intraretinal fluid in the left eye.

In conclusion, although multiple myeloma and related plasma cell dyscrasias associated with LCDD are rare causes of ocular disease, they should be considered in the differential diagnosis of macular edema not responsive to standard therapy, and there should be a low threshold to perform a systemic evaluation.