Immunogammopathies and Acquired Vitelliform Detachments: A Report of Four Cases IRENE M. RUSU, SARAH MREJEN, MICHAEL ENGELBERT, ROBERTO GALLEGO-PINAZO, MICHAEL D. OBER, MARK W. JOHNSON, ANITA LEYS, AND LAWRENCE A. YANNUZZI PURPOSE: To describe the nature and evolution of acquired macular detachments in patients with immunogammopathies and to propose a mechanism for their development. DESIGN: Retrospective observational case series. METHODS: Three patients with multiple myeloma and 1 with light chain deposition disease were diagnosed with vitelliform macular detachments based on clinical examination, fundus autofluorescence, fluorescein angiography, and optical coherence tomography. These patients were followed over time and their clinical examinations and imaging studies were compared and contrasted. RESULTS: Three patients (5 eyes) with multiple myeloma and 1 patient (2 eyes) with light chain deposition disease presented with acquired macular yellowish subretinal deposits on funduscopic examination that corresponded to hyperautofluorescent lesions on fundus autofluorescence imaging and subretinal hyperreflective material on spectral-domain optical coherence tomography. One patient (2 eyes) had diffuse serous retinal detachments involving not only the macular region but also the midperiphery of the retina. These acquired macular vitelliform detachments were not associated with signs of hyperviscosity retinopathy in 5 eyes and resolved after successful treatment of the multiple myeloma in 6 eyes. CONCLUSION: Patients with an immunogammopathy such as multiple myeloma or light chain deposition disease may develop serous elevations of the macula that we classify as acquired vitelliform detachments using multimodal imaging. Appropriate evaluation including serum protein electrophoresis and hematology consultation should be considered in the management of patients
Accepted for publication Nov 25, 2013. From the Department of Ophthalmology, New York University School of Medicine, New York, New York (I.M.R., M.E., L.A.Y.); Vitreous Retina Macula Consultants of New York, New York, New York (S.M., M.E., L.A.Y.); LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital-Northshore Long Island Jewish Hospital, New York, New York (S.M., M.E., L.A.Y.); Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, Spain (R.G.P.); Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, New York (M.E., L.A.Y.); Retina Consultants of Michigan, Southfield, Michigan (M.D.O.); Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan (M.W.J.); and University Hospitals Leuven, Leuven, Belgium (A.L.). Inquiries to Lawrence A. Yannuzzi, Vitreous Retina Macula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
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with acquired vitelliform detachments of uncertain etiology. (Am J Ophthalmol 2014;157:648–657. Ó 2014 by Elsevier Inc. All rights reserved.)
I
MMUNOGAMMOPATHIES ARE CLONAL PLASMA CELL
proliferative disorders characterized by deposition of light or heavy chain immunoglobulin fragments in tissues, leading to organ dysfunction. Within this spectrum of diseases are multiple myeloma, Waldenstrom’s macroglobulinemia, and benign monoclonal gammopathy, as well as light chain deposition disease. Ocular manifestations of immunogammopathies have been described in a variety of ocular structures, including the conjunctiva, cornea, uvea, and retina.1 Serous macular detachments in association with immunogammopathies, though rare, have been described.2–15 Ho and associates first reported serous macular detachments with or without subretinal precipitates or fundus signs of serum hyperviscosity in 1 patient with multiple myeloma, 1 patient with Waldenstrom’s macroglobulinemia, and 1 patient with benign polyclonal gammopathy.2 Specifically in multiple myeloma, only 1 report describes deposits on the posterior surface of the neurosensory retina and in the subretinal space anterior to the retinal pigment epithelium (RPE).2 This previous study did not include current imaging modalities such as spectral-domain optical coherence tomography (SD OCT) or fundus autofluorescence imaging. This is a report on an additional 4 patients—3 with multiple myeloma and 1 with light chain deposition disease— who have associated serous detachments evaluated with multimodal imaging including fluorescein angiography, fundus autofluorescence, and SD OCT. We also propose a mechanism that would explain the advent and course of these particular exudative detachments.
PATIENTS AND METHODS THE INSTITUTIONAL REVIEW BOARD (IRB) AT NORTHSHORE
Long Island Jewish Hospital waived IRB approval for this retrospective case series. The records of 4 patients with vitelliform macular detachments and an immunogammopathy were examined. The following data were collected for each of the 4 cases: Snellen visual acuity at presentation
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FIGURE 1. Multimodal imaging of both eyes of a 58-year-old woman with multiple myeloma presenting with atrophic descending tracts and bilateral acquired vitelliform detachments that resolved when the serum immunoglobulin levels decreased. (Top row) Fundus photographs show mild retinal pigment epithelium changes. (Second row) Fundus autofluorescence shows hyperautofluorescent macular lesions surrounded by a wider area of granular hypoautofluorescence, more prominent OS, and bilateral atrophic
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and subsequent visits, epidemiologic data, past medical history, and clinical signs of retinal vasculopathy. The following imaging was also collected: fundus photographs, fluorescein angiography, fundus autofluorescence, and optical coherence tomography (OCT).
RESULTS CASE 1:
A 58-year-old woman presented with bilateral, asymmetric decreased vision over the course of several weeks. Her past medical history included well-controlled diabetes, a remote history of skin melanoma removed from the leg 12 years prior with no metastasis, and multiple myeloma, for which she was undergoing treatment. The patient was enrolled in multiple myeloma trial IPH 2101203, a multicenter, open-label phase II clinical trial designed to evaluate IPH 2101, an anti-KIR monoclonal antibody potentiating the antitumor activity of NK cells in patients with previously untreated smoldering multiple myeloma. As part of this trial, the patient underwent regular chemotherapy administrations for 1 year with no change in her multiple myeloma numbers. She presented to us on month 8 of this trial. Her past ocular history included a branch retinal vein occlusion (BRVO) in the left eye (OS). Her best-corrected visual acuity (BCVA) was 20/30 in the right eye (OD) and 20/70 OS with no relative afferent pupillary defect. Slit-lamp biomicroscopy showed a normal anterior segment examination. Dilated fundus examination revealed mild RPE changes, extending inferiorly from the discs in both eyes (OU) (Figure 1, Top row). On fundus autofluorescence, hyperautofluorescent macular lesions surrounded by a wider area of granular hypoautofluorescence were present, more prominently OS and associated with bilateral hypoautofluorescent atrophic descending tracts (Figure 1, Second row). Fluorescein angiography revealed diffuse intraretinal leakage, optic disc leakage, and some retinal microvascular abnormalities, but the area of detachment was hypofluorescent (Figure 1, Third row). No leak or pooling was noted in the area of the macular detachments. SD OCT at the level of these lesions showed a macular detachment with vitelliform deposition on the anterior surface of the RPE and the posterior surface of the neurosensory retina with associated subretinal and intraretinal fluid, more prominent OS and associated with intraretinal cysts at the level of the outer nuclear layer (Figure 1, Fourth row). Enhanced depth imaging (EDI)
OCT revealed slightly increased subfoveal choroidal thickness measuring 347 mm OD and 305 mm OS. Treatment of the macular edema with 10 anti–vascular endothelial growth factor (VEGF) intravitreal injections was initiated and response was followed by SD OCT. Five months after completing the multiple myeloma trial, she was started on 50 mg (oral [PO]) prednisone and underwent chemotherapy with 2 cycles of Velcade, a mitogen-activated protein kinase enzyme inhibitor; Revlimid; and Cytoxin. By this point she had received 9 anti-VEGF intravitreal injections as treatment for her BRVO, with improvement, but no resolution, of subretinal and intraretinal fluid. Three months later, she underwent induction chemotherapy again with Velcade, Revlimid, and 50 mg PO prednisone. It was during this month that her multiple myeloma immunoglobulin numbers came down for the first time in 20 months. This reduction in serum immunoglobulin from an M-spike of 5.63 to an Mspike of 0.94 coincided with a resolution of her vitelliform macular detachments and associated intraretinal and subretinal fluid for the first time since initiating treatment (Figure 1, Bottom row). CASE 2:
A 59-year-old woman with light chain deposition disease presented with decreased vision OU. BCVA was 20/20 OD and 20/25 OS. Past medical history was positive for hypertension, anemia, and end-stage renal disease. Fundus examination revealed peculiar subretinal lesions (Figure 2, Top row). These lesions were hyperautofluorescent on fundus autofluorescence (Figure 2, Middle row). Although OCT OD was flat, OCT OS showed a subretinal deposit anterior to the RPE (Figure 2, Bottom row). After 7 years of follow-up, fundus examination revealed persistence of the subretinal lesions with progression to neurosensory detachments and 20/50 vision OU. At this time, 1 dotblot hemorrhage in the midperiphery of each eye was identified with no associated vein occlusion, microaneurysms, or venous congenstion. As the patient had uncontrolled arterial hypertension at the time of this visit, the dot-blot hemorrhages were deemed to be secondary to the hypertension. Currently, the patient is referred for plasmapheresis.
CASE 3: A 55-year-old man presented with multiple neurosensory detachments OU including the peripapillary retina and fovea. On fundus examination, there were also multifocal areas of subretinal yellow deposits OU (Figure 3, Top row). His past medical history was significant only for mild hypertension. Fluorescein angiogram
descending tracts. (Third row) Fluorescein angiography shows generalized intraretinal leakage, disc leakage, and some microvascular abnormalities. No pooling was noted in the area of the macular detachment. (Fourth row) Spectral-domain optical coherence tomography (SD OCT) at the level of these lesions shows a macular detachment with vitelliform deposition on the anterior surface of the retinal pigment epithelium and the posterior surface of the neurosensory retina, more prominent OS and associated with intraretinal vacuole formation at the level of the outer nuclear layer OS. (Bottom row) Follow-up SD OCT shows complete resolution of the vitelliform detachments after induction chemotherapy.
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and indocyanine green chorioangiography revealed no focal leakage, hyperpermeability, plaque, or hot spot, but the yellow deposits were hyperautofluorescent on fundus autofluorescence (Figure 3, Second row). SD OCT showed neurosensory detachments with vitelliform deposition on the posterior surface of the neurosensory retina OU (Figure 3, Third row). Over time the macular neurosensory detachment resolved OU, leaving RPE atrophy with a visual decline down to roughly the 20/50 level OD. Two years later, the patient returned with a nearly symmetrical neurosensory detachment in the peripapillary retina and central macula OS, in addition to several elevated areas along the arcades in both eyes. There were no hemorrhages, exudations, or vascular tortuosity. By this time, he had developed monoclonal gammopathy of undetermined significance. A new fluorescein angiogram revealed no focal leaks in the macula OU. There was RPE atrophy in the right eye, and again the yellow lesions were hyperautofluorescent OU. Fortunately, his vision remained at 20/20 OS, although he had a hyperopic shift, and there was some mild distortion. Half-fluence photodynamic therapy was applied to the left eye, which ultimately did not alter the neurosensory detachment or his vision in any way. Repeat laboratory evaluation at this point led to a new diagnosis of multiple myeloma. He subsequently developed a few intraretinal hemorrhages and mild vascular tortuosity indicative of hyperviscosity that was characterized as rather subtle. Although several sequential treatments with plasmapheresis yielded no change in the neurosensory detachment in the left eye, the hemorrhages and tortuosity improved. He underwent bone marrow transplant at this time. Three years after presentation, electrophysiologic testing revealed an electrooculogram (EOG) with a normal Arden ratio. The electroretinogram (ERG) showed a mildly abnormal scotopic and photopic response with significant cone dysfunction in both eyes, somewhat more advanced OD. After bone marrow transplant, SD OCT showed resolution of the vitelliform detachments with residual subretinal fibrosis OD (Figure 3, Bottom row). CASE 4:
A 62-year-old man presented with decreased vision OD of 1 month’s duration. BCVA OD was 20/30-1. The left eye was asymptomatic, with BCVA of 20/30þ1. Past medical history included hypertension and multiple myeloma. The patient was taking 20 mg dexamethasone daily and reported that he first noticed a change in his vision after using Velcade as part of the Velcade-Revlimid-Dexamethasone protocol for 15 weeks. At this time his M-spike was 0.61 and he was taken off the Velcade but restarted back on it 1 month later when his M-spike increased to 0.71. Fundus photographs showed serous pigment epithelial detachments OU (Figure 4, Top row) with hyperautofluorescent material on fundus autofluorescence more prominent OD (Figure 4, Second row), but no retinal vasculopathy OU. SD OCT showed vitelliform deposits
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below the neurosensory retina and above the RPE OD (Figure 4, Third row). EDI OCT revealed increased choroidal thickness measuring 450 mm OD and 350 mm OS. At this time he was started on a mineralocorticoid since he had findings resembling central serous chorioretinopathy (CSC), but this regimen did not produce any change for 3 months. Finally, his serous pigment epithelium detachments completely resolved 4 months later while he was still on the mineralocorticoid, 50 mg of oral prednisone, and Velcade (Figure 4, Bottom row). This improvement coincided with an Mspike of 0.34, a record-low multiple myeloma immunoglobulin number in this patient.
DISCUSSION SEROUS MACULAR DETACHMENTS WITH OR WITHOUT
subretinal deposits have been reported in a number of immunogammopathies, including Waldenstrom’s macroglobulinemia, light chain deposition disease, and, rarely, multiple myeloma. These exudative detachments of the retina are known to be ‘‘angiographically silent.’’2 To our knowledge, no neovascularization was reported in those prior cases. In our study, based on current multimodal imaging we identified these detachments as vitelliform. Multiple etiologies are associated with acquired vitelliform lesions, including conventional drusen, subretinal drusenoid deposits, cuticular drusen, some retinal dystrophies, tractional maculopathies,16 and central serous chorioretinopathy. Vitelliform deposits are usually hyperautofluorescent and more or less homogenous depending on their etiology. They consist of debris including lipofuscin, melanolipofuscin granules in macrophages, and extracellular material derived from photoreceptor outer segment discs that accumulates in the subretinal space from RPE dysfunction.17 Fundamentally, in the case of immunogammopathies we are not sure what causes the vitelliform. The acquired vitelliform detachments were macular in 6 of the 8 eyes in our series (Cases 1, 2, and 4); diffuse, involving the midperiphery in 2 eyes (Case 3); and overlying a serous pigment epithelium detachment in 1 eye (Case 4). Bilateral, atrophic descending tracts were also found in 2 eyes of 1 patient (Figure 1, Second row), suggesting previous gravitating serous retinal detachments with residual RPE and outer retinal atrophy (Table). In 2 of our 4 patients the vitelliform detachments improved while on cortical therapy (Case 1 and Case 4). This introduces at least 2 theories for the evolution of subretinal fluid and subsequent vitelliform formation: (1) osmotic factors created by proteinous exudations, and (2) diffuse RPE dysfunction, or a combination of both. The metabolic reabsorption of subretinal fluid is dependent upon 2 main mechanisms: active ionic transport across the RPE and passive passage of fluid driven by the oncotic
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FIGURE 2. Multimodal imaging of both eyes of a 59-year-old woman with light chain deposition disease presenting with bilateral isolated acquired vitelliform lesions. (Top row) Fundus examination reveals bilateral peculiar subretinal lesions at the level of the retinal pigment epithelium; (Middle row) lesions are hyperautofluorescent on fundus autofluorescence, consistent with the appearance of acquired vitelliform lesions. (Bottom row) Horizontal foveal optical coherence tomography (OCT) scans reveal corresponding subretinal hyperreflective deposits anterior to the retinal pigment epithelium OS and no abnormality OD. Note that the foveal OCT scan OD is not at the level of the vitelliform lesions identified on color photograph and fundus autofluorescence.
pressure gradient (higher in the choroid).18 These are the 2 main mechanisms that permanently dehydrate the subretinal space. Immunoglobulins are large proteins that cannot passively diffuse across the RPE. To the best of our knowledge, there is no specific active transporter of immunoglobulins at the level of the RPE. However, one can assume that immunoglobulins can accumulate in the subretinal space in immunogammopathies and increase the oncotic pressure of the subretinal space, inversing the oncotic pressure gradient across the RPE. Fluid can therefore accumulate in the subretinal space, driven by the reversed oncotic pressure gradient. The fluid accumulating in the subretinal space physically separates the RPE from the photoreceptors, impeding proper phagocytosis. Therefore, outer segments 652
containing fluorophores (A2E) shed and accumulate in the subretinal space, resulting in the hyperautofluorescent signal present on fundus autofluorescence. It has been proposed in the past that subretinal immunoglobulin leads to fluid accumulation and subsequent serous macular detachments.2 In Waldenstrom’s macroglobulinemia, the presence of IgM was identified in the superficial retina and around the photoreceptors by immunofluorescence.3,4 Protein spillover from a supersaturated retina in which the capacity of the RPE to pump fluid is overwhelmed may also result in fluid accumulation. In our series, only 1 out of the 4 subjects (Case 1) displayed bilateral, diffuse intraretinal leakage and some microvascular abnormalities on fluorescein angiography;
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FIGURE 3. Multimodal imaging of both eyes of a 55-year-old man with multiple myeloma presenting with multiple acquired vitelliform detachments involving the macula and midperiphery that resolved after bone marrow transplant. (Top row) Fundus photographs show multifocal areas of subretinal yellow deposits OU separate from the subretinal fluid; (Second row) these deposits are hyperautofluorescent on fundus autofluorescence and consistent with the appearance of acquired vitelliform lesions. (Third row) Spectraldomain optical coherence tomography shows neurosensory detachments with subretinal deposits; (Bottom row) these resolved after bone marrow transplant, with residual subretinal fibrosis OD.
this may be explained by a past medical history of diabetes, although it cannot be excluded that hyperviscosity played a role. Classically, the hyperviscosity syndrome is seen in Waldenstrom’s macroglobulinemia,19–21 but it has also been described in certain cases of multiple myeloma22 and light chain deposition diseases.23,24 Features of hyperviscosity retinopathy such as retinal venous occlusions and retinal capillary microaneurysms1,25 were present in only 3 of the 8 eyes in our series (Cases 1 and 3). The resolution of the acquired vitelliform detachments VOL. 157, NO. 3
that we observed in 3 of our 4 subjects after successful treatment of their multiple myeloma implicates a proteinous etiology to these detachments. Diffuse RPE dysfunction may also have contributed to the development of acquired vitelliform retinal detachments in our cases, since 1 subject presented with additional bilateral atrophic descending tracts (Case 1) and 1 with additional bilateral serous pigment epithelial detachments (Case 4). This constellation of findings is highly suggestive of a diagnosis of CSC. However, none of these patients showed the
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FIGURE 4. Multimodal imaging of both eyes of a 62-year-old man with multiple myeloma presenting with bilateral serous pigment epithelial detachments and an overlying acquired vitelliform lesion in the right eye that resolved when the serum immunoglobulin levels decreased. Fundus photographs show pigment epithelial detachments OU (Top row) with hyperautofluorescent material on fundus autofluorescence more prominent OD (Second row). (Third row) Spectral-domain optical coherence tomography (SD OCT) shows pigment epithelial detachments OU with an overlying subretinal hyperreflective deposit OD resembling an acquired vitelliform lesion. (Bottom row) Follow-up SD OCT shows resolution of the pigment epithelial detachments corresponding with a reduction in the multiple myeloma immunoglobulin numbers.
typical leakage pattern on fluorescein angiography, and all eyes in these subjects eyes actually improved after corticosteroid therapy as part of the multiple myeloma treatment (Case 1 and Case 4). These acquired vitelliform retinal detachments were chronic in all cases (more than 6 months) and improved in 3 patients (6 eyes) only after successful treatment of the multiple myeloma (Case 1, Case 3, and Case 4), suggesting a causal relationship between the concentration of immunoglobulins and the pathogenesis of these chronic acquired vitelliform retinal detachments. 654
The remaining subject in this series is still undergoing treatment; in Case 2 the subject was referred for bone marrow transplant. In Case 4 the subject is still undergoing chemotherapy. In all of the cases in this series in which the patients have completed treatment successfully, the vitelliform lesions resolved as the protein content decreased. Additionally, the corticotherapy improved the serous retinal detachments in both of the patients in our series (Case 1 and Case 4), whereas it has been shown to be a risk factor inducing or worsening CSC findings.26
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TABLE. Variations of the Clinical and Retinal Imaging Characteristics of Four Patients With Immunogammopathies and Acquired Vitelliform Detachments Characteristic
Patient 1
Patient 2
Clinical history
58-year-old woman with multiple myeloma
Presence of hyperviscosity retinopathy Fundus photographs
Branch retinal venule occlusion OS
59-year-old woman with light chain deposition disease None
Fundus autofluorescence
Fluorescein angiogram Optical coherence tomography
Follow-up
Patient 4
55-year-old man with multiple myeloma
62-year-old man with multiple myeloma
Few intraretinal hemorrhages and mild vascular tortuosity OU Macular and peripheral subretinal yellow deposits OU Hyperautofluorescent lesions in the macula and midperiphery OU
None
Not available
No focal leakage
Not available
Subretinal hyperreflective deposit OS
Neurosensory detachments with subretinal hyperreflective deposits OU Bone marrow transplant resulted in resolution of the vitelliform detachments
Subretinal hyperreflective deposits OD
Mild retinal pigment epithelial changes in the macula Hyperautofluorescent macular lesions OU Hypoautofluorescent atrophic descending tracts OU Diffuse intraretinal leakage Macular detachments with subretinal hyperreflective deposits OU
Macular subretinal yellow deposits OU
Induction chemotherapy resulted in reduced M-spike and resolution of the vitelliform macular detachments
Patient referred for plasmapheresis
Hyperautofluorescent macular deposits OU
The presence of atrophic descending tracts (Figure 1, Second row) is not pathognomonic of CSC but can rather demonstrate RPE dysfunction as a consequence of subretinal fluid accumulation in various chorioretinal diseases including CSC, choroidal hemangioma, choroidal nevus, age-related macular degeneration, and immunogammopathies. A relatively thickened choroid was present in 2 of our 4 cases (Cases 1 and 4). A postmortem histopathologic study of a patient with light chain deposition disease by Daicker and associates suggests that immunoglobulin deposition in the choroid could lead to RPE dysfunction. Light microscopy, immunofluorescence, and electron microscopy identified extensive deposition of kappa light chains in the uvea and choroid.27 Light chains were present in the deep choroid and were more pronounced in the central fundus, suggesting a local circulatory origin. Partial choriocapillary occlusion was associated with dense, yellow subretinal deposits in the posterior pole and an overlying exudative retinal detachment.27 A recent case series of 3 patients with light chain deposition disease11 and yellowish deposits consistent with acquired vitelliform lesions and the postmortem histopathology described above suggests that light chain deposition in the choroid impairs RPE function, leading to fluid retention and RPE detachments. VOL. 157, NO. 3
Patient 3
Macular serous pigment epithelial detachments OU Hyperautofluorescent macular deposit OD
Induction chemotherapy resulted in reduced M-spike and resolution of the vitelliform macular detachment
The mitogen-activated protein kinase enzyme inhibitors are a novel class of molecules, used as targeted therapies in a number of malignancies including multiple myeloma, that have been shown to have some ocular toxicities.28 Recently, 1 case report described bilateral multifocal CSC-like chorioretinopathy after use of a mitogenactivated protein kinase enzyme inhibitor in the treatment of metastatic cutaneous melanoma.29 It is unlikely that the use of mitogen-activated protein kinase enzyme inhibitors was responsible for the findings in our patients since the serous macular detachments (Case 1) and pigment epithelium detachments (Case 4) improved in both patients while on these medications. Despite the presence of serous macular detachments in our patients, the visual prognosis was good because none of the detachments were associated with choroidal neovascularization or macular hole formation. In a recent case series of patients with Waldenstrom’s macroglobulinemia and serous macular detachments, OCT showed a disruption of the outer retinal physiologic lines, suggesting that the disruption of the outer retina served as a track for intraretinal immunoglobulin M and fluid to enter the subretinal space.8 In our series of 4 patients, there was no persistent outer retinal disruption. With resolution of the acquired vitelliform detachments, we observed restoration of the
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normal outer retina and RPE anatomy on SD OCT in all of the eyes in our series except 1 that developed outer retinal and RPE atrophy with associated subretinal fibrosis, similar to the residual atrophy that may occur in other diseases as the vitelliform lesions resolve (Figure 3, Bottom row, left column). As expected, these nonvascularized retinal detachments did not respond effectively to anti-VEGF agents; rather, they resolved only with reversal of the disease process. Thus, treatment should not be aimed at reducing the fluid subretinally without oncologic treatment of the hyperproteinemia. To our knowledge, only 2 cases of serous retinal detachments with associated subretinal deposits in a patient with multiple myeloma have been reported.2,15 In the first of these cases, the right eye revealed yellow precipitates on the posterior surface of the neurosensory elevation, whereas the left macula showed a neurosensory detachment with yellow-white subretinal precipitates. There was no OCT or fundus autofluorescence imaging reported in this case, but these deposits seem clinically consistent with acquired vitelliform lesions. In the second of these cases, bilateral ‘‘vitelliform-like’’ macular lesions were identified in a patient later diagnosed with multiple myeloma.15 Similar pseudovitelliform, yellow, subretinal deposits with associated subretinal fluid were recently reported for the first time in a patient with light chain deposition disease.12 In this case, the SD OCT showed multiple small detach-
ments of the neurosensory retina associated with hyperreflective deposits that were hyperautofluorescent on fundus autofluorescence, consistent with the appearance of vitelliform.12 In our case series, we describe 4 patients with immunogammopathies and serous macular detachments that we classify as vitelliform detachments. Our study is limited because it included only 4 subjects and we did not look at all variants of immunogammopathies. Additionally, although we have long follow-up on 3 of our 4 subjects, we do not have follow-up through successful treatment of the underlying immunogammopathy in 2 of our 4 subjects who have persistent, active disease and have not yet undergone bone marrow transplant. It would be interesting to see how bone marrow transplant or myelosuppression affects the resolution of vitelliform in these 2 patients. In summary, we report the funduscopic, fluorescein angiogram, SD OCT, and fundus autofluorescence findings in 3 patients with multiple myeloma and 1 patient with light chain deposition disease who all presented with acquired vitelliform macular detachments. Despite no or subtle signs of classic hyperviscosity retinopathy, all 4 of our patients presented with vitelliform macular detachments with or without serous pigment epithelial detachments. Clinicians should be aware that the presence of a vitelliform macular detachment, even without signs of hyperviscosity-related retinopathy, may be attributable to plasma cell dyscrasias.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. This work was supported by the LuEsther T. Mertz Retinal Research Foundation New York, New York . Contributions of authors: design and conduct of study (I.M.R., S.M., M.E., R.G., M.O., M.J., A.L., L.W.); collection (I.M.R., S.M., M.E., L.Y.), management (I.M.R., S.M., M.E., L.Y.), analysis (I.M.R., S.M., M.E., M.O., L.Y.), and interpretation of the data (I.M.R., S.M., M.E., R.G., M.O., M.J., A.L., L.Y.); preparation, review, or approval of the manuscript (I.M.R., S.M., L.Y.).
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13. Brolly A, Janon C, Precausta F, Baudet J, Cohen SY. Pseudovitelliform subfoveal deposit in Waldenstrom’s macroglobulinemia. Case Rep Ophthalmol 2012;3(2):236–239. 14. Franklin RM, Kenyon KR, Green WR, et al. Epibulbar IgA plasmacytoma occurring in multiple myeloma [case report]. Arch Ophthalmol 1982;100(3):451–456. 15. Khan JM, McBain V, Santiago C, Lois N. Bilateral ‘vitelliformlike’ macular lesions in a patient with multiple myeloma. BMJ Case Rep 2010; http://dx.doi.org/10.1136/bcr.05.2010. 3049. 16. Dupas B, Tadayoni R, Eriginay A, Massin P, Gaudric A. Subfoveal deposits secondary to idiopathic epiretinal membranes. Ophthalmology 2009;116(9):1794–1798. 17. Freund KB, Laud K, Lima LH, et al. Acquired vitelliform lesions: correlation of clinical findings and multiple imaging analysis. Retina 2011;31(1):13–25. 18. Negi A, Marmor MF. Quantitative estimation of metabolic transport of subretinal fluid. Invest Ophthalmol Vis Sci 1986; 27(11):1564–1568. 19. Robbins SL, Cotran RS, Kumar V. Pathologic Basis of Disease. 3rd ed. Philadelphia: Saunders; 1984. chapter 15. 20. Alexanian R. Plasma cell neoplasms and related disorders. In: Petersdorf RG, Adams RD, Braunwald E, et al., eds. Harrison’s Principles of Internal Medicine. 10th ed. New York: McGraw-Hill; 1983. chapter 65.
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21. Bloch KJ, Maki DG. Hyperviscosity syndromes associated with immunoglobulin abnormalities. Semin Hematol 1973; 10(2):113–124. 22. Carter PW, Cohen HJ, Crawford J. Hyperviscosity syndrome in association with kappa light chain myeloma. Am J Med 1989;86:591. 23. Enzenauer RJ, Stock JG, Enzenauer RW, et al. Retinal vasculopathy associated with systemic light chain deposition disease. Am J Med 1989;86(5):591–595. 24. Khan P, Roth MS, Keren DF, et al. Light chain disease associated with the hyperviscosity syndrome. Cancer 1987;60(9): 2267–2268. 25. Carr RE, Henkind P. Retinal findings associated with serum hyperviscosity. Am J Ophthalmol 1963;56:23–31. 26. Haimovici R, Gragoudas ES, Duker JS, Sjaarda RN, Eliott D. Central serous chorioretinopathy associated with inhaled or intranasal corticosteroids. Ophthalmology 1997;104(10): 1653–1660. 27. Daicker BC, Mihatsch MJ, Strom EH, et al. Ocular pathology in light chain deposition disease. Eur J Ophthalmol 1995;5(2):75–81. 28. Renouf DJ, Velazquez-Martin JP, Simpson R, et al. Ocular toxicity of targeted therapies. J Clin Oncol 2012;30(26):3277–3286. 29. Schoenberger SD, Kim SJ. Bilateral multifocal central serous-like chorioretinaophty due to MEK inhibition for metastatic cutaneous melanoma. Case Rep Ophthalmol Med 2013;2013:673796.
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Biosketch Irene M. Rusu earned a BA with general honors from the University of Chicago in 2005 and then dedicated a year to the AmeriCorps, working on behalf of the American Red Cross in post-hurricane Katrina New Orleans. She received her MD from the University of Chicago, Pritzker School of Medicine in 2010. She is currently a third year Ophthalmology resident at New York University School of Medicine/Manhattan Eye, Ear, & Throat Hospital. She will start a vitreoretinal surgery fellowship at New York Hospital/Cornell in July 2014.
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Accepted for publication Nov 25, 2013. From the Department of Ophthalmology, New York University School of Medicine, New York, New York (I.M.R., M.E., L.A.Y.); Vitreous Retina Macula Consultants of New York, New York, New York (S.M., M.E., L.A.Y.); LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital-Northshore Long Island Jewish Hospital, New York, New York (S.M., M.E., L.A.Y.); Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, Spain (R.G.P.); Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, New York (M.E., L.A.Y.); Retina Consultants of Michigan, Southfield, Michigan (M.D.O.); Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan (M.W.J.); and University Hospitals Leuven, Leuven, Belgium (A.L.). Inquiries to Lawrence A. Yannuzzi, Vitreous Retina Macula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
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with acquired vitelliform detachments of uncertain etiology. (Am J Ophthalmol 2014;157:648–657. Ó 2014 by Elsevier Inc. All rights reserved.)
I
MMUNOGAMMOPATHIES ARE CLONAL PLASMA CELL
proliferative disorders characterized by deposition of light or heavy chain immunoglobulin fragments in tissues, leading to organ dysfunction. Within this spectrum of diseases are multiple myeloma, Waldenstrom’s macroglobulinemia, and benign monoclonal gammopathy, as well as light chain deposition disease. Ocular manifestations of immunogammopathies have been described in a variety of ocular structures, including the conjunctiva, cornea, uvea, and retina.1 Serous macular detachments in association with immunogammopathies, though rare, have been described.2–15 Ho and associates first reported serous macular detachments with or without subretinal precipitates or fundus signs of serum hyperviscosity in 1 patient with multiple myeloma, 1 patient with Waldenstrom’s macroglobulinemia, and 1 patient with benign polyclonal gammopathy.2 Specifically in multiple myeloma, only 1 report describes deposits on the posterior surface of the neurosensory retina and in the subretinal space anterior to the retinal pigment epithelium (RPE).2 This previous study did not include current imaging modalities such as spectral-domain optical coherence tomography (SD OCT) or fundus autofluorescence imaging. This is a report on an additional 4 patients—3 with multiple myeloma and 1 with light chain deposition disease— who have associated serous detachments evaluated with multimodal imaging including fluorescein angiography, fundus autofluorescence, and SD OCT. We also propose a mechanism that would explain the advent and course of these particular exudative detachments.
PATIENTS AND METHODS THE INSTITUTIONAL REVIEW BOARD (IRB) AT NORTHSHORE
Long Island Jewish Hospital waived IRB approval for this retrospective case series. The records of 4 patients with vitelliform macular detachments and an immunogammopathy were examined. The following data were collected for each of the 4 cases: Snellen visual acuity at presentation
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RIGHTS RESERVED.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.11.020
FIGURE 1. Multimodal imaging of both eyes of a 58-year-old woman with multiple myeloma presenting with atrophic descending tracts and bilateral acquired vitelliform detachments that resolved when the serum immunoglobulin levels decreased. (Top row) Fundus photographs show mild retinal pigment epithelium changes. (Second row) Fundus autofluorescence shows hyperautofluorescent macular lesions surrounded by a wider area of granular hypoautofluorescence, more prominent OS, and bilateral atrophic
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and subsequent visits, epidemiologic data, past medical history, and clinical signs of retinal vasculopathy. The following imaging was also collected: fundus photographs, fluorescein angiography, fundus autofluorescence, and optical coherence tomography (OCT).
RESULTS CASE 1:
A 58-year-old woman presented with bilateral, asymmetric decreased vision over the course of several weeks. Her past medical history included well-controlled diabetes, a remote history of skin melanoma removed from the leg 12 years prior with no metastasis, and multiple myeloma, for which she was undergoing treatment. The patient was enrolled in multiple myeloma trial IPH 2101203, a multicenter, open-label phase II clinical trial designed to evaluate IPH 2101, an anti-KIR monoclonal antibody potentiating the antitumor activity of NK cells in patients with previously untreated smoldering multiple myeloma. As part of this trial, the patient underwent regular chemotherapy administrations for 1 year with no change in her multiple myeloma numbers. She presented to us on month 8 of this trial. Her past ocular history included a branch retinal vein occlusion (BRVO) in the left eye (OS). Her best-corrected visual acuity (BCVA) was 20/30 in the right eye (OD) and 20/70 OS with no relative afferent pupillary defect. Slit-lamp biomicroscopy showed a normal anterior segment examination. Dilated fundus examination revealed mild RPE changes, extending inferiorly from the discs in both eyes (OU) (Figure 1, Top row). On fundus autofluorescence, hyperautofluorescent macular lesions surrounded by a wider area of granular hypoautofluorescence were present, more prominently OS and associated with bilateral hypoautofluorescent atrophic descending tracts (Figure 1, Second row). Fluorescein angiography revealed diffuse intraretinal leakage, optic disc leakage, and some retinal microvascular abnormalities, but the area of detachment was hypofluorescent (Figure 1, Third row). No leak or pooling was noted in the area of the macular detachments. SD OCT at the level of these lesions showed a macular detachment with vitelliform deposition on the anterior surface of the RPE and the posterior surface of the neurosensory retina with associated subretinal and intraretinal fluid, more prominent OS and associated with intraretinal cysts at the level of the outer nuclear layer (Figure 1, Fourth row). Enhanced depth imaging (EDI)
OCT revealed slightly increased subfoveal choroidal thickness measuring 347 mm OD and 305 mm OS. Treatment of the macular edema with 10 anti–vascular endothelial growth factor (VEGF) intravitreal injections was initiated and response was followed by SD OCT. Five months after completing the multiple myeloma trial, she was started on 50 mg (oral [PO]) prednisone and underwent chemotherapy with 2 cycles of Velcade, a mitogen-activated protein kinase enzyme inhibitor; Revlimid; and Cytoxin. By this point she had received 9 anti-VEGF intravitreal injections as treatment for her BRVO, with improvement, but no resolution, of subretinal and intraretinal fluid. Three months later, she underwent induction chemotherapy again with Velcade, Revlimid, and 50 mg PO prednisone. It was during this month that her multiple myeloma immunoglobulin numbers came down for the first time in 20 months. This reduction in serum immunoglobulin from an M-spike of 5.63 to an Mspike of 0.94 coincided with a resolution of her vitelliform macular detachments and associated intraretinal and subretinal fluid for the first time since initiating treatment (Figure 1, Bottom row). CASE 2:
A 59-year-old woman with light chain deposition disease presented with decreased vision OU. BCVA was 20/20 OD and 20/25 OS. Past medical history was positive for hypertension, anemia, and end-stage renal disease. Fundus examination revealed peculiar subretinal lesions (Figure 2, Top row). These lesions were hyperautofluorescent on fundus autofluorescence (Figure 2, Middle row). Although OCT OD was flat, OCT OS showed a subretinal deposit anterior to the RPE (Figure 2, Bottom row). After 7 years of follow-up, fundus examination revealed persistence of the subretinal lesions with progression to neurosensory detachments and 20/50 vision OU. At this time, 1 dotblot hemorrhage in the midperiphery of each eye was identified with no associated vein occlusion, microaneurysms, or venous congenstion. As the patient had uncontrolled arterial hypertension at the time of this visit, the dot-blot hemorrhages were deemed to be secondary to the hypertension. Currently, the patient is referred for plasmapheresis.
CASE 3: A 55-year-old man presented with multiple neurosensory detachments OU including the peripapillary retina and fovea. On fundus examination, there were also multifocal areas of subretinal yellow deposits OU (Figure 3, Top row). His past medical history was significant only for mild hypertension. Fluorescein angiogram
descending tracts. (Third row) Fluorescein angiography shows generalized intraretinal leakage, disc leakage, and some microvascular abnormalities. No pooling was noted in the area of the macular detachment. (Fourth row) Spectral-domain optical coherence tomography (SD OCT) at the level of these lesions shows a macular detachment with vitelliform deposition on the anterior surface of the retinal pigment epithelium and the posterior surface of the neurosensory retina, more prominent OS and associated with intraretinal vacuole formation at the level of the outer nuclear layer OS. (Bottom row) Follow-up SD OCT shows complete resolution of the vitelliform detachments after induction chemotherapy.
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and indocyanine green chorioangiography revealed no focal leakage, hyperpermeability, plaque, or hot spot, but the yellow deposits were hyperautofluorescent on fundus autofluorescence (Figure 3, Second row). SD OCT showed neurosensory detachments with vitelliform deposition on the posterior surface of the neurosensory retina OU (Figure 3, Third row). Over time the macular neurosensory detachment resolved OU, leaving RPE atrophy with a visual decline down to roughly the 20/50 level OD. Two years later, the patient returned with a nearly symmetrical neurosensory detachment in the peripapillary retina and central macula OS, in addition to several elevated areas along the arcades in both eyes. There were no hemorrhages, exudations, or vascular tortuosity. By this time, he had developed monoclonal gammopathy of undetermined significance. A new fluorescein angiogram revealed no focal leaks in the macula OU. There was RPE atrophy in the right eye, and again the yellow lesions were hyperautofluorescent OU. Fortunately, his vision remained at 20/20 OS, although he had a hyperopic shift, and there was some mild distortion. Half-fluence photodynamic therapy was applied to the left eye, which ultimately did not alter the neurosensory detachment or his vision in any way. Repeat laboratory evaluation at this point led to a new diagnosis of multiple myeloma. He subsequently developed a few intraretinal hemorrhages and mild vascular tortuosity indicative of hyperviscosity that was characterized as rather subtle. Although several sequential treatments with plasmapheresis yielded no change in the neurosensory detachment in the left eye, the hemorrhages and tortuosity improved. He underwent bone marrow transplant at this time. Three years after presentation, electrophysiologic testing revealed an electrooculogram (EOG) with a normal Arden ratio. The electroretinogram (ERG) showed a mildly abnormal scotopic and photopic response with significant cone dysfunction in both eyes, somewhat more advanced OD. After bone marrow transplant, SD OCT showed resolution of the vitelliform detachments with residual subretinal fibrosis OD (Figure 3, Bottom row). CASE 4:
A 62-year-old man presented with decreased vision OD of 1 month’s duration. BCVA OD was 20/30-1. The left eye was asymptomatic, with BCVA of 20/30þ1. Past medical history included hypertension and multiple myeloma. The patient was taking 20 mg dexamethasone daily and reported that he first noticed a change in his vision after using Velcade as part of the Velcade-Revlimid-Dexamethasone protocol for 15 weeks. At this time his M-spike was 0.61 and he was taken off the Velcade but restarted back on it 1 month later when his M-spike increased to 0.71. Fundus photographs showed serous pigment epithelial detachments OU (Figure 4, Top row) with hyperautofluorescent material on fundus autofluorescence more prominent OD (Figure 4, Second row), but no retinal vasculopathy OU. SD OCT showed vitelliform deposits
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below the neurosensory retina and above the RPE OD (Figure 4, Third row). EDI OCT revealed increased choroidal thickness measuring 450 mm OD and 350 mm OS. At this time he was started on a mineralocorticoid since he had findings resembling central serous chorioretinopathy (CSC), but this regimen did not produce any change for 3 months. Finally, his serous pigment epithelium detachments completely resolved 4 months later while he was still on the mineralocorticoid, 50 mg of oral prednisone, and Velcade (Figure 4, Bottom row). This improvement coincided with an Mspike of 0.34, a record-low multiple myeloma immunoglobulin number in this patient.
DISCUSSION SEROUS MACULAR DETACHMENTS WITH OR WITHOUT
subretinal deposits have been reported in a number of immunogammopathies, including Waldenstrom’s macroglobulinemia, light chain deposition disease, and, rarely, multiple myeloma. These exudative detachments of the retina are known to be ‘‘angiographically silent.’’2 To our knowledge, no neovascularization was reported in those prior cases. In our study, based on current multimodal imaging we identified these detachments as vitelliform. Multiple etiologies are associated with acquired vitelliform lesions, including conventional drusen, subretinal drusenoid deposits, cuticular drusen, some retinal dystrophies, tractional maculopathies,16 and central serous chorioretinopathy. Vitelliform deposits are usually hyperautofluorescent and more or less homogenous depending on their etiology. They consist of debris including lipofuscin, melanolipofuscin granules in macrophages, and extracellular material derived from photoreceptor outer segment discs that accumulates in the subretinal space from RPE dysfunction.17 Fundamentally, in the case of immunogammopathies we are not sure what causes the vitelliform. The acquired vitelliform detachments were macular in 6 of the 8 eyes in our series (Cases 1, 2, and 4); diffuse, involving the midperiphery in 2 eyes (Case 3); and overlying a serous pigment epithelium detachment in 1 eye (Case 4). Bilateral, atrophic descending tracts were also found in 2 eyes of 1 patient (Figure 1, Second row), suggesting previous gravitating serous retinal detachments with residual RPE and outer retinal atrophy (Table). In 2 of our 4 patients the vitelliform detachments improved while on cortical therapy (Case 1 and Case 4). This introduces at least 2 theories for the evolution of subretinal fluid and subsequent vitelliform formation: (1) osmotic factors created by proteinous exudations, and (2) diffuse RPE dysfunction, or a combination of both. The metabolic reabsorption of subretinal fluid is dependent upon 2 main mechanisms: active ionic transport across the RPE and passive passage of fluid driven by the oncotic
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FIGURE 2. Multimodal imaging of both eyes of a 59-year-old woman with light chain deposition disease presenting with bilateral isolated acquired vitelliform lesions. (Top row) Fundus examination reveals bilateral peculiar subretinal lesions at the level of the retinal pigment epithelium; (Middle row) lesions are hyperautofluorescent on fundus autofluorescence, consistent with the appearance of acquired vitelliform lesions. (Bottom row) Horizontal foveal optical coherence tomography (OCT) scans reveal corresponding subretinal hyperreflective deposits anterior to the retinal pigment epithelium OS and no abnormality OD. Note that the foveal OCT scan OD is not at the level of the vitelliform lesions identified on color photograph and fundus autofluorescence.
pressure gradient (higher in the choroid).18 These are the 2 main mechanisms that permanently dehydrate the subretinal space. Immunoglobulins are large proteins that cannot passively diffuse across the RPE. To the best of our knowledge, there is no specific active transporter of immunoglobulins at the level of the RPE. However, one can assume that immunoglobulins can accumulate in the subretinal space in immunogammopathies and increase the oncotic pressure of the subretinal space, inversing the oncotic pressure gradient across the RPE. Fluid can therefore accumulate in the subretinal space, driven by the reversed oncotic pressure gradient. The fluid accumulating in the subretinal space physically separates the RPE from the photoreceptors, impeding proper phagocytosis. Therefore, outer segments 652
containing fluorophores (A2E) shed and accumulate in the subretinal space, resulting in the hyperautofluorescent signal present on fundus autofluorescence. It has been proposed in the past that subretinal immunoglobulin leads to fluid accumulation and subsequent serous macular detachments.2 In Waldenstrom’s macroglobulinemia, the presence of IgM was identified in the superficial retina and around the photoreceptors by immunofluorescence.3,4 Protein spillover from a supersaturated retina in which the capacity of the RPE to pump fluid is overwhelmed may also result in fluid accumulation. In our series, only 1 out of the 4 subjects (Case 1) displayed bilateral, diffuse intraretinal leakage and some microvascular abnormalities on fluorescein angiography;
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FIGURE 3. Multimodal imaging of both eyes of a 55-year-old man with multiple myeloma presenting with multiple acquired vitelliform detachments involving the macula and midperiphery that resolved after bone marrow transplant. (Top row) Fundus photographs show multifocal areas of subretinal yellow deposits OU separate from the subretinal fluid; (Second row) these deposits are hyperautofluorescent on fundus autofluorescence and consistent with the appearance of acquired vitelliform lesions. (Third row) Spectraldomain optical coherence tomography shows neurosensory detachments with subretinal deposits; (Bottom row) these resolved after bone marrow transplant, with residual subretinal fibrosis OD.
this may be explained by a past medical history of diabetes, although it cannot be excluded that hyperviscosity played a role. Classically, the hyperviscosity syndrome is seen in Waldenstrom’s macroglobulinemia,19–21 but it has also been described in certain cases of multiple myeloma22 and light chain deposition diseases.23,24 Features of hyperviscosity retinopathy such as retinal venous occlusions and retinal capillary microaneurysms1,25 were present in only 3 of the 8 eyes in our series (Cases 1 and 3). The resolution of the acquired vitelliform detachments VOL. 157, NO. 3
that we observed in 3 of our 4 subjects after successful treatment of their multiple myeloma implicates a proteinous etiology to these detachments. Diffuse RPE dysfunction may also have contributed to the development of acquired vitelliform retinal detachments in our cases, since 1 subject presented with additional bilateral atrophic descending tracts (Case 1) and 1 with additional bilateral serous pigment epithelial detachments (Case 4). This constellation of findings is highly suggestive of a diagnosis of CSC. However, none of these patients showed the
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FIGURE 4. Multimodal imaging of both eyes of a 62-year-old man with multiple myeloma presenting with bilateral serous pigment epithelial detachments and an overlying acquired vitelliform lesion in the right eye that resolved when the serum immunoglobulin levels decreased. Fundus photographs show pigment epithelial detachments OU (Top row) with hyperautofluorescent material on fundus autofluorescence more prominent OD (Second row). (Third row) Spectral-domain optical coherence tomography (SD OCT) shows pigment epithelial detachments OU with an overlying subretinal hyperreflective deposit OD resembling an acquired vitelliform lesion. (Bottom row) Follow-up SD OCT shows resolution of the pigment epithelial detachments corresponding with a reduction in the multiple myeloma immunoglobulin numbers.
typical leakage pattern on fluorescein angiography, and all eyes in these subjects eyes actually improved after corticosteroid therapy as part of the multiple myeloma treatment (Case 1 and Case 4). These acquired vitelliform retinal detachments were chronic in all cases (more than 6 months) and improved in 3 patients (6 eyes) only after successful treatment of the multiple myeloma (Case 1, Case 3, and Case 4), suggesting a causal relationship between the concentration of immunoglobulins and the pathogenesis of these chronic acquired vitelliform retinal detachments. 654
The remaining subject in this series is still undergoing treatment; in Case 2 the subject was referred for bone marrow transplant. In Case 4 the subject is still undergoing chemotherapy. In all of the cases in this series in which the patients have completed treatment successfully, the vitelliform lesions resolved as the protein content decreased. Additionally, the corticotherapy improved the serous retinal detachments in both of the patients in our series (Case 1 and Case 4), whereas it has been shown to be a risk factor inducing or worsening CSC findings.26
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TABLE. Variations of the Clinical and Retinal Imaging Characteristics of Four Patients With Immunogammopathies and Acquired Vitelliform Detachments Characteristic
Patient 1
Patient 2
Clinical history
58-year-old woman with multiple myeloma
Presence of hyperviscosity retinopathy Fundus photographs
Branch retinal venule occlusion OS
59-year-old woman with light chain deposition disease None
Fundus autofluorescence
Fluorescein angiogram Optical coherence tomography
Follow-up
Patient 4
55-year-old man with multiple myeloma
62-year-old man with multiple myeloma
Few intraretinal hemorrhages and mild vascular tortuosity OU Macular and peripheral subretinal yellow deposits OU Hyperautofluorescent lesions in the macula and midperiphery OU
None
Not available
No focal leakage
Not available
Subretinal hyperreflective deposit OS
Neurosensory detachments with subretinal hyperreflective deposits OU Bone marrow transplant resulted in resolution of the vitelliform detachments
Subretinal hyperreflective deposits OD
Mild retinal pigment epithelial changes in the macula Hyperautofluorescent macular lesions OU Hypoautofluorescent atrophic descending tracts OU Diffuse intraretinal leakage Macular detachments with subretinal hyperreflective deposits OU
Macular subretinal yellow deposits OU
Induction chemotherapy resulted in reduced M-spike and resolution of the vitelliform macular detachments
Patient referred for plasmapheresis
Hyperautofluorescent macular deposits OU
The presence of atrophic descending tracts (Figure 1, Second row) is not pathognomonic of CSC but can rather demonstrate RPE dysfunction as a consequence of subretinal fluid accumulation in various chorioretinal diseases including CSC, choroidal hemangioma, choroidal nevus, age-related macular degeneration, and immunogammopathies. A relatively thickened choroid was present in 2 of our 4 cases (Cases 1 and 4). A postmortem histopathologic study of a patient with light chain deposition disease by Daicker and associates suggests that immunoglobulin deposition in the choroid could lead to RPE dysfunction. Light microscopy, immunofluorescence, and electron microscopy identified extensive deposition of kappa light chains in the uvea and choroid.27 Light chains were present in the deep choroid and were more pronounced in the central fundus, suggesting a local circulatory origin. Partial choriocapillary occlusion was associated with dense, yellow subretinal deposits in the posterior pole and an overlying exudative retinal detachment.27 A recent case series of 3 patients with light chain deposition disease11 and yellowish deposits consistent with acquired vitelliform lesions and the postmortem histopathology described above suggests that light chain deposition in the choroid impairs RPE function, leading to fluid retention and RPE detachments. VOL. 157, NO. 3
Patient 3
Macular serous pigment epithelial detachments OU Hyperautofluorescent macular deposit OD
Induction chemotherapy resulted in reduced M-spike and resolution of the vitelliform macular detachment
The mitogen-activated protein kinase enzyme inhibitors are a novel class of molecules, used as targeted therapies in a number of malignancies including multiple myeloma, that have been shown to have some ocular toxicities.28 Recently, 1 case report described bilateral multifocal CSC-like chorioretinopathy after use of a mitogenactivated protein kinase enzyme inhibitor in the treatment of metastatic cutaneous melanoma.29 It is unlikely that the use of mitogen-activated protein kinase enzyme inhibitors was responsible for the findings in our patients since the serous macular detachments (Case 1) and pigment epithelium detachments (Case 4) improved in both patients while on these medications. Despite the presence of serous macular detachments in our patients, the visual prognosis was good because none of the detachments were associated with choroidal neovascularization or macular hole formation. In a recent case series of patients with Waldenstrom’s macroglobulinemia and serous macular detachments, OCT showed a disruption of the outer retinal physiologic lines, suggesting that the disruption of the outer retina served as a track for intraretinal immunoglobulin M and fluid to enter the subretinal space.8 In our series of 4 patients, there was no persistent outer retinal disruption. With resolution of the acquired vitelliform detachments, we observed restoration of the
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normal outer retina and RPE anatomy on SD OCT in all of the eyes in our series except 1 that developed outer retinal and RPE atrophy with associated subretinal fibrosis, similar to the residual atrophy that may occur in other diseases as the vitelliform lesions resolve (Figure 3, Bottom row, left column). As expected, these nonvascularized retinal detachments did not respond effectively to anti-VEGF agents; rather, they resolved only with reversal of the disease process. Thus, treatment should not be aimed at reducing the fluid subretinally without oncologic treatment of the hyperproteinemia. To our knowledge, only 2 cases of serous retinal detachments with associated subretinal deposits in a patient with multiple myeloma have been reported.2,15 In the first of these cases, the right eye revealed yellow precipitates on the posterior surface of the neurosensory elevation, whereas the left macula showed a neurosensory detachment with yellow-white subretinal precipitates. There was no OCT or fundus autofluorescence imaging reported in this case, but these deposits seem clinically consistent with acquired vitelliform lesions. In the second of these cases, bilateral ‘‘vitelliform-like’’ macular lesions were identified in a patient later diagnosed with multiple myeloma.15 Similar pseudovitelliform, yellow, subretinal deposits with associated subretinal fluid were recently reported for the first time in a patient with light chain deposition disease.12 In this case, the SD OCT showed multiple small detach-
ments of the neurosensory retina associated with hyperreflective deposits that were hyperautofluorescent on fundus autofluorescence, consistent with the appearance of vitelliform.12 In our case series, we describe 4 patients with immunogammopathies and serous macular detachments that we classify as vitelliform detachments. Our study is limited because it included only 4 subjects and we did not look at all variants of immunogammopathies. Additionally, although we have long follow-up on 3 of our 4 subjects, we do not have follow-up through successful treatment of the underlying immunogammopathy in 2 of our 4 subjects who have persistent, active disease and have not yet undergone bone marrow transplant. It would be interesting to see how bone marrow transplant or myelosuppression affects the resolution of vitelliform in these 2 patients. In summary, we report the funduscopic, fluorescein angiogram, SD OCT, and fundus autofluorescence findings in 3 patients with multiple myeloma and 1 patient with light chain deposition disease who all presented with acquired vitelliform macular detachments. Despite no or subtle signs of classic hyperviscosity retinopathy, all 4 of our patients presented with vitelliform macular detachments with or without serous pigment epithelial detachments. Clinicians should be aware that the presence of a vitelliform macular detachment, even without signs of hyperviscosity-related retinopathy, may be attributable to plasma cell dyscrasias.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. This work was supported by the LuEsther T. Mertz Retinal Research Foundation New York, New York . Contributions of authors: design and conduct of study (I.M.R., S.M., M.E., R.G., M.O., M.J., A.L., L.W.); collection (I.M.R., S.M., M.E., L.Y.), management (I.M.R., S.M., M.E., L.Y.), analysis (I.M.R., S.M., M.E., M.O., L.Y.), and interpretation of the data (I.M.R., S.M., M.E., R.G., M.O., M.J., A.L., L.Y.); preparation, review, or approval of the manuscript (I.M.R., S.M., L.Y.).
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Biosketch Irene M. Rusu earned a BA with general honors from the University of Chicago in 2005 and then dedicated a year to the AmeriCorps, working on behalf of the American Red Cross in post-hurricane Katrina New Orleans. She received her MD from the University of Chicago, Pritzker School of Medicine in 2010. She is currently a third year Ophthalmology resident at New York University School of Medicine/Manhattan Eye, Ear, & Throat Hospital. She will start a vitreoretinal surgery fellowship at New York Hospital/Cornell in July 2014.
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