Paraprotein Maculopathy

Paraproteinemic Maculopathy

Ahmad M. Mansour, MD,1 J. Fernando Arevalo, MD,2 Josep Badal, MD,3 Ramana S. Moorthy, MD,4 Gaurav K. Shah, MD,6 Hernando Zegarra, MD,5 Jose S. Pulido, MD,7 Abdulrazzak Charbaji, PhD,8 Luis Amselem, MD,3 Alejandro Jose Lavaque, MD,9 Antonio Casella, MD,10 Baseer Ahmad, MD,6 Joshua G. Paschall, MD,4 Antonio Caimi, MD,11 Giovanni Staurenghi, MD11

Purpose: Paraproteinemia relates to monoclonal gammopathy-producing pathologic antibodies with serous macular detachment being an uncommon ocular manifestation. We ascertained the clinical course of maculopathy in paraproteinemia and investigated the effect of various therapeutic methods on the resolution of subretinal deposits. Design: Multicenter, retrospective, observational case series. Participants: The records of patients with paraproteinemia with optical coherence tomography (OCT) documentation of serous macular detachment were reviewed. Methods: Data collection included coexisting morbidity, rheology data (immunoglobulin level, hematocrit, and blood viscosity), clinical examination results, and OCT findings. Main Outcome Measures: Best-corrected visual acuity (BCVA), height and basal area of the serous macular detachment, and systemic versus local therapies. Results: A total of 33 cases were collected: 10 new and 23 previously reported in the literature. Diabetes was present in 7 patients, systemic hypertension in 9 patients, and anemia in 18. Mean initial immunoglobulin level was 6497 mg/dl, and mean serum viscosity was 5.5 centipoise (cP). Mean logarithm of the minimum angle of resolution initial vs. final BCVA was 0.55 (Snellen equivalent, 20/71) vs. 0.45 (20/56) in the right eye and 0.38 (20/48) vs. 0.50 (20/63) in the left eye. After mean follow-up of 7 months (range, 0-51 months). Systemic therapies included plasmapheresis (18), chemotherapy (30), blood transfusions (2), transplantation of progenitor hemato- poietic cells (2), and oral rituximab (10). Immunoglobulin levels normalized in 8 patients and were unchanged in 1 after plasmapheresis, chemotherapy, or both. Ocular therapy in 8 patients included vitrectomy (1), laser photo- coagulation (4), intravitreal bevacizumab (5), intravitreal triamcinolone (2), intravitreal dexamethasone implant (1), intravitreal rituximab (1), and sub-Tenon corticosteroid (1). The maculopathy resolved partially or completely in 17 patients and worsened or remained unchanged in 14 patients over median follow-up of 7 months. Maculopathy was unilateral in 9 cases and occurred at a lower initial immunoglobulin level in diabetics. There was a positive correlation between area of the detachment and serum viscosity. Conclusions: Paraproteinemic maculopathy can be unilateral. Decreasing the blood immunoglobulin level is the primary goal of therapy for paraproteinemic maculopathy, and this can be achieved by a systemic route. Coexisting diabetes facilitates leakage of immunoglobulins at lower levels than in nondiabetics. Ophthalmology 2014;121:1925- 1932 ª 2014 by the American Academy of Ophthalmology.

Supplemental material is available at www.aaojournal.org.

Paraproteinemia, or monoclonal gammopathy, is the presence stasis retinopathy, immunoprotein deposition in the cornea of excessive amounts of a single monoclonal g-globulin (or and pars plana, and IgM deposits in all layers of the paraprotein) in the blood. Monoclonal paraproteins are retina. A rare peculiar serous macular detachment in detected in the sera of 1% of the general population.1 This is paraproteinemia has been described.2e10 Herein, we review usually the result of an underlying immunoproliferative our case series and the literature to attempt to understand the disorder that includes multiple myeloma (MM), immu- causative factors involved in this maculopathy. nocytoma, and Waldenström macroglobulinemia (WM). Waldenström macroglobulinemia is a non-Hodgkin’sB-cell lymphoplasmacytic lymphoma affecting 3.8 per 1 million Methods people annually, approximately 2% of all hematologic The institutional review board approved the retrospective analysis malignancies, and involving the elderly with onset around of data for this observational case series. The records of patients 63 years of age. This monoclonal immunoglobulin M with paraproteinemia and macular pathologic features were (IgM) paraproteinemia is characterized clinically by signs reviewed. The following data were collected: Snellen best- and symptoms of serum hyperviscosity and hemorrhagic corrected visual acuity (BCVA; translated into logarithm of the tendency. Ocular manifestations of WM include venous minimum angle of resolution [logMAR] units), immunoglobulin

2014 by the American Academy of Ophthalmology ISSN 0161-6420/14/$ - see front matter 1925 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2014.04.007 Ophthalmology Volume 121, Number 10, October 2014 level, hematocrit, blood viscosity, associated systemic and ocular Five were white, 1 was Hispanic, and 4 were of unspecified race. comorbidities, and treatment methods and their effects as assessed The mean age was 59.8 years (range, 40e87 years). Systemic on optical coherence tomography (OCT). Therapies included diseases included WM (n ¼ 8), MM (n ¼ 2), diabetes mellitus (n ¼ various combinations of plasmapheresis (plasma exchange), 4), systemic hypertension (n ¼ 2), and anemia (n ¼ 6). The sub- chemotherapy, intravitreal bevacizumab (off label), triamcinolone retinal fluid under the fovea had a mean area of 2.4 DD for the right or rituximab (off label), and laser photocoagulation after informed eye and 2.1 DD for left eye (range, 1e4 DD) in 17 eyes of 10 consent was obtained. patients (Figs 1, 2, 3, and 4). The maculopathy was unilateral in 3 We also collected from the literature cases of paraproteinemic patients. maculopathy using Scopus, Google Scholar, and Medline searches To perform statistical analyses, we combined the current series through October 2013, searching for macula AND MM, WM, and with the literature review of 23 cases (Table 1). These 33 cases paraproteinemia, including polyneuropathy organomegaly endo- included 21 men and 11 women; 11 were white, 3 were black, 2 crinopathy M-protein and skin abnormalities syndrome and light- were Asian, and 1 was Hispanic. The mean age was 59 years chain deposition disease. Hypertension is defined as a systolic (range, 37e87 years). Waldenström macroglobulinemia was pre- blood pressure of 140 mmHg or more or a diastolic blood pressure sent in 20 patients, MM was present in 7 patients, benign gamm- of 90 mmHg or more. Anemia is defined as hematocrit of less than opathy was present in 3 patients, light-chain deposition disease was 40% for males and less than 35% for females. Correlation was present in 2 patients, and polyneuropathy organomegaly endo- carried out using correlation coefficient-adjusted r2, 1-way analysis crinopathy M-protein and skin abnormalities syndrome was present of variance, and standardized b regression coefficients using SPSS in 1 patient. Diabetes mellitus was present in 7 patients, systemic Statistics for Windows version 21.0 (IBM Corp., Armonk, NY). hypertension was present in 9 patients, renal failure was present in Area of the maculopathy and height were measured on fundus 5 patients, anemia was present in 18 patients, and carotid stenosis photography (reference being vertical disc diameter [DD]) and and systemic lupus erythematosus each were present in 1 patient. OCT (caliper tool; in older machines with no calipers, the macular Unilateral involvement occurred in 9 patients. Mean hematocrit retinal thickness was assumed at 300 mm), respectively. The hor- was 28.6% (median, 29%; n ¼ 14; range, 14.4%e40%). Mean izontal and vertical diameters of the sensory detachment were serum viscosity was 5.5 centipoise (cP; median, 4.2 cP; n ¼ 11; measured, and the longest of the 2 measurements was taken as the range, 2.5e9.1 cP; normal values, 1.5e1.9 cP). Mean initial area. Similarly, on OCT, the height of the sensory detachment was immunoglobulin level was 6497 mg/dl (median, 5888 mg/dl; measured on the vertical and horizontal scans through the foveola, range, 306e14,000 mg/dl; n ¼ 24; normal values, 820e2200 mg/ and the largest value was adopted for the height. dl). The mean diameter of the maculopathy was 2.0 DD (right eye, 2.0 DD [n ¼ 27]; and left eye, 2.0 DD [n ¼ 28]; range, 0.5e5 DD). Mean height of serous detachment was 435 mm in the right eye Results (range, 71e1167 mm[n¼ 16]) and 410 mm in the left eye (range, 50e1060 mm[n¼ 19]). Mean initial BCVA was 0.55 logMAR The current retrospective series included 10 subjects (Table 1, (Snellen equivalent, 20/71) in the right eye and 0.38 logMAR available at www.aaojournal.org) comprising 7 men and 3 women. (Snellen equivalent, 20/48) in the left eye. Final BCVA was 0.45

Figure 1. Fundus photographs of the (A) right eye and (B) left eye and (C, D) spectral-domain optical coherence tomography (OCT) images obtained at the initial visit. Venous dilation and tortuosity with peripheral capillary nonperfusion also was observed. The OCT scans show bilateral intraretinal edema and serous detachment of the neurosensory retina of the left eye. Best-corrected visual acuity was 20/20 in the right eye and 20/60 in the left eye.

1926 Mansour et al Paraproteinemic Maculopathy

Figure 2. After 6 weeks, (A, C) serous macular detachment with overlying cystoid macular edema was observed in the right eye, and (B, D) an increase in the subretinal fluid was observed in the left eye. Best-corrected visual acuity dropped to 20/60 in the right eye and 20/200 in the left eye.

Figure 3. After 3 monthly 2.5-mg/0.1-ml bevacizumab injections, (A, B) fundus photographs and (C, D) spectral-domain optical coherence tomography (SD OCT) images showed a mild reduction of both intraretinal and subretinal fluid in both eyes. The SD OCT images show refractory edema. Best-corrected visual acuity remained 20/60 in the right eye and 20/200 in the left eye. The SD OCT image from the right eye (C) shows unique stalactite-like projections of the outer retina.

1927 Ophthalmology Volume 121, Number 10, October 2014

Figure 4. Schematic diagram showing the pathogenesis of paraproteinemic maculopathy. BM ¼ Bruch’s membrane; CC ¼ choriocapillaris; IgM ¼ immunoglobulin M; RPE ¼ retinal pigment epithelium. logMAR (Snellen equivalent, 20/56) in the right eye and 0.50 (P ¼ 0.001 for the right eye and P ¼ 0.021 for the left eye) and did logMAR (Snellen equivalent, 20/63) in the left eye (Table 1). not correlate with immunoglobulin level, serum viscosity, hemat- Regarding therapy for the 33 patients, plasmapheresis was ocrit, age, diabetes, or area or height of the detachment. Diabetics administered in 18 patients, chemotherapy was administered in versus nondiabetics had the following mean values: age, 67.0 30 patients, blood transfusions were administered in 2 patients, versus 56.7 years (P ¼ 0.04); immunoglobulin level, of 4115 and transplant of progenitor hematopoietic cells was performed versus 7306 mg/dl (P ¼ 0.10; normal values, 820e2200 mg/dl); in 2 patients. Oral rituximab was used in 10 patients. Immuno- area of macular detachment, 2.2 versus 2.0 DD in the right eye globulin levels normalized in 8 patients and were unchanged in 1 (P ¼ 0.43) and 1.83 versus 1.98 DD in the left eye (P ¼ 0.40); and patient after plasmapheresis, chemotherapy, or both. Ocular ther- hematocrit, 28.6% versus 28.8% (P ¼ 0.50). Additional causes apy in 8 patients included vitrectomy in 1 patient, laser photoco- of leakage into the subretinal space included (1) disc edema in agulation in 4 patients, intravitreal bevacizumab in 5 patients 1 patient (patient 32), (2) severe ischemic diabetic retinopathy in 1 (Fig 3), intravitreal triamcinolone in 2 patients, intravitreal patient (patient 10), (3) occlusive choroidal and retinal disease in 1 dexamethasone implant in 1 patient, intravitreal rituximab in 1 patient (hence failure of the retinal pigment epithelium [RPE] patient (Fig 3), and sub-Tenon corticosteroid in 1 patient (Ta- pump; patient 4), and (4) deep retinal leakage sites in 2 patients (2 ble 1). The maculopathy resolved partially or completely in 17 sites in patient 8 and 1 site in patient 6), possibly related to outer patients and worsened or stayed unchanged in 14 patients over a retinal defects, as seen in patient 9. Of note is a peculiar finding of median follow-up of 7 months (mean, 19 months; 2 patients had no stalactite-like projections in the outer retina in macula of patient 9 follow-up). Immunoglobulins were unchanged in 1 patient and (see “Case Report”; Fig 3C). likewise for maculopathy after therapy in 1 case. Immunoglobulin decreased markedly, but maculopathy did not improve in 3 pa- Case Report tients. Immunoglobulin decreased and maculopathy improved in 5 patients. A 47-year-old white man with no significant medical history was There was a strong positive correlation between level of referred to our clinic for blurry vision in the left eye. Baseline immunoglobulin and serum viscosity (P ¼ 0.007). No correlation BCVA was 20/20 in the right eye and 20/60 in the left eye. Slit- was present between level of immunoglobulin and hematocrit, lamp biomicroscopy results were unremarkable, and intraocular diabetes (P ¼ 0.10), initial BCVA, area (P ¼ 0.33 for the right eye pressure was 12 mmHg in the right eye and 14 mmHg in the left and P ¼ 0.34 for the left eye), and height of the macular detach- eye. Fundus examination showed mild venous dilation and tortu- ment. There was no correlation between area of the detachment and osity in both eyes and a serous macular detachment with yellow presence of diabetes, age, or initial BCVA. There was a positive subretinal exudates in the left eye (Fig 1). Optical coherence correlation between area of the detachment and serum viscosity tomography revealed bilateral cystoid macular edema and (P ¼ 0.017 for the right eye and P ¼ 0.022 for the left eye). There detachment of the neurosensory retina. Fluorescein angiography was no correlation between initial BCVA and height or area of the showed peripheral vaso-occlusive disease with significant capil- macular detachment. Visual gain correlated with initial BCVA lary nonperfusion. Six weeks after initial presentation, BCVA

1928 Mansour et al Paraproteinemic Maculopathy decreased to 20/60 in the right eye and 20/200 in the left eye, and mechanism of the altered blooderetinal barrier results from OCT showed neurosensory detachment with overlying cystoid the altered permeability of retinal endothelial cells caused macular edema and bilateral disruption of the outer retina (Fig 2). by elevated levels of growth factors (such as vascular ’ The patient s blood pressure was 130/90 mmHg. Hyperviscosity endothelial growth factor), cytokines, and loss of pericytes syndrome was suspected, and blood tests revealed severe anemia (as occurs in diabetes). Subsequently, both paracellular and (hemoglobin, 7.9 mg/dl; normal values, 13.5e17.5 mg/dl) and a total serum protein level of 19.2 mg/dl (normal values, 6.0e8.0 transcellular transport across the retinal vascular wall increase mg/dl), with elevated monoclonal IgM of 10 500 mg/dl (normal via opening of the endothelial intercellular junctions and values, 45e153 mg/dl). Bone marrow biopsy showed massive increase in endothelial caveolar transcellular transport. There lymphoplasmacytoid infiltration. A diagnosis of WM was is histologic evidence that the bloodeneural barrier (which is made. Computed tomography of the abdomen showed multiple similar to the blooderetinal barrier) is affected in retroperitoneal lymphadenopathies (iliac and inguinal). Plasma- paraproteinemia. Kanda et al31 reported the pathologic pheresis was performed, followed by 8 cycles of systemic findings in a patient with sensorimotor neuropathy associated polychemotherapy with rituximab, cyclophosphamide, doxoru- with WM and monoclonal IgM, particularly in relation to bicin, vincristine, and steroids and 2 cycles of cladribine. bloodenerve barrier defects. A sural nerve biopsy specimen Systemic rituximab was not given until IgM levels decreased to revealed gaps between adjacent endothelial cells of small less than 5.0 mg/dl because rituximab is associated with sudden increase in IgM levels and should be avoided in patients with endoneurial vessels as well as the absence of some of the hyperviscosity. Simultaneously, 3 monthly 2.5-mg/0.1-ml intra- tight junctions between adjacent endothelial cells. Similarly, vitreal bevacizumab injections were administered in both eyes. in a sural nerve biopsy from a patient with benign Best-corrected visual acuity remained 20/60 in the right eye and monoclonal IgM k gammopathy and sensorimotor demyeli- 20/200 in the left eye, and OCT demonstrated a slight bilateral native neuropathy, Lash et al32 found that many endoneurial decrease in neurosensory detachment (Fig 3). At that time, the IgM capillaries were lined by fenestrated endothelium, indicating level dropped to 3925 mg/dl. Two months after the last intravitreal the breakdown of the normal bloodenerve barrier. The bevacizumab injection, 3 monthly intravitreal injections of endoneurium contained large amounts of extracellular rituximab (1 mg/0.1 ml) were administered in both eyes. Best- proteinaceous material containing IgM kg-globulin. corrected visual acuity remained unchanged and OCT demon- Brody et al10 suggested that macular exudative detachments strated a slight bilateral decrease in the amount of subretinal fluid (Fig 3). At that time, the IgM level dropped to 2943 mg/dl. After 2 from diabetic maculopathy can lead to increased leakage of years of follow-up, complete remission was not reached; BCVA immunoglobulins into the subretinal space. In a case with was 20/60 in the right eye and 20/400 in the left eye, and OCT polyneuropathy organomegaly endocrinopathy M-protein 3 showed no significant improvement. and skin abnormalities syndrome, Okada et al proposed that the high vascular endothelial growth factor level probably induced the retinal microvascular hyperpermeability, leading Discussion to leakage of immunoglobulin in the subretinal space. The maculopathy resolved 1 month after hematopoietic surgery, Serous macular detachment is an uncommon ocular mani- when serum vascular endothelial growth factor level festation of paraproteinemia.2e27 The absence of angio- decreased in response to autologous peripheral blood stem graphic leakage within the macular detachment does not cells. The sera of WM patients are known to be associated support the theory of angiographic exudation from the retinal with increased levels of angiogenic cytokines, such as or choroidal vasculature. In a few cases, there was leakage in angiogenin, vascular endothelial growth factor, and basic the deep retina (Table 1). Some investigators have focused on fibroblast growth factor.33 In normal bone marrow, the presence of IgM in the subretinal space,11,12 suggesting angiopoietin-1 consistently activates tyrosine kinase with that an increased osmotic gradient causes fluid accumulation immunoglobulin-like and epidermal growth factor-like do- under the retina. In support of this hypothesis, several his- mains-2 and stabilizes vessels by promoting interactions topathologic reports documented immunoglobulins in the between endothelial cells and surrounding pericytes. On subretinal space.11e13 High-molecular-weight immunoglob- the contrary, during the malignant process in WM, ulins lead to an osmotic gradient. Because IgM antibodies are increased angiopoietin-2 levels block tyrosine kinase with the the largest antibodies found in the blood and the lymph fluid, immunoglobulin-like and epidermal growth factor-like do- they rarely accumulate in pericardial, peritoneal, and pleural mains-2 receptor and lead to vessel destabilization by loos- effusions.28,29 Immunoglobulin M antibodies consist of a ening endothelialeperiendothelial cell interactions and heavy chain, a light chain, and 5 base units with a molecular degrading the extracellular matrix. The primary source of mass of 970 kDa in its pentamer form (molecular weight, angiopoietin-2 is endothelial cells because angiopoietin-2 is 0.6e1 000 000 kDa). Because IgM antibodies are very large stored in vesicles known as Weibel-Palade bodies and is molecules and cannot diffuse well, they are found in the released rapidly in response to hyperglycemia and ischemia. interstitium in extremely low quantities. When such large, Angiopoietin-2 seems to be an important mediator in the positively charged IgM molecules are present in excess, they alteration of the blooderetinal barrier in diabetes and other bind electrostatically to red cells, aggregating and forming retinal vascular disorders.30 rouleaux, with subsequent increase in the blood viscosity. As Ashton34 as well as Foos and Allen35 were among the first to the IgM protein concentration in the serum increases, the describe retinal and RPE detachment histologically in patients blood viscosity increases exponentially. It is somewhat with MM. The subpigment epithelial fluid is derived from intriguing to explain how IgM antibodies reach the subretinal choroidal vessels. The platelets can no longer fulfill their space (Fig 4). According to Klaassen et al,30 the central normal function of maintenance of endothelium because they

1929 Ophthalmology Volume 121, Number 10, October 2014 become covered by paraprotein. Moreover, the hyperviscosity 5.5 cP. Prompt referral to a hematologist or oncologist is can cause stasis and hypoxia, leading to endothelium necessary for systemic monitoring and treatment. The visual decompensation. There is secondary breakdown of the loss in paraproteinemic maculopathy may be similar to the blooderetinal barrier, in addition to the RPE decompensation visual loss in CSR, with proteinaceous subretinal fluid.40 from the underlying deposit and hypoxia. Coexisting anemia, Landa et al40 found a correlation between the subfoveal diabetes, and hypertension are additional risk factors for thickness of the protein deposit layer and visual acuity at retinal vascular endothelial damage and ischemic injury, baseline in 38 patients with CSR. No such relation was enhancing leakage and breakdown of the blooderetinal found in our series, possibly because of the retrospective barrier. Dumas et al36 explored the contribution of plasma nature of the study and the small size of the study group. viscosity and the endothelial cell monolayer to oxygen Usually, no treatment is indicated for asymptomatic dis- molecular transport processes using a fluorescence inhibition ease. Indications for initiating treatment include blood method. They found hypoxia induced by hyperviscosity hyperviscosity and ocular disturbance. The cardinal therapies plasmas from patients with WM to have increased include plasmapheresis (for patients with symptomatic intercellular adhesion molecule 1 expression on the surface of hyperviscosity), rituximab (anti-CD20 antibody, that is, endothelial cells, which could be the cause of vascular genetically engineered human monoclonal antibody directed disorders through the implication of polymorphonuclear against the CD20 antigen found on the surface of normal and neutrophils. malignant B lymphocytes), and chemotherapy (purine Baker et al2 demonstrated complete disruption of the nucleoside analogs, alkylating agents, thalidomide, and bor- outer retina within the detachment and proposed that these tezomib). Plasmapheresis is very useful in reducing serum focal outer retinal defects (Figs 2 and 3) slowly progress hyperviscosity and rapidly improving most ocular manifes- over time, eventually allowing a so-called track for intra- tations. According to Menke et al,41 plasmapheresis resulted retinal IgM. Our study was not aimed at estimating the in significant reductions in serum IgM (by 46.5%) and serum presence of such outer retinal defects. A pathologic viscosity (by 44.7%), and venous stasis retinopathy improved communication between the optic disc, the subarachnoid in all patients after plasmapheresis. Paraproteinemia-related space, and the subretinal space was proposed by Feigl et al16 venous stasis retinopathy mimics a central retinal vein and Khan et al.19 Feigl et al16 found a finger-like extension occlusion-like appearance (no thrombus) with normal retinal to the optic disc from the macular detachment by indoc- blood flow. In our review, the area of the macular detachment yanine angiography and proposed the disc as the cause of correlated with serum viscosity, and many eyes did not the macular detachment, similar to optic pit maculopathy. demonstrate resolution of the maculopathy despite improve- There is a lot of overlap between the pathogenesis of ment in both the serum viscosity and the venous stasis reti- central serous retinopathy (CSR) and paraproteinemic mac- nopathy. One possible reason could be the short follow-up ulopathy. Unilaterality of the maculopathy is one common in the current review; these immunoglobulins need a long finding in paraproteinemia and CSR, as found in the current time to resolve.42 Besides plasmapheresis, chemotherapy, series. In CSR, Prünte and Flammer37 detected capillary or especially with rituximab, remains the mainstay of therapy. venous congestion after ischemia in 1 or more choroidal Various intravitreal injections (bevacizumab, triamcinolone, lobules, and this finding may be the reason for choroidal rituximab43)failedtoshowadefinite benefit in the current hyperpermeability. Nicholson et al38 documented the series. presence of a thickened and engorged choroid in CSR In conclusion, this case series, along with the literature by enhanced depth OCT and proposed that these review, provide further evidence of the direct correlation hyperpermeable choroidal vessels produce increased tissue between IgM levels in the blood and the degree of subretinal hydrostatic pressure, promoting the formation of RPE fluid accumulation under the fovea in these patients. Clinical detachments, overwhelming the barrier function of the improvement clearly correlated with a decrease in serum RPE, and leading to fluid accumulation between the retina IgM. Maculopathy of paraproteinemia can mimic diabetic and the RPE. Optical coherence tomography also may retinopathy, adult vitelliform dystrophy, and CSR, espe- show an anatomic defect (microrip) in the RPE associated cially in the many patients with diabetes. Unilateral local- with fluid that is leaking into the subretinal space. ized macular detachment is noted commonly in patients with Likewise, there is venous congestion in the choroid and elevated serum IgM levels associated with WM. Para- retina in paraproteinemia, leading to choroidal ischemia proteinemic maculopathy often becomes symptomatic when and hyperpermeability, which leads to CSR (Fig 4). Zamir IgM levels exceed 7000 mg/dl (4000 mg/dl in diabetics) and and Chowers39 reported a patient with paraproteinemia who serum viscosity exceeds 5.5 cP. Therapy should be directed had CSR in the right eye and branch retinal vein occlusion toward decreasing the serum immunoglobulin level and the in the left eye, with normal maculae. Although CSR could serum viscosity. be the primary cause of the ocular condition, one could argue that paraproteinemia could have induced a CSR-like condition, as previously discussed. References Early treatment is necessary to prevent irreversible visual loss, especially with the currently lengthened expected life span. Paraproteinemic maculopathy becomes symptomatic 1. Saleun JP, Vicariot M, Deroff P, Morin JF. Monoclonal when IgM levels exceed 4000 mg/dl in diabetics and 7000 gammopathies in the adult population of Finistere, France. mg/dl in nondiabetics (Table 1) and serum viscosity exceeds J Clin Pathol 1982;35:63–8.

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40. Landa G, Barnett JA, Garcia PM, et al. Quantitative and macroglobulinemia. Invest Ophthalmol Vis Sci 2008;49: qualitative spectral domain optical coherence tomography 1157–60. analysis of subretinal deposits in patients with acute 42. Negi A, Marmor MF. Effects of subretinal and systemic central serous retinopathy. Ophthalmologica 2013;230: osmolality on the rate of subretinal fluid resorption. Invest 62–8. Ophthalmol Vis Sci 1984;25:616–20. 41. Menke MN, Feke GT, McMeel JW, Treon SP. Effect of 43. Larkin KL, Saboo US, Comer GM, et al. Use of intravitreal plasmapheresis on hyperviscosity-related retinopathy and rituximab for treatment of vitreoretinal lymphoma. Br J Oph- retinal hemodynamics in patients with Waldenstrom’s thalmol 2014;98:99–103.

Footnotes and Financial Disclosures

Originally received: January 22, 2014. 11 Department of Clinical Science “Luigi Sacco,” Sacco Hospital, Univer- Final revision: March 6, 2014. sity of Milan, Milan, Italy. Accepted: April 9, 2014. Financial Disclosure(s): Available online: June 17, 2014. Manuscript no. 2014-119. The author(s) have no proprietary or commercial interest in any materials 1 Departments of Ophthalmology, American University of Beirut and Rafic discussed in this article. Hariri University Hospital, Beirut, Lebanon. J.F.A.: Consultant - Second Sight LLC, Alcon Labs; Lecturer - Iridex, 2 Retina Departments, The King Khaled Eye Specialist Hospital, Riyadh, Optos Inc; Speakers Bureau - Novartis Pharmaceuticals, Alimera Sciences Kingdom of Saudi Arabia, and Wilmer Eye Institute, The Johns Hopkins Inc; Royalties - Springer, SBM LLC. University, Baltimore, Maryland. G.S.: Consultant - Heidelberg Engineering, Zeiss, QLT, GSK, Alcon, 3 Department of Ophthalmology, Hospital Moises Broggi Sant Joan Despi, Allergan, Bayer, Boheringer, Genentech, Roche, Novartis; Speakers Bureau e Barcelona, Spain. Zeiss, Heidelberg Engineering, Novartis, GSK; Patents - Ocular In- struments, Novartis. 4 Associated Vitreoretinal and Uveitis Consultants, Department of A.M.: Consultant, Lecturer - Bayer. Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana. Abbreviations and Acronyms: 5 BCVA ¼ cP ¼ CSR ¼ Retina Associates of Cleveland, Beachwood, Ohio. best-corrected visual acuity; centipoise; central serous retinopathy; DD ¼ disc diameter; IgM ¼ immunoglobulin M; 6 The Retina Institute, St. Louis, Missouri. logMAR ¼ logarithm of the minimum angle of resolution; MM ¼ multiple 7 Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota. myeloma; OCT ¼ optical coherence tomography; RPE ¼ retinal pigment ¼ 8 Department of Statistics and Research Methodology, Lebanese American epithelium; WM Waldenström macroglobulinemia. University and Lebanese University, Beirut, Lebanon. Correspondence: 9 Retina Service at Oftalmologica, San Miguel de Tucumán, Argentina. Ahmad M. Mansour, MD, Department of Ophthalmology, American 10 University of Beirut, P.O. Box 1136044, Beirut, Lebanon. E-mail: Department of Ophthalmology, Universidade Estadual de Londrina, [email protected]. Parana, Brazil.

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