Journal of Neuro-Ophthalmology, March 2011, Volume 31, Issue 1

Bilateral Simultaneous Central Retinal Vein Occlusions in an Otherwise Healthy Adult

Bilateral Simultaneous Central Retinal Vein Occlusions in an Otherwise Healthy Adult Ana G. Alzaga Fernandez, MD, Romina Shirka, DO, Barry Skarf, PhD, MD, Brian Silver, MD, Selma J. Matloob, MD, Michael D. Ober, MD, Patrick Luetmer, MD, Caterina Giannini, MD, PhD Dr. Skarf: A 53-year-old man presented with a 5-day history of pro-gressive painless loss of vision in his right eye and a 1-day history of a similar deterioration in the left eye. He denied headaches, diplopia, transient visual obscurations, or other neurological symptoms. He stated that he was in good health and denied any systemic diseases. He was a vegetarian who exercised regularly. Ophthalmological examination revealed that the pa-tient's best-corrected visual acuity was 20/200 in the right eye and 20/40 in the left eye. His pupils were equal and reactive to light; there was a questionable right relative afferent pupillary defect. Confrontation visual field testing showed that he could count fingers in all quadrants of both eyes. Kinetic perimetry of the right eye performed using the I-4e and I-2e test targets showed a moderately dense central scotoma, an enlarged blind spot, and slightly constricted peripheral isopters. The central scotoma in the right eye was confirmed using an Amsler grid. In the left eye, kinetic perimetry showed minimal constriction of the isopters superotemporally. With an Amsler grid, the patient noted distortion and waviness of lines superotemporally. The patient was able to identify 12 of 15 Ishihara plates with the right eye by fixating eccentrically with his nasal field. He identified all 15 color plates with his left eye. Extraocular movements were full, and the slit-lamp examination re-vealed no abnormalities. Intraocular pressures were within normal limits. Both optic discs were swollen and surrounded by multiple flame-shaped hemorrhages that radiated from the optic discs and obliterated the disc margins (Fig. 1). Small exudates and scattered dot and blot hemorrhages surrounded both optic discs; there was no substantial hemorrhage noted along the retinal vascular arcades outside the immediate peripapillary area. In both eyes, the retinal veins appeared distended and engorged, with boxcarring of the blood column. There were serous macular detachments in both eyes. There were no abnor-malities in the retinal periphery of either eye. Patient evaluation showed mild pancytopenia (white blood cell count, 3.1 K/mL; hemoglobin B, 9.7 g/dL; platelets, 135 K/mL), high serum protein, low serum albumin, and high lactate dehydrogenase. Serum vitamin B12, folate, and iron levels were normal. CT and MRI of the brain, MRA, and venography were performed. Dr. Luetmer: CT of the head without contrast shows no abnormalities; however, magnetic resonance studies reveal a poorly defined heterogeneous infiltrate involving the clivus consistent with a marrow replacement process (Fig. 2). Dr. Skarf: Given the magnetic resonance findings, a whole-body bone scan and a metastatic bone survey were performed. Dr. Luetmer: The bone scan shows multiple areas of uptake involving the ribs on both sides, the right scapula, and the left femur (Fig. 3). The metastatic bone survey reveals vague lucencies throughout the skull. Dr. Skarf: Serum electrophoresis with immunofixation revealed a large IgA lambda monoclonal protein in the beta region. The urine electrophoresis with immunofixation revealed similar results. The patient's serum viscosity was elevated at 7.24 centipoise. A bone marrow biopsy was performed. Dr. Giannini: The biopsy reveals diffuse infiltration by a monomorphous plasmacytic cell population, morphologically consistent Section Editor: Neil R. Miller, MD Departments of Neurology (RS, BSi) and Ophthalmology (AGAF, BSk, SJM, MDO), Henry Ford Health System, Detroit, Michigan; and Departments of Neuroradiology (PL) and Neuropathology (CG), Mayo Clinic, Rochester, Minnesota. A. G. Alzaga Fernandez and R. Shirka participated equally as first authors in the preparation of this article. Address correspondence to Ana G. Alzaga Fernandez, MD, Henry Ford Hospital, 2799 West Grand Boulevard. K-10, Detroit, MI 48202; E-mail: [e-mail] 78 Alzaga Fernandez et al: J Neuro-Ophthalmol 2011; 31: 78-82 Clinical-Pathological Case Study Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. with a plasma cell neoplasm (Fig. 4). According to the report (not shown), these cells are CD38- and CD56- positive and show exclusive cytoplasmic lambda light chain expression supportive of a clonal population and, therefore, of the proposed diagnosis of myeloma (Fig. 4). Pathological Diagnosis: Multiple myeloma IgA, lambda monoclonal type. Dr. Alzaga Fernandez: The patient underwent 2 courses of plasmapheresis in ad-dition to treatment with lenalidomide, allopurinol, zole-dronic acid, and dexamethasone. After the second plasmapheresis, the patient's visual acuity in the right eye improved to 20/80, but there was minimal improvement in the left eye. The retinal veins were less engorged, and there appeared to be fewer retinal hemorrhages. One month later, there was significant resorption of the retinal hemorrhages, improvement in the appearance of the retinal vessels, and improvement in visual acuity to 20/25 in both eyes. Shallow serous detachments were still present in both maculae. Six months after treatment, the patient's visual acuity was 20/20 in both eyes. The fundi demonstrated marked improvement (Fig. 5). The patient subsequently underwent an autologous bone marrow transplant and is asymptomatic 18 months after his initial presentation. DISCUSSION Dr. Alzaga Fernandez: Multiple myeloma is the most common of the plasma cell dyscrasias; it accounts for 10% of hematologic malignancies and 80% of plasma cell neoplasms (1). The median age of presentation is 72 years, with the most common features being bone pain, anemia, renal insufficiency, infection, and plasmacytomas (1,2). Although almost every part of the eye and visual pathways can be affected by multiple myeloma, ocular involvement rarely occurs early in the course of the FIG. 1. Initial appearance of the right (A) and left (B) eyes demonstrates bilateral optic disc swelling, dilated retinal veins, and extensive peripapillary and posterior pole hemorrhages consistent with bilateral CRVOs. FIG. 2. T1 sagittal MRI without contrast shows a poorly defined heterogeneous hypointense area with replacement of the normal fat signal from marrow in the clivus (arrows). FIG. 3. Technetium bone scan shows abnormal focal radiotracer uptake within multiple ribs bilaterally and in the superior right scapula. Alzaga Fernandez et al: J Neuro-Ophthalmol 2011; 31: 78-82 79 Clinical-Pathological Case Study Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. disease (3). The ocular manifestations can be separated into 2 categories: 1) those attributed to plasmacytoma growth in and about the eye, including deposition of light-chain immunoglobulin and 2) those due to hematologic abnor-malities such as hyperviscosity syndrome (4). Ocular find-ings in the first category include ciliary body cysts, ciliochoroidal effusions, uveal plasmacytomas, conjunctival and corneal deposits (both crystalline and noncrystalline), orbital involvement, detachment of the sensory retina, retinal pigment epithelium detachment, and optic nerve infiltration (1,3-5). Manifestations of the hematologic abnormalities in the second category mainly include the effects of hyperviscosity on the retinal, choroidal, and optic nerve blood supply (3,4). A third category of involvement has been proposed in which ocular signs are related to infection secondary to immunosuppression (4). Our patient's manifestations resulted from the effects of hyperviscosity, which results in impaired blood flow due to alterations in the rheologic properties of blood (6). This syndrome produces a variety of manifestations such as headache, vertigo, hearing loss, nystagmus, visual dis-turbances, retinal vein congestion, retinal hemorrhages, mucosal hemorrhages, congestive heart failure, and renal failure (2). Other symptoms include fatigue, anorexia, and weakness (7). Blood viscosity is measured in centipoise (cP) and varies according to the hematocrit, red cell aggregability, and plasma viscosity (6,7). Symptoms related to hyperviscosity syndrome occur more frequently when the viscosity is above 6 cps, as was the case in our patient; however, the level of viscosity at which the symptoms become apparent varies among patients (6). Symptoms usually occur when an excess of immunoglobulin interacts with other blood elements leading to impairment in blood flow and increased viscosity (7,8). Other laboratory findings such as hypercalcemia, pseudohyponatremia, and pseudohypoglycemia may sug-gest hyperviscosity indirectly (2,7). Hyperviscosity syndrome was first described with monoclonal gammopathies (6). It occurs in 10%-30% of patients with Waldenstrom macroglobulinemia, 3%-4% of IgG myeloma, and 5%-20% of IgA myeloma (6,9). Multiple myeloma is 10 times more common than Wal-denstrom macroglobulinemia and therefore a more frequent cause of hyperviscosity syndrome (2,6). The most common type of immunoglobulin associated with the syndrome is IgM; the association of IgA and IgG monoclonal FIG. 4. Low- (A) and high- (B) power views of the bone marrow biopsy show infiltration of the marrow with a neoplastic monomorphous plasma cell population. A. Hematoxylin and eosin: 3100. B. Hematoxylin and eosin: 3600. FIG. 5. Fundus appearance of the right (A) and left (B) eyes 6 months after the onset of treatment. There is almost complete absorption of blood, diminished swelling of the optic discs, and exudates in the inferior macula of each eye. 80 Alzaga Fernandez et al: J Neuro-Ophthalmol 2011; 31: 78-82 Clinical-Pathological Case Study Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. gammopathies with hyperviscosity syndrome is much less common (7,10). IgM is a larger molecular compound secreted as a pentamer and is found mainly in the intravascular compartment due to its size (11). IgM has the ability to bind with water and form aggregates that may contribute to increase blood viscosity (11). IgA normally is present as a monomer; however, in IgA multiple myeloma, a large amount of the IgA is present as a dimer in the serum, and this contributes to its hyperviscosity (12). Early funduscopic findings in hyperviscosity retinopathy include dilation and tortuosity of retinal veins secondary to stasis of blood flow (7,13). The pathognomonic finding is fundus paraproteinaemicus, a term used to describe engorged tortuous retinal veins that have a boxcar or ‘‘sausage-link'' appearance (7,8). This entity may progress to complete central retinal vein occlusion (CRVO), with flame-shaped hemorrhages, microaneurysms, or exudates, as found in our patient (7). Other diseases with similar funduscopic findings include leukemia and aplastic anemia (14-16). The first report of a patient with bilateral CRVO as the initial manifestation of multiple myeloma was that of a 65-year-old woman who was diagnosed with IgG-associated (kappa type) multiple myeloma (17). The second case was a 16-year-old boy who initially presented with bilateral blurry vision and epistaxis (8). He was treated for presumed papilledema with oral steroids and experienced a transient improvement of his symptoms. Three months later, the diagnosis of CRVO was established, and the patient was found to have IgA multiple myeloma. To our knowledge, our patient represents the third reported case with bilateral CRVO as the initial manifestation of multiple myeloma due to an IgA monoclonal gammopathy. Other entities to consider in patients with bilateral CRVO include systemic lupus erythematosus, antiphospholipid an-tibody syndrome, and hyperhomocysteinemia (18). Positive laboratory tests may include lupus anticoagulant antibodies, congenital deficiency of protein S, and activated protein C resistance (19,20). Defects in platelet function, acquired von Willebrand disease, inhibition of fibrin formation, and ac-quired factor X, IX, V, or II deficiency with amyloidosis have been associated with gammopathies and hyperviscosity syn-drome (6). Bilateral CRVO also has been induced iatrogen-ically in young patients, without preexisting comorbidities, who are treated with intravenous immunoglobulins and other medications for various disorders (21,22). There have also been reports of patients with congenital cardiac defects, such as Eisenmenger syndrome, who have developed bilateral CRVO (23). Therapeutic measures for hyperviscosity syndrome in-clude plasmapheresis to ameliorate the signs and symptoms associated with blood flow stasis (2). This is an effective but temporizing measure, as the immunoglobulin re-accumulates within a few days. Melphalan and prednisone have been the standard treatment for multiple myeloma for more than 40 years and are associated with a median survival of 28-37 months (24). Renal failure is associated with a poor outcome (2). The addition of bortezomib to melphalan and prednisone delays the onset of progression (24). For patients aged 65 or less with adequate perfor-mance status, American and European guidelines recom-mend high-dose melphalan therapy and autologous hematopoietic stem cell transplantation (25). In summary, patients who present with bilateral CRVO warrant a systemic investigation for underlying hypervis-cosity syndromes including blood dyscrasias such as multiple myeloma. An initial complete blood count may offer the first clue. With treatment, patients may experience excellent visual recovery. ACKNOWLEDGMENT The authors thank Ms. Elaine Lok, Ophthalmic Imaging, Henry Ford Hospital, who provided assistance and support in the preparation of the photographs for this article. REFERENCES 1. Yeung SN, Paton KE, Dorovini-Zis K, Chew JB, White VA. Histopathologic features of multiple myeloma involving the optic nerves. J Neuroopthalmol. 2008;28:12-16. 2. Anderson KC, Dzieczkowski J. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 13-1994: a 62-year-old man with epistaxis, confusion, renal failure, and bilateral central retinal vein thrombosis. N Engl J Med. 1994;330: 920-927. 3. Omoti AE, Omoti CE. 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