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Show ORIGINAL CONTRIBUTION Histopathologic Features of Multiple Myeloma Involving the Optic Nerves Sonia N. Yeung, MD, PhD, Katherine E. Paton, MD, Katerina Dorovini- Zis, MD, Jason B. Chew, MB, ChB, and Valerie A. White, MD, MHSc Abstract: We report a case of optic nerve involvement by multiple myeloma in which progressive visual loss heralded leukemic transformation and intracranial involvement. Imaging showed enhancing nodules in the intracranial segments of both optic nerves posterior to the optic canals and in the anterior optic tract, optic chiasm, and basal leptomeninges. Postmortem histopathologic examination disclosed malignant plasma cells in the subarachnoid spaces around the optic nerves and in the optic nerves. Infarctions were present in both optic nerves near their junction with the globes. Microscopic examination also showed malignant plasma cell infiltration of the leptomeninges of the cerebrum, brain stem, optic chiasm, pituitary gland, cranial bone marrow, and subarachnoid blood vessels. This is the first reported histopathologic examination in conjunction with MRI of multiple myeloma involving the anterior visual pathway. The mechanism of optic neuropathy in this case is probably related to infiltration of the optic nerve meninges by malignant plasma cells and impaired vascular supply caused by aggregated intraluminal plasma cells and monoclonal hypergammaglobulinemia. (/ Neuro- Ophthalmol 2008; 28: 12- 16) ultiple myeloma is a plasma cell malignancy characterized by monoclonal expansion of lympho-plasmacytic cells in the bone marrow ( 1). Extraskeletal involvement occurs most commonly in the spleen, liver, Department of Ophthalmology and Visual Sciences ( SNY, KEP, VAW), Eye Care Centre, and Department of Pathology and Laboratory Medicine ( KD- Z), Vancouver Hospital, University of British Columbia Vancouver, Vancouver, British Columbia, Canada; and Department of Radiology ( JBC), Royal Columbian Hospital, New Westminster, British Columbia, Canada. Address correspondence to Sonia N. Yeung, MD, PHD, Eye Care Centre, Vancouver Hospital 2550 Willow St., Vancouver, BC, Canada V5Z 3N9; E- mail: sonia. y@ gmail. com lymph nodes, and kidneys ( 2). Intracranial involvement with a visual presentation is rare. In this report, we describe a patient with multiple myeloma in whom a sudden decrease in vision signaled leukemic transformation and subsequent intracranial involvement. Treatment restored and preserved vision for the remaining month of his life. To our knowledge, myeloma-tous involvement of the optic nerves and brain demonstrated by both MRI and postmortem histopathologic analysis has not been previously reported. CASE REPORT A 69- year- old man was referred to the Ophthalmology Department at Vancouver General Hospital in April 2004 with a 10- day history of painless progressive blurring and dimming of vision in both eyes. Ten days earlier, visual acuity had been 20/ 50 in the right eye and 20/ 40 in the left eye. He also noted that colors appeared washed out to both eyes. He denied double vision and headache. There was no other significant ophthalmic history. The patient's medical history included a 1997 diagnosis of multiple myeloma, initially presenting with anemia and plasmacytosis. For the next 6 years, he had undergone treatment with melphalan, prednisone, thalidomide, repeated courses of cyclophosphamide with dexa-methasone, and irradiation to his sternum. In 2004, his hemoglobin was falling, and all chemotherapy was withdrawn. Even so, his general medical condition remained stable. He had also been treated for squamous cell carcinoma in situ in the perianal area by irradiation many years earlier. At the time of presentation, the patient was taking no prescribed medications and had no medication allergies. Our examination showed a best- corrected visual acuity of hand movements in the right eye and 20/ 200 in the left eye. Confrontation visual fields showed a small preserved superotemporal visual field in the right eye and a preserved peripheral visual field in the left eye. There was a right relative afferent pupil defect. Extraocular movements were full. There was no ptosis, demonstrable orbital masses, or color changes in the surrounding skin. There 12 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Multiple Myeloma J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 were no bony changes around the orbital margin and no proptosis. Eye movements were full, and the eyes were aligned. The cornea was clear, and the anterior chamber was quiet in both eyes. Intraocular pressures were normal, and fundus examination was completely unremarkable bilaterally. The history and clinical examination suggested an optic nerve or chiasmal process. MRI of the brain and orbits demonstrated multiple enhancing nodules in the intracranial segments of both optic nerves just posterior to the optic canals ( Fig. 1 A), in the left optic tract anteriorly, surrounding the left optic nerve immediately posterior to the globe, and around the chiasm. Multiple scattered additional nodular enhancing leptomeningeal deposits were noted ( Fig. IB), including one in the interpeduncular space. Lesions were also seen within the cerebellum and within the left fifth cranial nerve lateral to the pons. The patient's monoclonal peak was 56 g/ L ( normal 0 g/ L; IgG), hemoglobin was 80 g/ L ( normal 133- 165 g/ L), and platelet count was 45 X 107L ( normal 150- 400 X 109/ L). A peripheral blood smear showed plasma cells, and the diagnosis of plasma cell leukemia was made. Plasmapheresis was performed. The next day, a lumbar puncture showed malignant plasma cells in the cerebrospinal fluid ( CSF). He was subsequently treated for 5 days with whole brain x- irradiation and dexamethasone. Given the known poor prognosis of plasma cell leukemia ( 3), systemic therapy with chemotherapy was avoided. Five days after treatment, visual acuity had recovered to 20/ 25 in the right eye and 20/ 30 in the left eye. It remained at that level until 1 month after his presentation to the Ophthalmology Department, when his overall condition deteriorated rapidly and he died. HISTOPATHOLOGIC STUDY The autopsy was limited to the head. There was infiltration by malignant plasma cells of the subarachnoid spaces around the optic nerves and of the optic nerves themselves ( Fig. 2A- B). Tumor cells stained strongly for IgG immunoglobulin ( Fig. 2C). Small bilateral wedge-shaped infarctions of the proximal optic nerves were present approximately 2.8 cm posterior to the globe ( Fig. 2D). These showed infiltration by macrophages and loss of axons and myelin ( Fig. 2E). In no area was the entire cross-section of the nerves infarcted. Both globes were otherwise histologically within normal limits for age. Two small lytic lesions in the skull and one lesion in the sphenoid bone were identified. Microscopic examination showed focal infiltration by malignant plasma cells of the leptomeninges of the brain, brain stem, optic chiasm, and pituitary gland ( Fig. 2F). Some subarachnoid blood vessels contained intraluminal aggregates of neoplastic FIG. 1. MRI performed 1 month before death. A. Post-contrast T1 coronal study demonstrates bilateral enhancing lesions within the intracranial optic nerves ( arrows) bilaterally. B. Postcontrast T1 axial study demonstrates multiple enhancing leptomeningeal nodules ( arrows). 13 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Yeung et al * • * » * • & • K4 I W ; *: • , • « • • * • . \ « ' -. > £ v• v * ; • - * * » • :• ss,- A *% r *** p- lrl i •; pv . •*- FIG. 2. Postmortem histopathologic examination. A. Infiltration of the subarachnoid space of the optic nerve by malignant plasma cells ( hematoxylin and eosin; original magnification: X200). B. Infiltration of the optic nerve by malignant plasma cells ( hematoxylin and eosin; original magnification: X100). C. Plasma cells in the subarachnoid space ( anti- light chain, hematoxylin counterstain; original magnification: X100). D. Small wedge- shaped infarctions of the optic nerve ( hematoxylin and eosin; original magnification: X12.5). E. Loss of axons and myelin in the area of optic nerve infarction ( Luxol fast blue/ Bielschowsky stain; original magnification: X100). F. Focal infiltration of the leptomeninges of the brain by malignant plasma cells ( hematoxylin and eosin; original magnification: X400). C. Intraluminal aggregates of neoplastic plasma cells in a subarachnoid blood vessel ( hematoxylin and eosin; original magnification: X100). plasma cells ( Fig. 2G). The bone marrow was hypoplastic and focally infiltrated by neoplastic plasma cells. Some of the intraparenchymal microvessels in the brain were filled with gram- negative bacteria, indicating terminal septicemia. There was no evidence of metastatic squamous cell carcinoma in the optic nerves or brain. DISCUSSION Representing 80% of plasma cell neoplasms, multiple myeloma is the most common of the plasma cell dyscrasias, accounting for slightly more than 10% of hematologic malignancies ( 4). It presents at a median age of 72 years with bone pain, anemia, renal insufficiency, infection, and plasmacytomas ( 5- 7). The most common sites of extraskeletal involvement are the spleen, liver, lymph nodes, and kidneys ( 2). Ophthalmic manifestations of multiple myeloma are rare but can be the first sign of disease ( 8,9). Ocular findings include crystal ( 10) or copper ( 11) deposition in the cornea, ciliary body cysts ( 12,13), and retinopathy of hyperviscosity ( 14- 16). The iris ( 17,18), conjunctiva ( 1), or choroid ( 18) may also be involved. Orbital involvement is rare but can be the first manifestation ( 2,14). Plasmacytomas may arise in the soft tissues primarily or in the surrounding bones with secondary orbital invasion. Rodman and Font ( 2) noted proptosis to be the most frequent presentation of orbital infiltration by multiple myeloma. Other rare presentations include periocular xanthogranuloma, paraproteinemia- induced myositis, and opportunistic ocular infections ( 2,13,19). Optic nerve involvement is extremely rare in myeloma. In 1939, Langdon ( 20) described a patient with multiple myeloma and " retrobulbar neuritis." There was no pathologic study, and the retrobulbar neuritis was attributed to toxicity rather than to infiltration. Infiltration of the optic nerves by plasma cells was first reported by Gudas ( 21) in 1971. In 1974, Dahlmann et al ( 22) reported a patient with infiltration of the optic nerve by disseminated IgA myeloma. Optic nerve compression from an intracranial plasmacytoma has only rarely been described ( 23- 26). Cavernous degeneration of the optic nerve and generalized amyloidosis has been reported ( 27). Immune- mediated paraneoplastic optic neuropathy has been postulated in association with myeloma ( 28). Shimada et al ( 29) recently reported a case of multiple myeloma associated with bilateral optic neuropathy thought to be due to an effect of high immunoglobulin levels on neural conduction. 14 © 2008 Lippincott Williams & Wilkins Multiple Myeloma J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Intracranial involvement by multiple myeloma is rare, with an estimated overall frequency of 1% ( 30). It can present as either an intraparenchymal or leptomeningeal lesion, often with multiple neurologic symptoms and signs. These include altered mental status, cranial nerve palsies, limb weakness, and occasionally the effects of a space-occupying lesion and raised intracranial pressure ( 31- 33). Leptomeningeal spread can occur either by local invasion from the bone or by hematogenous dissemination ( 34). Obstructive hydrocephalus resulting from leptomeningeal infiltration has also been reported ( 35). The diagnosis is made by imaging studies and examination of plasma cells within the CSF. The prognosis of myelomatous involvement of the meninges is poor despite the use of aggressive local and systemic treatment ( 3). This poor prognosis is attributed to the fact that meningeal involvement generally occurs in patients with advanced disease. The average time from onset of neurologic symptoms to death has been reported to be 8 weeks ( 33). The pathophysiologic processes that give rise to a majority of the ophthalmic signs are direct infiltration by plasma cells, compression by tumor mass, meningeal metastases, and hematologic abnormalities ( 12,14,21,36). Hyperviscosity syndrome occurs in multiple myeloma owing to an overproduction of monoclonal immunoglobulin in the bone marrow. As a result, the microcirculation is impaired owing to increases in plasma viscosity. The mechanism of optic neuropathy in this case is probably related to infiltration of the optic nerve meninges by malignant plasma cells and impaired vascular supply caused by aggregated intraluminal plasma cells and monoclonal hypergammaglobulinemia. Neural conduction in the optic nerves may have also been compromised by excessive IgG, perhaps owing to a humoral mechanism ( 28,29,37). To what extent the infarctions evident on histopathologic examination accounted for the patient's loss of vision is uncertain, given that plasmapheresis and whole brain x- irradiation led to rapid recovery. Reduction of the plasma levels of monoclonal protein and a decrease in the burden of leptomeningeal disease by irradiation in our patient could have accounted for the prompt return of vision. REFERENCES 1. Adkins JW, Shields JA, Shields CL, et al. Plasmacytoma of the eye and orbit. Int Ophthalmol 1996; 20: 339^ 3. 2. Rodman HI, Font RL. 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