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Show MRI Restricted Diffusion in Lymphomatous Optic Neuropathy Padmaja Sudhakar, MD, Francisco Rivas Rodriguez, MD, Jonathan D. Trobe, MD Abstract: Restricted diffusion in the optic nerve detected with MRI has been previously reported in infarction and inflammation but not in infiltrative neoplasm. We report a 44-year-old man with recently diagnosed non-Hodgkin B-cell lymphoma who developed an acute left optic neu-ropathy. MRI showed no evidence of brain parenchymal or meningeal lymphoma but did show restricted diffusion in the intraorbital portion of the affected optic nerve. Despite treatment with corticosteroid, standard chemo-therapy, and orbital X-irradiation, visual function did not improve. The restricted diffusion persisted on a follow-up MRI performed 4 months after the onset, a phenomenon that is atypical for infarction. Perhaps, this persisting imaging abnormality in lymphomatous optic neuropathy reflects the dense cellularity of the neoplasm. Journal of Neuro-Ophthalmology 2011;31:306-309 doi: 10.1097/WNO.0b013e31821ee581 2011 by North American Neuro-Ophthalmology Society Diffusion-weighted imaging (DWI) has been largely applied to the diagnosis of acute cerebral infarction (1). Restricted diffusion onDWI has also been noted in brain parenchymal lymphomas and other brain tumors (2-5). Although this neuroimaging finding has been reported in ischemic and inflammatory optic neuropathies (6-14), it has not previously been reported in lymphomatous optic neuropathy. We describe such a case. CASE REPORT A 44-year-old man presented with sudden painful loss of vision in the left eye for 1-day duration. Four months earlier, he had been diagnosed with non-Hodgkin B-cell lymphoma following biopsy of a retroperitonealmass. He had completed 4 of 6 cycles of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone (CHOP) chemotherapy. Pre-contrast brain CT and complete blood counts obtained at the referring hospital after the vision loss were normal. On our examination, visual acuity was 20/20 in the right eye and no light perception in the left eye. There were no ocular adnexal abnormalities. There was tenderness to palpation of the left eye. Pupils were equal in size with a left relative afferent pupillary defect. Ocular movements were full, and eyes were aligned. The visual field was full to finger counting in the right eye. Slit-lamp biomicroscopy and intraocular pressures were normal in both the eyes. Ophthalmoscopy of the right eye was normal and disclosed mild swelling of the optic disc of the left eye. There were no other abnormalities on examination. MRI of the brain and orbits was performed with a 1.5-T Achieva magnetic resonance system (Philips Medical Sys-tems, Best, the Netherlands) using an 8-channel SENSE head coil and included the following pulse sequences: precontrast and postcontrast T1 fat saturated spin echo axial and coronal (time to recovery [TR]: 600 milliseconds, time to echo [TE]: 10 milliseconds, slice thickness 3 mm, with no interslice gap on axial and interslice gap 0.5 mm on coronal, matrix 336 3 165 axial and 256 3 165 coronal), T2 fat saturated spin echo coronal (TR: 3,500 milliseconds, TE: 120 milliseconds, slice thickness 3 mm, with 0.5 mm interslice gap, matrix 250 3 130), and FLAIR (TR: 11,000 milliseconds, TE: 140 milliseconds, slice thickness 5 mm, interslice gap 1 mm, matrix 288 3 160). Gadolinium pertechnetate 0.2 mL/kg was administered intravenously. Diffusion imaging data were obtained using an echo-planar single-shot technique with the shortest TR, 80-millisecond TE, and a 90 flip angle, and a b value of 1,000 s/mm2. The data were recorded on a 1283 256matrix and were zero-filled for a final resolution of 256 3 256. Axial slices with 6-mm slice thickness with no interslice gap were obtained. A SENSE P factor of 3 was used. Departments of Ophthalmology and Visual Sciences (PS) and Neurology (PS, JDT), W. K. Kellogg Eye Center; and Department of Radiology (FRR), University of Michigan Medical Center, Ann Arbor, Michigan. The authors report no conflicts of interest. Address correspondence to Jonathan D. Trobe, MD, Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105 0714; E-mail: jdtrobe@med. umich.edu 306 Sudhakar et al: J Neuro-Ophthalmol 2011; 31: 306-309 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Brain and orbit MRI showed no parenchymal or men-ingeal abnormalities, but the left intraorbital optic nerve showed increased T2 signal intensity, thickening, and min-imal enhancement (Fig. 1A, B). There was high signal on DWI and a corresponding area of darkness on the apparent diffusion coefficient (ADC) map (Fig. 1C-E). The ADC values were 0.590 3 1023 mm2/s in the affected left optic nerve and 0.974 3 1023 mm2/s in the fellow (unaffected) optic nerve. We found an average ADC value of 1.293 3 1023 mm2/s in 10 right optic nerves and an average ADC value of 1.109 3 1023 mm2/s in 10 left optic nerves of patients with neurologic symptoms but no manifestations of optic neuropathy. The calculations confirmed restricted diffusion in the affected left optic nerve. Cerebrospinal fluid (CSF) on lumbar puncture showed glucose: 53 mg/dL (normal: 50-70 mg/dL), protein:100 mg/dL (normal:15-45 mg/dL), and 22 white cells per cubic millimeter (68% lymphocytes). CSF flow cytometry and cytology were positive for a mature B-cell neoplasm, con-firming the diagnosis of lymphomatous meningitis. We attributed the optic neuropathy to lymphomatous infiltration and treated the patient with 1 gm of methyl-prednisolone per day for 3 days followed by prednisone at 1 mg/kg/day for 14 days. Previously obtained head, neck, and maxillofacial CT and chest CT were unremarkable. Abdominal and pelvic CT revealed a large retroperitoneal mass extending from the celiac axis to the iliac bifurcation. Positron emission tomography (PET) showed extensive metastatic disease in-volving the axial bones, lymph nodes, kidneys, adrenals, and the right testis. On review, the core biopsy of the abdominal mass showed abnormal lymphoid cells with high mitotic activity. Fluorescent in situ hybridization analysis revealed an 8;14 translocation consistent with Burkitt lymphoma. Repeat chest, abdomen, and pelvic CT and PET scan demonstrated a decrease in size of the previously seen lesions with no new areas of involvement. The patient underwent 4 cycles of high-dose intravenous methotrexate (3,500 mg/m2), cytarabine (2,000 mg/m2), rituximab (375 mg/m2), together with intrathecal metho-trexate and intrathecal cytarabine on days 2 and 8. After completion of chemotherapy, he underwent right orchi-ectomy and radiation to the left orbit and left scrotum. Within 5 weeks, the left optic disc became pale. Vision never improved. The right eye maintained normal visual function. MRI obtained 4 months after the presentation showed that the previously observed enhancement of the retrobulbar fat within the left orbit and the patchy enhancement of the left optic nerve was less intense than that in the prior study. However, it still showed an ADC value of 0.46531023mm2/s in the left optic nerve and 1.383 10-3 mm2/s in the right optic nerve (Fig. 2A-C), indicating persistent restricted diffusion in the left optic nerve. Multiple CSF studies obtained after the initiation of chemotherapy remained negative for neoplasm. FIG. 1. MRI performed at presentation. A. Precontrast T1 axial scan demonstrating high signal in the left intraconal space (arrow). B. Postcontrast T1 axial image showing mild enhancement of the left intraorbital optic nerve (arrow) and intraconal fat. C. Axial DWI reveals high signal in the left intraorbital optic nerve (arrow). D. Axial ADC map demon-strating a corresponding region of darkness (arrow). E. Axial exponential DWI showing a corresponding region of brightness, as expected with restricted diffusion (arrow). Sudhakar et al: J Neuro-Ophthalmol 2011; 31: 306-309 307 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. DISCUSSION Burkitt lymphoma in our patient infiltrated the left optic nerve and produced persistent restricted diffusion on DWI. To our knowledge, this is the first reported case of such a phenomenon. DWI is based on the Brownian motion of unbound water molecules in the extracellular space (1). It quantifies the diffusion of water molecules with a value known as apparent diffusion coefficient (ADC). Compromise of the extracellular space following cellular swelling in infarction (1,6) and the dense cellular packing typical of brain tumors restrict motion of extracellular water and produce restricted diffusion (3,15). DWI has shown restricted diffusion in 8 cases of optic nerve ischemia (6-12,14) and in 1 case of optic perineuritis (13) but not in neoplastic infiltration. The first reported case described a patient with bilateral posterior ischemic optic neuropathy attributed to hypotension in cardiac by-pass surgery. Restricted diffusion was seen within both intraorbital optic nerves on an MRI study obtained 4 days after vision loss (6). Follow-up MRI was not obtained. The second reported case described a 56-year-old woman with nonarteritic anterior ischemic optic neuropa-thy (7). MRI brain obtained within 2 weeks of visual loss showed restricted diffusion within the left intraorbital optic nerve. ADC was relatively decreased by 46% in the left optic nerve. Follow-up imaging was not done. The third reported case showed restricted diffusion in both optic nerves in a patient with ischemic optic neu-ropathy attributed to thrombocythemia (8). The fourth case involved a patient with bilateral cavernous sinus thrombosis who demonstrated restricted diffusion in both intraorbital optic nerves on MRI obtained within 2 weeks of visual loss (9). The ADC values within the affected optic nerves measured 0.168-0.7443 1023mm2/s compared to an ADC of 0.833-1.178 3 1023 mm2/s seen within the normal optic nerves. No follow-up imaging study was done. Three case reports have documented restricted diffusion in optic nerve infarction secondary to rhinocerebral mu-cormycosis. The first showed restricted diffusion in the distal right intraorbital optic nerve on an MRI obtained within 6 days of vision loss (10). The restricted diffusion became more apparent on an MRI obtained 15 days later. The second showed restricted diffusion in the distal left optic nerve on an MRI obtained within a few days of vision loss with an ADC value of 0.6353 1023 mm2/s (11). Both patients died within a few days of losing vision. In the third case of mucormycosis, a 29-year-old man suffered right eye vision loss from oph-thalmic artery, cavernous sinus, and superior ophthalmic vein occlusion (12). DWI obtained within 2 days of vision loss showed restricted diffusion not only in the right intraorbital optic nerve (ADC of 0.471 3 1023 mm2/s in the right eye and 1.6633 1023 mm2/s in the left eye) but also in the retina (ADC of 1.84 3 1023 mm2/s in the right retina and 2.60 3 1023 mm2/s in the left retina). Follow-up MRI obtained within 20 days of symptom onset revealed complete disap-pearance of these signal changes. Restricted diffusion was reported in the proximal intra-orbital segment of the right optic nerve in a 4-year-old healthy girl who developed central retinal artery and vein occlusion from optic perineuritis (13). MRI obtained within few days of vision loss showed an enhancing and thickened right optic nerve and high T2 signal in the intraconal fat surrounding the optic nerve, together with restricted diffusion in the proximal right intraorbital optic nerve. Imaging features were similar to those of our patient. Follow-upMRI obtained 4 months later documented the disappearance of restricted diffusion and partial reversal of optic nerve thickening. Restricted diffusion was reported in the left intraorbital optic nerve in a patient with ophthalmic artery occlusion following fat autotransplantation to the forehead for soft tissue augmentation of face (14). The MRI obtained on the third postoperative day showed subtle hyperintensity on DWI in the left middle cerebral arterial territory and left optic nerve (ADC value of 0.272 3 1023 mm2/s in left optic nerve and 1.46 3 1023 mm2/s in the right optic nerve). The MRI obtained on the fourth postoperative day showed more pronounced restricted diffusion in the left optic nerve (ADC of 0.237 3 1023 mm2/s in the left and 1.26 3 1023 mm2/s in the right). No follow-up imaging was obtained. Our case is unusual in that the restricted diffusion persisted for at least 4 months from the onset of optic neuropathy, unlike the pattern seen in cerebral infarction, where it disappears within 7-10 days (1). Follow-up FIG. 2. MRI performed 4 months after the presentation. A. Axial DWI showing persisting high signal in the left intraorbital optic nerve (arrow). B. Axial ADC map demonstrating a corresponding region of darkness (arrow). C. Axial exponential DWI reveals a corresponding region of brightness, as expected with restricted diffusion (arrow). 308 Sudhakar et al: J Neuro-Ophthalmol 2011; 31: 306-309 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. imaging has not been consistently performed in the reported cases of restricted diffusion of the optic nerve. Two case reports of optic nerve infarction have documented disap-pearance of restricted diffusion on follow-up DWI (12,13). In one, restricted diffusion had disappeared within 20 days of symptom onset (12), and in the other, disappearance was documented on DWI obtained 4 months later (13). We offer 2 explanations for persistent restricted diffusion in our patient. Perhaps, it can be attributed to the high cellularity of Burkitt lymphoma, although lymphoma cells were absent from the CSF on repeated lumbar punctures after the treatment. Previous studies have documented the presence of restricted diffusion with low ADC values in central nervous system lymphomas of B- and T-cell type (2-5,15-19). The high cellularity of lymphoma decreases the extracellular space and restricts the motion of extracellular water leading to restricted diffusion on MRI. The higher the cellularity, the lower the ADC value (3-5,15,16). In a DWI study of intracerebral masses, lymphoma was found to have higher cellularity on histopathology and correspondingly lower ADC values (average 0.58 3 1023 mm2/s) on DWI than gliomas (average ADC 1.14 3 1023 mm2/s) and metastatic cancers (average ADC 1.03 3 1023 mm2/s) (5). Other studies have shown similar results (3,4,19,20). One study (21) indicated that lymphomas with high cellularity and low ADC values tended to be relatively refractory to chemotherapy. The other postulated mechanism for re-stricted diffusion in brain parenchymal lymphoma is the increased viscosity characteristic of necrotic lymphomas (15). Prior studies have documented that lymphoma in the orbit (but not involving the optic nerve) restricts diffusion more than other orbital processes (22,23). 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