Sudhakar, Padmaja MD; Rodriguez, Francisco Rivas MD; Trobe, Jonathan D. MD
Diffusion-weighted imaging (DWI) has been largely applied to the diagnosis of acute cerebral infarction (1). Restricted diffusion on DWI 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.
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 retroperitoneal mass. He had completed 4 of 6 cycles of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone (CHOP) chemotherapy. Precontrast 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 Systems, 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 × 165 axial and 256 × 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 × 130), and FLAIR (TR: 11,000 milliseconds, TE: 140 milliseconds, slice thickness 5 mm, interslice gap 1 mm, matrix 288 × 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 128 × 256 matrix and were zero-filled for a final resolution of 256 × 256. Axial slices with 6-mm slice thickness with no interslice gap were obtained. A SENSE P factor of 3 was used.
Brain and orbit MRI showed no parenchymal or meningeal abnormalities, but the left intraorbital optic nerve showed increased T2 signal intensity, thickening, and minimal 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 × 10−3 mm2/s in the affected left optic nerve and 0.974 × 10−3 mm2/s in the fellow (unaffected) optic nerve. We found an average ADC value of 1.293 × 10−3 mm2/s in 10 right optic nerves and an average ADC value of 1.109 × 10−3 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, confirming the diagnosis of lymphomatous meningitis.
We attributed the optic neuropathy to lymphomatous infiltration and treated the patient with 1 gm of methylprednisolone 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 involving 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 methotrexate and intrathecal cytarabine on days 2 and 8. After completion of chemotherapy, he underwent right orchiectomy 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 0.465 × 10−3 mm2/s in the left optic nerve and 1.38 × 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.
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 bypass 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 neuropathy (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 neuropathy 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 0.168–0.744 × 10−3 mm2/s compared to an ADC of 0.833–1.178 × 10−3 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 mucormycosis. 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 0.635 × 10−3 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 ophthalmic 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 × 10−3 mm2/s in the right eye and 1.663 × 10−3 mm2/s in the left eye) but also in the retina (ADC of 1.84 × 10−3 mm2/s in the right retina and 2.60 × 10−3 mm2/s in the left retina). Follow-up MRI obtained within 20 days of symptom onset revealed complete disappearance of these signal changes.
Restricted diffusion was reported in the proximal intraorbital 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-up MRI 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 × 10−3 mm2/s in left optic nerve and 1.46 × 10−3 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 × 10−3 mm2/s in the left and 1.26 × 10−3 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 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 disappearance 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 × 10−3 mm2/s) on DWI than gliomas (average ADC 1.14 × 10−3 mm2/s) and metastatic cancers (average ADC 1.03 × 10−3 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 restricted 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). In a study that compared DWI intensities, ADC values, and ADC ratios of orbital cellulitis, orbital inflammatory syndrome, and conjunctival, eyelid, and extraconal lymphomas, more restricted diffusion with lower ADC values was found in lymphomas than in the other entities (22).
Given that none of the reported patients who have had restricted diffusion in the optic nerve have recovered vision, this imaging abnormality appears to augur a poor visual outcome, even in inflammatory or neoplastic conditions.
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