Ischemic Optic Neuropathy Secondary to Intravascular Lymphoma

Background: To describe a case of optic neuropathy associated with intravascular lymphoma (IVL). Methods: Case report and review of the literature. Results: A case of asymmetric binocular vision loss is described, preceded by transient vision loss. Associated optic perineural enhancement and enhancing and diffusion-positive cortical lesions were observed on magnetic resonance imaging. Biopsy of the cerebellum revealed exclusively intraluminal neoplastic B-cells consistent with IVL.Conclusions: Patients with IVL may rarely present with optic nerve involvement, presumably due to small vessel occlusion. The presentation may mimic features of anterior ischemic optic neuropathy including an acute onset and disc edema. Although optic nerve enhancement and associated white matter lesions may suggest optic neuritis, enhancement of the optic nerve sheath, as in this case, has a wide differential diagnosis, which includes giant cell arteritis. IVL should be considered in atypical cases of optic neuropathy accompanied by enhancing, diffusion-positive brain lesions that are not within a specific vascular territory.

Original Contribution Ischemic Optic Neuropathy Secondary to Intravascular Lymphoma Marc Dinkin, MD, Ehud Lavi, MD, Jacqueline Winterkorn, MD, PhD, Cristiano Oliveira, MD, Alexander E. Merkler, MD Background: To describe a case of optic neuropathy associated with intravascular lymphoma (IVL). Methods: Case report and review of the literature. Results: A case of asymmetric binocular vision loss is described, preceded by transient vision loss. Associated optic perineural enhancement and enhancing and diffusionpositive cortical lesions were observed on magnetic resonance imaging. Biopsy of the cerebellum revealed exclusively intraluminal neoplastic B-cells consistent with IVL. Conclusions: Patients with IVL may rarely present with optic nerve involvement, presumably due to small vessel occlusion. The presentation may mimic features of anterior ischemic optic neuropathy including an acute onset and disc edema. Although optic nerve enhancement and associated white matter lesions may suggest optic neuritis, enhancement of the optic nerve sheath, as in this case, has a wide differential diagnosis, which includes giant cell arteritis. IVL should be considered in atypical cases of optic neuropathy accompanied by enhancing, diffusion-positive brain lesions that are not within a specific vascular territory. CASE REPORT A 68-year-old woman with a history of hypertension and diabetes mellitus experienced 5 hours of painless visual loss Journal of Neuro-Ophthalmology 2019;39:313-318 doi: 10.1097/WNO.0000000000000722 © 2018 by North American Neuro-Ophthalmology Society I ntravascular lymphoma (IVL) is a rare form of extranodal B-cell lymphoma involving the lumina of small vessels, usually sparing the surrounding parenchyma. Multifocal central nervous system (CNS) or skin involvement is common, although nearly any organ can be affected. We evaluated a patient with IVL-related optic neuropathy, which was the initial manifestation of the disease and mimicked anterior ischemic optic neuropathy. Departments of Ophthalmology (MD, JW, CO), Neurology (MD, AEM), and Pathology (EL), Weill Cornell Medical College, New York, New York. The authors report no conflicts of interest. Address correspondence to Marc Dinkin, MD, Weill Cornell Ophthalmology, 1305 York Avenue, 11th Floor, New York, NY 10065; E-mail: [e-mail] Dinkin et al: J Neuro-Ophthalmol 2019; 39: 313-318 FIG. 1. A and B. Ultrasonographic study reveals a hypoechoic halo around the preauricular segment of the left temporal artery. C. There is no halo around the right temporal artery. 313 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. A. At initial presentation, automated (Humphrey) visual fields show an inferior defect in the right eye and near total loss of sensitivity in the left eye. B. The right optic disc is normal, and the left disc is pale. C. A temporal hemianopia is present in the right eye with further depression of the left visual field. LE, left eye; RE, right eye. FIG. 3. Orbital MRI. Initial study reveals perineural enhancement of the left optic nerve on postcontrast T1 axial (A) and coronal (B) images. Six weeks later, there is perineural enhancement of the right optic nerve on postcontrast coronal (C) scan and mild enhancement of the optic chiasm (D). 314 Dinkin et al: J Neuro-Ophthalmol 2019; 39: 313-318 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution in the left eye that completely recovered. Brain MRI showed a small left parietal infarct and the patient was prescribed 81 mg/d of aspirin. Erythrocyte sedimentation rate, C-reactive protein, and echocardiogram were normal. Transient vision loss of the left eye recurred 9 days later. The patient denied fever, headache, jaw claudication, scalp tenderness, night sweats, or lymphadenopathy. She was seen by her ophthalmologist 6 days later who observed "left optic disc swelling and arteriolar attenuation," without hemorrhages or cotton wool spots. Temporal artery (TA) ultrasound showed a hypoechoic halo around the left TA suspicious for giant cell arteritis (GCA) (Fig. 1). However, a TA biopsy was not performed and steroids were not started because the diagnosis was thought to be nonarteritic anterior ischemic optic neuropathy (NAION). Clopidogrel 75 mg/d was added to her aspirin therapy. The patient was referred to our neuro-ophthalmology service 1 month after her initial symptoms and examination revealed visual acuities of 20/15 in the right eye and 20/300 in the left eye. There was left dyschromatopsia and a left relative afferent pupillary defect. Automated visual fields showed an inferior arcuate defect in the right eye and severe field depression of the left eye (Fig. 2A). Funduscopy was normal in the right eye but showed left temporal optic disc pallor (Fig. 2B). Orbital MRI demonstrated enhancement of the left optic nerve sheath (Fig. 3A, B) and evidence of restricted diffusion. Six weeks later, visual acuity was 20/20 in the right eye and 20/50 in the left eye. Visual fields revealed a temporal hemianopia overlying the previous inferior defect in the right eye (Fig. 2C). Funduscopy was unchanged. Orbital MRI now showed mild enhancement around the right optic nerve and some enhancement of the FIG. 4. Brain MRI. Postcontrast axial T1 (A) and FLAIR (B) scans show a left frontal enhancing lesion with surrounding edema. This lesion spontaneously regressed 2 months later (C), offering false reassurance against a neoplasm. A subcortical lesion on the left side was detected on an axial FLAIR study (D) that showed restricted diffusion (E) and mild enhancement (F), consistent with an infarct. A vascular structure in the right cerebellar hemisphere, thought to be a developmental venous anomaly, demonstrated enhancement on postcontrast axial T1 scan (G) and hyperintense surrounding signal on axial FLAIR study. (H) This lesion shows susceptibility artifact on gradient echo sequence (I). FLAIR, fluid-attenuated inversion recovery. Dinkin et al: J Neuro-Ophthalmol 2019; 39: 313-318 315 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 5. Cerebellar biopsy specimen. A, B. There are large, neoplastic lymphoid cells with prominent nucleoli and mitotic figures present only within vascular spaces (hematoxylin & eosin ·200). C, D. Immunohistochemistry with DAB chromogen and hematoxylin background shows malignant cells within arterioles that stain for CD20 (C ·100; D ·200). Cerebellar tissue demonstrates foci of infarction and hyalinization (E) as well as loss of Purkinje cells due to ischemia (box) (F) (E and F, hematoxylin & eosin, ·40). optic chiasm (Fig. 3C, D). Brain MRI revealed several new enhancing lesions in the cerebral hemispheres as well as an enhancing lesion in the cerebellum, likely a vascular stricture because it demonstrated susceptibility artifact (Fig. 4). Positron emission tomography showed these lesions to be hypermetabolic. Cerebrospinal fluid (CSF) revealed elevated protein of 74 mg/dL (normal: 15-45 mg/dL), glucose 96 mg/dL, 1 white blood cell, and was negative for mycobacteria, fungi, human T-lymphotropic virus, and cryptococcus. CSF venereal disease research laboratory was positive at 1:8 but serum fluorescent treponemal antibody absorption and rapid plasma reagin were negative. Cytology and flow cytometry were negative. Sinus and lip biopsy were unrevealing. Three months later, MRI showed enhancement of the intracanalicular C5 and C6 nerve roots. Visual acuity in the left eye improved to 20/50 but 11 months after presentation, the patient developed episodic confusion, urinary incontinence, and ataxia. CSF cytology and flow cytometry again were negative. Biopsy of the cerebellar lesion showed large, CD20+ neoplastic lymphoid cells with prominent nucleoli and mitotic 316 figures present only within vascular spaces consistent with IVL (Fig. 5). Surrounding cerebellar tissue showed foci of infarction with extensive Purkinje cell loss attributed to ischemia. After treatment with cyclophosphamide, high-dose methotrexate, doxorubicin, vincristine, prednisolone, and rituximab (FCHOP), the encephalopathy improved. The patient remains in remission 9 years after initial presentation. DISCUSSION IVL is a rare aggressive form of B-cell lymphoma in which there is a tropism for the lumina of small blood vessels in multiple organs, especially in the CNS and skin. The neoplastic cells were originally considered to be endothelial in origin (1) but their lymphoid nature was confirmed decades later (2,3). Most IVL cells are CD20+ but, interestingly, the majority seem to be negative for molecules necessary for endothelial cell adhesion and transvascular migration, such as CD54 (ICAM-1) and CD29 (beta1 integrin subunit) (4) providing one explanation for their proclivity for the intravascular space. Dinkin et al: J Neuro-Ophthalmol 2019; 39: 313-318 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Neurological involvement of IVL manifests as regions of ischemia that do not correspond to large vessel territories. Typical presentations include encephalopathy, seizures, cranial neuropathies, tremor, myelopathies, headaches, and vertigo (5,6). MRI findings closely resemble CNS vasculitis, with multifocal T2 hyperintensities with or without restricted diffusion or meningeal enhancement (7). Imaging has shown concentric thickening and enhancement of the arterial wall, although this does not differentiate IVL from vasculitis (8). Neuro-ophthalmic symptoms from cortical involvement include homonymous hemianopia (9), but prechiasmatic involvement also rarely has been reported. In 2010, a case of orbital IVL was reported as the first of its kind (10), although a case of neoplastic angioendotheliosis (NA), which is now believed to be a form of IVL (11) had previously been reported with orbital invasion (12). We are aware of 2 previous descriptions of symptomatic optic nerve involvement in IVL. Baehring et al (13) described a patient with declining vision who was found to have T2 hyperintensity in the left optic nerve, but no ophthalmological examination was reported. In another patient with IVL, visual loss with optic atrophy occurred in the left eye but no further information was given (14). We describe a patient in which IVL caused bilateral optic neuropathy with unilateral optic disc edema, and in which binocular vision loss was preceded by transient monocular amaurosis, suggestive of occlusion of the small vessels of the optic nerve. The initial presence of disc edema suggested NAION. Although multiple vascular risk factors supported this diagnosis, retrobulbar optic nerve enhancement on MRI did not. The restricted diffusion of many of the subcortical lesions did not support the diagnosis of multiple sclerosis with associated optic neuritis. Optic nerve sheath enhancement is a feature of optic nerve sheath meningioma but this diagnosis seemed unlikely, given the rapidity of the visual decline. Optic perineuritis may result from granulomatous polyangiitis, sarcoidosis, idiopathic orbital inflammation (15), or syphilis (16), and has been increasingly recognized as a possible manifestation of GCA (17,18). In a report of this finding in a patient with GCA, biopsy of the optic nerve sheaths revealed "numerous arteries with intimal thickening and mild mural inflammation." (19). The optic nerve enhancement in our patient likely reflected infiltration of perineural small vessels with IVL cells and subsequent breakdown of the blood-brain barrier. The hypoechoic sign on TA ultrasound suggested GCA, but probably reflected luminal involvement by IVL. In the absence of headache, constitutional symptoms, and elevation of erythrocyte sedimentation rate or C-reactive protein, we did not suspect GCA. Visual recovery, resolution of spinal nerve root enhancement, and reduction in the enhancement of a left frontal lobe lesion all occurred before institution of chemotherapy, and provided false reassurance against malignant disease. Dinkin et al: J Neuro-Ophthalmol 2019; 39: 313-318 Such spontaneous improvement has been documented in IVL (20) and may be the result of apoptosis or an immune response against lymphomatous cells (21). The improvement in visual function may be due to incomplete occlusion of small vessels supplying the optic nerve that had led to reversible axonal dysfunction or demyelination. Our patient's course is remarkable in that it took a full year from presentation to diagnosis, and yet with treatment, she has survived an additional 8 years without recurrence, reflecting the improvement in overall and progression-free survival provided by B-cell depletion therapy, particularly rituximab (22). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. Dinkin and A. M. Merkler; b. Acquisition of data: M. Dinkin, J. Winterkorn, and A. M. Merkler; c. Analysis and interpretation of data: M. Dinkin, J. Winterkorn, and A. M. Merkler. Category 2: a. Drafting the manuscript: M. Dinkin and A. M. Merkler; b. Revising it for intellectual content: M. Dinkin and C. Oliveira. Category 3: a. Final approval of the completed manuscript: M. Dinkin, C. Oliveira, and A. M. Merkler. J. Winterkorn is deceased, but contributed to the patient's care. REFERENCES 1. Tappeiner J, Pfleger L. Angioendotheliomatosis proliferans systematisata. A clinically and pathohistologically new disease picture. Hautarzt. 1963;14:67-70. 2. Ansell J, Bhawan J, Cohen S, Sullivan J, Sherman D. Histiocytic lymphoma and malignant angioendotheliomatosis: one disease or two? Cancer. 1982;50:1506-1512. 3. Wick MR, Mills SE, Scheithauer BW, Cooper PH, Davitz MA, Parkinson K. Reassessment of malignant "angioendotheliomatosis." Evidence in favor of its reclassification as "intravascular lymphomatosis." Am J Surg Pathol. 1986;10:112-123. 4. Ponzoni M, Arrigoni G, Gould VE, Del Curto B, Maggioni M, Scapinello A, Paolino S, Cassisa A, Patriarca C. Lack of CD 29 (beta 1 integrin) and CD 54 (ICAM-1) adhesion molecules in intravascular lymphomatosis. Hum Pathol. 2000;31:220-226. 5. Beristain X, Azzarelli B. The neurological masquerade of intravascular lymphomatosis. Arch Neurol. 2002;59:439-443. 6. Tahsili-Fahadan P, Rashidi A, Cimino PJ, Bucelli RC, Keyrouz SG. Neurologic manifestations of intravascular large B-cell lymphoma. Neurol Clin Pract. 2016;6:55-60. 7. Yamamoto A, Kikuchi Y, Homma K, O'uchi T, Furui S. Characteristics of intravascular large B-cell lymphoma on cerebral MR imaging. AJNR Am J Neuroradiol. 2012;33:292- 296. 8. Schaafsma JD, Hui F, Wisco D, Staugaitis SM, Uchino K, Kouzmitcheva E, Jaigobin C, Hazrati LN, Mikulis DJ, Mandell DM. High-resolution vessel wall MRI: appearance of intravascular lymphoma mimics central nervous system vasculitis. Clin Neuroradiol. 2017;27:105-108. 9. Kageyama T, Yamanaka H, Nakamura F, Suenaga T. Persistent lesion hyperintensity on brain diffusion-weighted MRI is an early sign of intravascular lymphoma. BMJ Case Rep. 2017;8:2017. 10. Berbos ZJ, Lee MS, Zaldivar RA, Pambuccian S, Harrison AR. Intravascular lymphoma presenting as an orbital mass lesion: a case report. Orbit. 2010;29:91-93. 11. Ojeda VJ, Spagnola DV. Neoplastic angioendotheliosis is, in fact, intravascular malignant lymphoma. Acta Neuropathol. 1986;72:203. 12. Sato T, Goto H, Toratani A, Yamagata N, Ashihara E, Oku N, Inaba T, Fujita N, Shimazaki C, Nakagawa M. Neoplastic 317 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 13. 14. 15. 16. 17. 18. angioendotheliosis presenting Tolosa-Hunt syndrome, intraspinal invasion and intraorbital tumor [in Japanese]. Rinsho Ketsueki. 1994;35:557-561. Baehring JM, Henchcliffe C, Ledezma CJ, Fulbright R, Hochberg FH. Intravascular lymphoma: magnetic resonance imaging correlates of disease dynamics within the central nervous system. J Neurol Neurosurg Psychiatry. 2005;76:540- 544. Pless ML, Chen YB, Copen WA, Frosch MP. Case records of the Massachusetts General Hospital. Case 9-2010. A 37-year-old woman with paresthesias and ataxia. N Engl J Med. 2010;362:1129-1138. Purvin V, Kawasaki A, Jacobson DM. Optic perineuritis: clinical and radiographic features. Arch Ophthalmol. 2001;119:1299- 1306. Frohman L, Wolansky L. Magnetic resonance imaging of syphilitic optic neuritis/perineuritis. J Neuroophthalmol. 1997;17:57-59. Lee AG, Eggenberger ER, Kaufman DI, Manrique C. Optic nerve enhancement on magnetic resonance imaging in arteritic ischemic optic neuropathy. J Neuroophthalmol. 1999;19:235- 237. Mitchell JR, Krashin-Bichler I, Rosenblum M, Diamond EL, Dinkin MJ. Giant cell arteritis presenting with bilateral orbital 318 19. 20. 21. 22. inflammatory disease and enhancing superficial temporal arteries. Pract Neurol. 2014;14:446-447. Morgenstern KE, Ellis BD, Schochet SS, Linberg JV. Bilateral optic nerve sheath enhancement from giant cell arteritis. J Rheumatol. 2003;30:625-527. Chan AM, Huttner A, Baehring J. Disappearing Leukoencephalopathy: a case of relapsing-remitting intravascular large B-cell lymphoma with transient spontaneous radiographic regression. Clin Neuroradiol. 2018;28:455-459. Takahashi T, Ikejiri F, Takami S, Okada T, Kumanomidou S, Adachi K, Yumi J, Onishi C, Kawakami K, Moriyama I, Inoue M, Miyake T, Tanaka J, Maruyama R, Suzumiya J. Spontaneous regression of intravascular large B cell lymphoma and apoptosis of lymphoma cells: a case report. J Clin Exp Hematop. 2015;55:151-156. Shimada K, Matsue K, Yamamoto K, Murase T, Ichikawa N, Okamoto M, Niitsu N, Kosugi H, Tsukamoto N, Miwa H, Asaoku H, Kikuchi A, Matsumoto M, Saburi Y, Masaki Y, Yamaguchi M, Nakamura S, Naoe T, Kinoshita T. Retrospective analysis of intravascular large B-cell lymphoma treated with rituximabcontaining chemotherapy as reported by the IVL study group in Japan. J Clin Oncol. 2008;26:3189-3196. Dinkin et al: J Neuro-Ophthalmol 2019; 39: 313-318 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.