Optic Perineuritis Presenting as the Initial Manifestation of Central Nervous System Involvement in Rai Stage 0 Chronic Lymphocytic Leukemia

Background: To describe the first case of optic perineuritis because of meningeal involvement of early stage chronic lymphocytic leukemia (CLL). Methods: A case report and review of the literature. Results: A case of unilateral optic neuropathy associated with enhancement of the optic nerve sheath is described in a patient with a prior 2-year history of Rai Stage 0 CLL. Lumbar puncture revealed a lymphocytic pleocytosis. Cerebrospinal fluid flow cytometry revealed a monoclonal expansion of CD5+ B cells compatible with CLL, matching the flow cytometry characteristics of his peripheral blood. Conclusions: Optic perineuritis is often initially diagnosed as optic neuritis, yet the 2 have different etiologies and follow a different clinical course. Orbital MRI with contrast structurally separates the 2, revealing a characteristic pattern of peripheral optic nerve sheath rather than primary optic nerve enhancement. Etiologies of optic perineuritis are varied and include inflammatory, infectious, neoplastic, and toxic entities. Central nervous system (CNS) involvement by chronic lymphocytic leukemia is unusual, but cranial nerve and meningeal involvement have been reported. This case adds central nervous system chronic lymphocytic leukemia to the list of differential diagnostic possibilities for optic perineuritis. It also alerts clinicians to consider optic perineuritis as a potential presenting feature of CNS involvement in otherwise asymptomatic and stable CLL.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Optic Perineuritis Presenting as the Initial Manifestation of Central Nervous System Involvement in Rai Stage 0 Chronic Lymphocytic Leukemia James L. Parker, MD, Kevin M. Mays, MD, Parakash P. Pratibhu, MD, Peter W. Pick, MD, PhD, Danielle K. Block, BS Background: To describe the first case of optic perineuritis because of meningeal involvement of early stage chronic lymphocytic leukemia (CLL). Methods: A case report and review of the literature. Results: A case of unilateral optic neuropathy associated with enhancement of the optic nerve sheath is described in a patient with a prior 2-year history of Rai Stage 0 CLL. Lumbar puncture revealed a lymphocytic pleocytosis. Cerebrospinal fluid flow cytometry revealed a monoclonal expansion of CD5+ B cells compatible with CLL, matching the flow cytometry characteristics of his peripheral blood. Conclusions: Optic perineuritis is often initially diagnosed as optic neuritis, yet the 2 have different etiologies and follow a different clinical course. Orbital MRI with contrast structurally separates the 2, revealing a characteristic pattern of peripheral optic nerve sheath rather than primary optic nerve enhancement. Etiologies of optic perineuritis are varied and include inflammatory, infectious, neoplastic, and toxic entities. Central nervous system (CNS) involvement by chronic lymphocytic leukemia is unusual, but cranial nerve and meningeal involvement have been reported. This case adds central nervous system chronic lymphocytic leukemia to the list of differential diagnostic possibilities for optic perineuritis. It also alerts clinicians to consider optic perineuritis as a potential presenting feature of CNS involvement in otherwise asymptomatic and stable CLL. Journal of Neuro-Ophthalmology 2022;42:e187–e191 doi: 10.1097/WNO.0000000000001263 © 2021 by North American Neuro-Ophthalmology Society Division of Neuro-Ophthalmology (JLP), Sonny Montgomery V. A. Medical Center, Jackson, Mississippi; Department of Ophthalmology (KMM, DKB), University of Mississippi Medical Center, Jackson, Mississippi; and Department of Neurology (JLP, PPP, PWP), Sonny Montgomery V. A. Medical Center, Jackson, Mississippi. The authors report no conflicts of interest. This article has been read and approved by all the authors; the requirements for authorship have been met, and each author believes that the article represents honest work. Address correspondence to James L. Parker, MD, Routing Number 127, Sonny Montgomery V. A. Medical Center, 1500 East Woodrow Wilson Avenue, Jackson, MS 39216; E-mail: [e-mail] Parker et al: J Neuro-Ophthalmol 2022; 42: e187-e191 C hronic lymphocytic leukemia (CLL) is a B-cell neoplasm characterized by a monoclonal expansion of small mature lymphocytes. Chronic lymphocytic leukemia is the most common adult leukemia diagnosis in the United States, accounting for 25%–30% of cases, with an average age at diagnosis of 72 years (1). In the United States, the estimated incidence of CLL is 6.75 and 3.65 cases per 100,000 population in men and women, respectively (2). The diagnosis is suggested by peripheral lymphocytosis and confirmed by flow cytometry of peripheral blood, revealing a monoclonal expansion of abnormal circulating B lymphocytes (3). The natural history of CLL has often been characterized as indolent and may never require treatment with a lifespan of 10–20 years (4). However, median survival differs depending on the stage of the disease. Patients with Rai Stage 0 disease present with lymphocytosis alone, have a median survival of 13 years, and are normally not treated. Patients with Rai Stage I or II disease and Rai Stage III or IV disease have shorter median survival times of 8 years and 2 years, respectively, and are uniformly treated (5). Chronic lymphocytic leukemia usually involves peripheral blood, lymph nodes, or spleen. Extranodal involvement can also occur in the lymphoid tissue of any organ, most commonly the liver, skin, pleura, kidney, and gastrointestinal tract (3,5). Rarely, CLL has been reported to involve the central nervous system (CNS) and even more rarely the optic nerve or optic nerve sheath (6–9). We report what we believe to be the first case of early stage (Rai Stage 0) CLL with optic perineuritis as the presenting sign of CNS involvement. CASE REPORT A 58-year-old African American man was diagnosed with Rai Stage 0 CLL 2.5 years prior. He was found to have peripheral blood lymphocytosis without lymphadenopathy, splenomegaly, hepatomegaly, or cytopenia. Flow cytometry e187 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution revealed a monoclonal CD5+ B-cell population consistent with CLL. Peripheral hematologic profiling remained stable over time, and he was observed without treatment. He was referred from an emergency room visit with an initial diagnosis of optic neuritis. Visual loss developed in his left eye 4 days prior. Visual loss in the left eye progressed over the first day, until “everything looked gray and dim.” He denied pain in the left orbit, pain on eye movement, ptosis, ocular injection, or prominence. He complained of pain in his neck and occiput but denied temporal pain or generalized headache. There were also subjective paresthesias and weakness in his right face, felt related to a peripheral facial palsy diagnosed 16 months prior. MRI with contrast at that time was entirely normal. The best-corrected visual acuity was 20/30 in the right eye and 20/80 in the left eye. He exhibited a relative left afferent pupillary defect and a color vision defect in the left eye. Slit-lamp biomicroscopy, intraocular pressures, external examination, ocular motility, and exophthalmometry measurements were normal. Fundus examination showed edema of the left optic disc and peripapillary nerve fiber layer hemorrhages. Fundus photographs and fluorescein angiogram confirmed left disc edema and disc staining (Fig. 1). There were no fundus or fluorescein findings to suggest ischemic optic neuropathy, retinal vasculitis, viral infection, leukemic infiltration, or sarcoid. Automated visual field testing revealed a generalized central field depression in the left eye with an inferior nasal predominance (Fig. 2). Optical coherence tomography confirmed nerve fiber layer edema in the left eye alone (Fig. 2). The remainder of the neurological examination was normal other than a mild right peripheral facial palsy. There was no ear pain, no sign of zoster skin lesions in the ear canal, and no signs of aberrant regeneration. There was no nuchal rigidity. Gadolinium-enhanced orbital MRI was classical for optic perineuritis. Avid enhancement of the optic nerve sheath and adjacent orbital fat was demonstrated, without enhancement of the optic nerve parenchyma. This enhancement resembled a “tram-track” pattern (10) on axial views and a “doughnut” pattern (11) on coronal views (Fig. 3). No other orbital, ocular muscle, cerebral, brainstem, or meningeal abnormalities were noted. The entire course of the right seventh nerve was unremarkable. Computed tomography (CT) angiogram of cervical and cranial vessels was entirely normal. white blood cell was 13,300/cm. Erythrocyte sedimentation rate and C-reactive protein were elevated at 75 mm/h and 16.7 mg/dL, respectively. Blood and serum testing for B12, folate, thyroid panel, rapid plasma reagin, Neuromyelitis Optica Immunoglobulin (IgG), Covid-19 nasopharyngeal swab, HIV, protein electrophoresis, anticardiolipin antibodies, anti-nucleat antibodies, cryoglobulins, angiotensin converting enzyme, Lyme antibodies, antineutrophil cytoplasmic antibodies, and IgG4 subclass were unremarkable. Viral and hepatitis screens were either negative or did not show evidence of any active infection. CT of the thorax, abdomen, and pelvis did not reveal hilar, mediastinal, abdominal, or pelvic lymphadenopathy. No splenomegaly, hepatomegaly, or other findings of significance were reported. Left superficial temporal artery biopsy was negative for giant cell arteritis. Lumbar puncture revealed a normal opening pressure with an elevated cell count of 43 white blood cells/cmm (100% lymphocytes). Glucose was 80 mg/dL (serum 98 mg/dL), and protein was elevated at 96 mg/dL. Studies for bacterial, fungal, mycobacterial, treponemal, and viral infections were negative. Cerebrospinal fluid IGG, IGG synthesis rate, and myelin basic protein were mildly elevated, but no oligoclonal bands were present. Cerebrospinal fluid cytology was negative other than increased numbers of lymphocytes. Flow cytometry demonstrated a CD5+ monotypic B-cell population, mirroring flow cytometry results of the patient’s peripheral blood. A diagnosis of FIG. 1. Optic disc studies (A) color fundus photograph showing acute inflammation of the optic nerve head with peripapillary hemorrhages and nerve fiber layer edema. B. Early phase IVFA showing prepapillary blockage with obscuration of vessels from the peripapillary hemorrhages and fiber layer edema. C. Mid phase IVFA showing leakage along the elevated disc margin. There was no delayed filling of the arterial circulation. IVFA, intravenous fluorescein angiogram. e188 Parker et al: J Neuro-Ophthalmol 2022; 42: e187-e191 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. A. Optical coherence tomography of the left optic nerve on presentation. Acute thickening of the nerve fiber layer beyond age appropriate norms. B. Automated visual field perimetry. Generalized central field depression with an inferior nasal predominance. optic perineuritis because of CNS chronic lymphocytic leukemia was made. The patient was initially treated with 1,000 mg of methylprednisolone IV daily for 5 days, followed by 60 mg of oral prednisone daily. Hematology began initial treatment with ibrutinib starting at 140 mg daily and increasing over 3 weeks to 420 mg daily. Initial clinical response was good, with improvement in his early follow-up visual examination and MRI. The best-corrected visual acuity was 20/20 22 in the right eye and 20/30 +1 in the left eye. Fundus examination and nerve fiber layer optical coherence tomography demonstrated near total resolution of nerve fiber layer edema and mild (30%) improvement in the left eye central field defect. Repeat MRI confirmed improvement, but not total clearing of his optic nerve sheath thickening and enhancement. DISCUSSION Optic perineuritis causes a unilateral or bilateral optic neuropathy, with or without disc swelling, and in the presence of absence of discomfort. Initially, it is often incorrectly diagnosed as typical demyelinating optic neuritis (11). It is important to make the correct diagnosis of optic perineuritis, as the underlying etiologies, prognosis, and treatments differ between the 2 entities (12,13). Clinical differences between the 2 (optic perineuritis vs optic neuritis) include older age of onset (average age 55 Parker et al: J Neuro-Ophthalmol 2022; 42: e187-e191 years), mild loss of vision at onset, initial symptom progression over weeks, continuing progressive loss of vision over time if untreated, and more frequent paracentral or arcuate field loss (11,14). The diagnosis is confirmed by obtaining a fat suppressed, gadolinium-enhanced orbital MRI, showing characteristic avid enhancement of the optic nerve sheath and adjacent orbital fat rather than thickening and enhancement of the optic nerve (11). The parallel linear arrangement of enhancement at the edge of the optic nerve on axial views has been called the “tram-track sign,” and the circular enhancement around the optic nerve on coronal views has been called the “doughnut sign.” The etiologies that cause optic perineuritis comprise a diverse spectrum of inflammatory, infectious, neoplastic, and toxic entities including idiopathic inflammation (11), granulomatosis with polyangiitis (Wegener) (15), Behcet disease (16), giant cell arteritis (17), Crohn disease (18), sarcoidosis (19), herpes viruses (20,21), mycobacteria (22), syphilis (23), toxocara (20), Lyme disease (24), HIV (25), pre–B-cell acute lymphocytic leukemia (20), relapsing polychondritis (26), colon cancer with IgG4-related disease (27), neuromyelitis optica spectrum disorder (28), myelin oligodendrocyte glycoprotein antibody–associated disease (29), and toxic effects of imatinib, methotrexate, cytarabine, and linezolid (20). Phuljhele et al reported MRI imaging findings of optic nerve sheath enhancement in a case of diffuse large B-cell e189 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Fat suppression orbital MRI showing classic signs of optic perineuritis. A. “Tram-track sign” of the left optic nerve on axial view. B. “Doughnut sign” of the left optic nerve on coronal view. gastric lymphoma but did not specifically diagnose optic perineuritis (30). Our patient presented with optic perineuritis as the initial sign of CNS involvement with early stage B-cell chronic lymphocytic leukemia. Clinical and imaging findings confirmed that this was optic perineuritis and not primary optic nerve inflammation or infiltration. Infectious, autoimmune, and other neoplastic etiologies of optic perineuritis were eliminated by thorough testing. Central nervous system involvement with CLL is rare with less than 100 cases reported in several comprehensive reviews extending through 2016 (6,8). In one series, CNS symptoms in a decreasing order of frequency were as follows: cognitive-behavioral changes, headache, meningitis with cranial nerve findings, cerebellar signs, sensory loss, motor weakness, gait disorder, and seizures (6). In some series, CNS involvement by CLL heralds transformation to a more aggressive cell type or occurs late in the terminal stages of the disease (31). However, this is not uniformly the case. Other reports indicate CNS involvement may occur in early stages of CLL and may be the presenting sign of CLL development beyond monoclonal peripheral blood lymphocytosis (6,9). Although optic nerve infiltration has been reported with multiple neoplastic entities, including lymphoma and leukemia (20,30,32), CLL presenting as optic neuropathy is rare (7,9). Even more unusual is the situation in our case, with isolated optic perineuritis. It is important to note that CLL is variably reported to involve the CNS in 8%–71% of autopsy pathological series. However, clinical presentations of CNS involvement by CLL are seen less frequently, from 0.8% to 2% in reported series (8). These disparate statistics suggest that CLL may be present in the CNS but remain asymptomatic in many individuals (6,8). Therefore, to demonstrate that an individual’s specific neurological sign is indeed because of underlying CLL, corroboration is needed with either tissue biopsy, imaging findings, or a meningeal/cranial nerve pree190 sentation with increased CSF cells on lumbar puncture replicating flow cytometry characteristics of peripheral blood. In our patient, clinical and imaging features pointed to active cranial nerve and meningeal involvement, with inflammation and loss of the blood–brain barrier involving the meningeal left optic nerve sheath. Lumbar puncture revealed an increased cell count, and CSF flow cytometry characteristics matched the patient’s peripheral blood flow cytometry profile. In addition to CNS lymphoma causing this patient’s optic neuropathy, arguably his peripheral facial palsy could also be due to CNS involvement. Although initial and follow-up MRIs did not show any sign of active brainstem, seventh nerve fascicle, or local perineural seventh nerve meningeal signal changes, a negative MRI does not rule out microscopic involvement of the facial nerve or perineural meninges by CNS lymphoma. Treatment of CLL formerly consisted of the use of glucocorticoids and chemotherapeutic agents, either alkylating agents or nucleoside analogs. Central nervous system involvement was generally treated with intrathecal methotrexate and/or irradiation. Survival improved with the advent of chemoimmunotherapy using anti–B-cell CD20 monoclonal antibodies (rituximab, ofatumumab, and obinutuzumab). The current advent of targeted molecular therapies has further prolonged progression free survival and has been successful in treating CNS involvement as well. The most recent treatments either block B-cell receptor signaling pathways or inhibit proteins that promote B-cell survival. These include BTK inhibitors (ibrutinib and acalabrutinib), a BCL2 antagonist (venetoclax), and a PI3Kgamma inhibitor (idelalisib). For aggressive cases, treatment with allogenic hematopoietic stem-cell transplantation is a final option (5). Our patient was treated with high dose IV methylprednisolone for 5 days with an oral taper and ibrutinib. He had a good initial clinical and MRI response. We believe this is the first reported case of optic perineuritis associated with CLL. Kahn et al reported an optic neuropathy proven to be due to CLL by optic nerve sheath biopsy. Parker et al: J Neuro-Ophthalmol 2022; 42: e187-e191 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution However, MRI demonstrated bilateral patchy optic nerve enlargement and enhancement rather than perineural enhancement (7). We did not discover a prior report of classic optic perineuritis associated with any stage of CLL. Clinicians should now be aware that optic perineuritis may rarely be the presenting feature of CNS involvement in chronic lymphocytic leukemia. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. L. Parker; b. Acquisition of data: J. L. Parker, K. M. Mays, P. P. Pratibhu, D. K. Block, and P. W. Pick; c. Analysis and interpretation of data: J. L. Parker, K. M. Mays, D. K. Block, and P. W. Pick. Category 2: a. Drafting the manuscript: J. L. Parker; b. Revising it for intellectual content: J. L. Parker and P. W. Pick. Category 3: a. Final approval of the completed manuscript: J. L. Parker, K. M. Mays, P. P. Pratibhu, D. K. Block, and P. W. Pick. REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30. 2. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997–2002. Cancer Causes Control. 2008;19:379–390. 3. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating M, Montserrat E, Chiorazzi N, Stilgenbauer S, Rai KR, Byrd JC, Eichhorst B, O’Brien S, Robak T, Seymour JF, Kipps TJ. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745– 2760. 4. Guarini A, Gianluca G, Mauro FR, Capello D, Mancini F, De Propris MS, Mancini M, Orsini E, Gentile M, Breccia M, Cuneo A, Castoldi G, Foa R. Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features. Blood. 2003;102:1035–1041. 5. Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383:460–473. 6. Strati P, Uhm JH, Kaufmann TJ, Nabhan C, Parikh SA, Hanson CA, Chaffee KG, Shanafelt TD. Prevalence and characteristics of central nervous system involvement by chronic lymphocytic leukemia. Haematologica. 2016;101:458–465. 7. Khan K, Malik AI, Almarzouqi SJ, Morgan ML, Yalamanchili S, Chevez-Barrios P, Lee AG. Optic neuropathy due to chronic lymphocytic leukemia proven with optic nerve sheath biopsy. J Neuroophthalmol. 2016;36:61–66. 8. Moazzam AA, Drappatz J, Kim RY, Kesari S. Chronic lymphocytic leukemia with central nervous system involvement: report of two cases with a comprehensive literature review. J Neurooncol. 2012;106:185–200. 9. Maleita D, Pereira R, Hipolito-Fernandes D, Moura-Coelho N, Cunha JP, Ferreira JT. Optic neuropathy due to chronic lymphocytic leukemia: the first manifestation of the disease. Amer J Ophthalmol Case Rep. 2020;18:1–6. 10. Kanamalla US. The optic nerve tram-track sign. Radiology. 2003;227:718–719. 11. Purvin V, Kawasaki A, Jacobson DM. Optic perineuritis, clinical and radiographic features. Arch Ophthalmol. 2001;119:1299– 1306. Parker et al: J Neuro-Ophthalmol 2022; 42: e187-e191 12. Hickman SJ. Optic perineuritis. Curr Neurol Neurosci Rep. 2016;16:16. 13. Bergman O, Anderson T, Zetterberg M. Optic perineuritis: a retrospective case series. Int Med Case Rep J. 2017;10:181– 188. 14. Min ET, Tevaraj JM, Thavarantnam JM, Noor LK, Mohd RA, Salmah WM, Hazabbah WH. A review of optic perineuritis. Int Eye Sci. 2017;17:213–216. 15. Purvin V, Kawaski A. Optic perineuritis secondary to Wegener’s granulomatosis. Clin Exp Ophthalmol. 2009;37:712–717. 16. Lai C, Sun Y, Wang J, Purvin V, He Y, Yang Q, Jing Y, Hongxia Y, Zhu J. Optic perineuritis in Behcet’s disease. J Neuroophthalmol. 2015;35:342–347. 17. Pappolla A, Silveira F, Norscini J, Miquelini L, Patrucco L. Bilateral optic perineuritis as initial presentation of giant cell arteritis. Neurologist. 2019;24:26–28. 18. McClelland C, Zaveri M, Walsh R, Fleisher J, Galetta S. Optic perineuritis as the presenting feature of Crohn Disease. J Neuroophthalmol. 2012;32:345–347. 19. Micieli JA, Streutker CJ, McIntyre K. Isolated optic perineuritis as the presenting sign of sarcoidosis. J Neuroophthalmol. 2020;40:255–257. 20. Townsend JH, Dubovy SR, Pasol J, Lam BL. Transient optic perineuritis as the initial presentation of central nervous system involvement by pre-b cell lymphocytic leukemia. J Neuroophthalmol. 2013;33:162–164. 21. Bansai R, Singh R, Takkar A, Lai V. Combined central retinal artery and vein occlusion with optic perineuritis following herpes zoster dermatitis in an immunocompetent child. Indian J Ophthalmol. 2017;65:1233–1235. 22. Yates WB, Nothling S, Lawlor M. Optic perineuritis due to tuberculosis. J Neuroophthalmol. 2019;39:257–259. 23. Rush JA, Ryan EJ. Syphilitic optic perineuritis. Amer J Ophthalmol. 1981;91:404–406. 24. Ozello DJ, Moster ML. Optic Perineuritis Due to Lyme Disease. Newtown Square, PA: Wills Eye Resident Case SeriesDiagnosis and discussion, 2017. 25. Winward KE, Hamed LM, Glaser JS. The spectrum of optic nerve disease in human immunodeficiency virus infection. Amer J Ophthalmol. 1989;107:373–380. 26. Miura Y, Fukuda K, Taniguchi Y, Komori M, Fukushima A. Recurrent optic perineuritis as the first manifestation of relapsing polychondritis. J Neuroophthalmol. 2019;39:513–514. 27. Lemaitre S, Esquerda GM, Guardiola AC, Agustin JT, Sanda N, Gonzalez-Candial M. Colon cancer and IgG4-related disease with orbital inflammation and bilateral optic perineuritis. Medicine (Baltimore). 2018;97:1–7. 28. Kamaluddin NA, Tai E, Wan H, Hiltan WH, Ibrahim M, Samsudin AH. Optic perineuritis in neuromyelitis optica spectrum disorder. Cureus. 2019;11:e4834. 29. Lopez-Chiriboga AS, Van Stavern G, Flanagan EP, Pittock SJ, Fryer J, Bhatti MT, Chen JJ. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-positive optic perineuritis. Neuroophthalmology. 2019;44:1–4. 30. Phuljhele S, Agarwal D, Ramteke PP, Shashni A, Sharma P. Perineurits or infiltration of optic nerve sheath? A presentation of diffuse large B cell gastric lymphoma. Indian J Ophthalmol. 2020;68:1212–1214. 31. Cramer S, Glaspy JA, Efird JT, Louis DN. Chronic lymphocytic leukemia and the central nervous system: a clinical and pathological study. Neurology. 1996;46:19–25. 32. Ra YH, Park SY, IM SA, Kim JY, Chung NG, Cho B. Enhancement of optic nerve in leukemic patients: leukemic infiltration of optic nerve versus optic neuritis. Invest Magn Reson Imaging. 2016;20:167–174. e191 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.