Enhancement of Optic Nerve in Leukemic Patients: Leukemic Infiltration of Optic Nerve versus Optic Neuritis

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1 pissn eissn imri 2016;20: Enhancement of Optic Nerve in Patients: Infiltration of Optic Nerve versus Optic Neuritis Yo Han Ra 1, Sun Young Park 1, Soo Ah Im 1*, Jee Young Kim 1, Nak Gyun Chung 2, Bin Cho 2 1 Department of Radiology, Seoul St. Mary s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea 2 Department of Pediatrics, Seoul St. Mary s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea Original Article Received: August 19, 2016 Revised: September 22, 2016 Accepted: September 23, 2016 Correspondence to: Soo Ah Im, M.D. Department of Radiology, Seoul St. Mary s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. Tel Fax saim@catholic.ac.kr This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose: To identify magnetic resonance imaging (MRI) findings of leukemic nerve and optic neuritis in leukemic patients with emphasis of clinical findings as reference standard to differentiate them. Materials and Methods: MRI and clinical findings of 7 patients diagnosed as leukemic nerve (n = 5) and optic neuritis (n = 2) in our institution between July 2006 and August 2015were reviewed retrospectively. In particular, MR imaging findings involved perineural enhancement and thickening nerve and its degree, signal intensity, laterality (unilateral/bilateral), intraconal fat and its degree, and associated central nervous system abnormalities. Results: Of 5 cases of leukemic nerve, 4 cases showed positive cerebrospinal fluid (CSF) study for leukemia relapse and 1 case was positive on bone marrow (BM) biopsy only. Moreover, of 5 leukemic nerve, 2 cases showed the most specific MR findings for leukemic central nervous system involvement including 1 prominent leptomeningeal enhancement and 1 chloroma. However, other MR imaging findings of the patients with leukemic or optic neuritis such as thickening and perineural enhancement nerves are overlapped. Conclusion: Enhancement and thickening nerve were overlapped MR findings in leukemic nerve and optic neuritis. Our findings suggest that enhancing optic nerve thickening with associated central nervous system MR abnormality favors the diagnosis of leukemic nerve, especially in patients with history of acute lymphoblastic leukemia. However, CSF and BM study were required for differentiation between leukemic nerve and optic neuritis. Keywords: Leukemia; Magnetic resonance imaging; Optic nerve; Optic neuropathy Copyright 2016 Korean Society of Magnetic Resonance in Medicine (KSMRM) INTRODUCTION In the past, leukemic involvement of central nervous system (CNS) was uncommon 167

2 Optic Nerve Enhancement in Leukemia Yo Han Ra, et al. because leukemia rapidly progressed and was often fatal. However, the frequency of leukemic involvement of the CNS has increased due to prolonged survival associated with development of treatment (1-4). involvement of the eye may be present over the optic nerve, orbit, uveal, choroidal or retinal layer. While leukemic of the orbit is common, leukemic involvement of the optic nerve is relatively rare. Nevertheless, leukemic of the optic nerve is clinically significant because it may be an isolated manifestation of leukemia relapse and local treatment such as radiation therapy may be required (4, 5). When the enhancing optic nerve thickening in leukemic patients is seen on magnetic resonance imaging (MRI), this finding may suggest leukemic involvement nerve (6). But, the possibility neuritis cannot be excluded. nerve and optic neuritis has similar imaging and clinical findings, and it is difficult to make a differentiation between these only based on imaging finding. Therefore, the additional examinations (such as cerebrospinal fluid [CSF] or bone marrow [BM] study) are recommended and helpful for accurate diagnosis and proper management of patients with history of leukemia. Because the treatments of leukemic nerve and optic neuritis are critically different, the differentiation between two diseases is very important. To date, on the basis of imaging findings, a few cases of Table 1. Clinical Findings for the 7 Patients with Leukemia Whose MRI Showed Optic Nerve Enhancement Age (years)/ Leukemia Disease status of Symptoms and BM biopsy or Final Follow up Case Treatments sex type leukemia signs CSF study diagnosis exams Outcome 1. Second complete 1. Decreased visual acuity (L) CSF study for leukemia (+) CTx CSF study (-) Died 1 6/M ALL 2. 3 weeks after completion of treatment 2. Foreign body sensation of L orbit nerve (L) 2 7/M ALL 3 10/M ALL 4 25/F ALL 5 27/M AML 6 11/M ALL 7 60/F CML 1. Second complete 2. During chemotherapy after BMT 1. First complete months after completion of treatment 1. Refractory state 2. Conservative treatment 1. Second complete 2. During chemotherapy 1. First complete 2. 5 months after completion of treatment During treatment with imatinib 1. Decreased visual acuity (L) 2. Fever Diplopia Decreased visual acuity (L) Painful swelling of orbit (L) Decreased visual acuity (R) Visual field defect (R) 1. CSF study (-) 2. BM biopsy for leukemia relapse (+) 1. CSF study for leukemia (+) 2. BM biopsy for leukemia relapse (+) CSF study for leukemia (+) CSF study for leukemia (+) CSF study (-) nerve (L) nerve (B) nerve (L) nerve (L) Optic neuritis (R) Not performed Optic neuritis (R) CTx IT CTx and RT MRI: regression CSF (-) MRI: regression Loss of follow up of leukemia RT CSF (-) Died RT Pulse steroid therapy Pulse steroid therapy CSF (-) MRI: regression Not performed Not performed Died Neuritis: Improved Leukemia: relapsed Neuritis: Improved Leukemia: complete ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia; B = both; BM = bone marrow; BMT = bone marrow transplantation; CML = chronic myelogenous leukemia; CSF = cerebrospinal fluid; CTx = chemotherapy; IT = intrathecal; L = left; MRI = magnetic resonance imaging; R = right; RT = radiation therapy 168

3 this entity have been reviewed (3, 6-10). Herein, we describe clinical and MRI findings in 5 cases of leukemic nerve and 2 cases neuritis in this study with review of literatures. MATERIALS AND METHODS Our study was approved by our Institutional Review Boards. We retrospectively reviewed the brain and orbit MRI of 7 patients with leukemia diagnosed with leukemic nerve (n = 5) and optic neuritis (n = 2) in our institution between July 2006 and August The diagnosis of leukemic nerve and optic neuritis was established on the basis of the combination of histologic evidence of CSF involvement by leukemia, treatment response, and progress of underlying leukemia. Using both 1.5T system (Signa Excite; GE Healthcare, Madison, WI, USA) and 3.0T system (MagnetomVerio; Siemens Medical Solutions, Erlangen, Germany), we obtained various sequence imagings, including T1-weighted, fat-suppressed T1-weighted, fat-suppressed T2-weighted, and contrast-enhanced fat-suppressed T1-weighted images. All MR images were retrospectively reviewed by 2 radiologists blinded to the histologic diagnosis and decisions were reached by consensus. Imaging features included the presence of perineural enhancement and thickening nerve and its degree, signal intensity, laterality (unilateral/bilateral), intraconal fat and its degree, and associated CNS abnormalities such as accentuated leptomeningeal enhancement or chloroma. The medical records including sex, age at diagnosis, symptom, disease status of leukemia at diagnosis of optic nerve lesion, treatment and outcome were carefully reviewed. The results of CSF studies and BM biopsies were also reviewed. RESULTS Clinical Data Table 1 shows clinical findings of 7 cases. Of the 7 patients, 5 were men and 2 were women between 6 and 60 years of age (mean age, 21 years). The patients had one of three types of leukemia, including 5 cases of acute lymphoblastic leukemia (ALL), 1 case of acute myelogenous leukemia (AML), and 1 case of chronic myelogenous leukemia (CML). The disease status of patients were first complete (n = 2), second complete (n = 3), refractory state (n = 1) and 1 of 7 patients was being treated with imatinib at the time of presentation. Patient symptoms included only decreased visual acuity (n = 2) or decreased visual acuity with foreign body sensation (n = 1) or fever (n = 1), visual field defect (n = 1), diplopia (n = 1), and painful swelling of the eye (n = 1). a b Fig. 1. of left optic nerve in a 27-year-old man. He had a complaint of painful swelling of left eye, which occurred during chemotherapy after achieving second complete of acute myelogenous leukemia. (a, b) Axial fat-suppressed T1-weighted MR image (a) and contrast-enhanced, fat-suppressed, axial T1-weighted MR image (b) show diffuse thickening and perineural enhancement of left optic nerve with intraconal fat (arrows). 169

4 Optic Nerve Enhancement in Leukemia Yo Han Ra, et al. Table 2. Imaging Findings for the 7 Patients with Leukemia Whose MRI Showed Optic Nerve Enhancement Case Age (years)/ Leukemia sex type 1 6/M ALL 2 7/M ALL 3 10/M ALL 4 25/F ALL 5 27/M AML 6 11/M ALL 7 60/F CML Final diagnosis of optic nerve (L) of optic nerve (L) of optic nerve (B) of optic nerve (L) of optic nerve (L) Optic neuritis (R) Optic neuritis (R) MRI findings of L optic nerve 2. Intraconal fat of L optic nerve 2. Intraconal fat 3. Chloroma arising from dura and extension to R cerebellar hemisphere of B optic nerves 2. Intraconal fat 3. Prominent leptomeningeal enhancement of brain of L optic nerve 2. Intraconal fat of L optic nerve 2. Intraconal fat of Roptic nerve 2. Intraconal fat of R optic nerve 2. Intraconal fat Optic nerve thickening Perineural Intraconal fat enhancement / ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia; B = both; CML = chronic myelogenous leukemia; L = left; MRI = magnetic resonance imaging; R = right, degree: + (mild), ++ (moderate), +++ (severe) Imaging Findings The MR imaging features of 7 cases are summarized in the Table 2. Of 5 leukemic nerve, 4 cases showed unilateral involvement and 1 case showed bilateral involvement (Figs. 1-3). All 2 optic neuritis lesions showed unilateral involvement (Fig. 4). All 7 cases displayed enhancing thickening nerve, with variable degree of enhancement and thickening without significant difference between two groups. All cases also showed variable intraconal fat. The signal intensity of leukemic nerve and optic neuritis on unenhanced MR imaging was similar, and all lesions showed low signal intensity to isointensity on T1-weighted images and high signal intensity on T2-weighted images. After gadoliniumbased contrast administration, all 7 cases showed perineural enhancement. Of the 5 leukemic s nerve, 2 cases showed imaging findings consistent with leukemia including prominent leptomeningeal enhancement (n = 1) and chloroma (n = 1) (Fig. 2c and 3d). Histologic Findings, Treatment and Outcome The leukemic nerve was diagnosed by histologic evidence of CSF study and BM biopsy. Of the 5 leukemic s nerve, according to the order in Table 1, case number 1, 4, and 5 showed positive CSF study for leukemia relapse. Case number 2 of the 5 leukemic s nerve showed normal CSF study and positive BM biopsy for leukemia relapse. Case number 3 of the 5 leukemic s nerve showed positive results on both CSF study and BM biopsy for leukemia relapse. In these cases, the diagnosis of leukemic nerve was proposed, and chemotherapy or radiation therapy or cytoreduction was started. In case number 1 and 4 of 5 leukemic s nerve, follow-up MRI was not performed, but follow-up CSF study showed regression of leukemia involvement 8 and 30 days after initiation of anti-leukemic therapy. In these cases, one patient died due to gastrointestinal bleeding and pulmonary hemorrhage after 3 months; another patient died of 170

5 a b Fig. 2. of left optic nerve in a 7-yearold boy. He complained of decreased visual acuity of left orbit and fever, which occurred during chemotherapy for acute lymphoblastic leukemia. (a) Fat-suppressed axial T2weighted MR image shows thickening and high IS of left optic nerve (arrow). (b) Contrast-enhanced, fat-suppressed axial T1-weighted MR image shows diffuse thickening with perineural enhancement of left optic nerve with intraconal fat (arrow). (c) Contrast-enhanced axial T1weighted MR image with fat-suppression of the brain demonstrates a chloroma arising from dura and extension to right cerebellar hemisphere (arrow). c pneumonia, which occurred during chemotherapy for fourth CNS relapse after 4 years. In a case number 5 of the 5 leukemic s nerve, follow-up MRI and CSF study showed regression of leukemia involvement 2-3 months after the initiation of anti-leukemic therapy. This patient died due to pulmonary hemorrhage and respiration failure after 3 years. In a case number 2 of the 5 leukemic s nerve, the initial CSF study was found to be negative for leukemic involvement but subsequent BM biopsy revealed leukemic involvement. Follow-up MRI showed regression of leukemia involvement 1 month after the initiation of anti-leukemic therapy, and further followup BM biopsy showed leukemic involvement. The patient was transferred to another hospital and there was no further follow-up of the patient. In a case number 3 of the 5 leukemic s nerve, follow-up MRI and CSF study showed regression of leukemic involvement 2 weeks after the initiation of anti-leukemic therapy. He had achieved complete and he has undertaken followup examination. However, 3 patients (case number 1, 4, and 5) of 5 the leukemic s nerve died within 3 years after this recurrence, one (case number 2) of the rest patients was transferred to another hospital and another patient (case number 3) has been in complete for 8 years after this recurrence. In 1 case (case number 7) of 2 patients with optic neuritis, CSF study and BM biopsy was not performed. And another case (case number 6) showed normal CSF study. In these cases, the clinical diagnosis neuritis had been proposed, and pulse steroid therapy was started. The symptoms and signs were improved 10 and 14 days after 171

6 Optic Nerve Enhancement in Leukemia Yo Han Ra, et al. a b c d Fig. 3. of bilateral optic nerves in a 10-year-old boy. He showed diplopia, which occurred 29 months after achieving a first complete of acute lymphoblastic leukemia. (a, b) Axial fat-suppressed, T1-weighted MR (a) and contrast-enhanced, fat-suppressed axial T1-weighted MR (b) images show subtle thickening with perineual enhancement of both optic nerves (arrows). (c) Contrast-enhanced, fat-suppressed coronal T1-weighted imaging also demonstrates mild neural thickening with perineural enhancement of both optic nerves (arrows). (d) Contrast-enhanced, axial T1-weighted image of the brain shows prominent leptomeningeal enhancement in the prepontine cistern and along the cerebellar folia (arrow). undertaking steroid therapy and they had undertaken maintenance therapy. DISCUSSION The thickening and enhancement nerve in patients with underlying leukemia should be suspected of leukemic nerve and should be differentiated from optic neuritis. The leukemic nerve and optic neuritis has comparable symptoms and signs, similar to that observed in our cases. The leukemic nerve is also more common in children than in adults (6, 8). In our series, all 5 patients 172 with leukemic nerve had previous history of ALL, raising the possibility that the leukemic nerve occurs most frequently in patients with ALL (6). The optic nerve is one of leukemia relapse sites because the chemotherapeutic drugs cannot penetrate blood-brain barrier and the invasion of leukemic cells in the small optic canal can interfere with the flow of CSF. In rarer cases, the optic nerve is the only initial manifestation site of leukemia relapse in a patient with prior complete (6, 7, 11). Similarly, in our series, 4 of 5 patients with leukemic nerve achieved complete and had no previous history of central nervous system

7 a Fig. 4. Right optic neuritis in an 11-year-old boy. He had a symptom of decreased visual acuity of right eye, which occurred 5 months after achieving a first complete in acute lymphoblastic leukemia. (a, b) Fat-suppressed axial T1-weighted MR (a) and contrast-enhanced, fat-suppressed axial T1-weighted MR (b) images demonstrate mild thickening and perineural enhancement of right optic nerve with mild intraconal fat (arrows). b Table 3. Literature Review of 6 Cases of Infiltrations of Optic Nerve Case First author, year Madani A, 2000 Porter RP, 2004 Lin YC, 2004 Towsend JH, 2013 Age Leukemia (years)/ type sex 10/M ALL 8/M ALL 40/M ALL 20/M ALL Disease status of leukemia During continuation of therapy for ALL Symptoms and signs MRI findings BM biopsy or CSF study Final diagnosis Treatment Follow up exam Outcome Seizure Bilateral asymmetrical enlargement and 1. CSF: 2% blasts Leukmic MRI: complete enhancement nerves extending to chiasm 2. BM biopsy (-) nerves (B) CTx regression after 2 months for 2 years after recurrence Blurred peripheral Mild enlargement and Leukmic vision enhancement nerves nerves (B) Progressive visual Thickening and Leukmic loss in both eyes perineural enhancement CT: RT of both optic nerves regression nerves (B) Right eye pain Thickening and 1. CSF study (+) Leukmic perineural enhancement 2. BM biopsy (-) of right optic nerve with 3. Rt. optic perineural fat stranding nerve biopsy (+) nerve (R) Thickening and Leukmic Died 10 enhancement of months nerve optic nerves after orbital sheath, papilla, (B) presentation choroid and perineural tissues Painless reduced Asymmetric bilateral Leukmic RT and IT Visual Remission vision in left eye optic nerve s CTx improvement nerves (B) Decreased 5 visual acuity, de Fatima headache, Soares M, 12/F ALL nystagmus and 2005 bilateral facial palsy Remission Puvanach with monthly 6 andra, 14/M ALL maintenance 2010 of intrathecal chemotherapy ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia; BM = bone marrow; CML = chronic myelogenous leukemia; CSF = cerebrospinal fluid; CTx = chemotherapy; IT = intrathecal; MRI = magnetic resonance imaging; = not available; RT = radiation therapy 173

8 Optic Nerve Enhancement in Leukemia Yo Han Ra, et al. involvement. Due to their low prevalence, only a few literatures have addressed the MR imaging findings of leukemic nerve (6, 8-13). A search of the literature in English showed 6 cases of leukemic s nerve (Table 3). MR imaging finding of the leukemic nerve is thickening of the optic nerve with enhancement (6, 8-13). Enhancing optic nerve thickening is also noted in patients with optic neuritis, however, no case neuritis in leukemic patient has been reported yet. In our results, all 2 patients with optic neuritis and 5 patients with leukemic nerve show variable enhancement and thickening nerve with variable perilesional intraconal fat on MRI, without significant difference between two groups. However, MR imaging findings of associated other CNS involvement are helpful in distinguishing the leukemic of optic nerve from optic neuritis. In our series, 2 of the 5 patients with leukemic nerve showed leptomeningeal enhancement or intracranial chloroma on MRI. In 5 patients with leukemic nerve, follow-up MRI or CSF studies showed regression of leukemic after receiving chemotherapy and radiation therapy, but 3 of the 5 patients died. In 2 patients with optic neuritis, their symptoms improved after receiving pulse steroid therapy and they had undertaken maintenance therapy with longer survival rate. This study has a limitation due to very small sample size and this is not enough to represent the overall entity. However, the treatment and prognosis of leukemic nerve and optic neuritis are generally different (5, 12). Thus it is important to differentiate them. Thus, future studies should increase the sample size and demonstrate helpful imaging and clinical findings in distinguishing the leukemic nerve from optic neuritis. In conclusion, enhancing optic nerve thickening is overlapped MR imaging findings between leukemic nerve and optic neuritis. However, the most specific MR findings for CNS involvement of leukemia include leptomeningeal or parenchymal abnormalities. Then, our findings suggested that in patients with history of ALL (6), enhancing optic nerve thickening with associated CNS abnormality favor the diagnosis as leukemic of optic nerve. However, the possibility neuritis cannot be excluded, therefore, CSF and BM biopsy are necessary for differentiation. REFERENCES 1. Chen CY, Zimmerman RA, Faro S, Bilaniuk LT, Chou TY, Molloy PT. Childhood leukemia: central nervous system abnormalities during and after treatment. AJNR Am J Neuroradiol 1996;17: Brenner H, Kaatsch P, Burkhardt-Hammer T, Harms DO, Schrappe M, Michaelis J. Long-term survival of children with leukemia achieved by the end of the second millennium. Cancer 2001;92: Ginsberg LE, Leeds NE. Neuroradiology of leukemia. AJR Am J Roentgenol 1995;165: Camera A, Piccirillo G, Cennamo G, et al. Optic nerve involvement in acute lymphoblastic leukemia. Leuk Lymphoma 1993;11: Lin YC, Wang AG, Yen MY, Hsu WM. Leukaemic of the optic nerve as the initial manifestation of leukaemic relapse. Eye (Lond) 2004;18: Madani A, Christophe C, Ferster A, Dan B. Peri-optic nerve during leukaemic relapse: MRI diagnosis. Pediatr Radiol 2000;30: Vazquez E, Lucaya J, Castellote A, et al. Neuroimaging in pediatric leukemia and lymphoma: differential diagnosis. Radiographics 2002;22: Arrigan M, Smyth L, Harmon M, Flynn C, Sheehy N. Imaging findings in recurrent extramedullary leukaemias. Cancer Imaging 2013;13: Porter RP, Kaste SC. Imaging findings of recurrent acute lymphoblastic leukemia in children and young adults, with emphasis on MRI. Pediatr Radiol 2004;34: de Fatima Soares M, Braga FT, da Rocha AJ, Lederman HM. Optic nerve by acute lymphoblastic leukemia: MRI contribution. Pediatr Radiol 2005;35: Rosenthal AR. Ocular manifestations of leukemia. A review. Ophthalmology 1983;90: 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: Puvanachandra N, Goddard K, Lyons CJ. Dramatic visual recovery after prompt radiotherapy and chemotherapy for leukaemic of the optic nerve in a child. Eye (Lond) 2010;24: