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Ra, Park, Im, Kim, Chung, and Cho: Enhancement of Optic Nerve in Leukemic Patients: Leukemic Infiltration of Optic Nerve versus Optic Neuritis
Original Article

Investigative Magnetic Resonance Imaging 2016; 20(3): 167-174.

Published online: 30 September 2016

DOI: https://doi.org/10.13104/imri.2016.20.3.167

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

Yo Han Ra1, Sun Young Park1, Soo Ah Im1, Jee Young Kim1, Nak Gyun Chung2, Bin Cho2

1Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

2Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

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. +82-2-2258-1455, Fax. +82-2-599-6771, saim@catholic.ac.kr

Received 19 August 2016       Revised 22 September 2016       Accepted 23 September 2016

Copyright © 2016 Korean Society of Magnetic Resonance in Medicine (KSMRM)

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

To identify magnetic resonance imaging (MRI) findings of leukemic infiltration of optic 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 infiltration of optic 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 of optic nerve and its degree, signal intensity, laterality (unilateral/bilateral), intraconal fat infiltration and its degree, and associated central nervous system abnormalities.

Results

Of 5 cases of leukemic infiltration of optic 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 infiltration of optic 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 infiltration or optic neuritis such as thickening and perineural enhancement of optic nerves are overlapped.

Conclusion

Enhancement and thickening of optic nerve were overlapped MR findings in leukemic infiltration of optic nerve and optic neuritis. Our findings suggest that enhancing optic nerve thickening with associated central nervous system MR abnormality favors the diagnosis of leukemic infiltration of optic nerve, especially in patients with history of acute lymphoblastic leukemia. However, CSF and BM study were required for differentiation between leukemic infiltration of optic nerve and optic neuritis.

Keywords: Leukemia, Magnetic resonance imaging, Optic nerve, Optic neuropathy

INTRODUCTION

In the past, leukemic involvement of central nervous system (CNS) was uncommon 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 (1234). Leukemic involvement of the eye may be present over the optic nerve, orbit, uveal, choroidal or retinal layer. While leukemic infiltration of the orbit is common, leukemic involvement of the optic nerve is relatively rare. Nevertheless, leukemic infiltration 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 (45).
When the enhancing optic nerve thickening in leukemic patients is seen on magnetic resonance imaging (MRI), this finding may suggest leukemic involvement of optic nerve (6). But, the possibility of optic neuritis cannot be excluded. Leukemic infiltration of optic 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 infiltration of optic 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 this entity have been reviewed (3678910). Herein, we describe clinical and MRI findings in 5 cases of leukemic infiltration of optic nerve and 2 cases of optic 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 infiltration of optic nerve (n = 5) and optic neuritis (n = 2) in our institution between July 2006 and August 2015. The diagnosis of leukemic infiltration of optic 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 of optic nerve and its degree, signal intensity, laterality (unilateral/bilateral), intraconal fat infiltration 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 remission (n = 2), second complete remission (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).

Imaging Findings

The MR imaging features of 7 cases are summarized in the Table 2. Of 5 leukemic infiltration of optic nerve, 4 cases showed unilateral involvement and 1 case showed bilateral involvement (Figs. 1,2,3). All 2 optic neuritis lesions showed unilateral involvement (Fig. 4). All 7 cases displayed enhancing thickening of optic nerve, with variable degree of enhancement and thickening without significant difference between two groups. All cases also showed variable intraconal fat infiltration. The signal intensity of leukemic infiltration of optic 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 infiltrations of optic 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 infiltration of optic nerve was diagnosed by histologic evidence of CSF study and BM biopsy. Of the 5 leukemic infiltrations of optic 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 infiltrations of optic nerve showed normal CSF study and positive BM biopsy for leukemia relapse. Case number 3 of the 5 leukemic infiltrations of optic nerve showed positive results on both CSF study and BM biopsy for leukemia relapse. In these cases, the diagnosis of leukemic infiltration of optic nerve was proposed, and chemotherapy or radiation therapy or cytoreduction was started. In case number 1 and 4 of 5 leukemic infiltrations of optic 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 pneumonia, which occurred during chemotherapy for fourth CNS relapse after 4 years. In a case number 5 of the 5 leukemic infiltrations of optic 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 infiltrations of optic 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 follow-up 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 infiltrations of optic 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 remission and he has undertaken follow-up examination.
However, 3 patients (case number 1, 4, and 5) of 5 the leukemic infiltrations of optic 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 remission 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 of optic neuritis had been proposed, and pulse steroid therapy was started. The symptoms and signs were improved 10 and 14 days after undertaking steroid therapy and they had undertaken maintenance therapy.

DISCUSSION

The thickening and enhancement of optic nerve in patients with underlying leukemia should be suspected of leukemic infiltration of optic nerve and should be differentiated from optic neuritis. The leukemic infiltration of optic nerve and optic neuritis has comparable symptoms and signs, similar to that observed in our cases. The leukemic infiltration of optic nerve is also more common in children than in adults (68). In our series, all 5 patients with leukemic infiltration of optic nerve had previous history of ALL, raising the possibility that the leukemic infiltration of optic 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 remission (6711). Similarly, in our series, 4 of 5 patients with leukemic infiltration of optic nerve achieved complete remission and had no previous history of central nervous system involvement.
Due to their low prevalence, only a few literatures have addressed the MR imaging findings of leukemic infiltration of optic nerve (68910111213). A search of the literature in English showed 6 cases of leukemic infiltrations of optic nerve (Table 3). MR imaging finding of the leukemic infiltration of optic nerve is thickening of the optic nerve with enhancement (68910111213). Enhancing optic nerve thickening is also noted in patients with optic neuritis, however, no case of optic neuritis in leukemic patient has been reported yet. In our results, all 2 patients with optic neuritis and 5 patients with leukemic infiltration of optic nerve show variable enhancement and thickening of optic nerve with variable perilesional intraconal fat infiltration on MRI, without significant difference between two groups. However, MR imaging findings of associated other CNS involvement are helpful in distinguishing the leukemic infiltration of optic nerve from optic neuritis. In our series, 2 of the 5 patients with leukemic infiltration of optic nerve showed leptomeningeal enhancement or intracranial chloroma on MRI.
In 5 patients with leukemic infiltration of optic nerve, follow-up MRI or CSF studies showed regression of leukemic infiltration 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 infiltration of optic nerve and optic neuritis are generally different (512). 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 infiltration of optic nerve from optic neuritis.
In conclusion, enhancing optic nerve thickening is overlapped MR imaging findings between leukemic infiltration of optic 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 infiltration of optic nerve. However, the possibility of optic neuritis cannot be excluded, therefore, CSF and BM biopsy are necessary for differentiation.

Figures and Tables

Fig. 1

Leukemic infiltration 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 remission 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 infiltration (arrows).

imri-20-167-g001
Fig. 2

Leukemic infiltration of left optic nerve in a 7-year-old boy. He complained of decreased visual acuity of left orbit and fever, which occurred during chemotherapy for acute lymphoblastic leukemia. (a) Fat-suppressed axial T2-weighted 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 infiltration (arrow). (c) Contrast-enhanced axial T1-weighted MR image with fat-suppression of the brain demonstrates a chloroma arising from dura and extension to right cerebellar hemisphere (arrow).

imri-20-167-g002
Fig. 3

Leukemic infiltration of bilateral optic nerves in a 10-year-old boy. He showed diplopia, which occurred 29 months after achieving a first complete remission 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).

imri-20-167-g003
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 remission 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 infiltration (arrows).

imri-20-167-g004
Table 1

Clinical Findings for the 7 Patients with Leukemia Whose MRI Showed Optic Nerve Enhancement

imri-20-167-i001
Case Age (years)/sex Leukemia type Disease status of leukemia Symptoms and signs BM biopsy or CSF study Final diagnosis Treatments Follow up exams Outcome
1 6/M ALL 1. Second complete remission 1. Decreased visual acuity (L) CSF study for leukemia (+) Leukemic infiltration of optic nerve (L) CTx CSF study (-) Died
2. 3 weeks after completion of treatment 2. Foreign body sensation of L orbit
2 7/M ALL 1. Second complete remission 1. Decreased visual acuity (L) 1. CSF study (-) Leukemic infiltration of optic nerve (L) CTx MRI: regression Loss of follow up
2. During chemotherapy after BMT 2. Fever 2. BM biopsy for leukemia relapse (+)
3 10/M ALL 1. First complete remission Diplopia 1. CSF study for leukemia (+) Leukemic infiltration of optic nerve (B) IT CTx and RT CSF (-) MRI: regression Complete remission of leukemia
2. 29 months after completion of treatment 2. BM biopsy for leukemia relapse (+)
4 25/F ALL 1. Refractory state Decreased visual acuity (L) CSF study for leukemia (+) Leukemic infiltration of optic nerve (L) RT CSF (-) Died
2. Conservative treatment
5 27/M AML 1. Second complete remission Painful swelling of orbit (L) CSF study for leukemia (+) Leukemic infiltration of optic nerve (L) RT CSF (-) MRI: regression Died
2. During chemotherapy
6 11/M ALL 1. First complete remission Decreased visual acuity (R) CSF study (-) Optic neuritis (R) Pulse steroid therapy Not performed Neuritis: Improved Leukemia: relapsed
2. 5 months after completion of treatment
7 60/F CML During treatment with imatinib Visual field defect (R) Not performed Optic neuritis (R) Pulse steroid therapy Not performed Neuritis: Improved Leukemia: complete remission

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

Table 2

Imaging Findings for the 7 Patients with Leukemia Whose MRI Showed Optic Nerve Enhancement

imri-20-167-i002
Case Age (years)/sex Leukemia type Final diagnosis MRI findings Optic nerve thickening Perineural enhancement Intraconal fat infiltration
1 6/M ALL Leukemic infiltration of optic nerve (L) 1. Thickening and perineural enhancement of L optic nerve ++ ++ ++
2. Intraconal fat infiltration
2 7/M ALL Leukemic infiltration of optic nerve (L) 1. Thickening and perineural enhancement of L optic nerve + ++ +
2. Intraconal fat infiltration
3. Chloroma arising from dura and extension to R cerebellar hemisphere
3 10/M ALL Leukemic infiltration of optic nerve (B) 1. Thickening and perineural enhancement of L optic nerve + + -/+
2. Intraconal fat infiltration
3. Prominent leptomeningeal enhancement of brain
4 25/F ALL Leukemic infiltration of optic nerve (L) 1. Thickening and perineural enhancement of L optic nerve + ++ +
2. Intraconal fat infiltration
5 27/M AML Leukemic infiltration of optic nerve (L) 1. Thickening and perineural enhancement of L optic nerve ++ ++ ++
2. Intraconal fat infiltration
6 11/M ALL Optic neuritis (R) 1. Thickening and perineural enhancement of Roptic nerve + ++ ++
2. Intraconal fat infiltration
7 60/F CML Optic neuritis (R) 1. Thickening and perineural enhancement of R optic nerve ++ ++ +
2. Intraconal fat infiltration

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)

Table 3

Literature Review of 6 Cases of Leukemic Infiltrations of Optic Nerve

imri-20-167-i003
Case First author, year Age (years)/sex Leukemia type Disease status of leukemia Symptoms and signs MRI findings BM biopsy or CSF study Final diagnosis Treatment Follow up exam Outcome
1 Madani A, 2000 10/M ALL Complete remission Seizure Bilateral asymmetrical enlargement and enhancement of optic nerves extending to chiasm 1. CSF: 2% blasts Leukmic infiltration of optic nerves (B) CTx MRI: complete regression after 2 months Complete remission for 2 years after recurrence
2. BM biopsy (-)
2 Porter RP, 2004 8/M ALL During continuation of therapy for ALL Blurred peripheral vision Mild enlargement and enhancement of optic nerves NA Leukmic infiltration of optic nerves (B) NA NA NA
3 Lin YC, 2004 40/M ALL Complete remission Progressive visual loss in both eyes Thickening and perineural enhancement of both optic nerves NA Leukmic infiltration of optic nerves (B) RT CT: regression NA
4 Towsend JH, 2013 20/M ALL Complete remission Right eye pain Thickening and perineural enhancement of right optic nerve with perineural fat stranding 1. CSF study (+) Leukmic infiltration of optic nerve (R) NA NA Complete remission
2. BM biopsy (-)
3. Rt. Optic nerve biopsy (+)
5 de Fatima Soares M, 2005 12/F ALL Decreased visual acuity, headache, nystagmus and bilateral facial palsy Thickening and enhancement of optic nerve sheath, papilla, choroid and perineural tissues NA Leukmic infiltration of optic nerves (B) NA NA Died 10 months after orbital presentation
6 Puvanach andra, 2010 14/M ALL Remission with monthly maintenance of intrathecal chemotherapy Painless reduced vision in left eye Asymmetric bilateral optic nerve infiltrations NA Leukmic infiltration of optic nerves (B) RT and IT CTx Visual improvement Remission

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; NA = not available; RT = radiation therapy

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