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

INTRODUCTION

In the past, leukemic involvement of central nervous system (CNS) was uncommon

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.

Received: August 19, 2016Revised: September 22, 2016Accepted: 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. +82-2-2258-1455Fax. +82-2-599-6771Email: [email protected]

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

iMRI 2016;20:167-174 http://dx.doi.org/10.13104/imri.2016.20.3.167

Original Article 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

pISSN 2384-1095eISSN 2384-1109

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, Korea2Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

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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). 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 (4, 5).

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

Table 1. Clinical Findings for the 7 Patients with Leukemia Whose MRI Showed Optic Nerve Enhancement

CaseAge (years)/

sexLeukemia

typeDisease status of

leukemiaSymptoms and

signsBM biopsy or

CSF studyFinal

diagnosisTreatments

Follow up exams

Outcome

1 6/M ALL

1. Second complete remission

2. 3 weeks after completion of treatment

1. Decreased visual acuity (L)

2. Foreign body sensation of L orbit

CSF study for leukemia (+)

Leukemic infiltration of optic nerve (L)

CTx CSF study (-) Died

2 7/M ALL


2. During chemotherapy after BMT

1. Decreased visual acuity (L)

2. Fever

1. CSF study (-) 2. BM biopsy

for leukemia relapse (+)


CTx MRI: regression

Loss of follow up

3 10/M ALL

1. First complete remission

2. 29 months after completion of treatment

Diplopia 1. CSF study for leukemia (+)

2. BM biopsy for leukemia relapse (+)

Leukemic infiltration of optic nerve (B)

IT CTx and RT

CSF (-) MRI: regression

Complete remission

of leukemia

4 25/F ALL

1. Refractory state2. Conservative treatment

Decreased visual acuity (L)



RT CSF (-) Died

5 27/M AML


2. During chemotherapy

Painful swelling of orbit (L)



RT CSF (-) MRI: regression

Died

6 11/M ALL

1. First complete remission

2. 5 months after completion of treatment

Decreased visual acuity (R)

CSF study (-) Optic neuritis (R)

Pulse steroid therapy

Not performed

Neuritis: Improved Leukemia: relapsed

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

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http://dx.doi.org/10.13104/imri.2016.20.3.167

this entity have been reviewed (3, 6-10). 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 DataTable 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).

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).

a b

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Imaging FindingsThe 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. 1-3). 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 gadolinium-based 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 OutcomeThe 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

Table 2. Imaging Findings for the 7 Patients with Leukemia Whose MRI Showed Optic Nerve Enhancement

CaseAge (years)/

sexLeukemia

typeFinal diagnosis MRI findings

Optic nerve thickening

Perineural enhancement

Intraconal fat infiltration

1 6/M ALLLeukemic infiltration of

optic nerve (L)1. Thickening and perineural enhancement

of L optic nerve2. Intraconal fat infiltration

++ ++ ++

2 7/M ALL


1. Thickening and perineural enhancement of L optic nerve

2. Intraconal fat infiltration3. 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 B optic nerves

2. Intraconal fat infiltration3. Prominent leptomeningeal enhancement

of brain

+ + -/+

4 25/F ALLLeukemic infiltration of



+ ++ +

5 27/M AMLLeukemic infiltration of



++ ++ ++

6 11/M ALLOptic neuritis (R) 1. Thickening and perineural enhancement

of Roptic nerve2. Intraconal fat infiltration

+ ++ ++

7 60/F CMLOptic neuritis (R) 1. Thickening and perineural enhancement

of R optic nerve2. 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)

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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

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).

a

c

b

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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 (6, 8). 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 (6, 7, 11). 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

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).

a b

c d

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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).

a b

Table 3. Literature Review of 6 Cases of Leukemic Infiltrations of Optic Nerve

CaseFirst

author, year

Age (years)/

sex

Leukemia type

Disease status of leukemia

Symptoms and signs

MRI findingsBM biopsy or

CSF studyFinal

diagnosisTreatment

Follow up exam

Outcome

1Madani

A, 200010/M ALL

Complete

remission

Seizure Bilateral asymmetrical

enlargement and

enhancement of optic

nerves extending to

chiasm

1. CSF: 2%

blasts

2. BM biopsy

(-)

Leukmic

infiltration

of optic

nerves (B)

CTx

MRI:

complete

regression

after 2

months

Complete

remission

for 2 years

after

recurrence

2Porter RP,

20048/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

3Lin YC,

200440/M ALL

Complete

remission

Progressive visual

loss in both eyes

Thickening and

perineural enhancement

of both optic nervesNA

Leukmic

infiltration

of optic

nerves (B)

RTCT:

regressionNA

4Towsend

JH, 201320/M ALL

Complete

remission

Right eye pain Thickening and

perineural enhancement

of right optic nerve with

perineural fat stranding

1. CSF study (+)

2. BM biopsy (-)

3. Rt. optic

nerve biopsy (+)

Leukmic

infiltration

of optic

nerve (R)

NA NAComplete

remission

5de 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

6Puvanach

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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involvement. Due to their low prevalence, only a few literatures have

addressed the MR imaging findings of leukemic infiltration of optic nerve (6, 8-13). 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 (6, 8-13). 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 (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 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.

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Molloy PT. Childhood leukemia: central nervous system abnormalities during and after treatment. AJNR Am J Neuroradiol 1996;17:295-310

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3. Ginsberg LE, Leeds NE. Neuroradiology of leukemia. AJR Am J Roentgenol 1995;165:525-534

4. Camera A, Piccirillo G, Cennamo G, et al. Optic nerve involvement in acute lymphoblastic leukemia. Leuk Lymphoma 1993;11:153-155

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8. Arrigan M, Smyth L, Harmon M, Flynn C, Sheehy N. Imaging findings in recurrent extramedullary leukaemias. Cancer Imaging 2013;13:26-35

9. Porter RP, Kaste SC. Imaging findings of recurrent acute lymphoblastic leukemia in children and young adults, with emphasis on MRI. Pediatr Radiol 2004;34:400-408

10. de Fatima Soares M, Braga FT, da Rocha AJ, Lederman HM. Optic nerve infiltration by acute lymphoblastic leukemia: MRI contribution. Pediatr Radiol 2005;35:799-802

11. Rosenthal AR. Ocular manifestations of leukemia. A review. Ophthalmology 1983;90:899-905

12. 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

13. Puvanachandra N, Goddard K, Lyons CJ. Dramatic visual recovery after prompt radiotherapy and chemotherapy for leukaemic infiltration of the optic nerve in a child. Eye (Lond) 2010;24:927-928

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