Diffuse Leukoencephalopathy and Brain Edema: UnusualPresentations of CNS Relapse of Acute Myeloid Leukemia

Michael Schumann, MD, Philipp Kiewe, MD, Sissel Hartlieb, MD, Martin Neumann, MD, Andreas Schilling, MD,Hans-Christian Koch, MD, Eckhard Thiel, MD (full professor), Agnieszka Korfel, MD (assistant professor)From the Departments of Gastroenterology (MS); Radiology (SH, AS, H-CK); and Hematology (PK, MN, ET, AK). Campus Benjamin Franklin, Charite, Berlin, Germany.

Keywords: Acute myeloid leukemia, leu-koencephalopathy, meningeosis.

Acceptance: Received June 7, 2008.Accepted for publication August 9, 2008.

Correspondence: Address correspon-dence to Michael Schumann, MD, De-partment of Gastroenterology, CampusBenjamin Franklin, Charite Berlin,Germany. E-mail: michael.schumann@charite.de.

J Neuroimaging 2010;20:198-200.DOI: 10.1111/j.1552-6569.2008.00300.x

A B S T R A C TAn isolated CNS relapse is rarely seen in acute myeloid leukemia. However, it has apotentially fatal clinical outcome. We herein present the case of a 39-year-old man,who presented to our emergency room with horizontal diplopic images, vertigo, bilateraldeafness, and progressing somnolence. Cerebral imaging revealed cerebral and cerebellaredema and a diffuse leukoencephalopathy. With the one-year-old history of an initiallysuccessfully treated FAB-M0 acute myeloid leukemia (AML) in mind, a lumbar puncturewas carried out that showed a vast number of myeloid blasts in the morphologic analysisof the cerebrospinal fluid. In conjunction with normal findings in the peripheral blood-count with differential and the bone marrow examination a diagnosis of an isolated CNSrelapse of the AML was made. Cytarabine chemotherapy was initiated and the symptomsresolved rapidly. To our surprise, cerebral imaging in the course of the treatment not onlyshowed a resolution of the brain edema but also of the leukoencephalopathy, pointingto a direct infiltration of brain parenchyma by leukemic blasts. The case highlights therelevance of the CNS as a pharmacologic “sanctuary” for tumor cells in patients that onprior treatments have not received intrathecal chemotherapy or chemotherapeutics thatcross the blood-brain barrier.

IntroductionA 39-year-old man presented to the emergency departmentwith a 2-month history of pain in his head and neck, horizontaldiplopic images, especially when looking to the far left, non-directional vertigo, and bilateral deafness. A cerebral magneticresonance imaging (MRI) performed 1 day before admissionshowed a diffuse leukoencelopathy (Fig 1A, arrows) and a mildcerebellar edema with marginal narrowing of the cisterna am-biens (Fig 1C, arrows). One year before, he had been diagnosedwith acute myeloid leukemia (AML), M0 according to French-American-British (FAB) classification, with trisomy of chromo-some 11 in two of 26 metaphases, and successfully treated withtwo cycles of low-dose cytarabine and doxorubicin, followedby high-dose chemotherapy with treosulfan and fludarabineand allogenic stem cell transplantation from his HLA-identicbrother.

The lumbar puncture revealed a cell count of 720 cells perμL (normal <4/μL), an elevated protein of 110 mg/dL (nor-mal 20-50 mg/dL) and a normal glucose level of 41 mg/dL. Themorphologic examination of cerebrospinal fluid (CSF) revealedmyeloid blasts (Fig 2) confirmed by immunocytologic examina-tion (strong expression of CD34, CD33, HLA-DR, CD117, andaberrant expression of CD4). The peripheral blood-count withdifferential were normal and no significant blast populationswere found on cytologic and immunocytologic bone marrowexamination with a complete chimerism on moleculargeneticanalysis. Thus, a diagnosis of isolated CNS relapse of the AMLwas made.

A few hours following admission, the patient’s condition de-teriorated with nausea, vomiting, and progressing somnolence.A cerebral CT scan showed fulminant cerebral and cerebellaredema, pronounced in the posterior fossa with a risk of ver-tical herniation. The fourth ventricle (Fig 3A, arrow) and theprepontine and cerebellopontine cisterns (Fig 3A, arrowheads)were markedly compressed. The patient was transferred to theintensive care unit for monitoring and a systemic chemotherapywith cytarabine (1.5 g twice daily) together with dexamethasonewas started. After only two administrations the clinical condi-tion of the patient substantially improved. The cyto-reductivetreatment was continued with systemic high-dose cytarabinefor a total of nine doses, and the neurologic deficits improvedcontinuously with a regression of leukoencephalopathy on MRI(Fig 1B, arrows) and a marked reduction of the cerebellar edemaon both MRI and CT (Fig 1D and 3B).

An isolated CNS relapse of AML occurs with a frequencyof 4.7% in children,1 and even less frequent in adults. In pe-diatric leukemia, age < 2 years, enlarged liver/spleen or CNSdisease at diagnosis, high WBC count, FAB M5, and chromo-some 11 abnormalities were associated with CNS relapse.1 Ina study with adults, extramedullary manifestations, includingCNS, were significantly associated with CD56 expression byleukemic blasts and 11q23 karyotypic abnormalities.2 Of thesefeatures, only a trisomy for chromosome 11 was found in ourpatient. CNS relapse in the undifferentiated FAB M0 subgroupof AML is extremely rare—to our knowledge only one casehas been reported in the literature thus far.3 In our patient,

198 Copyright ◦C 2008 by the American Society of Neuroimaging

Fig 1. Cerebral MRI scan (T2-weighted) one day before admission (A and C) and three weeks later (B and D).

neither intrathecal chemotherapy nor chemotherapeutics ableto cross the blood-brain barrier have been used for induc-tion and conditioning chemotherapy. Thus, it can be specu-

Fig 2. Cytology of the cerebrospinal fluid (Cytospin preparationand May-Gruenwald/Giemsa staining).

lated that the lack of any prophylaxis of CNS involvementfavored the CNS—a pharmacologic “sanctuary”—as a site ofrelapse.4

CNS leukemia usually involves the leptomeninges. A dis-seminated leukoencephalopathy in an AML patient mayhave a range of causes, including infections, vascular le-sions, treatment-related disseminated necrotizing lesions andleukemic infiltrates. In such cases, ultimate diagnosis usuallyrests on the collection of cerebrospinal fluid, however, some-times it is not enough for definite diagnosis. In our patient, theleukoencephalopathy might have been caused by direct infiltra-tion of brain parenchyma by leukemic blasts or, alternatively,by brain edema due to diffuse infiltration of small brain ves-sels. Due to the rapid deterioration, time-consuming diagnos-tic procedures were not performed. The rapid improvementwith resolution of the leukoencephalopathy on MRI underchemotherapy (persisting without steroids) supports the diag-nosis of diffuse brain infiltration by AML. So far, only twocases of diffuse brain infiltration by acute leukemia detected byMRI were reported.5,6 The patient was discharged and remainswithout neurologic deficits four months after diagnosis of theCNS relapse.

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Fig 3. Cerebral CT scan at the of admission (A) and two weeks later (B).

References1. Johnston DL, Alonzo TA, Gerbing RB, et al. Risk factors and therapy

for isolated central nervous system relapse of pediatric acute myeloidleukemia. J Clin Oncol 2005;23:9172-9178.

2. Chang H, Brandwein J, Yi QL, et al. Extramedullary infiltrates ofAML are associated with CD56 expression, 11q23 abnormalities andinferior clinical outcome. Leuk Res 2004;28:1007-1011.

3. Chen MT, Wu HJ. Acute leukemia presenting as diabetes insipidusand bilateral exudative retinal detachment–a case report. KaohsiungJ Med Sci 2001;17:150-155.

4. Seo S, Kami M, Honda H, et al. Extramedullary relapse in the so-called ‘sanctuary’ sites for chemotherapy after donor lymphocyteinfusion. Bone Marrow Transpl 2000;25:226-227.

5. Wagiel E, Rokicka-Milewska R, Wagiel K, et al. Magnetic resonanceimaging: more sensitive method in the detection of leukemic cen-tral nervous system infiltration. Wiad Lek 1998;51(Suppl 4): 97-102.(Polish).

6. Imataki O, Tamai Y, Inoue N, et al. A case of relapsed acute myeloidleukemia with brain white matter lesions. Gan To Kagaku Ryoho2007;34:643-646. (Japanese).

200 Journal of Neuroimaging Vol 20 No 2 April 2010