- Email: [email protected]
Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study
ARTICLE IN PRESS The Egyptian Journal of Radiology and Nuclear Medicine (2016) xxx, xxx–xxx
Egyptian Society of Radiology and Nuclear Medicine
The Egyptian Journal of Radiology and Nuclear Medicine www.elsevier.com/locate/ejrnm www.sciencedirect.com
ORIGINAL ARTICLE
Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study Nagat Mansour Khalifa a, Wafa Fagieri Mohamed Nour b, Noha Abd ElShafy ElSaid a,*, Rania Zakaria Abu El Ezz c, Hassan Ali El-kiki c a
Department of Diagnostic Radiology, National Cancer Institute, Cairo University, Egypt Cairo University, Egypt c Department of Diagnostic Radiology, Faculty of Medicine, Cairo University, Egypt b
Received 9 March 2016; accepted 31 May 2016 Available online xxxx
KEYWORDS Childhood; Leukemia; Chemotherapy; Neurotoxicity; Brain MRI
Abstract Aim of the study: To evaluate the role of MRI in the detection of the side effects of chemotherapy on the brain in leukemic children presenting with clinical symptoms. Patients and methods: 20 pediatric patients aged between 1 and 16 years receiving or have received chemotherapy for acute leukemia have undergone MR examination of the brain for evaluation of neurological symptoms related to treatment from August to December 2015. Written consent was taken from the patients. Results: This study included 20 children, 15 (75%) were males and 5 (25%) were females. Their ages at the time of the study ranged from 1 to 16 years. 17 patients (85%) were on maintenance chemotherapy, 2 patients (10%) were on induction and 1 patient (5%) had finished treatment. Multiple complications were recorded by MRI and its correlation to the treatment phase of the cases. All cases of Sino-venous thrombosis and hemorrhage occurred within the maintenance phase. Leukoencephalopathy was divided equally between maintenance and induction phases. Brain atrophy was divided equally between induction and maintenance phases. PRES occurred within the maintenance phase. Most of infection cases (sinusitis and otitis media) occurred within maintenance; only one case was seen in a patient who just ended his chemotherapy. Conclusion: Chemotherapy is associated with certain side effects that can be evaluated by utilization of MRI. An elevated degree of suspicion is needed to recognize the radiological features of CNS complications of chemotherapy and familiarity with the imaging findings is essential for proper diagnosis and further treatment of neurological symptoms in pediatric patients with leukemia. Ó 2016 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
* Corresponding author. E-mail address: [email protected] (N.A.E. ElSaid). Peer review under responsibility of The Egyptian Society of Radiology and Nuclear Medicine. http://dx.doi.org/10.1016/j.ejrnm.2016.05.020 0378-603X Ó 2016 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS 2
N.M. Khalifa et al. Table 1
Phase of chemotherapy at study time.
Table 2
MR findings among the studied groups.
Phase
No.
%
Finding
No
%
Induction Intensification Maintenance Finished
2 0 17 1
10 0 85 5
PRES Sino-venous thrombosis Hemorrhage Leukoencephalopathy Brain atrophy Sinusitis Middle ear infection
1 6 2 2 2 6 1
5 30 10 10 10 30 5
1. Introduction Leukemia is the most common malignancy in children. Acute lymphoblastic leukemia accounts for one-fourth of all childhood cancers and approximately 75% of all childhood leukemia. The peak of it occurs between 2 and 5 years (1). The etiology of leukemia is unknown, but some factors predispose to it as ionizing radiation, chemicals, and drugs. Genetic factors also may predispose to it as increased incidence in siblings of leukemia, trisomy 21, Fanconi anemia, congenital Agammaglobulinemia, and neurofibromatosis (2). Diagnosis depends on blood count which shows blast cells, that is confirmed by bone marrow aspiration containing more than 55 blasts/mm3 (3). Modern treatment protocols have dramatically improved the prognosis. Therapeutic approaches consist of multimodal chemotherapy and radiotherapy. Prognostic factors include age, sex, race, nutritional status, the immunologic subtype, platelet count, rapidity of cytoreduction, and the presence of organomegaly or lymphadenopathy (3). As advances in cancer therapy improve the prognosis of patients with childhood malignancies, awareness of the consequences of treatment methods assumes increasing importance (4). Some types of chemotherapy can leave young patients with short-term or long-term neurological side effects. Methotrexate can cause neurotoxicity and cognition impairment within 3 days of administration (5). Up to 2% of patients treated with l-asparaginase develop hemorrhagic or nonhemorrhagic infarcts, usually secondary to sinovenous occlusion (6). Agents, particularly methotrexate, cisplatin, arabinosylcytosine, carmustine, and thiotepa, occasionally cause cerebral white matter anomalies (7). Central nervous system prophylactic treatment as well as other disease complications may produce many abnormalities
100 80 60 40 20 0 Induction
Fig. 1
Intensification
Maintenance
Finished
Phase of chemotherapy at study time.
Fig. 2
MR Findings among the studied group.
Fig. 3 Frequency of the MRI diagnoses within the phases of chemotherapy.
seen on the cranial MRI. Cortical atrophy, ventricular dilatation and white matter hyperintensities are documented (8). Both the underlying malignancy and the anti-neoplastic therapy can cause immunosuppression, leading to infection. Fungi are the most frequent causal microorganisms and typically affect patients having absolute granulocytic counts of less than 100/mm3 for more than 2 weeks (9). MRI is known for its superior soft tissue imaging. The use of MRI in the early detection of chemotherapy side effects on pediatrics brain prompts early management and avoidance or at least minimizing long term side effects (10). The aim of this prospective study was to evaluate the role of MRI in the detection of the side effects of chemotherapy on the brain in leukemic children presenting with clinically related symptoms.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study 2. Patients and methods
Table 3 Frequency of the MRI diagnoses within the phases of chemotherapy. MRI abnormality
PRES Hemorrhage Sinovenous thrombosis Leukoencephalopathy Brain atrophy Otitis media Sinusitis
2.1. Patients
Phase of chemo. Induction
1 1
Maintenance
Finished
1 2 6 1 1 1 5
1
3
Twenty children had undergone MR imaging, and they were sent from the pediatric oncology department and the intensive care to the radiology department from August to December 2015. Written consent was taken from patients. Essential inclusion criteria included the following: 1. Pediatricians age 1–16 years. 2. Confirmed case of leukemia.
a
b
T1
T2
c
d
FLAIR
DWI (b 800)
e ADC Fig. 4 (a, b, c, d & e): case (1). Case 1: 4-year-old female, with acute lymphoblastic leukemia, started chemotherapy one year ago, now on maintenance chemotherapy presented with hemiplegia and recurrent fits. MRI (a, b, c & e) was done .T1 WI (a) shows no significant abnormalities. Bilateral diffuse cerebral areas of abnormal MR signal involving cortical, sub-cortical and deep white matter more on the right side eliciting high T2 and FLAIR WIs SI (b) and (c) (arrows). DWI (d) and ADC (e) show area of restricted diffusion at the occipital lobe (arrows). Diagnosis: posterior reversible encephalopathy syndrome (PRES).
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS 4
N.M. Khalifa et al.
a
b T1
T2
c
d FLAIR
e
DWI (b0)
f DWI b 1000
g ADC
MRV
Fig. 5 (a, b, c, d, e, f & g): Case (2). Case 2: 9-year-old patient with ALL, on maintenance chemotherapy and enoxaparin for previous thrombotic event. MRI was done (a, b, c, d, e, f & g) T1 WI (a) shows right temporal lobe cortical (opercula) area of high T1 signal (arrow). T2 WI (b) and FLAIR (c) show right temporal lobe and supra-tentorial white matter high signal intensity with hypointense rim of hemosiderin (arrows). DWI (b0 & 1000) (d) and (e) and ADC (f) show foci of restricted diffusion at the right temporal lobe (arrows) representing areas of hemorrhage and infarction. MRV (g) shows attenuated right transverse and sigmoid sinuses (arrows). Diagnosis: Hemorrhagic ischemic insult secondary to venous impairment and Supra-tentorial leukoencephalopathy.
3. Leukemia patients ended or under chemotherapy with positive neurological symptoms. Exclusion criteria included those who receive radiotherapy or combined radio and chemotherapy, and patients with leukemic infiltrates. The study includes 15 males and 5 females. 2.2. Magnetic resonance imaging The MRI examinations were performed to all the cases. They were done on a 1.5 tesla super conducting system
(Phillips MRI machine) using an extremity coil of the appropriate size. Pre-imaging preparation: 1. Fasting for 4 h. 2. Cannula: 24G or 22G. 3. Sedation was performed with oral 10% chloral hydrate (50–75 mg/kg) under supervision of an experienced pediatrician for irritable patients; otherwise, they were not sedated.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study
a
b
5
c
T1
T2
T2
d DWI (b 1000 )
e
f Gradient echo
MRV
Fig. 6 (a, b, c, d, e & f): Case (3). Case 3: Male patient 4-year-old with ALL, on maintenance chemotherapy, presented with persistent headache. MRI was done (a, b, c, d, e & f) T1 & T2 WIs (a, b & c) show left cerebellar hemisphere area of high signal intensity and scattered foci of high signal intensity are seen at the centrum semi-ovale and left frontal subcortical region (arrows). DWI b1000 (d) Shows left cerebellar hemisphere area of restricted diffusion (reduced ADC) (arrow). Gradient echo WIs (d) shows left cerebellar area of low SI and high SI at its lateral aspect (arrow). MRV (e) shows attenuated anterior aspect of superior sagittal and left transverse sinuses (arrows). Diagnosis: Left cerebellar hemorrhagic infarction secondary to venous impairment and white matter acute ischemic foci.
Protocol of MRI: 1. T1 weighted spin-echo images and its value (TR = 400500 ms, TE = 15–20 ms, FOV = 200 mm, acquisition matrix = 256 141 pixels, slice thickness = 4 mm, with 0.5 mm gap). Axial and sagittal T1 weighted images pre & post contrast administration for depicting parenchymal volume, ischemia, hemorrhage and focal lesions features that may have important diagnostic and prognostic implications. 2. T2 weighted spin-echo images and its value (TR = 3500– 5000 ms, TE = 100–120 ms, FOV = 200 mm, acquisition matrix = 512 301 pixel, slice thickness = 4 mm, with 0.5 mm gap). Axial and sagittal T2-weighted MR image provides good contrast between gray and white matter, allowing identification of any white matter signal intensity abnormalities. 3. Axial fluid attenuated inversion recovery (FLAIR) images (TR = 11000 ms, TE = 140 ms, inversion time = 2800 ms, FOV = 200 mm, acquisition matrix = 256 137 pixels, slice thickness = 4 mm, with 0.5 mm gap).
4. Axial diffusion weighted images and its value (TR = 3160 ms, TE = 100 ms, FOV = 200 mm, acquisition matrix = 256 77 pixels, slice thickness = 4 mm, with 0.5 mm gap). The high water content in the extracellular space and rapid water molecular diffusion affect the appearance of the brain on diffusion-weighted image. 5. MRV: Time-of-flight MR venography was performed in patients with cerebrovascular disorders. The parameters used with this technique were as follows: 30/9/1: field of view, 22–25 cm; matrix, 219 250; flip angle, 50°; section thickness, 3 mm; section slab thickness, 3–7.5. Interpretation of MRI findings: 1. 2. 3. 4. 5.
Assessment of the brain volume and Ventricular system. Reporting intra- or extra-axial hemorrhage. Assessment of the white matter for signal changes. Assessment of cerebral venous sinuses. Monitoring of complications as intracranial infections.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS 6
N.M. Khalifa et al.
3. Results This prospective study included 20 children, 15 (75%) were males and 5 (25%) were females. All of them were confirmed cases of acute leukemia receiving chemotherapy at different phases. Their ages at the time of the study ranged from 1 to 16 years. 19 patients (95%) had acute lymphoblastic leukemia (ALL), and only 1 patient (5%) had acute myeloid leukemia. 17 patients (85%) were on maintenance chemotherapy, 2 patients (10%) were on induction and 1 patient (5%) had finished treatment (Table 1 and Fig. 1). According to the clinical presentation MRI was performed to our 20 patients and the following conditions were diagnosed from the obtained MR images: 1. 1 patient (5%) developed Posterior reversible encephalopathy syndrome (PRES). 2. 6 patients (30%) developed Sino-venous thrombosis. 3. 2 patients (10%) developed intra-cerebral hemorrhage. 4. 2 patients (10%) developed white matter changes (Leukoencephalopathy). 5. 7 patients (35%) developed infection: 6 patients (30%) had sinusitis. 1 patient (5%) had middle ear infection. 6. 2 patients (10%) developed brain atrophy (Table 2 and Fig. 2).
The frequency by which each MRI diagnosis was seen at each phase of chemotherapy is depicted in the following Table 3 and Fig. 3. In Table 3 and Fig. 3 we can see that: 1. all cases of Sino-venous thrombosis and hemorrhage occurred within the maintenance phase, 2. leukoencephalopathy was divided equally between maintenance and induction phases, 3. brain atrophy was divided equally between induction and maintenance phases, 4. PRES occurred within the maintenance phase, and 5. most of infection cases (sinusitis and otitis media) occurred within maintenance, and only one case was seen in a patient who had just ended his chemotherapy. 4. Discussion Leukemia is the most common type of cancer in children. The majority of childhood leukemia is of the ALL type which is responsible for about 1,400 deaths a year in the U.S., and it can progress quickly if untreated. However, ALL is one of the most curable cancers and survival rates are now high. Despite contemporary treatment approaches which favor the use of chemotherapy (including intrathecal therapy) over radiotherapy in the treatment of CNS leukemia, children still occasionally experience morbid neurotoxicity.
a
b T2
c
FLAIR
d FLAIR
e DWI (b 800)
ADC
Fig. 7 (a, b, c, d & e): Case (4). Case 4: Male patient, 6-year-old, with ALL, MRI was done as routine at week 48 of chemotherapy. MRI (a, b, c, d & e) revealed: T2 WIs show bilateral maxillary and ethmoidal sinusitis. FLAIR (b & c) abnormal FLAIR signal in the right globe of hemorrhagic changes and faint abnormal high signal in periventricular white matter (arrow). DWI (d) and ADC (e) show no abnormal diffusion signal in periventricular white matter (FLAIR is more sensitive). Diagnosis: Post therapeutic encephalopathy, bilateral maxillary and ethmoidal sinusitis and right globe of hemorrhagic changes.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study Standard neuroimaging is sufficient to identify a variety of neurotoxic sequelae in children, and often suggest specific etiologies. Specific neuroimaging findings frequently indicate a need to alter anti-leukemia therapy (11). According to the clinical presentation MRI was performed on our 20 patients and the following conditions were diagnosed from the obtained MR images: 1 patient (5%) developed Posterior reversible encephalopathy syndrome (PRES), 6 patients (30%) developed Sino-venous thrombosis, 2 patients (10%) developed intra-cerebral hemorrhage, 2 patients (10%) developed white matter changes (leukoencephalopathy), 7 patients (35%) developed infection, 6 patients (30%) had sinusitis, 1 patient (5%) had middle ear infection and 2 patients (10%) developed brain atrophy (see cases 1–6) (Figs. 4–9). In a recent retrospective study carried out by Roula et al. (12) data were obtained from chart review of 196 pediatric patients with ALL treated between January 2002 and July 2012, 94 patients had neuroimaging studies of those, 60 were normal and 34 (36.1%) patients had abnormalities. The most encountered findings in their study were brain atrophy (n = 11 patients) and dural venous thrombosis (n = 10). Their
a
7
diagnosis was based on radiological features with or without tissue confirmation based on the clinical presentation. They concluded that CNS complications are common in ALL during therapy and require prompt diagnosis and timely intervention for better outcome and can provide essential information for delineating priorities for neuroimaging in the detection of CNS complications (12). In a study done by Katsimpardi et al. (13) infectious complications were the most common involving (35%) of patients, which match our study (35%). Most cases {85.7% (6 out of 7 patients)} occurred during maintenance while {14.3% (1 out of 7 patients)} had ended chemotherapy. 85.7% of our patients had sinusitis, the remaining patient had otitis media, and none of our patients had brain tissue infection which in a study done by Kishikawa et al. (14) accounted for 18% of patients with CNS symptoms. In our study dural venous thrombosis came as second most common complication at 30% after infections. Most commonly involved location was superior sagittal sinus (83.3%) followed by the transverse and sigmoid sinuses together (16.7%). Other venous sinus involvements were not encountered in our study. 83.3% of sinus thromboses occurred in
b T2
T2
c MRV Fig. 8 (a,b,c): Case (5). Case 5: Male patient 7-year-old, Down syndrome, ALL, patient shifted to second line chemotherapy after relapse during maintenance chemotherapy. C/O: severe headache. MR revealed: T2WI (a & b) ventriculomegaly with widened CSF cisterns and deep cortical sulci and early bi-temporal CSF hygromas are noted (arrows). MRV (c) shows superior sagittal sinus thrombosis, mainly anterior 2/3 with attempted partial recanalization of its posterior 1/3 (arrows). Diagnosis: Thrombotic process of SSS and atrophic changes of the brain.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS 8
N.M. Khalifa et al.
a
b T2
FLAIR
c T2 Fig. 9 (a,b,c): Case (6). Case 6: Male patient-4 year-old, ALL, on maintenance chemotherapy, MRI was done as routine at week 48 of chemotherapy. MR revealed: T2 WIs and FLAIR (a & b) show subtle bilateral symmetrical high signal in occipital periventricular white matter (arrows). Bilateral maxillary sinusitis (c). Diagnosis: Subtle element of supra-tentorial leukoencephalopathy, and bilateral maxillary sinusitis.
ALL patients and 16.7% occurred with AML and all the cases were encountered during the maintenance phase of chemotherapy. In a study done by Athale et al. (15) the risk of thrombosis is increased in ALL patients. Its frequency ranges between 1.1% and 36.7%, a quite large variation related to several factors, such as different definitions of thrombosis (symptomatic vs. asymptomatic), diagnostic methods for its detection, study design (prospective vs. retrospective), and differences in treatment protocols. CT scan with contrast misses the diagnosis of dural sinus thrombosis in up to 40% of patients. MRI is more sensitive for detection of early infarction. Post-contrast MRI and MR venography identify dural sinus thrombus when only subtle infarction is visible on plain CT. CT venography or MRI with venous MRV is now the methods of choice for investigation. The diagnosis is established by demonstrating a lack of flow in the dural sinuses and cerebral veins, with or without typical images of brain infarcts. Parenchymal MR and MRV are important in the demonstration of both the infarct and the thrombus within the sinuses. On MRI, the thrombus is readily recognizable in the sub-acute phase, when it is of high signal intensity on T1-weighted images; MRV is then often not required. In the acute phase, the thrombus shows iso-intense signal intensity on T1-weighted and low sig-
nal on T2-weighted imaging. This can be mistaken for flowing blood but MRV will demonstrate an absence of flow in the thrombosed sinus (16). In our study equal percentage of patients developed hemorrhagic complication, leukoencephalopathy & brain atrophy each presenting (10%). In a study done by Chamberlain (17) hemorrhagic complications were common in patients with acute leukemia (approximately 20%) which doubles our result; this may be attributed to the small number of cases in our study. Other studies showed that hemorrhage is seen in 2.7% in ALL kids, Laningham et al. (11), 6% in AML, 18.4% in APL (acute promyelocytic leukemia) and 5% in non-APL, Chen et al. (18), shows that the type of leukemia also affects the risk of hemorrhage. In a study done by Barkovich et al. (19), leukoencephalopathy was seen in 10% of patients treated with intrathecal methotrexate which matches our result. In our study leukoencephalopathy cases were seen in maintenance in induction phases equally. In a study by Laningham et al. (11) 16% were seen at the beginning of consolidation therapy, 60% at the beginning of maintenance therapy, 76% after all courses, and 52% at 1 year after diagnosis, and our study covered a short time period to show such results.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study In a study done by Prassopolous et al. (20) diffuse brain atrophy was observed in 74% and 65% of the CT examinations performed during and after cessation of treatment, respectively. The highest incidence of brain atrophy (78%) occurred during the administration of intrathecal chemotherapy. All children younger than 2 years exhibited brain atrophy. In our study only 10% of the patients showed this consequence which is big difference that could be attributed to the small sample size in our study. In our study PRES came as the least encountered complication involving 5% of the patients phase. Case reports of approximately 40 children treated for ALL are discussed in the literature (21). In our study PRES occurred during the maintenance phase of ALL treatment. This does not correspond to other reports of PRES (22–26) which all report PRES during the induction phase. Because of the administration of multiple drugs in a short time it is difficult to identify the drug potentially responsible for PRES. We conclude that MRI is a valuable modality in early detection of CNS complication in leukemia patients under chemotherapy. It acts as a helpful guide for clinicians to regulate anti-leukemia therapy. Conflict of interests Authors have no conflict of interest. References (1) Greenlee RT, Murray T, Bolden S, et al. Cancer statistics 2000, CA. Cancer J Clin 2000;50:7–34. (2) Dordelmann M, Schrappe M, Reiter A, et al. Down’s syndrome in childhood ALL. Leukemia 1998;12:645–51. (3) LanzKowsky P. Manual of pediatric hematology and oncology, 3rd ed.; 2000. p. 359–89. (4) Parisi MT, Fahmy JL, Kaminsky CK, Malogolowkin MH. Complications of cancer therapy in children: a radiologist’s guide. RadioGraphics 1999;19:283–97. (5) Dorfman Ava Ph.D. A study of the acute effects of chemotherapy on neurocognitive function among pediatric cancer patients. Fordham University; 2011. 209 pp. 3495887. (6) Fleischhack G, Solymosi L, Reiter A, Bender-Gotze C, Eberl W, Bode U. Imaging methods in diagnosis of cerebrovascular complications with L-asparaginasetherapy. Klin Padiatr 1994;206:334–41. (7) Ball Jr WS, Prenger EC, Ballard ET. Neurotoxicity of radio/ chemotherapy in children: pathologic and MR evaluation. AJNR Am J Neuroradiol 1992;13:761–76. (8) Surtrees R, Clelland J, Hann I. Demyelination and single – carbon transfer pathway metabolites during the treatment of ALL: CSF studies. J Clin Oncol 1998;16:1505–11. (9) Chen C, Zimmerman RA, Faro S, et al. Childhood leukemia: CNS abnormalities during and after treatment. AJNR Am J Neuroradiol 1996;17:295–310.
9
(10) Yag˘murlu B, Akyu¨rek S, Fitoz S, Demirkazik A. MRI of nonneoplastic cranial complications of malignant disorders. Diagn Interv Radiol 2008;14(2):61–8. (11) Laningham FH, Kun LE, Reddick WE, et al. Childhood central nervous system leukemia: historical perspectives, current therapy, and acute neurological sequelae. Neuroradiology 2007;49:873–88. (12) Roula H, Samar M, Malak I, Raya S, Miguel A, Howayda Al, et al. Neuroimaging findings in children with acute lymphoblasic leukemia a case series and review of literature. J Neurol Disorders 2015;3:14. (13) Katsimpardi K et al. Infections in a pediatric patient cohort with acute lymphoblastic leukemia during the entire course of treatment. Support Care Cancer 2006;14(3):277–84. (14) Kishikawa T, Hara T, Miyazaki S. Central nervous system complications in childhood leukemia: correlation between clinical & computed tomography findings. Am J Pediatr Hematol Oncol 1984;6(2):129–36. (15) Athale U, Siciliano S, Thabane L, et al. Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer. Pediatr Blood Cancer 2008;51:792–7. (16) Connor SE, Jarosz JM. Magnetic resonance imaging of cerebral venous sinus thrombosis. Clin Radiol 2002;57:449–61. (17) Chamberlain Marc C. Leukemia and the nervous system. Current Oncol Rep 2005;7(1):66–73. (18) Chen C et al. Prediction of fatal intracranial hemorrhage in patients with acute myeloid leukemia. Ann Oncol 2009;20 (6):1100–4. (19) Barcovich J, Raybaud C. Metabolic, toxic and inflammatory brain disorders. In: Mitchel CW, editor. Pediatric neuroimaging. PA: Lippincott William & Wilkins; 2012. p. 117–8. (20) Prassopoulos P, Cavouras D, et al. Quantitative assessment of cerebral atrophy during and after treatment in children with acute lymphoblastic leukemia. Invest Radiol 1996;31(12):749–54. (21) Panis B, Vlaar AMM, Van Well G, Th J, et al. Posterior reversible encephalopathy syndrome in pediatric leukemia. J Pediatr Neurol 2010;14:539–45. (22) Hurwitz RL, Mahoney Jr DH, Armstrong DL, Browder TM. Reversible encephalopathy and seizures as a result of conventional vincristine administration. Med Pediatr Oncol 1988;16:216–9. (23) Cooney MJ, Bradley WG, Symko SC, Patel ST, Groncy PK. Hypertensive encephalopathy: complication in children treated for myeloproliferative disorders–report of three cases. Radiology 2000;214:711–6. (24) Norman JK, Parke JT, Wilson DA, McNall-Knapp RY. Reversible posterior leukoencephalopathy syndrome in children undergoing induction therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer 2007;49:198–203. (25) Morris EB, Laningham FH, Sandlund JT, Khan RB. Posterior reversible encephalopathy syndrome in children with cancer. Pediatr Blood Cancer 2007;48:152–9. (26) Gupta A, Swaroop C, Rastogi R, Garg R, Bakhshi S. Simultaneous occurrence of posterior reversible leukoencephalopathy syndrome in two cases of childhood acute lymphoblastic leukemia induction chemotherapy. Pediatr Hematol Oncol 2008;25:351–8.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
Egyptian Society of Radiology and Nuclear Medicine
The Egyptian Journal of Radiology and Nuclear Medicine www.elsevier.com/locate/ejrnm www.sciencedirect.com
ORIGINAL ARTICLE
Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study Nagat Mansour Khalifa a, Wafa Fagieri Mohamed Nour b, Noha Abd ElShafy ElSaid a,*, Rania Zakaria Abu El Ezz c, Hassan Ali El-kiki c a
Department of Diagnostic Radiology, National Cancer Institute, Cairo University, Egypt Cairo University, Egypt c Department of Diagnostic Radiology, Faculty of Medicine, Cairo University, Egypt b
Received 9 March 2016; accepted 31 May 2016 Available online xxxx
KEYWORDS Childhood; Leukemia; Chemotherapy; Neurotoxicity; Brain MRI
Abstract Aim of the study: To evaluate the role of MRI in the detection of the side effects of chemotherapy on the brain in leukemic children presenting with clinical symptoms. Patients and methods: 20 pediatric patients aged between 1 and 16 years receiving or have received chemotherapy for acute leukemia have undergone MR examination of the brain for evaluation of neurological symptoms related to treatment from August to December 2015. Written consent was taken from the patients. Results: This study included 20 children, 15 (75%) were males and 5 (25%) were females. Their ages at the time of the study ranged from 1 to 16 years. 17 patients (85%) were on maintenance chemotherapy, 2 patients (10%) were on induction and 1 patient (5%) had finished treatment. Multiple complications were recorded by MRI and its correlation to the treatment phase of the cases. All cases of Sino-venous thrombosis and hemorrhage occurred within the maintenance phase. Leukoencephalopathy was divided equally between maintenance and induction phases. Brain atrophy was divided equally between induction and maintenance phases. PRES occurred within the maintenance phase. Most of infection cases (sinusitis and otitis media) occurred within maintenance; only one case was seen in a patient who just ended his chemotherapy. Conclusion: Chemotherapy is associated with certain side effects that can be evaluated by utilization of MRI. An elevated degree of suspicion is needed to recognize the radiological features of CNS complications of chemotherapy and familiarity with the imaging findings is essential for proper diagnosis and further treatment of neurological symptoms in pediatric patients with leukemia. Ó 2016 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
* Corresponding author. E-mail address: [email protected] (N.A.E. ElSaid). Peer review under responsibility of The Egyptian Society of Radiology and Nuclear Medicine. http://dx.doi.org/10.1016/j.ejrnm.2016.05.020 0378-603X Ó 2016 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS 2
N.M. Khalifa et al. Table 1
Phase of chemotherapy at study time.
Table 2
MR findings among the studied groups.
Phase
No.
%
Finding
No
%
Induction Intensification Maintenance Finished
2 0 17 1
10 0 85 5
PRES Sino-venous thrombosis Hemorrhage Leukoencephalopathy Brain atrophy Sinusitis Middle ear infection
1 6 2 2 2 6 1
5 30 10 10 10 30 5
1. Introduction Leukemia is the most common malignancy in children. Acute lymphoblastic leukemia accounts for one-fourth of all childhood cancers and approximately 75% of all childhood leukemia. The peak of it occurs between 2 and 5 years (1). The etiology of leukemia is unknown, but some factors predispose to it as ionizing radiation, chemicals, and drugs. Genetic factors also may predispose to it as increased incidence in siblings of leukemia, trisomy 21, Fanconi anemia, congenital Agammaglobulinemia, and neurofibromatosis (2). Diagnosis depends on blood count which shows blast cells, that is confirmed by bone marrow aspiration containing more than 55 blasts/mm3 (3). Modern treatment protocols have dramatically improved the prognosis. Therapeutic approaches consist of multimodal chemotherapy and radiotherapy. Prognostic factors include age, sex, race, nutritional status, the immunologic subtype, platelet count, rapidity of cytoreduction, and the presence of organomegaly or lymphadenopathy (3). As advances in cancer therapy improve the prognosis of patients with childhood malignancies, awareness of the consequences of treatment methods assumes increasing importance (4). Some types of chemotherapy can leave young patients with short-term or long-term neurological side effects. Methotrexate can cause neurotoxicity and cognition impairment within 3 days of administration (5). Up to 2% of patients treated with l-asparaginase develop hemorrhagic or nonhemorrhagic infarcts, usually secondary to sinovenous occlusion (6). Agents, particularly methotrexate, cisplatin, arabinosylcytosine, carmustine, and thiotepa, occasionally cause cerebral white matter anomalies (7). Central nervous system prophylactic treatment as well as other disease complications may produce many abnormalities
100 80 60 40 20 0 Induction
Fig. 1
Intensification
Maintenance
Finished
Phase of chemotherapy at study time.
Fig. 2
MR Findings among the studied group.
Fig. 3 Frequency of the MRI diagnoses within the phases of chemotherapy.
seen on the cranial MRI. Cortical atrophy, ventricular dilatation and white matter hyperintensities are documented (8). Both the underlying malignancy and the anti-neoplastic therapy can cause immunosuppression, leading to infection. Fungi are the most frequent causal microorganisms and typically affect patients having absolute granulocytic counts of less than 100/mm3 for more than 2 weeks (9). MRI is known for its superior soft tissue imaging. The use of MRI in the early detection of chemotherapy side effects on pediatrics brain prompts early management and avoidance or at least minimizing long term side effects (10). The aim of this prospective study was to evaluate the role of MRI in the detection of the side effects of chemotherapy on the brain in leukemic children presenting with clinically related symptoms.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study 2. Patients and methods
Table 3 Frequency of the MRI diagnoses within the phases of chemotherapy. MRI abnormality
PRES Hemorrhage Sinovenous thrombosis Leukoencephalopathy Brain atrophy Otitis media Sinusitis
2.1. Patients
Phase of chemo. Induction
1 1
Maintenance
Finished
1 2 6 1 1 1 5
1
3
Twenty children had undergone MR imaging, and they were sent from the pediatric oncology department and the intensive care to the radiology department from August to December 2015. Written consent was taken from patients. Essential inclusion criteria included the following: 1. Pediatricians age 1–16 years. 2. Confirmed case of leukemia.
a
b
T1
T2
c
d
FLAIR
DWI (b 800)
e ADC Fig. 4 (a, b, c, d & e): case (1). Case 1: 4-year-old female, with acute lymphoblastic leukemia, started chemotherapy one year ago, now on maintenance chemotherapy presented with hemiplegia and recurrent fits. MRI (a, b, c & e) was done .T1 WI (a) shows no significant abnormalities. Bilateral diffuse cerebral areas of abnormal MR signal involving cortical, sub-cortical and deep white matter more on the right side eliciting high T2 and FLAIR WIs SI (b) and (c) (arrows). DWI (d) and ADC (e) show area of restricted diffusion at the occipital lobe (arrows). Diagnosis: posterior reversible encephalopathy syndrome (PRES).
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS 4
N.M. Khalifa et al.
a
b T1
T2
c
d FLAIR
e
DWI (b0)
f DWI b 1000
g ADC
MRV
Fig. 5 (a, b, c, d, e, f & g): Case (2). Case 2: 9-year-old patient with ALL, on maintenance chemotherapy and enoxaparin for previous thrombotic event. MRI was done (a, b, c, d, e, f & g) T1 WI (a) shows right temporal lobe cortical (opercula) area of high T1 signal (arrow). T2 WI (b) and FLAIR (c) show right temporal lobe and supra-tentorial white matter high signal intensity with hypointense rim of hemosiderin (arrows). DWI (b0 & 1000) (d) and (e) and ADC (f) show foci of restricted diffusion at the right temporal lobe (arrows) representing areas of hemorrhage and infarction. MRV (g) shows attenuated right transverse and sigmoid sinuses (arrows). Diagnosis: Hemorrhagic ischemic insult secondary to venous impairment and Supra-tentorial leukoencephalopathy.
3. Leukemia patients ended or under chemotherapy with positive neurological symptoms. Exclusion criteria included those who receive radiotherapy or combined radio and chemotherapy, and patients with leukemic infiltrates. The study includes 15 males and 5 females. 2.2. Magnetic resonance imaging The MRI examinations were performed to all the cases. They were done on a 1.5 tesla super conducting system
(Phillips MRI machine) using an extremity coil of the appropriate size. Pre-imaging preparation: 1. Fasting for 4 h. 2. Cannula: 24G or 22G. 3. Sedation was performed with oral 10% chloral hydrate (50–75 mg/kg) under supervision of an experienced pediatrician for irritable patients; otherwise, they were not sedated.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study
a
b
5
c
T1
T2
T2
d DWI (b 1000 )
e
f Gradient echo
MRV
Fig. 6 (a, b, c, d, e & f): Case (3). Case 3: Male patient 4-year-old with ALL, on maintenance chemotherapy, presented with persistent headache. MRI was done (a, b, c, d, e & f) T1 & T2 WIs (a, b & c) show left cerebellar hemisphere area of high signal intensity and scattered foci of high signal intensity are seen at the centrum semi-ovale and left frontal subcortical region (arrows). DWI b1000 (d) Shows left cerebellar hemisphere area of restricted diffusion (reduced ADC) (arrow). Gradient echo WIs (d) shows left cerebellar area of low SI and high SI at its lateral aspect (arrow). MRV (e) shows attenuated anterior aspect of superior sagittal and left transverse sinuses (arrows). Diagnosis: Left cerebellar hemorrhagic infarction secondary to venous impairment and white matter acute ischemic foci.
Protocol of MRI: 1. T1 weighted spin-echo images and its value (TR = 400500 ms, TE = 15–20 ms, FOV = 200 mm, acquisition matrix = 256 141 pixels, slice thickness = 4 mm, with 0.5 mm gap). Axial and sagittal T1 weighted images pre & post contrast administration for depicting parenchymal volume, ischemia, hemorrhage and focal lesions features that may have important diagnostic and prognostic implications. 2. T2 weighted spin-echo images and its value (TR = 3500– 5000 ms, TE = 100–120 ms, FOV = 200 mm, acquisition matrix = 512 301 pixel, slice thickness = 4 mm, with 0.5 mm gap). Axial and sagittal T2-weighted MR image provides good contrast between gray and white matter, allowing identification of any white matter signal intensity abnormalities. 3. Axial fluid attenuated inversion recovery (FLAIR) images (TR = 11000 ms, TE = 140 ms, inversion time = 2800 ms, FOV = 200 mm, acquisition matrix = 256 137 pixels, slice thickness = 4 mm, with 0.5 mm gap).
4. Axial diffusion weighted images and its value (TR = 3160 ms, TE = 100 ms, FOV = 200 mm, acquisition matrix = 256 77 pixels, slice thickness = 4 mm, with 0.5 mm gap). The high water content in the extracellular space and rapid water molecular diffusion affect the appearance of the brain on diffusion-weighted image. 5. MRV: Time-of-flight MR venography was performed in patients with cerebrovascular disorders. The parameters used with this technique were as follows: 30/9/1: field of view, 22–25 cm; matrix, 219 250; flip angle, 50°; section thickness, 3 mm; section slab thickness, 3–7.5. Interpretation of MRI findings: 1. 2. 3. 4. 5.
Assessment of the brain volume and Ventricular system. Reporting intra- or extra-axial hemorrhage. Assessment of the white matter for signal changes. Assessment of cerebral venous sinuses. Monitoring of complications as intracranial infections.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS 6
N.M. Khalifa et al.
3. Results This prospective study included 20 children, 15 (75%) were males and 5 (25%) were females. All of them were confirmed cases of acute leukemia receiving chemotherapy at different phases. Their ages at the time of the study ranged from 1 to 16 years. 19 patients (95%) had acute lymphoblastic leukemia (ALL), and only 1 patient (5%) had acute myeloid leukemia. 17 patients (85%) were on maintenance chemotherapy, 2 patients (10%) were on induction and 1 patient (5%) had finished treatment (Table 1 and Fig. 1). According to the clinical presentation MRI was performed to our 20 patients and the following conditions were diagnosed from the obtained MR images: 1. 1 patient (5%) developed Posterior reversible encephalopathy syndrome (PRES). 2. 6 patients (30%) developed Sino-venous thrombosis. 3. 2 patients (10%) developed intra-cerebral hemorrhage. 4. 2 patients (10%) developed white matter changes (Leukoencephalopathy). 5. 7 patients (35%) developed infection: 6 patients (30%) had sinusitis. 1 patient (5%) had middle ear infection. 6. 2 patients (10%) developed brain atrophy (Table 2 and Fig. 2).
The frequency by which each MRI diagnosis was seen at each phase of chemotherapy is depicted in the following Table 3 and Fig. 3. In Table 3 and Fig. 3 we can see that: 1. all cases of Sino-venous thrombosis and hemorrhage occurred within the maintenance phase, 2. leukoencephalopathy was divided equally between maintenance and induction phases, 3. brain atrophy was divided equally between induction and maintenance phases, 4. PRES occurred within the maintenance phase, and 5. most of infection cases (sinusitis and otitis media) occurred within maintenance, and only one case was seen in a patient who had just ended his chemotherapy. 4. Discussion Leukemia is the most common type of cancer in children. The majority of childhood leukemia is of the ALL type which is responsible for about 1,400 deaths a year in the U.S., and it can progress quickly if untreated. However, ALL is one of the most curable cancers and survival rates are now high. Despite contemporary treatment approaches which favor the use of chemotherapy (including intrathecal therapy) over radiotherapy in the treatment of CNS leukemia, children still occasionally experience morbid neurotoxicity.
a
b T2
c
FLAIR
d FLAIR
e DWI (b 800)
ADC
Fig. 7 (a, b, c, d & e): Case (4). Case 4: Male patient, 6-year-old, with ALL, MRI was done as routine at week 48 of chemotherapy. MRI (a, b, c, d & e) revealed: T2 WIs show bilateral maxillary and ethmoidal sinusitis. FLAIR (b & c) abnormal FLAIR signal in the right globe of hemorrhagic changes and faint abnormal high signal in periventricular white matter (arrow). DWI (d) and ADC (e) show no abnormal diffusion signal in periventricular white matter (FLAIR is more sensitive). Diagnosis: Post therapeutic encephalopathy, bilateral maxillary and ethmoidal sinusitis and right globe of hemorrhagic changes.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study Standard neuroimaging is sufficient to identify a variety of neurotoxic sequelae in children, and often suggest specific etiologies. Specific neuroimaging findings frequently indicate a need to alter anti-leukemia therapy (11). According to the clinical presentation MRI was performed on our 20 patients and the following conditions were diagnosed from the obtained MR images: 1 patient (5%) developed Posterior reversible encephalopathy syndrome (PRES), 6 patients (30%) developed Sino-venous thrombosis, 2 patients (10%) developed intra-cerebral hemorrhage, 2 patients (10%) developed white matter changes (leukoencephalopathy), 7 patients (35%) developed infection, 6 patients (30%) had sinusitis, 1 patient (5%) had middle ear infection and 2 patients (10%) developed brain atrophy (see cases 1–6) (Figs. 4–9). In a recent retrospective study carried out by Roula et al. (12) data were obtained from chart review of 196 pediatric patients with ALL treated between January 2002 and July 2012, 94 patients had neuroimaging studies of those, 60 were normal and 34 (36.1%) patients had abnormalities. The most encountered findings in their study were brain atrophy (n = 11 patients) and dural venous thrombosis (n = 10). Their
a
7
diagnosis was based on radiological features with or without tissue confirmation based on the clinical presentation. They concluded that CNS complications are common in ALL during therapy and require prompt diagnosis and timely intervention for better outcome and can provide essential information for delineating priorities for neuroimaging in the detection of CNS complications (12). In a study done by Katsimpardi et al. (13) infectious complications were the most common involving (35%) of patients, which match our study (35%). Most cases {85.7% (6 out of 7 patients)} occurred during maintenance while {14.3% (1 out of 7 patients)} had ended chemotherapy. 85.7% of our patients had sinusitis, the remaining patient had otitis media, and none of our patients had brain tissue infection which in a study done by Kishikawa et al. (14) accounted for 18% of patients with CNS symptoms. In our study dural venous thrombosis came as second most common complication at 30% after infections. Most commonly involved location was superior sagittal sinus (83.3%) followed by the transverse and sigmoid sinuses together (16.7%). Other venous sinus involvements were not encountered in our study. 83.3% of sinus thromboses occurred in
b T2
T2
c MRV Fig. 8 (a,b,c): Case (5). Case 5: Male patient 7-year-old, Down syndrome, ALL, patient shifted to second line chemotherapy after relapse during maintenance chemotherapy. C/O: severe headache. MR revealed: T2WI (a & b) ventriculomegaly with widened CSF cisterns and deep cortical sulci and early bi-temporal CSF hygromas are noted (arrows). MRV (c) shows superior sagittal sinus thrombosis, mainly anterior 2/3 with attempted partial recanalization of its posterior 1/3 (arrows). Diagnosis: Thrombotic process of SSS and atrophic changes of the brain.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS 8
N.M. Khalifa et al.
a
b T2
FLAIR
c T2 Fig. 9 (a,b,c): Case (6). Case 6: Male patient-4 year-old, ALL, on maintenance chemotherapy, MRI was done as routine at week 48 of chemotherapy. MR revealed: T2 WIs and FLAIR (a & b) show subtle bilateral symmetrical high signal in occipital periventricular white matter (arrows). Bilateral maxillary sinusitis (c). Diagnosis: Subtle element of supra-tentorial leukoencephalopathy, and bilateral maxillary sinusitis.
ALL patients and 16.7% occurred with AML and all the cases were encountered during the maintenance phase of chemotherapy. In a study done by Athale et al. (15) the risk of thrombosis is increased in ALL patients. Its frequency ranges between 1.1% and 36.7%, a quite large variation related to several factors, such as different definitions of thrombosis (symptomatic vs. asymptomatic), diagnostic methods for its detection, study design (prospective vs. retrospective), and differences in treatment protocols. CT scan with contrast misses the diagnosis of dural sinus thrombosis in up to 40% of patients. MRI is more sensitive for detection of early infarction. Post-contrast MRI and MR venography identify dural sinus thrombus when only subtle infarction is visible on plain CT. CT venography or MRI with venous MRV is now the methods of choice for investigation. The diagnosis is established by demonstrating a lack of flow in the dural sinuses and cerebral veins, with or without typical images of brain infarcts. Parenchymal MR and MRV are important in the demonstration of both the infarct and the thrombus within the sinuses. On MRI, the thrombus is readily recognizable in the sub-acute phase, when it is of high signal intensity on T1-weighted images; MRV is then often not required. In the acute phase, the thrombus shows iso-intense signal intensity on T1-weighted and low sig-
nal on T2-weighted imaging. This can be mistaken for flowing blood but MRV will demonstrate an absence of flow in the thrombosed sinus (16). In our study equal percentage of patients developed hemorrhagic complication, leukoencephalopathy & brain atrophy each presenting (10%). In a study done by Chamberlain (17) hemorrhagic complications were common in patients with acute leukemia (approximately 20%) which doubles our result; this may be attributed to the small number of cases in our study. Other studies showed that hemorrhage is seen in 2.7% in ALL kids, Laningham et al. (11), 6% in AML, 18.4% in APL (acute promyelocytic leukemia) and 5% in non-APL, Chen et al. (18), shows that the type of leukemia also affects the risk of hemorrhage. In a study done by Barkovich et al. (19), leukoencephalopathy was seen in 10% of patients treated with intrathecal methotrexate which matches our result. In our study leukoencephalopathy cases were seen in maintenance in induction phases equally. In a study by Laningham et al. (11) 16% were seen at the beginning of consolidation therapy, 60% at the beginning of maintenance therapy, 76% after all courses, and 52% at 1 year after diagnosis, and our study covered a short time period to show such results.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020
ARTICLE IN PRESS Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study In a study done by Prassopolous et al. (20) diffuse brain atrophy was observed in 74% and 65% of the CT examinations performed during and after cessation of treatment, respectively. The highest incidence of brain atrophy (78%) occurred during the administration of intrathecal chemotherapy. All children younger than 2 years exhibited brain atrophy. In our study only 10% of the patients showed this consequence which is big difference that could be attributed to the small sample size in our study. In our study PRES came as the least encountered complication involving 5% of the patients phase. Case reports of approximately 40 children treated for ALL are discussed in the literature (21). In our study PRES occurred during the maintenance phase of ALL treatment. This does not correspond to other reports of PRES (22–26) which all report PRES during the induction phase. Because of the administration of multiple drugs in a short time it is difficult to identify the drug potentially responsible for PRES. We conclude that MRI is a valuable modality in early detection of CNS complication in leukemia patients under chemotherapy. It acts as a helpful guide for clinicians to regulate anti-leukemia therapy. Conflict of interests Authors have no conflict of interest. References (1) Greenlee RT, Murray T, Bolden S, et al. Cancer statistics 2000, CA. Cancer J Clin 2000;50:7–34. (2) Dordelmann M, Schrappe M, Reiter A, et al. Down’s syndrome in childhood ALL. Leukemia 1998;12:645–51. (3) LanzKowsky P. Manual of pediatric hematology and oncology, 3rd ed.; 2000. p. 359–89. (4) Parisi MT, Fahmy JL, Kaminsky CK, Malogolowkin MH. Complications of cancer therapy in children: a radiologist’s guide. RadioGraphics 1999;19:283–97. (5) Dorfman Ava Ph.D. A study of the acute effects of chemotherapy on neurocognitive function among pediatric cancer patients. Fordham University; 2011. 209 pp. 3495887. (6) Fleischhack G, Solymosi L, Reiter A, Bender-Gotze C, Eberl W, Bode U. Imaging methods in diagnosis of cerebrovascular complications with L-asparaginasetherapy. Klin Padiatr 1994;206:334–41. (7) Ball Jr WS, Prenger EC, Ballard ET. Neurotoxicity of radio/ chemotherapy in children: pathologic and MR evaluation. AJNR Am J Neuroradiol 1992;13:761–76. (8) Surtrees R, Clelland J, Hann I. Demyelination and single – carbon transfer pathway metabolites during the treatment of ALL: CSF studies. J Clin Oncol 1998;16:1505–11. (9) Chen C, Zimmerman RA, Faro S, et al. Childhood leukemia: CNS abnormalities during and after treatment. AJNR Am J Neuroradiol 1996;17:295–310.
9
(10) Yag˘murlu B, Akyu¨rek S, Fitoz S, Demirkazik A. MRI of nonneoplastic cranial complications of malignant disorders. Diagn Interv Radiol 2008;14(2):61–8. (11) Laningham FH, Kun LE, Reddick WE, et al. Childhood central nervous system leukemia: historical perspectives, current therapy, and acute neurological sequelae. Neuroradiology 2007;49:873–88. (12) Roula H, Samar M, Malak I, Raya S, Miguel A, Howayda Al, et al. Neuroimaging findings in children with acute lymphoblasic leukemia a case series and review of literature. J Neurol Disorders 2015;3:14. (13) Katsimpardi K et al. Infections in a pediatric patient cohort with acute lymphoblastic leukemia during the entire course of treatment. Support Care Cancer 2006;14(3):277–84. (14) Kishikawa T, Hara T, Miyazaki S. Central nervous system complications in childhood leukemia: correlation between clinical & computed tomography findings. Am J Pediatr Hematol Oncol 1984;6(2):129–36. (15) Athale U, Siciliano S, Thabane L, et al. Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer. Pediatr Blood Cancer 2008;51:792–7. (16) Connor SE, Jarosz JM. Magnetic resonance imaging of cerebral venous sinus thrombosis. Clin Radiol 2002;57:449–61. (17) Chamberlain Marc C. Leukemia and the nervous system. Current Oncol Rep 2005;7(1):66–73. (18) Chen C et al. Prediction of fatal intracranial hemorrhage in patients with acute myeloid leukemia. Ann Oncol 2009;20 (6):1100–4. (19) Barcovich J, Raybaud C. Metabolic, toxic and inflammatory brain disorders. In: Mitchel CW, editor. Pediatric neuroimaging. PA: Lippincott William & Wilkins; 2012. p. 117–8. (20) Prassopoulos P, Cavouras D, et al. Quantitative assessment of cerebral atrophy during and after treatment in children with acute lymphoblastic leukemia. Invest Radiol 1996;31(12):749–54. (21) Panis B, Vlaar AMM, Van Well G, Th J, et al. Posterior reversible encephalopathy syndrome in pediatric leukemia. J Pediatr Neurol 2010;14:539–45. (22) Hurwitz RL, Mahoney Jr DH, Armstrong DL, Browder TM. Reversible encephalopathy and seizures as a result of conventional vincristine administration. Med Pediatr Oncol 1988;16:216–9. (23) Cooney MJ, Bradley WG, Symko SC, Patel ST, Groncy PK. Hypertensive encephalopathy: complication in children treated for myeloproliferative disorders–report of three cases. Radiology 2000;214:711–6. (24) Norman JK, Parke JT, Wilson DA, McNall-Knapp RY. Reversible posterior leukoencephalopathy syndrome in children undergoing induction therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer 2007;49:198–203. (25) Morris EB, Laningham FH, Sandlund JT, Khan RB. Posterior reversible encephalopathy syndrome in children with cancer. Pediatr Blood Cancer 2007;48:152–9. (26) Gupta A, Swaroop C, Rastogi R, Garg R, Bakhshi S. Simultaneous occurrence of posterior reversible leukoencephalopathy syndrome in two cases of childhood acute lymphoblastic leukemia induction chemotherapy. Pediatr Hematol Oncol 2008;25:351–8.
Please cite this article in press as: Khalifa NM et al., Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study, Egypt J Radiol Nucl Med (2016), http://dx.doi.org/10.1016/j.ejrnm.2016.05.020