Original Article

Study of Posterior Reversible Encephalopathy Syndrome in Children With Acute Lymphoblastic Leukemia After Induction Chemotherapy

Journal of Child Neurology 1-6 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815589758 jcn.sagepub.com

Ji-Hong Tang, MD1, Jian-Mei Tian, BS2, Mao Sheng, MS3, Shao-Yan Hu, MD4, Yan Li, BS1, Li-Ya Zhang, MS4, Qing Gu, MS1, and Qi Wang, BS3

Abstract Increasing occurrence of posterior reversible encephalopathy syndrome has been reported in children with acute lymphoblastic leukemia. However, the etiology of posterior reversible encephalopathy syndrome is not clear. To study the possible pathogenetic mechanisms and treatment of this complication, we reported 11 cases of pediatric acute lymphoblastic leukemia who developed posterior reversible encephalopathy syndrome after induction chemotherapy. After appropriate treatment, the clinical symptoms of posterior reversible encephalopathy syndrome in most cases disappeared even though induction chemotherapy continued. During the 1-year follow-up, no recurrence of posterior reversible encephalopathy syndrome was observed. Although the clinical and imaging features of posterior reversible encephalopathy syndrome may be diverse, posterior reversible encephalopathy syndrome should be recognized as a possible important complication of acute lymphoblastic leukemia when neurologic symptoms appear. In line with previous reports, our study also indicated that posterior reversible encephalopathy syndrome was reversible when diagnosed and treated at an early stage. Thus, the occurrence of posterior reversible encephalopathy syndrome should be considered and investigated to optimize the early induction scheme of acute lymphoblastic leukemia treatment. Keywords posterior reversible encephalopathy syndrome, magnetic resonance imaging (MRI), induction chemotherapy, childhood, acute lymphoblastic leukemia Received January 21, 2015. Received revised April 17, 2015. Accepted for publication April 21, 2015.

Pediatric acute lymphoblastic leukemia accounts for 20% to 30% of all childhood malignancies.1,2 The Children Oncology Group has recently reported 5-year event-free survival in 88% to 95% of low-risk acute lymphoblastic leukemia patients diagnosed in the period 2006 to 2009.3 However, the prognosis of high-risk acute lymphoblastic leukemia remains unsatisfactory.4,5 To date, chemotherapy is still the major strategy for pediatric acute lymphoblastic leukemia.4,6 Despite the proven efficacy toward significantly improved overall prognosis, intensive chemotherapy has significantly increased the occurrence and severity of adverse events.7 For example, the addition of intrathecal methotrexate to treatment protocols has increased survival rates in childhood acute lymphoblastic leukemia but is also associated with various degrees of neurotoxicity.8 Posterior reversible encephalopathy syndrome is a neuroradiologic disease entity not yet fully understood.9 The most common risk factors of this syndrome are sudden arterial hypertension, pre-eclampsia, eclampsia, uremia, immunosuppressive

drug treatment, and cancer chemotherapies such as cyclosporine, L-asparaginase, vincristine, cytarabine, and cisplatin, which are typically used for hematopoietic malignancies.10-13 Increasing posterior reversible encephalopathy syndrome occurrence has been reported in pediatric acute lymphoblastic leukemia and is most often observed during acute lymphoblastic leukemia

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Department of Neurology, Children’s Hospital Affiliated to Soochow University, Suzhou, China 2 Department of Internal Medicine, Children’s Hospital Affiliated to Soochow University, Suzhou, China 3 Radiology Department, Children’s Hospital Affiliated to Soochow University, Suzhou, China 4 Department of Hematology and Oncology, Children’s Hospital of Soochow University, Suzhou, China Corresponding Author: Jian-Mei Tian, BS, Department of Internal Medicine, Children’s Hospital Affiliated to Soochow University, Suzhou 215003, China. Email: [email protected]

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induction chemotherapy and hematopoietic stem cell transplantation.14 Posterior reversible encephalopathy syndrome is highly treatable when recognized early, and generally reversible. However, longstanding neurologic sequelae can occur if it is not recognized and promptly treated.15 In the present study, we investigated the clinical presentation, initial and follow-up radiologic features, and the neurologic outcome of Chinese pediatric acute lymphoblastic leukemia patients with posterior reversible encephalopathy syndrome during induction chemotherapy.

Methods Subjects This study was conducted between July 2006 and July 2013 at the local Children Hospital. The diagnosis and treatment of acute lymphoblastic leukemia was performed according to the guidelines of the Pediatric Association of Chinese Medical Association.16 During the remission induction chemotherapy consisting of methotrexate, cytarabine, daunorubicin, vincristine, prednisone, and L-asparaginase, the following clinical and imaging conditions were included for posterior reversible encephalopathy syndrome diagnosis11,17,18: (1) Patients showed acute clinical manifestations such as headache, altered mental status, epileptic seizure or visual changes, accompanied or unaccompanied by blood pressure increase. (2) Patients met posterior reversible encephalopathy syndrome risk factors such as usage of immunosuppressant or cytotoxic drugs. (3) Brain magnetic resonance imaging (MRI) revealed reversible white matter edema in bilateral posterior cerebral hemisphere. Other areas of the brain affected also included the lateralis of lateral ventricles, cerebellum, and brain stem. (4) Imaging showed that the lesions completely disappeared or clinical symptoms were obviously ameliorated or disappeared after reasonable treatment. (5) Other possible leukoencephalopathy was excluded in the posterior reversible encephalopathy syndrome diagnosis. No patients had any central nervous system infection or central nervous system leukemic infiltration. There were 11 acute lymphoblastic leukemia patients who developed posterior reversible encephalopathy syndrome after induction chemotherapy from July 2006 to July 2013, and these cases were included in this study. This study was approved by the Children’s Hospital of Soochow University Ethics Committee (no. SUEC2006025). Written informed consent was obtained from the guardians of all participating children.

Imaging All 11 patients received a magnetic resonance imaging plain scan, and 5 of them received an enhancement scan. All patients were reexamined 1, 3, 6, and 12 months after first imaging. A symphony 1.5-T scanner (Siemens, Erlangen, Germany) was used to assess head phased-array coil and brain magnetic resonance imaging sequences including fast spin echo T2-weighted image, spin echo T1-weighted image and fluid-attenuated inversion recovery sequences. All the sequences had a thickness of 5 mm, layer spacing of 1 mm, and field of view of 220  230 mm. An enhancement scan was performed as follows: intravenous drip of magnevist solution (gadolinium diethylenetriamine penta-acetic acid, 0.1 mL/kg, 2.5-3.0 mL/s) in the forelimb. Once morbidity was observed, magnetic resonance imaging examination was performed within 2 days, and the imaging abnormity

positions were evaluated by 2 experienced neuroradiologists. Other possible leukoencephalopathy, central nervous system leukemic infiltration, central nervous system infection, tumor and ischemic lesions were excluded according to the patients’ clinical data and imaging examination.

Data Collection During inpatient admission to the department of hematology and oncology, the medical history and physical examination details of the children were recorded systematically by 2 physicians. The following clinical data were obtained for every patient from their hospital records: (1) patient demographics such as age on admission and gender; (2) history of seizure and other nervous system diseases; (3) history of hypertension, blood pressure on admission, and at diagnosis of posterior reversible encephalopathy syndrome; (4) cerebrospinal fluid examination; and (5) seizure characteristics. Additionally, electroencephalogram in all patients was also recorded on the next day.

Results Baseline Characteristics of the Patients As shown in Table 1, a total of 11 children (7 boys and 4 girls) who had acute lymphoblastic leukemia were retrospectively reviewed in the study, with an average age of 8.5 years old (5-14 years old). All of them developed posterior reversible encephalopathy syndrome during inductive chemotherapy.

Clinical Features of Posterior Reversible Encephalopathy Syndrome None of the 11 patients had history of epileptic seizure or high blood pressure. During the acute lymphoblastic leukemia inductive treatment, 4 patients had an obvious increase in blood pressure (36.4%), whereas the rest of the patients retained a normal blood pressure (63.6%). VDLD (vincristine, daunorubicin, L-asparaginase, dexamethasone) chemotherapy was used in the induction treatment, during which intrathecal chemotherapy (methotrexate, cytosine arabinoside, dexamethasone) was also administered. During the chemotherapy period of days 7 to 30, patients developed acute brain dysfunction, and major symptoms were recorded as headache (10/11), epileptic seizure (7/11), visual impairment (blurred vision, decreased visual acuity or cortical blindness, 6/11), disturbance of consciousness (drowsiness, exanimation, mental confusion or delirium, 5/11), and ambulatory instability (2/11). All of the 7 cases of epileptic seizure had generalized convulsions. Most of the these seizure patients had a seizure 1 to 4 times, which lasted 1 to 4 minutes, with only 1 patient having an epileptic state.

Routine Examination One to 2 days after symptoms occurred, cerebrospinal fluid examination was performed. Cerebrospinal fluid routine and biochemical examinations revealed no abnormality, and no leukemic cells were found. Electroencephalogram examination showed that 2 cases were in the normal range and 9 cases were

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Table 1. Case Summary of Posterior Reversible Encephalopathy Syndrome Patients. Patient no. Sex/age

CT scheme

Blood Interval between pressure initiation of CT and PRES Clinical symptoms; sequelae (mmHg) MRI findings; time of resolution of the abnormalities

1 2 3

M/7 M/5 F/9

VDLD VDLDþIC VDLDþIC

22 d 11 d 24 d

4 5

M/14 F/11

VDLDþIC VDLD

30 d 12 d

6

M/8

VDLDþIC

7d

7

M/6

VDLDþIC

9d

8 9

M/7 F/10

VDLDþIC VDLDþIC

22 d 10 d

10

M/11

VDLD

17 d

11

F/5

VDLDþIC

21 d

HA, seizure, AMF; none Seizure, VD; none HA, VD; minor VD

148/90 Bilateral frontal and parieto-occipital regions; 1 mo 90/60 Bilateral parieto-occipital regions; 1 mo 100/65 Right frontal and bilateral parieto-occipital regions; 1 mo HA, seizure, VD, AMF; none 143/100 Bilateral frontal and occipital regions; 1 mo HA, UG; none 150/95 Bilateral parieto-occipital and cerebellar regions; 1 mo HA, seizure, AMF; none 95/65 The deep white matter of bilateral periventricular and centrum semiovale; 6 mo HA, seizure, VD; none 90/56 Bilateral occipital, parietal, temporal and frontal regions; 3 mo HA, AMF; none 104/70 Bilateral parieto-occipital regions; 1 mo HA, seizure, VD; epilepsy 164/102 Left temporal and bilateral parieto-occipital regions; follow-up imaging 12 mo later showed only residual left temporal lesions. HA, VD, UG; none 110/74 The deep white matter of bilateral periventricular and centrum semiovale; 3 mo HA, seizure, AMF/none 98/70 Bilateral occipital, parietal, temporal and frontal regions; 1 mo

Abbreviations: ALL, acute lymphoblastic leukemia; AMF, altered mental function; CT, chemotherapy; F, female; HA, headache; IC, intrathecal chemotherapy; M, male; MRI, magnetic resonance imaging; PRES, posterior reversible encephalopathy syndrome; UG, unstable gait; VD, visual disturbance; VDLD, vincristine, daunorubicin, L-asparaginase, dexamethasone chemotherapy.

abnormal. Those who were abnormal manifested as diffuse slow wave, mainly in the occipital lobe, temporal lobe, and parietal lobe. Four weeks later, electroencephalogram re-examination revealed 1 case of y wave paroxysm in the left temporoparietal lobe, whereas no abnormality was observed in the remaining cases.

Imaging Examination A magnetic resonance imaging scan was performed within 2 days after the symptoms occurred, which revealed multiple lesions. Most of the lesions were in the rear part of the brain hemisphere and had a bilateral symmetric distribution. Slightly low signals or equal signals were observed in T1-weighted image, whereas large signals were observed in T2-weighted image and fluid-attenuated inversion recovery (Figure 1). The lesion distribution was as follows: occipital lobe (9/11), parietal lobe (8/11), frontal lobe (5/11), temporal lobe (3/11), deep white matter of bilateral periventricular and centrum semiovale (2/11), and hemisphaerium cerebelli (1/11). The results showed that the frontal lobe was often involved in the disease, accounting for 45.5% of all cases.

follow-up, all patient lesions shrunk and partial lesions disappeared after 2-week treatments. The lesions disappeared in 7 patients after 4 weeks, in 2 patients after 12 weeks, and in 1 patient after 24 weeks treatment. Only 1 patient (no. 9) retained detectable lesions in the left temporal lobe after 24 weeks treatment. No obvious lesion development was observed by enhanced scan in 5 patients. Accordingly, the clinical symptoms of posterior reversible encephalopathy syndrome appeared to disappear within 2 to 4 weeks. After 1-year follow-up, 9 patients had good prognosis and no sequelae, 1 patient (no. 9) had symptomatic epilepsy (brain magnetic resonance imaging scan showed lesions in the left temporal lobe), and 1 patient (no. 3) had slight visual impairment. For the patients with epileptic seizures, antiepileptic drugs were gradually stopped when the clinical symptoms and brain lesions disappeared, and no epileptic seizures occurred again. The improvement in magnetic resonance image lesions happened later than that with clinical symptoms. During the 1-year follow-up, all patients continuously received acute lymphoblastic leukemia chemotherapy16 and no posterior reversible encephalopathy syndrome was observed thereafter.

Discussion Treatment and Prognosis After the diagnosis of posterior reversible encephalopathy syndrome, patients stopped chemotherapy courses and were treated with 20% mannitol (dehydration), captopril (blood pressure control), and valproic acid (epileptic seizure control). During the period of brain magnetic resonance imaging

In the current study, we investigated 11 cases of pediatric acute lymphoblastic leukemia who developed posterior reversible encephalopathy syndrome following chemotherapy (VDLD regimen). Posterior reversible encephalopathy syndrome is an increasing central nervous system complication during acute lymphoblastic leukemia therapy in hematologic-oncologic

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Figure 1. Brain magnetic resonance imaging scan in patients 1, 6, and 11. (A) Brain magnetic resonance imaging scan in patient 1. (a and b) Axial fluid-attenuated inversion recovery images. (c and d) Axial T1-weighted images. (B) Brain magnetic resonance imaging scan in patient 6. (a) Axial fluid-attenuated inversion recovery and (b) T2-weighted images. (c) Axial fluid-attenuated inversion recovery and (d) T2-weighted images after 6 months. (C) Brain magnetic resonance imaging scan in patient 11. (a and b) Axial fluid-attenuated inversion recovery and (c and d) T2-weighted images. (e and f) Axial fluid-attenuated inversion recovery and (g and h) T2-weighted images taken after 1 month.

children.7,8,19 A previous report by Kim et al14 has analyzed predisposing factors of 19 pediatric acute lymphoblastic leukemia patients who developed posterior reversible encephalopathy syndrome and found that posterior reversible encephalopathy syndrome often occurs after induction chemotherapy, and second in hematopoietic stem cell transplantation when anti-hypertension or immunosuppression drugs are used. In this study, all 11 cases received VDLD and intrathecal chemotherapy, and all of them showed symptoms of posterior reversible encephalopathy syndrome between days 7 and 30 of inductive treatment, supporting previous finding that the drugs used in VDLD and intrathecal chemotherapy are likely to be the risk factors for posterior reversible encephalopathy syndrome.8,9,11-13,15 In addition, the present case series indicated that PRES was likely to occur in pediatric acute lymphoblastic leukemia patients 7 to 30 days after VDLD chemotherapy, which may be an important time window for early diagnosis of this complication. The clinical symptoms of posterior reversible encephalopathy syndrome are headache, epileptic seizure, visual impairment, and conscious disturbance. It has been reported that epileptic seizure is a major feature of posterior reversible encephalopathy syndrome, accounting for 90% of all reported cases.20,21 Belaramani et al11 analyzed significance of posterior reversible encephalopathy syndrome caused by chemotherapy in Chinese children with acute lymphoblastic leukemia, and found that epileptic seizure (100%), conscious disturbance (100%), visual impairment (60%), and headache (40%) are the main symptoms of posterior reversible encephalopathy syndrome. However, the clinical outcomes of the cases in our study were different from previous reports, with headache the most common symptom in our group, and epileptic seizure to

be the second most common symptom. The diversity of clinical symptoms may correlate with age, pathogenesis, lesion position and disease severity.22 The significant imaging features typical of posterior reversible encephalopathy syndrome are reversible posterior white matter damage mainly in the bilateral parieto-occipital lobe.17 With the development of imaging techniques, our study revealed that the pathological changes mainly involved the parieto-occipital lobe, frontal lobe, temporal lobe, cerebellum, the deep white matter of the bilateral periventricular, and central semiovale. Two cases (patients 6 and 10) should be noted because the pathologic changes observed were around the white matter of the lateral ventricle in the hemispheres and not distributed in the back of the bilateral cerebral hemisphere, which is similar to the brain imaging changes observed in metachromatic leukodystrophy. We believe this rare abnormality extends the radiologic spectrum of posterior reversible encephalopathy syndrome.23 To date, there have not been any similar reports describing deep white matter changes typical of posterior reversible encephalopathy syndrome caused by acute lymphoblastic leukemia inductive treatment. Shimizu and colleagues described a case of isolated posterior fossa involvement of posterior reversible encephalopathy syndrome that occurred during remission induction chemotherapy for acute lymphoblastic leukemia and demonstrated that the knowledge of atypical radiological features of posterior reversible encephalopathy syndrome is essential for prompt diagnosis.24 For cases with atypical lesions, judgement should be made upon the combination of pathogenesis, clinical and imaging features. There are many factors that could lead to posterior reversible encephalopathy syndrome, and more new predisposing factors are being reported.8,9,12,13,15,21,25 Hypertension has been

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suggested as a most common cause for development of posterior reversible encephalopathy syndrome.7,8,26 Panis et al21 reported 4 cases of pediatric acute lymphoblastic leukemia with posterior reversible encephalopathy syndrome during inductive treatment and suggested that hypertension caused by glucocorticoids might trigger posterior reversible encephalopathy syndrome. However, hypertension does not necessarily lead to posterior reversible encephalopathy syndrome. In our study, 7 cases had normal blood pressure when posterior reversible encephalopathy syndrome occurred, indicating that hypertension is not the only reason and cannot completely explain the pathologic mechanism for posterior reversible encephalopathy syndrome. For many posterior reversible encephalopathy syndrome patients with normal blood pressure, vascular endothelial cell damage may contribute to the pathology.15 Drugs used in the inductive treatment may also cause vascular endothelial cell damage, destroying the blood-brain barrier, contributing to the cause of posterior reversible encephalopathy syndrome.7,8,15,26 Because the inductive treatment of our patients involved many drugs, it was very difficult to demonstrate which drug could independently cause posterior reversible encephalopathy syndrome. In conclusion, our data emphasize the importance of timeline for posterior reversible encephalopathy syndrome during chemotherapy for acute lymphoblastic leukemia. Early diagnosis and proper treatment are essential for acute lymphoblastic leukemia patients to recover from posterior reversible encephalopathy syndrome. Author Contributions

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JHT thought of the concept, collected the data, and wrote the first draft. JMT and SYH participated in the design of the study and revised the article for important intellectual content. JHT, MS, and QW analyzed and interpreted the data. YL, LYZ, and QG collected the data. All authors read and approved the final manuscript.

Declaration of Conflicting Interests

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The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

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The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was financially supported by the Natural Science Foundation of Jiangsu Province of China (BK2011309), and Social Development, Science and Technology Projects of Suzhou of China (SYS201349).

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Ethical Approval This study was approved by the Children’s Hospital of Soochow University Ethics Committee (no. SUEC2006-025).

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