Reversible Cerebral Vasoconstriction Syndrome during Chemotherapy for Acute Lymphoblastic Leukemia

Abstract

A previously healthy 7-year-old boy, who was diagnosed with B-cell precursor acute lymphoblastic leukemia without central nervous system infiltration, was being treated with the standard risk protocol of the Japanese Pediatric Leukemia/Lymphoma Study Group B12. He had already completed induction therapy, early intensification, and intensification without any severe adverse effects, and had just started the first reinduction therapy. After he had received oral dexamethasone 10 mg/m2 daily from day 1, vincristine 1.5 mg/m2 and pirarubicin 25 mg/m2 on day 1, and L-asparaginase 10 000 U/m2 on days 1 and 4, thunderclap headaches developed on days 6 and 7 without high blood pressure or abnormal electrolytes. Although the headaches improved with loperamide, cerebral magnetic resonance angiography on day 7 revealed vasoconstriction (Figure, A). Cerebrospinal fluid examination on the following day was normal. He continued with chemotherapy along with nifedipine and did not develop a headache until after finishing the entire chemotherapy regimen. Antithrombin III was replaced when its activity was <70%. The irregular narrowing arteries disappeared in 5 months without any parenchymal abnormalities (Figure, B), and we diagnosed it as reversible cerebral vasoconstriction syndrome (RCVS).1Calabrese L.H. Dodick D.W. Schwedt T.J. Singhal A.B. Narrative review: reversible cerebral vasoconstriction syndromes.Ann Intern Med. 2007; 146: 34-44Crossref PubMed Scopus (653) Google Scholar RCVS is characterized by thunderclap headaches with or without additional neurologic symptoms and vasoconstriction of the cerebral arteries. It spontaneously resolves in 1-3 months.2Ducros A. Reversible cerebral vasoconstriction syndrome.Lancet Neurol. 2012; 11: 906-917Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar Although anticancer drugs are not generally considered to be putative precipitants, a few cases of RCVS complicated with cerebral infarction in pediatric patients with leukemia have been recently reported.3Pound C.M. Keene D.L. Udjus K. Humphreys P. Johnston D.L. Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia.J Pediatr Hematol Oncol. 2007; 29: 183-186Crossref PubMed Scopus (15) Google Scholar, 4Yoon J.H. Yoon J.Y. Park H.J. Son M.H. Kim S.H. Kim W. et al.Diffuse cerebral vasospasm with infarct after intrathecal cytarabine in childhood leukemia.Pediatr Int. 2014; 56: 921-924Crossref Scopus (9) Google Scholar, 5Tibussek D. Natesirinilkul R. Sun L.R. Wasserman B.A. Brandão L.R. Severe cerebral vasospasm and childhood arterial ischemic stroke after intrathecal cytarabine.Pediatrics. 2016; 137: 1-5Crossref Scopus (18) Google Scholar Tibussek et al5Tibussek D. Natesirinilkul R. Sun L.R. Wasserman B.A. Brandão L.R. Severe cerebral vasospasm and childhood arterial ischemic stroke after intrathecal cytarabine.Pediatrics. 2016; 137: 1-5Crossref Scopus (18) Google Scholar suspected that intrathecal cytarabine was associated with the vasoconstriction. However, our patient had not received intrathecal cytarabine for >3 weeks; the other drugs could have induced the condition. L-asparaginase is well known to cause thrombosis during chemotherapy induction, but that disorder is venous in general and does not appear similar to the arterial findings in our patient.6Gugliotta L. Mazzucconi M.G. Leone G Mattioli-Belmonte M. Defazio D. Annino L. et al.Incidence of thrombotic complications in adult patients with acute lymphoblastic leukaemia receiving L-asparaginase during induction therapy: a retrospective study. The GIMEMA Group.Eur J Haematol. 1992; 49: 63-66Crossref PubMed Scopus (107) Google Scholar As cerebral infarction usually occurs after the first thunderclap headache,2Ducros A. Reversible cerebral vasoconstriction syndrome.Lancet Neurol. 2012; 11: 906-917Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar appropriate intervention in RCVS may prevent the complications, such as infarction and hemorrhage. Nimodipine is usually given for the treatment and prevention of RCVS.2Ducros A. Reversible cerebral vasoconstriction syndrome.Lancet Neurol. 2012; 11: 906-917Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar