November 1980 TheJournalofPEDIATRICS 829 Intracranial hemorrhage and focal seizures secondary to use of L-asparaginase during induction therapy of acute lymphocytic leukemia L-Asparaginase is commonly used for induction therapy of acute lymphocytic leukemia of childhood. Severe clinical bleeding secondary to clot(ing dysfunction has not been previously reported. We observed intracranial hemorrhagic infarcts with focal seizures and hemiparesis associated with clotting abnormalities, including severe hypofibrinogenemia, probably the result of L-asparaginase administered during induction therapy of acute lymphocytic leukemia. M i t c h e l l S. C a i r o , M . D . , K e n L a z a r u s , M . D . , R i c h a r d L. G i l m o r e , M . D . , and Robert, L. Baehner, M . D . , Indianapolis, Ind. THE USE of L-asparaginase, an enzyme derived and purified from Escherichia coli B, has improved the rate of remission when employed with vincristine and prednisone for induction therapy of acute lymphocytic leukemia? However, L-asparaginase therapy has been associated with various forms of toxicity, including coagulation abnormalities. 2-4 Despite the presence of marked aberrations of clotting, bleeding definitely attributable to the use of L-asparaginase has not been observed. We describe the case histories of two children with acute lymphocytic leukemia who developed focal seizures and transient hemiparesis during induction therapy with vincristine, prednisone, and L-asparaginase. Neither child had evidence for metabolic, infectious, traumatic, or neoplastic etiology for their neurologic signs. However, both children had coagulation abnormalities, including severe hypofibrinogenemia, associated with a focal area of intracranial hemorrhagic infarct. From the Division of Pediatric Hematology-Oncology, James Whitcomb Riley Hospital for Children, and Department of Pediatrics and Radiology, Indiana University School of Medicine. Supported by Public Health Service Grant CCSG No. 50-860-48 and a Grant from the Riley Memorial Association. Reprint address: Division of Pediatric Hematology-Oneology, James Whiteomb Riley Hospitalfor Children, Indianapolis, IN 46223. 0022-3476/80/110829 + 05500.50/0 9 1980 The C. V. Mosby Co. CASE REPORTS Patient I. This 28/l~-year-old white girl had a two-week history of decreased activity, fever, and bone pain. Initial physical examination was within normal limits but her CBC revealed a WBC of 1,760//~1 with 85% lymphocytes, 13% PMN, and 2% monocytes, a platelet count of 215,000//~1, and a hematocrit of 26%. A bone marrow aspirate revealed 70% L1 lymphoblasts, CSF was within normal limits, and quantitative immunologic cell markers revealed null cell leukemia. Initial coagulation studies Abbreviations used PT: prothrombin time PTT: partial thromboplastin time CAT: computed axial tomography EEG: electroencephalogram were within normal limits. She was begun on chemotherapy according to the 162 protocol of the Children's Cancer Study Group, which included prednisone 40 mg/m ~ daily; vincristine 1.5 mg/m 2 weekly; 10 mg of intrathecat methotrexate on day 1 and day 14; and L-asparaginase 6,000 units/m 2, to start on day 4 and continue for nine doses over the subsequent three weeks. On day 17 of induction therapy, following three weekly doses of vincristine and six intramuscular doses of L-asparaginase, she developed a focal seizure of her right arm. Her neurologic exam revealed generalized paresis of the right upper extremity, normal mental status, and normal visual fields. Diagnostic studies included normal CSF, normal serum concentrations of electrolytes, calcium, and liver transaminases, and negative blood, urine, and CSF cultures. Initial PT was 39 seconds, PTT was 110 Vol. 97, No. 5, pp. 829-833 830 Cairo et aL The Journal of Pediatrics November 1980 Fig. 1. A, CAT scan initially within normal limits. B, CAT scan taken four days later reveals left focal intracranial hemorrhage. Table. C o a g u l a t i o n a b n o r m a l i t i e s at various times d u r i n g clinical c o u r s e Time Patient 1 Diagnosis of leukemia Neurologic complications Following replacement therapy Patient 2 Diagnosis of leukemia Neurologic complications Following replacement therapy Normal values PT (sec) I I I PTT (see) Fibrinogen (mg/dl) Platelet (ul) FSP (units) 10 39 13 22 110 32.5 5 / 10 10 105 215,000 67,500 . . 10-20 . 10.5 19.5 13.5 24 38 28 335 29 60 44,000 185,000 . . . . 10-20 . 10-13 28-35 200-400 150,000450,000 10-20 I Factor IX [ (%) ] 30 Factor X1 (%) 68 . . . 90 66 100-200 100-200 . PT = Prothrombin time; PTr = partial thromboplastin time; FSP = fibrin-split product. seconds, fibrinogen concentration was less than l0 rag/d1, platelet count was 67,500/A, fibrin-split products were within normal limits (Table). Red blood cell morphology was normal on Wright-stained smears. She was given 10 ml/kg of fresh-frozen plasma and 5 mg vitamin K intravenously, as well as 10 ml/kg of cryoprecipate. Initial CAT scan of the head was within normal limits. However, a repeat CAT scan four days later (Fig. 1) revealed a focal intracranial hemorrhage involving the left hemisphere, and her EEG showed diffuse slowing over the same area. Factor IX level five days after admission was 30% (NL 60 to 140%) and Factor XI 68% (NL 65 to 135%). Repeat coagulation studies 10 days after her last dose of L-asparaginase were within normal limits. The L-asparaginase was discontinued, but she completed her induction course of vincristine, prednisone, and intrathecal methotrexate. She had no subsequent seizures and her right hemiparesis cleared. She remains in remission six months later and is receiving maintenance chemotherapy. Patient 2. This 5-year-old white boy had a one-week history of fever, lethargy, headache, and bilateral knee pain. Physical examination was unremarkable and admission CBC revealed a WBC of 4,810/~1 with 35% lymphoblasts, hematocrit of 26%, and platelet count of 44,000/~1. A bone marrow revealed 85% L, lymphoblasts, null cell type, and the CSF was within normal limits. Initial coagulation studies were also normal at this time (Table). He was given chemotherapy according to the 161 protocol of the Children's Cancer Study Group which included prednisone 40 m g / m V d a y by mouth weekly, vincristine 1.5 m g / m 2 intravenously, L-asparaginase 6,000 units/m ~ intramuscularly to begin on day 4 for nine total doses during the subsequent three weeks, and methotrexate 12 mg intrathecally on day 1 and day 14. On day 20 of therapy, following three weekly doses of vincristine, two intrathecal doses of methotrexate and eight intramuscular doses of L-asparaginase, he was readmitted because of a right focal seizure. The neurologic examination revealed right upper and lower extremity motor weakness, normal visual fields, and normal mental status. Diagnostic studies included normal CSF, normal concentrations of serum electrolytes, calcium, and liver transaminases, and negative blood, urine, and CSF cultures. Initial PT was 19.5 seconds, PTT was 38 seconds, fibrinogen 29 mg/dl, Factor IX 90%, Factor XI Volume 97 Number 5 Intraeranial hemorrhage and seizures secondary to L-asparaginase therapy 83 1 Fig. 2. C, CAT scans initially within normal limits. D, CAT scans taken five days later reveals left focal intracranial hemorrhagic infarct. 66%, fibrin-split products were normal, platelet count 185,000/~1, and normal Wright-stained peripheral blood smear without microangiopathic changes (Table). He was given 10 ml/kg of fresh-frozen plasma and 5 mg vitamin K intravenously. Initial CAT scan of the head was within normal limits. However, repeat CAT scan five days later (Fig. 2) revealed a focal hemorrhagic infarct over the left hemisphere, and the EEG showed focal slowing over the same area. His last dose of L-asparaginase was cancelled and he finished his induction course with vincristine, prednisone, and methotrexate intrathecally. He had no further seizures and his hemiparesis cleared. He remains in remission six months later, receiving maintenance chemotherapy. DISCUSSION L-Asparaginase exerts its effect by hydrolyzing z-asparagine and thus depletes the supply of this amino acid to tumor cells, which fail to synthesize it? -7 In addition, L-asparaginase inhibits protein synthesis, resulting in hypoalbuminemia, hypofibrinogemia, and generalized decrease in alpha and beta g l o b u l i n s ? ~ 8 Coagulopathy associated with L-asparaginase therapy is well recognized. The most c o m m o n coagulation abnormalities include hypofibrinogenemia and low Factor IX and XI levels? 4, 9-11Hypofibrinogemia has occurred in 50 to 100% of patients studied during treatment?. 4. o-n but none have bad episodes of clinical bleedingY .... Although hypofibrinogenemia was originally believed to be the result of increased protein degradation, it has subsequently been shown to be secondary to decreased protein synthesis? ..... 3 In addition, between 75 and 100% of children prospectively studied during induction therapy were found to have decreased Factor IX and XI values, also associated with no bleeding."' lo Since bleeding induced by L-asparaginase has not been well documented, an intense search was made for other causes of a coagulopathy. Disseminated intravascular coagulation was ruled out by relatively normal platelet counts, normal fibrin-split products, negative cultures, and no evidence of a microangiopathic hemolytic anemia. Intracranial hemorrhage secondary to acute lymphocytic leukemia was also dismissed as a possibility. This disorder usually occurs during the first few days of therapy and appears to be related to the following: thrombocytopenia of less than 20,000//A, leukemic infiltration of blood vessels, hyperleukocytosis with white blood counts greater than 300,000/~1, sepsis, consumption coagulopathy, or leukemic relapse.' .... Other coagulation abnormalities associated with hypo- 832 Cairo et al. fibrinogenemia have been reported with vincristine and prednisone therapy. F o u r such patients have been described and none had an associated clinical bleeding disorder. Two of the four patients were studied with 1311 fibrinogen, and both demonstrated decreased fibrinogen survival? ~ Several other possible causes for seizures and neurologic dysfunction other than intracranial hemorrhage were considered unlikely in these two children, Vincrisfine-induced seizures have an incidence between 1 and 4%, are usually generalized and without focal abnormalities, and occur five to six da3~s after treatment or are related to hyponatremia secondary to an inappropriate antidiuretic hormone secretion. 1~-~ Intrathecal use of methotrexate appears to also be an unlikely cause for our patients' seizures and transient hemiparesis. Three distinct types of neurologic dysfunction have been described with intrathecal administration of methotrexate. The first is the acute reaction, occurring within hours to days with meningeal irritation, chemical arachnoiditis, and CSF pleocytosisY. TM ~ The second type is a subacute reaction, Occurring days to weeks after multiple doses, and is manifested by a myelopathy with motor dysfunction of the spinal cordY -~" The third type, or chronic form, develops m o n t h s tO years following treatment and is associated with a progressive leukoencephalopathy 30-33.35, ~ In addition, neurologic dysfunction secondary to L-asparaginase therapy, and unrelated to coagulation abnormalities, appears to be unlikely and related to metabolic alterations of the CSF caused by depletion of L-asparagine and L-glutamine from surrounding spinal fluid. This syndrome has been associated with somnolence, lethargy, and confusion, and only rarely have generalized seizures occurred?' ~, :'~'33 Lastly, leukemic infiltrations of the central nervous system were also considered as a possibility. Such children usually present with symptoms and signs of increased intracranial Pressurel In a series of 656 cases, only 3% had seizures, hemiplegia; or both?' ~. . . . . . . Thus, the focal seizures and transient hemiparesi s were most likely related to the areas of intracranial hemorrhage or hemorrhagic infarct demonstrated by CAT scan, The striking finding of marked hypofibrinogenemia appears to be the most likely cause of the intracranial event. The majority of children with acute lymphocytic leukemia and hypofibfinogenemia previously studied (85%) had low fibrinogen values, but the values were consistently above 30 mg/dl?' TM There is a low risk for spontaneous bleeding when fibrinogen concentrations are greater than 50 rag/ dl, even though these values are far below ~the normal range of 200 to 400 mg/dl. In contrast, patients with The Journal of Pediatrics November 1980 congenital hypofibrinogenemia often have fibrinogen concentrations less than 50 mg/dl, and spontaneous bleeding is a common occurrence. Hematemesis, melena, umbilical bleeding, hemarthrosis, mucous membrane bleeding, and spontaneous intracranial hemorrhage all have been described in patients with congenital hypofibrinogenemia.3~. ~0 In summary, focal seizures and hemiparesis occurred in two children receiving L-asparaginase during induction therapy of acute lymphocytic leukemia. Although there were minimal depressions of Factor IX and Factor XI values, the intracranial hemorrhage and hemorrhagic infarct most likely resulted from sever e hypofibrinogihernia secondary to impaired protein synthesis. Cessation of L-asparaginase therapy and employment of freshfrozen plasma, vitamin K, and/or cryoprecipitate resulted in rapid resolution of the neurologic deficits and correction of the coagulation abnormalities. REFERENCES 1. 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