Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2019; 18: 22-33
Клинические и электрофизиологические аспекты метотрексатовой энцефалопатии в педиатрической практике
https://doi.org/10.24287/1726-1708-2019-18-1-22-33Аннотация
Один из побочных эффектов метотрексата - подострая энцефалопатия, которая характеризуется рядом определенных неврологических симптомов, наличием лейкоэнцефалопатии, по данным магнитно-резонансной томографии (МРТ), и медленноволновой активностью на электроэнцефалограмме (ЭЭГ). Цель работы - определение клинико-электрофизиологических характеристик метотрексатовой энцефалопатии у детей с различными типами опухолей, а также сопоставление полученных данных с литературными. Данное исследование поддержано Независимым этическим комитетом и утверждено решением Ученого совета НМИЦ ДГОИ. Проведен ретроспективный анализ результатов лечения 31 пациента в взрас-те от 1,5 до 17 лет с подострой метотрексатовой энцефалопатией. У большинства пациентов (n = 26) был диагностирован острый лимфобластный лейкоз. Согласно терапевтическим протоколам пациенты получали внутривенное, интратекальное и интравентрикулярное введение метотрексата. Степень тяжести метотрексатовой энцефалопатии опеределяли по шкале NCI-CTCAE, версия 4.0. ЭЭГ-исследования проводили всем; МРТ - 26 пациентам. Мето-трексатовая энцефалопатия развилась через 2-12 сут (в среднем 5,3 ± 3,2 сут) после введения метотрексата. Энцефалопатия 1-й степени тяжести имела место в 35,5% случаев; 2-й степени -в 19,4%; 3-й и 4-й степеней - в 25,8 и 19,4% случаев соответственно. Повторные симптомы при продолжении терапии развились у 5 пациентов. Наиболее частые неврологические симптомы: патологическая сонливость (50,1%), нарушение сознания (32,3%), когнитивные нарушения (25,8%), эпилептические приступы (19,6%) и атаксия (19,6%). Регресс неврологических симптомов наблюдался у 26 пациентов через 1-10 сут (в среднем 3,3 ± 2,2 сут); у 5 пациентов сохранялся стойкий неврологический дефицит. ЭЭГ-паттерн был представлен диффузной тета-активностью (39%), тета-дельта активностью (42%), дельта-активностью (6,5%), бета-активностью (3,0%), снижением амплитуды альфа-ритма (6,5%) и не был изменен у 1 пациента. По данным МРТ, в 84,6% случаев выявлены признаки лейкоэнцефалопатии. Установлена завсимость между изменениями на ЭЭГ, сроками дебюта и разрешения энцефалопатии. При этом между тяжестью энцефалопатии, ЭЭГ-картиной, способом введения метотрексата, возрастом пациента, клиренсом метотрексата и сопутствующей неврологической патологией связи не отмечено. Полученные нами результаты в целом сходны с зарубежными данными о клинической картине и сроках дебюта метотрексатовой энцефалопатии. У пациентов с метотрексатовой энцефалопатией ЭЭГ не всегда была представлена диффузной медленноволновой активностью тета-диапазона. Для корректной оценки результатов электрофизиологического исследования при метотрекса-товой энцефалопатии пациентам рекомендовано проведение инициального ЭЭГ-исследования. Требуется дальнейшее изучение факторов риска метотрексатовой энцефалопатии.
Список литературы
1. Bhojwani D., Sabin N.D., Pei D., Yang J.J., Khan R.B., Panetta J.C., et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 2014; 32: 949-59.
2. Lo Nigro L., Di Cataldo A., Schiliro G. Acute neurotoxicity in children with B-lineage acute lymphoblastic leukemia (B-ALL) treated with intermediate risk protocols. Med Pediatr Oncol 2000; 35 (5): 449-55.
3. Mahoney D.H.Jr., Shuster J.J., Nitsch-ke R., Lauer S.J., Steuber C.P., Winick N., et al. Acute neurotoxicity in children with B-percursor acute lymphoid leukaemia: an association with intermediate dose intravenous methotrexate and intrathecal triple therapy - a Pediatric Oncology Group study. J Clin Oncol 1998; 16: 1712-22.
4. Asato R., Akiyama Y., Ito M., Kubota M., Okumura R., Miki Y., et al. Nuclear magnetic resonance abnormalities of the cerebral white matter in children with acute lymphoblastic leukemia and malignant lymphoma during and after central nervous system prophylactic treatment with intrathecal methotrexate. Cancer 1992; 70 (7): 1997-2004.
5. Kim J.Y., Kim S.T., Nam D.H., Lee J.I., Park K., Kong D.S. Leukoencephalopathy and disseminated necrotizing leuko-encephalopathy following intrathecal methotrexate chemotherapy and radiation therapy for central nerve system lymphoma or leukemia. J Korean Neurosurg Soc 2011; 50 (4): 304-10.
6. Millan N.C., Pastrana A., Guitter M.R., Zubizarreta P.A., Monges M.S., Felice M.S. Acute and sub-acute neurological toxicity in children treated for acute lymphoblastic leukemia. Leuk Res 2018; 65: 86-93.
7. Dufourg M.N., Landman-Parker J., Auclerc M.F., Schmitt C., Perel Y., Michel G., et al. Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children. Leukemia 2007; 21 (2): 238-47.
8. Rubnitz J.E., Relling M.V., Harrison P.L., Sandlund J.T., Ribeiro R.C., Rivera G.K., et al. Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia. Leukemia 1998;12 (8): 1176-81.
9. Howard S.C., McCormick J., Pui C.H., Buddington R.K., Harvey R.D. Preventing and Managing Toxicities of High-Dose Methotrexate. Oncologist 2016; 21 (12): 1471-82.
10. Troen A.M., Chao W.H., Crivello N.A., D'Anci K.E., Shukitt-Hale B., Smith D.E., et al. Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine. Journal of Nutrition 2008; 138: 2502-9.
11. Weng Q., Wang J., Wang J., Tan B., Wang J., Wang H., et al. Folate Metabolism Regulates Oligodendrocyte Survival and Differentiation by Modulating AMPKa Activity. Sci Rep 2017 May 11; 7 (1): 1705.
12. Mizusawa S., Kondoh Y., Murakami M., Nakamichi H., Sasaki H., Komatsu K., et al. Effect of methotrexate on local cerebral blood flow in conscious rats. Jpn J Pharmacol 1988; 48 (4): 499-501.
13. Haugvicova R., Mares P. Seizures induced by homocysteic acid in immature rats are prevented by group III metabotropic glutamate receptoragonist (R,S)-4-phosphonophenylglycine. Experimental Neurology 2003; 180: 46-54.
14. Bernini J.C., Fort D.W., Griener J.C., Kane B.J., Chappell W.B., Kam-en B.A. Aminophylline for methotrexate-induced neurotoxicity. Lancet 1995; 345 (8949): 544-7.
15. Ayromlou H., Hajipour B., Hossenian M.M., Khodadadi A., Vatankhah A.M. Oxidative effect of methotrexate administration in spinal cord of rabbits. J Pak Med Assoc 2011; 61 (11): 1096-9.
16. Inaba H., Khan R.B., Laningham F.H., Crews K.R., Pui C.H., Daw N.C. Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol 2008; 19 (1): 178-84.
17. Jaffe N., Takaude Y., Anzai T., Robertson R. Transient neurologoc disturbances induced by high-dose Methotrexate treatment. Cancer 1985; 56: 1356-60.
18. Harila M.J., Winqvist S., Lanning M., Bloigu R., Harila-Saari A.H. Progressive neurocognitive impairment in young adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2009; 53: 156-61.
19. Kay H.E., Knapton P.J., O'Sullivan J.P., Wells D.G., Harris R.F., Innes E.M., et al. Encephalopathy in Acute Leukaemia Associated with Methotrexate Therapy. Archives of Disease in Childhood 1972; 47: 344.
20. Valle D.A., Kakehasi F.M., Melo R.M., Siqueira C.M., Soares T.F., Rodrigues K.E. Stroke-like encephalopathy following high-dose intravenous methotrexate in an adolescent with osteosarcoma: a case report. Rev Bras Hematol Hemoter 2016; 38 (4): 364-7.
21. Fisher M.J., Khademian Z.P., Simon E.M., Zimmerman R.A., Bilaniuk L.T. Diffusion-Weighted MR Imaging of Early Methotrexate-Related Neurotoxicity in Children. American Journal of Neuroradiology August 2005, 26 (7): 1686-9.
22. Haykin M.E., Gorman M., van Hoff J., Fuibright R.K., Baehring J.M. Diffusion-weighted MRI correlates of subacute methotrexate-related neurotoxicity. Journal of Neuro-Oncology Jan 2006; 76, Issue 2: 153-7.
23. Korinthenberg R., Lutkenhoner B.,Palm D., Ritter J. EEG-slowing after high-dose Methotrexate with citrovorumfac-tor-rescue. A spectralanalytic study. EEG EMG Z Elektroenzephalogr Elektromyogr Verwandte Geb 1982; 13 (1): 22-7.
24. Kiu M.C., Liaw C.C., Yang T.S., Lai G.M., Hsi S.N., Lu C.S. Transient neurological disturbances induced by the chemotherapy of high-dose methotrexate for osteogenic sarcoma. Anticancer Drugs 1994; 5 (4): 480-2.
25. Goldenberg-Stern H., Cohen R., Pollak L., Kivity S., Eidlitz-Markus T., Stark B., et al. The mystery of electroencephalography in acute lymphoblastic leukemia. Seizure 2011; 20 (3): 194-6.
26. Korinthenberg R., Scheuring B., Boos J., Niemeyer C. On the origin of EEG-slowing and encephalopathy during induction treatment of acute lymphoblastic leukemia. Med Pediatr Oncol 2002; 39 (6): 566-72.
27. Sainio K., Rautonen J., Siimes M.A. Value of EEG in childhood acute lymphoblastic leukemia. Neuropediatrics 1989; 20 (2): 82-3.
28. Korinthenberg R., Schneider A., Nieme-yer C. Central nervous system prophylaxis with high-dose methotrexate does not give rise to significant electroen-cephalographic changes in children with acute lymphoblastic leukemia. J Child Neurol 2002; 17 (6): 409-12.
29. Battaglia A., Franzoni E. Medulloblastoma in young children: some EEG aspects. Ital J Neurol Sci 1981; 2 (1): 11-5.
Pediatric Hematology/Oncology and Immunopathology. 2019; 18: 22-33
Clinical and electrophysiological characteristics of methotrexate encephalopathy in paediatric practice
https://doi.org/10.24287/1726-1708-2019-18-1-22-33Abstract
Methotrexate-induced subacute encephalopathy is one of the side effects of the aforementioned drug. The effect is characterized by certain neurological symptoms, presence of leukoencephalopathy on a magnetic resonance imaging (MRI) and slow-wave activity shown on an electroencephalogram (EEG). The aim of this work is to determine the clinical and electrophysiological characteristics of methotrexate-induced encephalopathy in paediatric patients with various types of cancer, as well as to compare the obtained data with researches and precedents presented in medical literature. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. A retrospective analysis of treatment results was performed on 31 patients aged 1.5-17 who had subacute methotrexate-induced encephalopathy. Most patients (n = 26) have been diagnosed with acute lymphoblastic leukemia (ALL). According to the theurapeutic protocols, the patients received intravenous, intrathecal and intraventricular methotrexate treatment. The severity of methotrexate-induced encephalopathy was determined according to the NCI-CTCAE scale (version 4.0). All the patients underwent the EEG study. MRI was performed on 26 patients. Methotrexate-induced encephalopathy developed after 2-12 (on average 5.3 ± 3.1) days after methotrexate administration. Encephalopathy of grade I occurred in 35.45% of cases, of grade II - in 19.6%, of grade III and IV - in 25.8 and 19.4% of cases. 5 patients had symptoms recurred after therapy continuation. The most frequent neurological symptoms were: pathological level of sleepiness (50.1%), impaired consciousness (32.3%), cognitive impairment (25.8%), epileptic seizures (19.6%) and ataxia (19.6%). Regression of neurological symptoms occurred in 26 patients after 1-10 (on average 3.3 ± 2.2) days, 5 patients had persistent neurological deficit. The EEG pattern was represented by diffuse theta-wave activity (39%), theta-delta activity (42%), delta activity (6.5%), beta activity (3.0%), a decrease of alpha rhythm amplitude (6.5%), where no changes occurred for only 1 patient. Pathologic changes were seen on MRI in 84.6% of cases. The interdependence between the EEG changes, the time of debut and resolution of encephalopathy has been established. However, there has been no connection found between the severity of encephalopathy, the EEG pattern, the way of methotrexate administration, the age of the patients, the clearance of methotrexate and previous neurological disoders. The data obtained on the clinical picture and the time frame of methotrexate-induced encephalopathy initiation were similar to foreign ones. In different cases of patients with methotrexate-induced encephalopathy, EEG is not always represented as diffuse slow-wave theta-activity. The patients are recommended to undergo initial EEG in order for the electrophysiological studies on methotrexate encephalopathy to be assessed correctly. Further studies of the risk factors of methotrexate-induced encephalopathy are required.
References
1. Bhojwani D., Sabin N.D., Pei D., Yang J.J., Khan R.B., Panetta J.C., et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 2014; 32: 949-59.
2. Lo Nigro L., Di Cataldo A., Schiliro G. Acute neurotoxicity in children with B-lineage acute lymphoblastic leukemia (B-ALL) treated with intermediate risk protocols. Med Pediatr Oncol 2000; 35 (5): 449-55.
3. Mahoney D.H.Jr., Shuster J.J., Nitsch-ke R., Lauer S.J., Steuber C.P., Winick N., et al. Acute neurotoxicity in children with B-percursor acute lymphoid leukaemia: an association with intermediate dose intravenous methotrexate and intrathecal triple therapy - a Pediatric Oncology Group study. J Clin Oncol 1998; 16: 1712-22.
4. Asato R., Akiyama Y., Ito M., Kubota M., Okumura R., Miki Y., et al. Nuclear magnetic resonance abnormalities of the cerebral white matter in children with acute lymphoblastic leukemia and malignant lymphoma during and after central nervous system prophylactic treatment with intrathecal methotrexate. Cancer 1992; 70 (7): 1997-2004.
5. Kim J.Y., Kim S.T., Nam D.H., Lee J.I., Park K., Kong D.S. Leukoencephalopathy and disseminated necrotizing leuko-encephalopathy following intrathecal methotrexate chemotherapy and radiation therapy for central nerve system lymphoma or leukemia. J Korean Neurosurg Soc 2011; 50 (4): 304-10.
6. Millan N.C., Pastrana A., Guitter M.R., Zubizarreta P.A., Monges M.S., Felice M.S. Acute and sub-acute neurological toxicity in children treated for acute lymphoblastic leukemia. Leuk Res 2018; 65: 86-93.
7. Dufourg M.N., Landman-Parker J., Auclerc M.F., Schmitt C., Perel Y., Michel G., et al. Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children. Leukemia 2007; 21 (2): 238-47.
8. Rubnitz J.E., Relling M.V., Harrison P.L., Sandlund J.T., Ribeiro R.C., Rivera G.K., et al. Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia. Leukemia 1998;12 (8): 1176-81.
9. Howard S.C., McCormick J., Pui C.H., Buddington R.K., Harvey R.D. Preventing and Managing Toxicities of High-Dose Methotrexate. Oncologist 2016; 21 (12): 1471-82.
10. Troen A.M., Chao W.H., Crivello N.A., D'Anci K.E., Shukitt-Hale B., Smith D.E., et al. Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine. Journal of Nutrition 2008; 138: 2502-9.
11. Weng Q., Wang J., Wang J., Tan B., Wang J., Wang H., et al. Folate Metabolism Regulates Oligodendrocyte Survival and Differentiation by Modulating AMPKa Activity. Sci Rep 2017 May 11; 7 (1): 1705.
12. Mizusawa S., Kondoh Y., Murakami M., Nakamichi H., Sasaki H., Komatsu K., et al. Effect of methotrexate on local cerebral blood flow in conscious rats. Jpn J Pharmacol 1988; 48 (4): 499-501.
13. Haugvicova R., Mares P. Seizures induced by homocysteic acid in immature rats are prevented by group III metabotropic glutamate receptoragonist (R,S)-4-phosphonophenylglycine. Experimental Neurology 2003; 180: 46-54.
14. Bernini J.C., Fort D.W., Griener J.C., Kane B.J., Chappell W.B., Kam-en B.A. Aminophylline for methotrexate-induced neurotoxicity. Lancet 1995; 345 (8949): 544-7.
15. Ayromlou H., Hajipour B., Hossenian M.M., Khodadadi A., Vatankhah A.M. Oxidative effect of methotrexate administration in spinal cord of rabbits. J Pak Med Assoc 2011; 61 (11): 1096-9.
16. Inaba H., Khan R.B., Laningham F.H., Crews K.R., Pui C.H., Daw N.C. Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol 2008; 19 (1): 178-84.
17. Jaffe N., Takaude Y., Anzai T., Robertson R. Transient neurologoc disturbances induced by high-dose Methotrexate treatment. Cancer 1985; 56: 1356-60.
18. Harila M.J., Winqvist S., Lanning M., Bloigu R., Harila-Saari A.H. Progressive neurocognitive impairment in young adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2009; 53: 156-61.
19. Kay H.E., Knapton P.J., O'Sullivan J.P., Wells D.G., Harris R.F., Innes E.M., et al. Encephalopathy in Acute Leukaemia Associated with Methotrexate Therapy. Archives of Disease in Childhood 1972; 47: 344.
20. Valle D.A., Kakehasi F.M., Melo R.M., Siqueira C.M., Soares T.F., Rodrigues K.E. Stroke-like encephalopathy following high-dose intravenous methotrexate in an adolescent with osteosarcoma: a case report. Rev Bras Hematol Hemoter 2016; 38 (4): 364-7.
21. Fisher M.J., Khademian Z.P., Simon E.M., Zimmerman R.A., Bilaniuk L.T. Diffusion-Weighted MR Imaging of Early Methotrexate-Related Neurotoxicity in Children. American Journal of Neuroradiology August 2005, 26 (7): 1686-9.
22. Haykin M.E., Gorman M., van Hoff J., Fuibright R.K., Baehring J.M. Diffusion-weighted MRI correlates of subacute methotrexate-related neurotoxicity. Journal of Neuro-Oncology Jan 2006; 76, Issue 2: 153-7.
23. Korinthenberg R., Lutkenhoner B.,Palm D., Ritter J. EEG-slowing after high-dose Methotrexate with citrovorumfac-tor-rescue. A spectralanalytic study. EEG EMG Z Elektroenzephalogr Elektromyogr Verwandte Geb 1982; 13 (1): 22-7.
24. Kiu M.C., Liaw C.C., Yang T.S., Lai G.M., Hsi S.N., Lu C.S. Transient neurological disturbances induced by the chemotherapy of high-dose methotrexate for osteogenic sarcoma. Anticancer Drugs 1994; 5 (4): 480-2.
25. Goldenberg-Stern H., Cohen R., Pollak L., Kivity S., Eidlitz-Markus T., Stark B., et al. The mystery of electroencephalography in acute lymphoblastic leukemia. Seizure 2011; 20 (3): 194-6.
26. Korinthenberg R., Scheuring B., Boos J., Niemeyer C. On the origin of EEG-slowing and encephalopathy during induction treatment of acute lymphoblastic leukemia. Med Pediatr Oncol 2002; 39 (6): 566-72.
27. Sainio K., Rautonen J., Siimes M.A. Value of EEG in childhood acute lymphoblastic leukemia. Neuropediatrics 1989; 20 (2): 82-3.
28. Korinthenberg R., Schneider A., Nieme-yer C. Central nervous system prophylaxis with high-dose methotrexate does not give rise to significant electroen-cephalographic changes in children with acute lymphoblastic leukemia. J Child Neurol 2002; 17 (6): 409-12.
29. Battaglia A., Franzoni E. Medulloblastoma in young children: some EEG aspects. Ital J Neurol Sci 1981; 2 (1): 11-5.
