J Huazhong Univ Sci Technol [Med Sci] 33(5):656-660,2013 DOI 10.1007/s11596-013-1176-x J Huazhong Univ Sci Technol [Med Sci] 33(5):2013
656
Analysis of Seizure Risk Factors after Allogeneic Hematopoietic Stem Cell Transplantation: A 8 Case Report and Literature Review* Zhao-dong ZHONG (仲照东)†, Lei LI (李 蕾)†, Yao-hui WU (吴耀辉)#, Yong YOU (游 泳), Wei-ming LI (黎纬明), Ping ZOU (邹 萍) Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China © Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2013
Summary: The clinical characteristics of patients with seizures after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were analyzed. A total of 8 cases of seizures after allo-HSCT were investigated. Clinical data of these cases were studied retrospectively. Of 159 cases subjected to allo-HSCT, seizure occurred in 8 cases during 29–760 days after transplantation, median survival time was 46 days, and there were 6 cases of tonic-clonic seizure. The incidence of seizure after matched unrelated HSCT was higher than that after related HSCT (P=0.017). Of 7 cases treated with cyclosporine A (CsA), 4 cases obtained high blood levels of CsA. In addition, hyponatremia was diagnosed in 5 cases. Abnormal electroencephalogram and brain MRI findings were found in some cases. During 20 days after seizure, 2 cases died due to infection and graft-versus-host disease (GVHD), respectively. It was suggested that multiple factors are associated with seizures after allo-HSCT. Rapid identification and correction of the causative factors are very important to prevent permanent central nervous system damage and reduce the mortality. Key words: hematopoietic stem cell; transplantation; seizure
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective therapy for hematologic malignancies, solid tumors and immunodeficiency diseases[1]. Due to high-dose chemotherapy during the preconditioning stage, and long-term immunosuppressive regimens after HSCT and hematopoietic chimerism status, the incidence of HSCT-related complications is high, including bacterial and fungal infections, interstitial pneumonia, hepatic veno-occlusive disease (VOD), hemorrhagic cystitis, graft-versus-host disease (GVHD) and central nervous system (CNS) complications[2, 3]. The seizure is one of the common manifestations of CNS complications and is attributed to multiple factors[4, 5]. We reported 8 leukemia patients complicated with seizures following allo-HSCT in recent years, and analyzed the clinical features, stem cells resources and CsA level.
1 SUBJECTS AND METHODS 1.1 Patients We reviewed the medical records of 159 consecutive patients who underwent allo-HSCT for malignant hematologic diseases at Institute of Hematology, Union Zhao-dong ZHONG, E-mail: [email protected]; Lei LI, E-mail: [email protected] † These authors contributed equally to this work. # Corresponding author, E-mail: [email protected] * This project was supported by the National Natural Science Foundation of China (No. 81000211).
Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, between January 2001 and February 2008. Eight cases developed seizures at days 29 and 760 (5 men, 3 women, mean 18 years, range 14–44 years). Underlying diseases were 2 cases of chronic myeloid leukemia and 6 cases of acute leukemia (AL), including acute myeloid leukemia (AML) in 4, acute lymphoblastic leukemia (ALL) in 2. AlloHSCT of 2 CML cases was in second chronic-phase CML, 5 AL cases in remission stage and 1 AL case in non-remission (NR) stage, including a myelodysplastic syndrome (MDS) transformed AML which got remission before transplantation. Informed consent was obtained from the patients and the study was approved by the Ethics Committee of Tongji Medical College. 1.2 Stem Cell Source and HLA Typing Of 159 cases, 53 cases received unrelated HSCT and 106 related HSCT respectively. Of 8 cases of seizures, 6 cases received unrelated HSCT and 2 related HSCT. DNA typing for HLA A, B and DR was performed by using polymerase chain reaction (PCR) with sequence specific primers (SSP). 1.3 Preconditioning Regimen Patients with AML and CML-CP2 were treated with a modified BuCy2-based preconditioning regimen. These patients received oral 40 mg/kg hydroxyurea (HU) twice for 1 day, 2 g/m2 cytarabine (Ara-C) for 1 day, intravenous injection of 0.8 mg/kg Myleran (busulfan) every 6 h for 3 days (oral 1 mg/kg Myleran prior to 2006, every 6 h for 3 days), 1.8 g/m2 cyclophosphamide (CTX) for 2 days and oral 250 mg/m2 semustine (Me-CCNU) for 1
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J Huazhong Univ Sci Technol [Med Sci] 33(5):2013
day. ALL patients were treated with the TBI+Cy preconditioning regimen, and received 8 Gy total body irradiation (TBI) and 60 mg/kg CTX for 2 days. As for patients with poor prognosis, 30 mg idarubicin (IDA) or 40 mg/kg etoposide (VP-16) could be included in the preconditioning regimen, once for each. Two cases undergoing unrelated HSCT were treated with 2.5 mg/kg antithymocyte globulin (rabbit anti-ATG) for 3 days (from 4th day before transplantation to 2nd day before). 1.4 Prevention of GVHD The 8 cases of seizures were all orally administered with the classic cyclosporine A (CsA, 10 mg·kg–1·d–1, one day before transplantation, and the trough level maintained within 200–300 ng/mL and then tapered)+short-term methotrexate (MTX, 15 mg/m2 at 1st day and 10 mg/m2 at 3rd, 6th, 11th days after transplantion)-based regimen; unrelated HSCT patients took mycophenolate mofetil (MMF, 0.5 g at 7th day after transplantion, twice per day) orally, and 3 of the 8 patients also took the CD25 monoclonal antibody (20 mg/day, from transplantation day to 4th day after transplantation). 1.5 Diagnosis of Seizures Following Allo-HSCT Seizures were primarily diagnosed by clinical manifestations, electroencephalograms (EEGs) and brain magnetic resonance imaging (MRI) comprehensively. Seizure types were classified according to criteria for seizure diagnosis issued by the International League against Epilepsy (ILAE) in 1989. Time and body temperature of patients following the first attack of seizures were recorded, and the CsA trough level and serum Na+ level were detected. 1.6 Statistical analysis All values were expressed as ±s, 2 test was used
to determine the significance of differences. A value of P500 ng/mL in 4 of these cases; the CsA was reduced during the treatment of controlling seizure progression in time, which further supports the possibility of CsA inducing seizures. Brain MRI of case 3 showed obvious abnormal signals at the first day after attack of seizures and recovered to normal at the 44th day. This reversible change showed that seizures in these patients were very likely to result from CsA neurotoxicity. In addition, methylprednisolone, busulfan and methotrexate may also induce seizures in patients after transplantation, which are more apt to occur in combination with CsA[1]. Six of all the cases in this study were administered with large dose busulfan during preconditioning treatment for HSCT, and all the 8 cases were administered with short term methylprednisolone and methotrexate to prevent GVHD. The united application of these drugs might be more liable to induce seizures. Metabolic encephalopathy is one of the common CNS complications following allo-HSCT, and often occurs within one year post HSCT, usually at the end-stage of visceral function impairment resulting from various causes after HSCT and sometimes accompanied by seizures. Electrolyte imbalance is one of the major reasons of seizures, especially for those induced by hyponatremia[12]. Due to sodium loss, extracellular fluid is hypotonic, osmotic pressure gradient forms in the extracellular fluid, and then moisture from extracellular fluid enters into cells to induce brain cell edema. The occurrence of hyponatremia symptoms and their severity are related with the severity of sodium loss and the developing speed of hyponatremia. Castilla-Guerra reported that seizures triggered by severe and rapid hyponatremia were frequently manifested by generalized tonic-clonic seizures[12]. Five cases in our study developed hyponatremia at attack of seizures, and 3 of them with the Na+ concentration lower than 125 mmol/L developed generalized tonicclonic seizures, in accordance with what has been reported formerly. CNS infections, especially virus and fungus (disseminated Aspergillus) infections induce brain parenchymal damage to develop seizures, but virus and fungus infections seldom involve and injury the CNS due to effective treatment. Preconditioning before HSCT impairs the hematopoietic and immune system functions of the body, and reconstruction of hematopoietic and immune functions by the implanted bone marrow still re-
660 quires a certain period of time to be accomplished, so patients are liable to be affected prior to hematopoietic and immune function reconstruction, more often by conditioned pathogens[13]. Moreover, to prevent the occurrence of GVHD following HSCT, long-term application of immunosuppressant may also lead to infections, more often at the post-HSCT earlier period[14]. In our study, 6 cases were complicated with pulmonary infections, but no evidence of CNS infections has been collected. In addition, the complicated CNS vasculitis in patients after HSCT is mainly manifested by acute and subacute nerve function defects, brain diseases or neuropsychiatric disorders clinically, including seizures. Daikeler et al hold the viewpoint that vasculitis after HSCT is mainly due to local invasion of lymph monocytes mediated by immune response, which is considered to be correlated with GVHD[15]. In this study, 4 cases were complicated with different extents of GVHD following the attack of seizures, which could be controlled after immunosuppressant strengthening and anti-epilepsy treatment, in accordance with the abovementioned viewpoint. To sum up, the seizure is one of the commonly seen CNS complications following allo-HSCT, and the relevant factors are diversified and pathogenesis is complex. The fundamental principle for treatment is treatment of causes, elimination of incentives, expectant treatment and supportive treatment. Prognosis is dependent on timely and correct diagnosis, and treatment is crucial for the reduction in the fatality rate. It has been found in this study that unrelated HSCT is closely related to postHSCT seizures, and prognosis for most cases is favorable after timely treatment, which lay the foundation for early diagnosis of complicated post-HSCT seizures in future clinical medicine. In addition, HLA matching in 4 of the 6 unrelated HSCT patients has one unmatched antigen and (or) gene, but the correlation between unmatched typing and seizures remains to be unclear, which still needs further investigation in future. Conflict of Interest Statement The authors declare that there is no conflict of interest with any financial organization or corporation or individual that can inappropriately influence this work. REFERENCES 1 Krouwer HG, Wijdicks EF. Neurologic complications of bone marrow transplantation. Neurol Clin, 2003,21(1): 319-352 2 Kishi Y, Miyakoshi S, Kami M, et al. Early central nervous system complications after reduced-intensity stem cell transplantation. Biol Blood Marrrow Transplant, 2004,10 (8):561-568
J Huazhong Univ Sci Technol [Med Sci] 33(5):2013
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Sostak P, Padovan CS, Yousry TA, et al. Prospective evaluation of neurological complications after allergenic bone marrow transplantation. Neurology, 2003,60(5):842- 848 Uckan D, Cetin M, Yigitkanli I, et al. Life-threatening neurological complications after bone marrow transplantation in children. Bone Marrow Transplant, 2005,35(1): 71-76 Zhang XH, Xu LP, Liu DH, et al. Epileptic seizures in patients following allogeneic hematopoietic stem cell transplantation: a retrospective analysis of incidence, risk factors, and survival rates. Clin Transplant, 2013,27(1): 80-89 Faraci M, Lanino E, Dallorso S, et al. Mesial temporal sclerosis-a late complication in four allogeneic pediatric recipients with persistent seizures after an acute episode of cyclosporine-A neurotoxicity. Bone Marrow Transplant, 2003,31(10):919-922 Cordelli DM, Masetti R, Bernardi B, et al. Status epilepticus as a main manifestation of posterior reversible encephalopathy syndrome after pediatric hematopoietic stem cell transplantation. Pediatr Blood Cancer, 2012,58 (5):785-790 Bechstein W. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int, 2000,13(5): 313-326 Chang SH, Lim CS, Low TS, et al. Cyclosporine associated encephalopathy: a case report and literature review. Transplant Proc, 2001,33(7):3700-3701 Woong M, Yamada KA. Cyclosporine induces epileptiform activity in a vitro model. Epilepsia, 2000,41(3): 271-276 Dehghani M, Davarpanah MA. Epididymo-orchitis and central nervous system nocardiosis in a bone marrow transplant recipient for acute lymphoblastic leukemia. Exp Clin Transplant, 2009,7(4):264-266 Castilla-Guerra L, del Carmen Fernández-Moreno M, López-Chozas JM, et al. Electrolytes disturbances and seizures. Epilepsia, 2006,47(12):1990-1998 Reddy SM, Winston DJ, Territo MC, et al. CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency. Bone Marrow Transplant, 2010,45(6):979-984 Padovan CS, Gerbitz A, Sostak P, et al. Cerebral involvement in graft-versus-host disease after murine bone marrow transplantation. Neurology, 2001,56(8):1106- 1108 Daikeler T, Labopin M, Di Gioia M, et al. Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party. Blood, 2011,118(6): 1693-1698 (Received Nov. 30, 2012; revised May 30, 2013)
656
Analysis of Seizure Risk Factors after Allogeneic Hematopoietic Stem Cell Transplantation: A 8 Case Report and Literature Review* Zhao-dong ZHONG (仲照东)†, Lei LI (李 蕾)†, Yao-hui WU (吴耀辉)#, Yong YOU (游 泳), Wei-ming LI (黎纬明), Ping ZOU (邹 萍) Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China © Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2013
Summary: The clinical characteristics of patients with seizures after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were analyzed. A total of 8 cases of seizures after allo-HSCT were investigated. Clinical data of these cases were studied retrospectively. Of 159 cases subjected to allo-HSCT, seizure occurred in 8 cases during 29–760 days after transplantation, median survival time was 46 days, and there were 6 cases of tonic-clonic seizure. The incidence of seizure after matched unrelated HSCT was higher than that after related HSCT (P=0.017). Of 7 cases treated with cyclosporine A (CsA), 4 cases obtained high blood levels of CsA. In addition, hyponatremia was diagnosed in 5 cases. Abnormal electroencephalogram and brain MRI findings were found in some cases. During 20 days after seizure, 2 cases died due to infection and graft-versus-host disease (GVHD), respectively. It was suggested that multiple factors are associated with seizures after allo-HSCT. Rapid identification and correction of the causative factors are very important to prevent permanent central nervous system damage and reduce the mortality. Key words: hematopoietic stem cell; transplantation; seizure
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective therapy for hematologic malignancies, solid tumors and immunodeficiency diseases[1]. Due to high-dose chemotherapy during the preconditioning stage, and long-term immunosuppressive regimens after HSCT and hematopoietic chimerism status, the incidence of HSCT-related complications is high, including bacterial and fungal infections, interstitial pneumonia, hepatic veno-occlusive disease (VOD), hemorrhagic cystitis, graft-versus-host disease (GVHD) and central nervous system (CNS) complications[2, 3]. The seizure is one of the common manifestations of CNS complications and is attributed to multiple factors[4, 5]. We reported 8 leukemia patients complicated with seizures following allo-HSCT in recent years, and analyzed the clinical features, stem cells resources and CsA level.
1 SUBJECTS AND METHODS 1.1 Patients We reviewed the medical records of 159 consecutive patients who underwent allo-HSCT for malignant hematologic diseases at Institute of Hematology, Union Zhao-dong ZHONG, E-mail: [email protected]; Lei LI, E-mail: [email protected] † These authors contributed equally to this work. # Corresponding author, E-mail: [email protected] * This project was supported by the National Natural Science Foundation of China (No. 81000211).
Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, between January 2001 and February 2008. Eight cases developed seizures at days 29 and 760 (5 men, 3 women, mean 18 years, range 14–44 years). Underlying diseases were 2 cases of chronic myeloid leukemia and 6 cases of acute leukemia (AL), including acute myeloid leukemia (AML) in 4, acute lymphoblastic leukemia (ALL) in 2. AlloHSCT of 2 CML cases was in second chronic-phase CML, 5 AL cases in remission stage and 1 AL case in non-remission (NR) stage, including a myelodysplastic syndrome (MDS) transformed AML which got remission before transplantation. Informed consent was obtained from the patients and the study was approved by the Ethics Committee of Tongji Medical College. 1.2 Stem Cell Source and HLA Typing Of 159 cases, 53 cases received unrelated HSCT and 106 related HSCT respectively. Of 8 cases of seizures, 6 cases received unrelated HSCT and 2 related HSCT. DNA typing for HLA A, B and DR was performed by using polymerase chain reaction (PCR) with sequence specific primers (SSP). 1.3 Preconditioning Regimen Patients with AML and CML-CP2 were treated with a modified BuCy2-based preconditioning regimen. These patients received oral 40 mg/kg hydroxyurea (HU) twice for 1 day, 2 g/m2 cytarabine (Ara-C) for 1 day, intravenous injection of 0.8 mg/kg Myleran (busulfan) every 6 h for 3 days (oral 1 mg/kg Myleran prior to 2006, every 6 h for 3 days), 1.8 g/m2 cyclophosphamide (CTX) for 2 days and oral 250 mg/m2 semustine (Me-CCNU) for 1
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J Huazhong Univ Sci Technol [Med Sci] 33(5):2013
day. ALL patients were treated with the TBI+Cy preconditioning regimen, and received 8 Gy total body irradiation (TBI) and 60 mg/kg CTX for 2 days. As for patients with poor prognosis, 30 mg idarubicin (IDA) or 40 mg/kg etoposide (VP-16) could be included in the preconditioning regimen, once for each. Two cases undergoing unrelated HSCT were treated with 2.5 mg/kg antithymocyte globulin (rabbit anti-ATG) for 3 days (from 4th day before transplantation to 2nd day before). 1.4 Prevention of GVHD The 8 cases of seizures were all orally administered with the classic cyclosporine A (CsA, 10 mg·kg–1·d–1, one day before transplantation, and the trough level maintained within 200–300 ng/mL and then tapered)+short-term methotrexate (MTX, 15 mg/m2 at 1st day and 10 mg/m2 at 3rd, 6th, 11th days after transplantion)-based regimen; unrelated HSCT patients took mycophenolate mofetil (MMF, 0.5 g at 7th day after transplantion, twice per day) orally, and 3 of the 8 patients also took the CD25 monoclonal antibody (20 mg/day, from transplantation day to 4th day after transplantation). 1.5 Diagnosis of Seizures Following Allo-HSCT Seizures were primarily diagnosed by clinical manifestations, electroencephalograms (EEGs) and brain magnetic resonance imaging (MRI) comprehensively. Seizure types were classified according to criteria for seizure diagnosis issued by the International League against Epilepsy (ILAE) in 1989. Time and body temperature of patients following the first attack of seizures were recorded, and the CsA trough level and serum Na+ level were detected. 1.6 Statistical analysis All values were expressed as ±s, 2 test was used
to determine the significance of differences. A value of P500 ng/mL in 4 of these cases; the CsA was reduced during the treatment of controlling seizure progression in time, which further supports the possibility of CsA inducing seizures. Brain MRI of case 3 showed obvious abnormal signals at the first day after attack of seizures and recovered to normal at the 44th day. This reversible change showed that seizures in these patients were very likely to result from CsA neurotoxicity. In addition, methylprednisolone, busulfan and methotrexate may also induce seizures in patients after transplantation, which are more apt to occur in combination with CsA[1]. Six of all the cases in this study were administered with large dose busulfan during preconditioning treatment for HSCT, and all the 8 cases were administered with short term methylprednisolone and methotrexate to prevent GVHD. The united application of these drugs might be more liable to induce seizures. Metabolic encephalopathy is one of the common CNS complications following allo-HSCT, and often occurs within one year post HSCT, usually at the end-stage of visceral function impairment resulting from various causes after HSCT and sometimes accompanied by seizures. Electrolyte imbalance is one of the major reasons of seizures, especially for those induced by hyponatremia[12]. Due to sodium loss, extracellular fluid is hypotonic, osmotic pressure gradient forms in the extracellular fluid, and then moisture from extracellular fluid enters into cells to induce brain cell edema. The occurrence of hyponatremia symptoms and their severity are related with the severity of sodium loss and the developing speed of hyponatremia. Castilla-Guerra reported that seizures triggered by severe and rapid hyponatremia were frequently manifested by generalized tonic-clonic seizures[12]. Five cases in our study developed hyponatremia at attack of seizures, and 3 of them with the Na+ concentration lower than 125 mmol/L developed generalized tonicclonic seizures, in accordance with what has been reported formerly. CNS infections, especially virus and fungus (disseminated Aspergillus) infections induce brain parenchymal damage to develop seizures, but virus and fungus infections seldom involve and injury the CNS due to effective treatment. Preconditioning before HSCT impairs the hematopoietic and immune system functions of the body, and reconstruction of hematopoietic and immune functions by the implanted bone marrow still re-
660 quires a certain period of time to be accomplished, so patients are liable to be affected prior to hematopoietic and immune function reconstruction, more often by conditioned pathogens[13]. Moreover, to prevent the occurrence of GVHD following HSCT, long-term application of immunosuppressant may also lead to infections, more often at the post-HSCT earlier period[14]. In our study, 6 cases were complicated with pulmonary infections, but no evidence of CNS infections has been collected. In addition, the complicated CNS vasculitis in patients after HSCT is mainly manifested by acute and subacute nerve function defects, brain diseases or neuropsychiatric disorders clinically, including seizures. Daikeler et al hold the viewpoint that vasculitis after HSCT is mainly due to local invasion of lymph monocytes mediated by immune response, which is considered to be correlated with GVHD[15]. In this study, 4 cases were complicated with different extents of GVHD following the attack of seizures, which could be controlled after immunosuppressant strengthening and anti-epilepsy treatment, in accordance with the abovementioned viewpoint. To sum up, the seizure is one of the commonly seen CNS complications following allo-HSCT, and the relevant factors are diversified and pathogenesis is complex. The fundamental principle for treatment is treatment of causes, elimination of incentives, expectant treatment and supportive treatment. Prognosis is dependent on timely and correct diagnosis, and treatment is crucial for the reduction in the fatality rate. It has been found in this study that unrelated HSCT is closely related to postHSCT seizures, and prognosis for most cases is favorable after timely treatment, which lay the foundation for early diagnosis of complicated post-HSCT seizures in future clinical medicine. In addition, HLA matching in 4 of the 6 unrelated HSCT patients has one unmatched antigen and (or) gene, but the correlation between unmatched typing and seizures remains to be unclear, which still needs further investigation in future. Conflict of Interest Statement The authors declare that there is no conflict of interest with any financial organization or corporation or individual that can inappropriately influence this work. REFERENCES 1 Krouwer HG, Wijdicks EF. Neurologic complications of bone marrow transplantation. Neurol Clin, 2003,21(1): 319-352 2 Kishi Y, Miyakoshi S, Kami M, et al. Early central nervous system complications after reduced-intensity stem cell transplantation. Biol Blood Marrrow Transplant, 2004,10 (8):561-568
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Sostak P, Padovan CS, Yousry TA, et al. Prospective evaluation of neurological complications after allergenic bone marrow transplantation. Neurology, 2003,60(5):842- 848 Uckan D, Cetin M, Yigitkanli I, et al. Life-threatening neurological complications after bone marrow transplantation in children. Bone Marrow Transplant, 2005,35(1): 71-76 Zhang XH, Xu LP, Liu DH, et al. Epileptic seizures in patients following allogeneic hematopoietic stem cell transplantation: a retrospective analysis of incidence, risk factors, and survival rates. Clin Transplant, 2013,27(1): 80-89 Faraci M, Lanino E, Dallorso S, et al. Mesial temporal sclerosis-a late complication in four allogeneic pediatric recipients with persistent seizures after an acute episode of cyclosporine-A neurotoxicity. Bone Marrow Transplant, 2003,31(10):919-922 Cordelli DM, Masetti R, Bernardi B, et al. Status epilepticus as a main manifestation of posterior reversible encephalopathy syndrome after pediatric hematopoietic stem cell transplantation. Pediatr Blood Cancer, 2012,58 (5):785-790 Bechstein W. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int, 2000,13(5): 313-326 Chang SH, Lim CS, Low TS, et al. Cyclosporine associated encephalopathy: a case report and literature review. Transplant Proc, 2001,33(7):3700-3701 Woong M, Yamada KA. Cyclosporine induces epileptiform activity in a vitro model. Epilepsia, 2000,41(3): 271-276 Dehghani M, Davarpanah MA. Epididymo-orchitis and central nervous system nocardiosis in a bone marrow transplant recipient for acute lymphoblastic leukemia. Exp Clin Transplant, 2009,7(4):264-266 Castilla-Guerra L, del Carmen Fernández-Moreno M, López-Chozas JM, et al. Electrolytes disturbances and seizures. Epilepsia, 2006,47(12):1990-1998 Reddy SM, Winston DJ, Territo MC, et al. CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency. Bone Marrow Transplant, 2010,45(6):979-984 Padovan CS, Gerbitz A, Sostak P, et al. Cerebral involvement in graft-versus-host disease after murine bone marrow transplantation. Neurology, 2001,56(8):1106- 1108 Daikeler T, Labopin M, Di Gioia M, et al. Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party. Blood, 2011,118(6): 1693-1698 (Received Nov. 30, 2012; revised May 30, 2013)
