Pediatr Transplantation 2014: 18: 58–63
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12198
Tacrolimus-related seizure after pediatric liver transplantation – A single-center experience Xie M, Rao W, Sun L-Y, Zhu Z-J, Deng Y-L, Shen Z-Y, Jia J-D. Tacrolimus-related seizure after pediatric liver transplantation – A single-center experience.
Man Xie1, Wei Rao2, Li-Ying Sun2, Zhi-Jun Zhu2, Yong-Lin Deng2, Zhong-Yang Shen2 and Ji-Dong Jia1 1
Abstract: To identify the risk factors for new-onset seizures after pediatric LT and to assess their clinical implications and long-term prognosis. The clinical and laboratory data of 27 consecutive children who underwent LT from January 2007 to December 2010 in our center were analyzed retrospectively. Patients were divided into seizures group and a non-seizures group. Pre-operative, intra-operative, and postoperative data were collected. Seizures occurred in four children, an incidence of 14.8%. All exhibited generalized tonic–clonic seizures within the first two wk after LT. Univariate analysis showed that the risk factors associated with seizures after pediatric LT included gender, pediatric end-stage liver disease score before surgery, Child–Pugh score before surgery, serum total bilirubin after surgery, and trough TAC level. Multivariate analysis showed that trough TAC level was the only independent risk factor associated with the seizures. All children who experienced seizures survived with good graft function and remained seizure-free without anti-epileptic drugs over a mean follow-up period of 33.7 14.6 months. High trough TAC level was the predominant factor that contributed to seizures in the early post-operative period after pediatric LT. High PELD and Child-Pugh scores before LT and high post-operative serum Tbil may be contributory risk factors for TAC-related seizures.
Although remarkable advances have been made in the field of LT, neurologic complications are still common. Their incidence ranges from 5% to 59% in published series, and they are associated with significantly higher morbidity and mortality (1–4). Compared with other solid organ transplantation recipients, LT recipients are vulnerable to neurologic complications (2, 5), with seizures being one of the most common, occurring with a frequency of 2.8–42% (3, 6–8). To
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China, 2Organ Transplantation Department, First Central Hospital, Tianjin, China
Key words: pediatric liver transplantation – risk factors – tacrolimus – seizures Jia Ji-dong, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing 100050, China Tel.: 86 10 6313 9816 Fax: 86 10 8316 5944 E-mail: [email protected] Accepted for publication 25 October 2013
date, a considerable number of studies have documented seizures in adults after LT worldwide, while only few studies have examined seizures in children after LT. The clinical characteristics of pediatric LT patients differ from those of adults. We retrospectively studied the clinical course and laboratory data of pediatric LT recipients to identify the potential causes and risk factors for the onset seizures after transplantation and to assess the long-term prognosis. Material and methods
Abbreviations: BAZ, body-mass-index-for-age z-score; BMI, body-mass-index; CT, computed tomography; CYP, cytochrome P450; DDLT, deceased donor liver transplants; EEG, electroencephalography; GRWR, graft volume-torecipient weight ratio; HAZ, height-for-age z-score; Hb, hemoglobin; LDLT, live donor liver transplants; LT, liver transplantation; MRI, magnetic resonance imaging; PELD, pediatric of end-stage liver disease; PRES, posterior reversible encephalopathy syndrome; s.d., standard deviation; TAC, tacrolimus; WAZ, weight-for-age z-score.
58
We reviewed 27 consecutive pediatric LT cases performed from January 2007 to December 2010 in our center; 13 underwent DDLT, and 14 received LDLT. The cohort consisted of 13 boys and 14 girls, with a median age of 4.1 5.2 yr (range from 6 months to 17 yr). The indications for LT are presented in Table 1. All patients received a piggyback transplant with choledochojejunostomy, and their post-operative management was similar. All received TAC-based immunosuppressive
TAC-related seizure after pediatric LT therapy after LT. TAC was administrated orally, beginning on the second post-operative day, with an initial dose of 0.05 mg/kg/day to maintain serum trough levels at 7–10 ng/ mL. Neurologic examination had been normal before LT, and no child had a history of seizures. Seizures were diagnosed by clinical assessment including neurologic examination and investigations including CT imaging and EEG. Diagnoses were confirmed by two experienced neurologists. Anthropometric and biochemical measures were used to assess the nutritional status of our pediatric patients. Z-scores for WAZ, HAZ, BMI for age (BAZ) were computed using the WHO AnthroPlus software (WHO, Geneva, Switzerland) Four of the 27 children died: three as a result of non-neurologic complications during the first two post-operative weeks after LT and one as a result of Epstein-Barr virus infection 18 months after LT. Actual graft survival rates for those children at one month, one, three, and five yr were 88.9%, 88.9%, 85.0%, and 85.0%, respectively (Fig. 1). Conduct of our study was approved by the ethical affairs committee of Tianjin First Central Hospital and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patients’ parents or guardians.
Table 1. Indications for LT Disease
Number
Congenital biliary atresia Autoimmune cirrhosis Caroli’s disease Congenital intrahepatic arterioportal fistula syndrome Primary hyperoxaluria type I Methylmalonic acidemia
21 2 1 1 1 1
Fig. 1. Survival analysis of the 27 PLT patients (Kaplan– Meier method, v2 = 0.757, p = 0.384).
Statistical analysis We analyzed the data of the four children with seizures and the 16 children without seizures, having excluded the records of three children who died during first two wk after LT. We excluded two children older than 16 yr and two patients whose data were incomplete. Continuous variables are presented as the mean s.d.; categorical variables are presented as proportions. Kaplan–Meier method was used to survival analysis. Independent t-tests and the chi-square test were used to compare continuous variables and categorical variables, respectively. Linear regression was used for multivariate analysis. Statistical analyses were undertaken using SPSS version 17.0 (IBM Inc., Chicago, IL, USA). A p-value < 0.05 was considered statistically significant.
Results
In our series of 27 children, seizures occurred in four after LT, an incidence of 14.8%; two children had two seizure episodes. All exhibited generalized tonic–clonic seizures; all occurred during the first two wk after surgery (median 7.5 days; range 3–14 days). A total of 4 EEGs were performed in the four seizure patients immediately after the first seizures controlled, and two patients had abnormal EEG. One patient showed continuous slowed generalized, who had other seizures one day later; another patient showed theta slowing. Epileptiform activity on the EEGs was not found. CT was performed in all the four seizure patients within the day seizures occurred. Mild cerebral edema was showed in one patient. Two of the four patients showed normal EEG and CT. Univariate analysis showed the risk factors associated with seizures after pediatric LT included gender (no seizures in seven girls vs. six seizures in four boys, p = 0.045), PELD score before surgery (20.3 6.0 vs. 9.5 6.8, p = 0.009), Child–Pugh score before surgery (11.0 1.4 vs. 8.7 1.9, p = 0.016), serum total bilirubin (Tbil) after surgery (12.0 6.3 vs. 6.0 4.4 mg/dL, p = 0.04), and trough TAC level (17.9 2.3 vs. 7.3 2.3 ng/mL, p < 0.001). There were no significant differences between the two groups in terms of age (6.4 4.7 vs. 2.6 4.0 yr, p = 0.118), serum bilirubin before surgery (15.6 15.1 vs. 13.6 9.6 mg/dL, p = 0.734), Kasai portoenterostomy (yes/no: 3/1 vs. 12/3, p = 0.827), pre-operative HAZ ( 1.6 2.8 vs. 1.7 1.9, p = 0.950), pre-operative WAZ ( 0.2 2.0 vs. 1.4 1.4, p = 0.266) and preoperative BAZ ( 0.9 1.5 vs. 1.9 2.2, p = 0.202), Hb level before surgery (11.3 0.8 vs. 11.8 1.0 mg/dL, p = 0.346), albumin level before surgery (28.3 4.7 vs. 33.3 4.3 g/L, p = 0.057), the type of graft (one out of three DDLT recipients vs. seven of nine LDLT 59
Xie et al.
recipients, p = 0.519), GRWR% (1.8 1.0 vs. 2.5 0.6, p = 0.076), duration of operation (12.5 3.9 vs. 9.4 2.3 h, p = 0.053), serum level of magnesium (0.77 0.13 vs. 0.81 0.11 mM, p = 0.324), daily TAC dose (0. 0.7 vs. 0.2 0.1 mg/kg, p = 0.057), or donor age (22.5 3.8 vs. 29.2 6.6 yr, p = 0.071, Table 2). Multivariate analysis showed that the serum trough TAC level was the only independent risk factor associated with seizures after surgery (p < 0.001, Table 2). All children who had seizures were treated with carbamazepine, and TAC was reduced or withdrawn. One child was converted to cyclosporine thereafter; however, an acute rejection episode was precipitated necessitating a change back to TAC. Carbamazepine was discontinued within one wk in all cases. All children survived with good graft function and remained free of seizures without anti-epileptic medication for a mean follow-up period of 33.7 14.6 months (range, 13.2–60.7 months). Discussion
Seizures are the most common neurologic complications in children after LT (9–11). The reported incidence ranges from 9.0% to 16.9%, apparently having declined in recent years (9, 10). In our series, the incidence of seizures was 14.8%, which is comparable with other recently
published studies. The majority of seizures after LT are thought to occur in the early postoperative period, and the risk decreases over time, a trend also observed in our cohort. It is presumed that metabolic derangements caused by transplantation and alteration in the permeability of the blood–brain barrier may render LT recipients more vulnerable to neurologic complications shortly after surgery; however, one recent study found that most seizures in children receiving LT occurred three months after surgery (10). The cause of seizures after a liver transplant is multifactorial, but sometimes may be difficult to determine. Immunosuppressant drugs (mainly cyclosporine and TAC), metabolic derangements, cerebrovascular events, and central nervous system infections are generally considered to be responsible, the former being the most common cause (7, 10–13). Despite efficacy as an immunosuppressant, TAC is an important contributor to the onset of neurologic complications after LT in children and adults, especially in the early post-operative period. TAC can cause neurotoxicity ranging from mild, non-specific symptoms, such as restlessness, anxiety, tremor, headaches, and insomnia, to severe symptoms, such as cognitive impairment, seizures, and coma. The incidence of TAC-related neurotoxicity is 5–30% in adults, (13) and the prevalence of TAC-related seizures ranges between 5% and
Table 2. Univariate and multivariate analysis of risk factors for suffering seizures after pediatric LT p-value Risk factors Gender: female/male (n/n) Recipient age (yr) Serum total bilirubin before surgery (mg/dL) PELD score before surgery Child-Pugh score before surgery Pre-operative HAZ Pre-operative WAZ Pre-operative BAZ Hb level before surgery (mg/dL) Albumin before surgery (g/L) Graft type: LDLD/DDLT (n/n) Kasai portoenterostomy: yes/no (n/n) Duration of surgery (h) GRWR (%) Total serum bilirubin after surgery (mg/dL) Dose of TAC (mg/kg/day) Serum trough TAC level (ng/mL) Serum magnesium level (mM) Age of donor (yr)
Seizure group (n = 4) 0/4 6.4 15.6 20.3 11.0 1.6 0.2 0.9 11.3 28.3 3/1 3/1 12.5 1.8 12.0 0.1 17.9 0.77 22.5
4.7 15.1 6.0 1.4 2.8 2.0 1.5 0.8 4.7
3.9 1.0 6.3† 0.7† 2.3† 0.13† 3.8
No seizure group (n = 16)
Univariate
7/9 2.6 13.6 9.5 8.7 1.7 1.4 1.9 11.8 33.3 9/7 12/3* 9.3 2.5 6.0 0.2 7.3 0.81 29.2
0.045 0.118 0.734 0.009 0.016 0.950 0.266 0.202 0.346 0.057 0.519 0.827 0.053 0.076 0.040 0.057
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12198
Tacrolimus-related seizure after pediatric liver transplantation – A single-center experience Xie M, Rao W, Sun L-Y, Zhu Z-J, Deng Y-L, Shen Z-Y, Jia J-D. Tacrolimus-related seizure after pediatric liver transplantation – A single-center experience.
Man Xie1, Wei Rao2, Li-Ying Sun2, Zhi-Jun Zhu2, Yong-Lin Deng2, Zhong-Yang Shen2 and Ji-Dong Jia1 1
Abstract: To identify the risk factors for new-onset seizures after pediatric LT and to assess their clinical implications and long-term prognosis. The clinical and laboratory data of 27 consecutive children who underwent LT from January 2007 to December 2010 in our center were analyzed retrospectively. Patients were divided into seizures group and a non-seizures group. Pre-operative, intra-operative, and postoperative data were collected. Seizures occurred in four children, an incidence of 14.8%. All exhibited generalized tonic–clonic seizures within the first two wk after LT. Univariate analysis showed that the risk factors associated with seizures after pediatric LT included gender, pediatric end-stage liver disease score before surgery, Child–Pugh score before surgery, serum total bilirubin after surgery, and trough TAC level. Multivariate analysis showed that trough TAC level was the only independent risk factor associated with the seizures. All children who experienced seizures survived with good graft function and remained seizure-free without anti-epileptic drugs over a mean follow-up period of 33.7 14.6 months. High trough TAC level was the predominant factor that contributed to seizures in the early post-operative period after pediatric LT. High PELD and Child-Pugh scores before LT and high post-operative serum Tbil may be contributory risk factors for TAC-related seizures.
Although remarkable advances have been made in the field of LT, neurologic complications are still common. Their incidence ranges from 5% to 59% in published series, and they are associated with significantly higher morbidity and mortality (1–4). Compared with other solid organ transplantation recipients, LT recipients are vulnerable to neurologic complications (2, 5), with seizures being one of the most common, occurring with a frequency of 2.8–42% (3, 6–8). To
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China, 2Organ Transplantation Department, First Central Hospital, Tianjin, China
Key words: pediatric liver transplantation – risk factors – tacrolimus – seizures Jia Ji-dong, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing 100050, China Tel.: 86 10 6313 9816 Fax: 86 10 8316 5944 E-mail: [email protected] Accepted for publication 25 October 2013
date, a considerable number of studies have documented seizures in adults after LT worldwide, while only few studies have examined seizures in children after LT. The clinical characteristics of pediatric LT patients differ from those of adults. We retrospectively studied the clinical course and laboratory data of pediatric LT recipients to identify the potential causes and risk factors for the onset seizures after transplantation and to assess the long-term prognosis. Material and methods
Abbreviations: BAZ, body-mass-index-for-age z-score; BMI, body-mass-index; CT, computed tomography; CYP, cytochrome P450; DDLT, deceased donor liver transplants; EEG, electroencephalography; GRWR, graft volume-torecipient weight ratio; HAZ, height-for-age z-score; Hb, hemoglobin; LDLT, live donor liver transplants; LT, liver transplantation; MRI, magnetic resonance imaging; PELD, pediatric of end-stage liver disease; PRES, posterior reversible encephalopathy syndrome; s.d., standard deviation; TAC, tacrolimus; WAZ, weight-for-age z-score.
58
We reviewed 27 consecutive pediatric LT cases performed from January 2007 to December 2010 in our center; 13 underwent DDLT, and 14 received LDLT. The cohort consisted of 13 boys and 14 girls, with a median age of 4.1 5.2 yr (range from 6 months to 17 yr). The indications for LT are presented in Table 1. All patients received a piggyback transplant with choledochojejunostomy, and their post-operative management was similar. All received TAC-based immunosuppressive
TAC-related seizure after pediatric LT therapy after LT. TAC was administrated orally, beginning on the second post-operative day, with an initial dose of 0.05 mg/kg/day to maintain serum trough levels at 7–10 ng/ mL. Neurologic examination had been normal before LT, and no child had a history of seizures. Seizures were diagnosed by clinical assessment including neurologic examination and investigations including CT imaging and EEG. Diagnoses were confirmed by two experienced neurologists. Anthropometric and biochemical measures were used to assess the nutritional status of our pediatric patients. Z-scores for WAZ, HAZ, BMI for age (BAZ) were computed using the WHO AnthroPlus software (WHO, Geneva, Switzerland) Four of the 27 children died: three as a result of non-neurologic complications during the first two post-operative weeks after LT and one as a result of Epstein-Barr virus infection 18 months after LT. Actual graft survival rates for those children at one month, one, three, and five yr were 88.9%, 88.9%, 85.0%, and 85.0%, respectively (Fig. 1). Conduct of our study was approved by the ethical affairs committee of Tianjin First Central Hospital and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patients’ parents or guardians.
Table 1. Indications for LT Disease
Number
Congenital biliary atresia Autoimmune cirrhosis Caroli’s disease Congenital intrahepatic arterioportal fistula syndrome Primary hyperoxaluria type I Methylmalonic acidemia
21 2 1 1 1 1
Fig. 1. Survival analysis of the 27 PLT patients (Kaplan– Meier method, v2 = 0.757, p = 0.384).
Statistical analysis We analyzed the data of the four children with seizures and the 16 children without seizures, having excluded the records of three children who died during first two wk after LT. We excluded two children older than 16 yr and two patients whose data were incomplete. Continuous variables are presented as the mean s.d.; categorical variables are presented as proportions. Kaplan–Meier method was used to survival analysis. Independent t-tests and the chi-square test were used to compare continuous variables and categorical variables, respectively. Linear regression was used for multivariate analysis. Statistical analyses were undertaken using SPSS version 17.0 (IBM Inc., Chicago, IL, USA). A p-value < 0.05 was considered statistically significant.
Results
In our series of 27 children, seizures occurred in four after LT, an incidence of 14.8%; two children had two seizure episodes. All exhibited generalized tonic–clonic seizures; all occurred during the first two wk after surgery (median 7.5 days; range 3–14 days). A total of 4 EEGs were performed in the four seizure patients immediately after the first seizures controlled, and two patients had abnormal EEG. One patient showed continuous slowed generalized, who had other seizures one day later; another patient showed theta slowing. Epileptiform activity on the EEGs was not found. CT was performed in all the four seizure patients within the day seizures occurred. Mild cerebral edema was showed in one patient. Two of the four patients showed normal EEG and CT. Univariate analysis showed the risk factors associated with seizures after pediatric LT included gender (no seizures in seven girls vs. six seizures in four boys, p = 0.045), PELD score before surgery (20.3 6.0 vs. 9.5 6.8, p = 0.009), Child–Pugh score before surgery (11.0 1.4 vs. 8.7 1.9, p = 0.016), serum total bilirubin (Tbil) after surgery (12.0 6.3 vs. 6.0 4.4 mg/dL, p = 0.04), and trough TAC level (17.9 2.3 vs. 7.3 2.3 ng/mL, p < 0.001). There were no significant differences between the two groups in terms of age (6.4 4.7 vs. 2.6 4.0 yr, p = 0.118), serum bilirubin before surgery (15.6 15.1 vs. 13.6 9.6 mg/dL, p = 0.734), Kasai portoenterostomy (yes/no: 3/1 vs. 12/3, p = 0.827), pre-operative HAZ ( 1.6 2.8 vs. 1.7 1.9, p = 0.950), pre-operative WAZ ( 0.2 2.0 vs. 1.4 1.4, p = 0.266) and preoperative BAZ ( 0.9 1.5 vs. 1.9 2.2, p = 0.202), Hb level before surgery (11.3 0.8 vs. 11.8 1.0 mg/dL, p = 0.346), albumin level before surgery (28.3 4.7 vs. 33.3 4.3 g/L, p = 0.057), the type of graft (one out of three DDLT recipients vs. seven of nine LDLT 59
Xie et al.
recipients, p = 0.519), GRWR% (1.8 1.0 vs. 2.5 0.6, p = 0.076), duration of operation (12.5 3.9 vs. 9.4 2.3 h, p = 0.053), serum level of magnesium (0.77 0.13 vs. 0.81 0.11 mM, p = 0.324), daily TAC dose (0. 0.7 vs. 0.2 0.1 mg/kg, p = 0.057), or donor age (22.5 3.8 vs. 29.2 6.6 yr, p = 0.071, Table 2). Multivariate analysis showed that the serum trough TAC level was the only independent risk factor associated with seizures after surgery (p < 0.001, Table 2). All children who had seizures were treated with carbamazepine, and TAC was reduced or withdrawn. One child was converted to cyclosporine thereafter; however, an acute rejection episode was precipitated necessitating a change back to TAC. Carbamazepine was discontinued within one wk in all cases. All children survived with good graft function and remained free of seizures without anti-epileptic medication for a mean follow-up period of 33.7 14.6 months (range, 13.2–60.7 months). Discussion
Seizures are the most common neurologic complications in children after LT (9–11). The reported incidence ranges from 9.0% to 16.9%, apparently having declined in recent years (9, 10). In our series, the incidence of seizures was 14.8%, which is comparable with other recently
published studies. The majority of seizures after LT are thought to occur in the early postoperative period, and the risk decreases over time, a trend also observed in our cohort. It is presumed that metabolic derangements caused by transplantation and alteration in the permeability of the blood–brain barrier may render LT recipients more vulnerable to neurologic complications shortly after surgery; however, one recent study found that most seizures in children receiving LT occurred three months after surgery (10). The cause of seizures after a liver transplant is multifactorial, but sometimes may be difficult to determine. Immunosuppressant drugs (mainly cyclosporine and TAC), metabolic derangements, cerebrovascular events, and central nervous system infections are generally considered to be responsible, the former being the most common cause (7, 10–13). Despite efficacy as an immunosuppressant, TAC is an important contributor to the onset of neurologic complications after LT in children and adults, especially in the early post-operative period. TAC can cause neurotoxicity ranging from mild, non-specific symptoms, such as restlessness, anxiety, tremor, headaches, and insomnia, to severe symptoms, such as cognitive impairment, seizures, and coma. The incidence of TAC-related neurotoxicity is 5–30% in adults, (13) and the prevalence of TAC-related seizures ranges between 5% and
Table 2. Univariate and multivariate analysis of risk factors for suffering seizures after pediatric LT p-value Risk factors Gender: female/male (n/n) Recipient age (yr) Serum total bilirubin before surgery (mg/dL) PELD score before surgery Child-Pugh score before surgery Pre-operative HAZ Pre-operative WAZ Pre-operative BAZ Hb level before surgery (mg/dL) Albumin before surgery (g/L) Graft type: LDLD/DDLT (n/n) Kasai portoenterostomy: yes/no (n/n) Duration of surgery (h) GRWR (%) Total serum bilirubin after surgery (mg/dL) Dose of TAC (mg/kg/day) Serum trough TAC level (ng/mL) Serum magnesium level (mM) Age of donor (yr)
Seizure group (n = 4) 0/4 6.4 15.6 20.3 11.0 1.6 0.2 0.9 11.3 28.3 3/1 3/1 12.5 1.8 12.0 0.1 17.9 0.77 22.5
4.7 15.1 6.0 1.4 2.8 2.0 1.5 0.8 4.7
3.9 1.0 6.3† 0.7† 2.3† 0.13† 3.8
No seizure group (n = 16)
Univariate
7/9 2.6 13.6 9.5 8.7 1.7 1.4 1.9 11.8 33.3 9/7 12/3* 9.3 2.5 6.0 0.2 7.3 0.81 29.2
0.045 0.118 0.734 0.009 0.016 0.950 0.266 0.202 0.346 0.057 0.519 0.827 0.053 0.076 0.040 0.057
