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J Neurol (2006) 253 : 612–617 DOI 10.1007/s00415-006-0069-3
Fuat H. Saner Yanli Gu Shahin Minouchehr Kavuk Ilker Nils R. Fruhauf Andreas Paul Arnold Radtke Marc Dammann Zaza Katsarava Susanne Koeppen Massimo Malagó Christoph E. Broelsch
■ Abstract Problems related to the central nervous system have a major impact on survival and quality of life. The aim of this retrospective study was to evaluate the incidence of neurological complications after liver transplantaReceived: 11 July 2005 Received in revised form: 11 October 2005 Accepted: 20 October 2005 Published online: 6 March 2006
Dr. med. F. Saner, DEAA () · Y. Gu, MD · S. Minouchehr, MD · N. R. Fruhauf, MD · A. Paul, MD · A. Radtke, MD · M. Dammann, MD · M. Malagó, MD · Ch. E. Broelsch, MD, FACS University Hospital Essen Department of General Surgery and Transplantation Hufelandstr. 55 45122 Essen, Germany Tel.: +49-201/723-1177 Fax: +49-201/723-1196 E-Mail:
[email protected] K. Ilker, MD · Z. Katsarava, MD · S. Koeppen, MD Department of Neurology University Hospital Essen Hufelandstr. 55 45122 Essen, Germany
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ORIGINAL COMMUNICATION
Neurological complications after cadaveric and living donor liver transplantation
tion (LT), including both cadaveric and living donor liver transplantation. Between April 2001 and March 2004 174 patients (120 cadaveric liver transplantations, 54 living donor transplantations) were admitted to our intensive care after liver transplantation. Of the transplanted patients 24.7 % developed neurological complications.These patients’ stay in the intensive care (14.2 ± 17.2 days) was much longer than that of all admitted patients (8.4 ± 10.5 days, p < 0.05).The most common neurological complications were encephalopathy (72.1 %) and seizures (11.6 %).The incidence of neurological complications in living donor liver transplanted patients was significantly lower than in cadaveric transplantation patients (20.4 % vs 26.7 %). The cold ischemia time in living donor transplanted patients was significantly shorter in comparison with cadaveric transplanted patients (215 ± 119.3 vs. 383.7 ± 214.7). The survival rate after liver transplantation of patients with neurological compli-
JON 2069
Introduction Liver transplantation (LT) was first performed in 1963 [31]. Initially it was considered a high-risk procedure and there was a one-year survival rate of only 20 %. The
cations was lower than that of patients without, but not significantly different (79.1 % vs. 82.4 %, p > 0.05). The incidence of neurological symptoms was found to be similar between the patients treated with cyclosporine (25 %) and tacrolimus (23.8 %) in this study. In conclusion, there was a high incidence of neurological complications after LT, prolonging the patients’ stay in intensive care significantly.The major neurological manifestation in our patients was encephalopathy followed by seizures. Living donor liver transplantation was associated with a significantly lower incidence of neurological complications compared with patients who had received a cadaveric graft. This might be due to the good quality of the organ and the much shorter cold ischemia time of the graft when the donor was alive. ■ Key words encephalopathy · liver transplantation · neurological complication · immunosuppression · living donor
most common reason for death was an acute or chronic rejection of the graft. Since the introduction of cyclosporine A (CsA) as an immunosuppressive agent [5] for clinical use in 1983 the survival rate has increased from 20 % to nearly 80 % at the same center [32]. In the last 20 years tacrolimus (TAC) has been used and con-
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sidered as effective as CsA for preventing allograft rejection. However, the toxic side effects, including toxicity of the central nervous system, of these immunosuppression drugs have been noted during their widespread clinical use. These complications include changes in mental state ranging from mild encephalopathy to coma, severe headache, depression, psychotic disorders, seizures, and strokes [1, 29]. 13 % – 43 % LT patients experienced neurological complications (NCs) with increased morbidity and mortality [1, 29]. Owing to longer stays in hospital the health care costs increase. The health-related quality of life of these patients decreases [2]. Causes of mental state changes after LT include factors related to recipient pre-LT status, intraoperative factors and post-LT factors. The drug-specific toxicity of immunosuppression was considered the main effect [4]. However, in a proportion of post-LT patients a clear cause for their altered sensorium cannot be identified. Because of the severe shortage of donor livers, living donor liver transplantation (LDLT) was developed by Broelsch [3] for pediatric patients. Because the 3-year survival rates (SVR) were 50–70 % [23] this technique in adult populations was adopted with end-stage liver disease (ESLD). In Western countries, at present, LDLT accounts for approximately 10 % of LT performed in adults. As a result of this increasing number of patients vascular complications like hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT), and stenosis of hepatic venous outflow have been reported. Better surgical technique (use of microscopically guided vascular anastomosis and the larger diameter of HA and PV) may have contributed to a decreased incidence of HAT and PVT in nonpediatric LDLT patients [19, 27]. The main impact on survival rate in adult-to adult LDLT has been the graft-size. The necessary hepatic functional mass has been determined as a ratio between graft volume and recipient body weight (GVRBWR), which should be 0.8 % to 1 % [13, 16]. In LDLT clinical signs such as enhanced hepatocyte injury, delayed synthetic function, and prolonged ventilation support have been reported [14]. Although NCs occurred frequently following cadaveric LT, there have been no reports of NCs after LDLT. We would expect an increased rate of NCs due to reduced liver mass compared with cadaveric liver transplantation. The aim of this study was to evaluate the incidence of NCs after liver transplantation, including cadaveric LT and LDLT, and the impact of immunosuppressies on the NCs.
Patients and methods A total of 174 patients received LT and were observed at our Intensive Care Unit (ICU) from April 2001 to March 2004 (68 men, 111 women), average age 51 ± 11.6. Fifty-four patients received LDLT (31 %), 120 patients received cadaveric LT (69 %). The primary liver diagnoses in
all patients are summarized in Table 1.At our center, the status of liver transplant candidates has changed over the last few years. A major portion of the recipients were Eurotransplant T2, which is comparable to United Network for Organ Sharing status 2a. Besides standard indications, the acute decompensation of advanced liver cirrhoses requiring preoperative intensive care treatment were also included. All operations were performed using standard techniques and postoperative care was similar for all patients. The warm and cold ischemia time was recorded. All patients received immunosuppressive therapy based on corticosteroids, mycophenolatmofetile (MMF, 1 g/12h) (CellCept®, Roche), cyclosporine (CsA, 5 mg/kg/12h orally) (Sandimmune®, Novartis, n = 132) or tacrolimus (TAC, 0.05 mg/kg/12h orally) (Prograf®, Fujisawa, n = 42). Daily doses and trough levels of CsA or TAC were measured. The length of all patients’ stay in ICU was recorded. The laboratory data on systemic infection and the function of the liver and the kidney were measured daily. All patients received a renal replacement therapy – continuous veno-venous hemodialysis (CVVHD) if creatinine exceeded 2.5 mg/dl or blood urea nitrogen exceeded 100 mg/dl. The observation time of all patients after LT was one year. Diagnoses of NCs were assessed by neurological examinations,including symptoms, cerebral computed tomography (cCT) or cerebral magnetic resonance tomography (cMRT). ■ Statistical analysis All measurements and calculations were analyzed using SPSS 11.0. The significance of differences was analyzed using the chi-square test and two tailed Student’s t-test. The result was considered significant if the p value was lower than 0.05.
Results ■ Incidence of NCs following LT NCs occurred in 43 patients (29 men; 14 women, age 48 ± 13.2), resulting in an incidence of 24.7 % of all LT patients (43/174). The neurological symptoms occurred on postoperative day (POD) 4.7 ± 5.1 (range: POD1–21). The most common complication was encephalopathy including somnolence, mental changes and confabulaTable 1 The primary liver diagnoses Diagnoses
Number of Patients (%)
Alcoholic cirrhosis Hepatitis B Hepatitis C PSC PBC Autoimmune Budd-Chiari ALF Hemochromatosis Carcinoid Total
49 (28.2) 30 (17.2) 25 (14.4) 7 (4.0) 6 (3.5) 9 (5.2) 7 (4.0) 25 (14.3) 10 (5.8) 6 (3.5) 174
PSC primary sclerosing cholangitis; PBS primary biliary cholangitis; ALF acute liver failure; Autoimmune autoimmune hepatitis
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whereas only 5 out of 54 patients (9.3 %) received CVVHD in the LDLT group. It was significantly lower than that in the cadaveric group (p < 0.05).
Table 2 The types of NCs following LT Complications
n
Incidence
1. Encephalopathy 2. Seizure 3. Miscellaneous Cortical blindness Severe headache Severe tremor 4. PLE 5. ICB 6. Ischemic stroke Total
31 5 4 1 2 1 2 2 1 43
72.1% 11.6% 9.3%
■ Influence of NC on the survival rate after LT The survival rate (SVR) after LT of patients with NC was lower (79.1 % (34/43)) compared with patients without NC (82.4 % (108/131), but no significant difference was identified (p = 0.06).
4.7% 4.7% 2.3%
■ Effect of CSA and TAC on NC
LT liver transplantation; ICB intracranial bleeding; NCs neurological complication; PLE posterior leukencephalopathy syndrome
tion, which occurred in 72.1 % of the patients (31/43). Seizures occurred in 11.6 % (5/43). Miscellaneous complications (9.3 %) included cortical blindness (n = 1), severe headache (n = 2) and severe tremor (n = 1). Two patients (4.7 %) experienced intracranial hemorrhage and another one ischemic stroke (2.3 %). Two patients (4.7 %) developed a TAC-induced posterior leukencephalopathy syndrome (PLE). One of these patients died. The other one survived without neurological deficiency after switching to CsA. Two patients developed ICB (4.7 %). The length of the stay in ICU of patients with NC was 14.2 ± 17.2 days. This was significantly longer compared with the total of patients (8.4 ± 10.5 days, p < 0.05).
NCs occurred in 25 % of CsA-treated patients and 23.8 % of TAC-treated patients. There was no significant difference between these two groups (p > 0.05). Neurological symptoms were similar between these 2 groups. The mean onset of symptoms was on POD 4.1 (range: POD1–10) in the CsA-treated group. Symptoms occurred on POD 7.6 (range: POD1–21) in the TAC-treated group. Neurological symptoms seemed to develop earlier in CsA-treated patients than in patients who received TAC (p > 0.05) (Table 5).
■ Effect of primary diagnoses on NC Alcoholic cirrhosis, Hepatitis B and Hepatitis C were the most common causes of liver failure (Table 1). However, no correlation between primary diagnosis and the incidence of NCs was found (r = 0.37, p > 0.05) (Table 6).
■ Incidence of NCs following LDLT Table 4 Influence of NC on the survival rate (SVR) after LT
Eleven out of 54 patients receiving LDLT developed NC (20.4 %). This was significantly lower than the incidence of NC in the cadaveric group (26.7 %, p < 0.05) (Table 3). The age and the use of immunosuppression did not vary significantly. The warm ischemia time (WIT) of the graft was similar in both groups. However, the cold ischemia time (CIT) in the LDLT group was only about half that of the cadaveric group (p < 0.01). Out of 120 patients 41 (34.4 %) in the cadaveric LT group developed acute renal failure after LT and received CVVHD, Table 3 Effect of LDLT on NC
Groups
n
SVR
NC (+) NC (–) Total
43 131 174
34 (79.1%)* 108 (82.4%)* 142 (81.6%)
NC neurological complication; LT liver transplantation * p = 0.06
Type of LT
n
Age (years) (mean ± SD)
Incidence of NCs
WIT (min) (mean ± SD)
CIT (min) (mean ± SD)
CVVHD
LDLT Cadaveric LT
54 120
51.8±1.4 47.6±13.9
11 (20.4%)* 32 (26.7%)*
32.4±8.3 33.0±13.0
215±119.3** 383.7±214.7**
5 of 54 (9.3 %)* 41 of 120 (34.4 %)*
* P < 0.05; ** P < 0.01 LDLT living donor liver transplantation; LT liver transplantation; NC neurological complication; WIT warm ischemia time; CIT cold ischemia time; CVVHD continuous veno-venous hemodialysis
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Table 5 Effect of CsA and TAC on NC Treatment
All patients
Patients with NC
Incidence
Onset (POD)
CSA TAC Total
132 42 174
33 10 43
25.0%* 23.8%* 24.7%
4.1+3.8* 7.6+8.2* 4.7+5.1
NC neurological complication; POD postoperative day; CsA Cyclosporin A; TAC Tacrolimus * p > 0.05
Table 6 Effect of primary diagnoses on NC
Alcoholic cirrhosis Hepatitis B Hepatitis C PSC PBC Autoimmune hepatitis Budd-Chiari ALF Hemochromatosis. Carcinoid Total
All patients
Patients with NC post-LT
incidence of NC
49 30 25 7 6 9 7 25 10 6 174
13 7 6 2 1 2 2 7 2 1 43
26.5% 23.3% 24.0% 28.6% 16.7% 22.2% 28.6% 28.0% 20.0% 16.7%
NC neurological complication; LT liver transplantation; PSC primary sclerosing cholangitis; PBS primary biliary cholangitis; ALF acute liver failure
Discussion Neurological complications occurred frequently following LT. Those complications are associated with significant mortality and morbidity, and lead to a longer stay in hospital [29]. We found that major NCs affected 24.7 % of all LT patients. The reported incidence of NC was variable for different centres. Mueller [25] reported about a rate of 21 % for NCs following LT, whereas a 42 % rate was reported by Vogt et al. [34]. A diffuse encephalopathy is considered the most common complication after liver transplantation. Adams [1] reported an encephalopathy rate of 76 % in his series. Similar results were presented by Moreno [24], who reported an encephalopathy rate of 73 %. The underlying mechanisms are unknown, although in a large prospective study the authors diagnosed a diffuse encephalopathy (anoxic, septic, or metabolic) as the most common complication occurring in 56.5 % of NC in LT patients [29]. Post mortem studies show diffuse anoxic-ischemic changes as the most common neuropathological finding [8, 20]. The incidence of seizures following liver transplanta-
tion was reported as ranging from 0 % to over 40 % and was higher in some small series with large numbers of retransplantations [1, 7, 29, 34]. The incidence of seizures after LT appears to be declining. One group reported that a relatively high seizure rate in their first study was reduced from 42 % to 0 % [33, 34]. The cause for these reductions seems to be the improvement in the management of multiple metabolic and toxic abnormalities. The PLE consists of headache, visual disturbance, seizures and a somnolent state, which can be caused by a variety of conditions and immunosuppressant [12, 26]. The current term is misleading because the condition is not always restricted to posterior structures or white matter, nor reversible [10]. The accurate incidence of PLE is difficult to determine. Nevertheless it has been reported to apply to about 5 % of patients after LT [1, 6, 7, 24, 33, 34]. In our study we identified 4 % of cases, which is in the same range as in earlier reports already described. A neurologist would be needed to assess the accurate incidence of this complication through meticulous clinical examination supported by neuroimaging such as cCT or cMRT. Infections of the central nervous system (CNS) have been reported in previous studies [1, 17, 29], and occurred in about 5 % of patients. In our study no patient experienced CNS infection. Cerebrovascular complications occur in about 4 % of cases in clinical series [1, 24, 29]. In our series 4.7 % of cases developed an intracranial hemorrhage and 2.3 % experienced an ischemic stroke. In addition, we found no correlation between primary diagnosis and the incidence of NC. Lewis [15] reported a higher rate of NC after transplantation for primary biliary cirrhosis and alcoholic cirrhosis. Ghaus et al. [11] reported a very high incidence of neurological complications following LT, regardless of liver diagnosis (75 %). In our study the survival rate between LT patients with NCs and without NCs were not significantly different. Pujol et al. [29] prospectively evaluated 84 consecutive adult patients with chronic liver disease before and after liver transplantation. Patients who had NCs had a significantly higher mortality rate than those without (55 % versus 17 %, p = 0.012). Wijdecks et al. [36] described no impact of NC on the survival rate after LT. Miller [23] and Marcos [19] reported a 1-year survival rate of 85 % and 88 % in adult LDLT respectively. Santori [30] reported a mortality rate of 21 % in LT in high-risk patients. Malagó described in LDLT a survival rate of 69 % at our center [18]. We accept a wide range of extended indications for liver transplantation. Especially in our LDLT group we have a high percentage of recipients with advanced oncological conditions and decompensated liver cirrhosis with preoperative intensive care support.
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LDLT was first introduced and developed by Broelsch [3]. Currently LDLT are performed not only in adult-tochildren but also in adult-to-adult programs. The total numbers and experience are still less than in cadaveric LT. A significantly lower incidence of NCs in LDLT in comparison with cadaveric LT was observed in our study. The reason for this phenomenon remains uncertain. Menegaux [22] showed an age-related rate of NCs after LT. The occurrence in pediatric transplantation was significantly lower than in adults (8 % vs. 23 % in adults). However, the age of patients in both groups (LDLT and the cadaver LT) in our study did not differ significantly.A significantly shorter CIT was recorded in the LDLT group, which could be correlated with a better quality of the transplanted graft and also an improved detoxification power in comparison with a longer CIT. Moreover, the lower incidence of hemodialysis in the LDLT group might also affect the patients’ mental status. Nevertheless, further prospective trials with this aim would be needed to explain the reasons. The application of CsA or TAC after LT has been reported to have a different effect on the incidence of neurological complications [25]. In a prospective randomized trial McDiarmid reported a higher incidence of minor NCs, like insomnia or tremor, in TAC-based immunosuppression compared with CsA (24 % versus 15 % for insomnia; 10 % versus 5 % for tremor). In particular major neurological events, such as coma, seizures and encephalopathy, occurred only in the TAC group in this study [21]. TAC was used intravenously in the first 5 days, which is associated with a higher rate of neurological complications as previously described [21]. Mueller et al. showed a higher incidence of NCs for TAC in comparison with CsA as well (31.1 % vs. 25 %) [25, 34]. Wijdecks [35] reported TAC-induced neurotoxicity in 14 of 44 (31.8 %) consecutively treated patients following LT. None of these patients had toxic levels of TAC, and the
levels at the time of neurotoxicity were similar in the patients without NCs. The mechanisms of entering the blood-brain barrier and inducing NC could not be determined in his study. However, in our study a similar incidence of neurological symptoms was found between the patients treated with CsA and TAC. The same observations were made by Freise [9] and Lewis et al. [15]. Headaches and tremor are very common complaints among patients given CsA or TAC [28], but they are only mentioned in a few studies as a neurological complication [22, 33]. The incidence of these and other relatively minor complications is always likely to be underestimated in a retrospective study. We identified 2 patients with severe headaches, which were successfully treated with a switch from CSA to TAC. One patient suffers from severe tremor, which was treated with a β-blocker. One patient developed cortical blindness. After switching from CsA to TAC the symptoms were completely reversed. In conclusion, a high incidence of neurological complications after LT occurred, which led to these patients staying longer in ICU. The major NCs manifestation in our patients was encephalopathy followed by seizures. LDLT was associated with a significantly lower incidence of NCs compared with patients who received a cadaveric graft. This might be due to the good quality of the organ and the much shorter cold ischemia time of the graft when LDLT was performed. In our study the incidence of NCs was unaffected by the calcineurininhibitor used. In order to clearly define the causes and consequences of NCs in LT recipients, a routine preoperative neurological evaluation and careful post-operative examination are necessary. A meticulous approach to recognition and diagnosis of central nervous system lesions after LT and prompt treatment would be essential for the recipients.
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