Objectives: Neurologic complications occur frequently after liver transplants. Up to 43% of patients experience severe postsurgical neurologic complications. These complications are significantly associated with longer hospital stay, morbidity, and mortality. The aim of this retrospective study was to evaluate the type and incidence of neurologic complications after liver transplants in adult patients.

Materials and Methods: We retrospectively evaluated the medical records of 176 adult patients who had undergone liver transplants between 1995 and 2013. We recorded the demographic data, type of neurologic complications, type, and level of immunosuppressive treatment, and cause of liver failure.

Results: Our study sample consisted of 48 deceased-donor liver transplants and 128 living-donor transplants (n = 176). Fifty-three of the patients (30.1%) were female. The age range of the total sample was 18 to 66 years (mean age, 43.1 ± 13.7 y). As immunosuppressive treatment, most patients received tacrolimus alone (52%) or tacrolimus combined with mycophenolate mofetil (33%). Neurologic complications occurred in 74 of the patients (42%). The most common neurologic complications were diffuse encephalopathy (22.2%) and seizure (14.2%). Other neurologic complications were posterior reversible ence­phalopathy (1.7%), peripheral neuropathy (1.7%), cerebrovascular disease (1.1%), and central nervous system infection (1.1%). Age, cause of liver failure, and type of transplant were not associated with occurrence of neurologic complications.

Conclusions: There was a high incidence of neurologic complications after liver transplants. Diffuse encephalopathy and seizure were common complications. Physicians should be aware of the high risk of neurologic complications after liver transplants. Factors such as immunosuppressive toxicity and metabolic imbalance that predispose patients to neurologic complications after liver transplants should be evaluated immediately, and treatment of postoperative neurologic complications should be initiated as early as possible.

Key words : Liver transplant, Neurologic complication, Encephalopathy, Seizure

Introduction

Liver transplant (LT) is the primary treatment option for patients with end-stage liver disease, and it has been performed since 1963.¹ Neurologic complications (NCs) are a common postoperative problem in patients who undergo LT, with up to 43% experiencing severe NCs.1 Neurologic com­plications can occur at any time after LT, especially in the early period after surgery.^2,3 Neurologic complications can be caused in several ways, such as by surgery, immunosuppressive treatment, and metabolic disturbance.3 Diffuse encephalopathy, seizure, cerebrovascular disorder, neuromuscular disease, central nervous system infection, and central pontine myelinolysis (CPM) are the major complications.^2,3 Diffuse encephalopathy is the most common NC in patients who undergo LT, and CPM is a characteristic complication.^1-3 These complications may lead to longer hospital stay, mortality, and morbidity.^4,5

The aim of this retrospective study was to evaluate the types and incidence of NCs after LT in adult patients at a single tertiary center.

Materials and Methods

We retrospectively evaluated the medical data of 176 adult patients who had undergone LT between 1995 and 2013 in Baskent University Hospital, Ankara, Turkey. We reviewed the following data from the medical records: age at the time of LT, sex, cause of hepatic failure, type of NC, possible precipitating factor of the NC, immunosuppressive drug type, and the drug level in blood at the time of the NC.

Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 11.0, IBM Corporation, Armonk, NY, USA). Data are expressed as percentages for the categorical variables and as means and standard deviations for the continuous variables. The chi-square test was used to compare categorical variables, and the t test was used for continuous variables. P values < .05 were considered significant. The study was approved by the Ethical Review Committee of the Institute. All of the protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration.

Results

Of the 176 included patients, 53 were female (30.1%) and 123 were male (69.9%). Age at the time of LT ranged from 18 to 66 years (mean age, 43.1 ± 13.7 y).

The primary liver disease diagnoses are summarized in Table 1. The miscellaneous group includes Budd–Chiari syndrome (n = 6), hydatid cyst (n = 3), acute liver failure (n = 3), Caroli disease (n = 1), congenital hepatic fibrosis (n = 1), familial intrahepatic cholestasis (n = 1), von Gierke disease (n = 1), portal hypertension (n = 1), Alagille syndrome (n = 1), hemangiosarcoma (n = 1), and familial hypercholesterolemia (n = 1). Living-donor transplants were performed in 128 patients (72.7%), and the remaining transplants were from deceased donors.

Immunosuppressive treatment was based on calcineurin inhibitors in 174 patients. Of these 174 patients, 92 received tacrolimus alone (52%), 58 received tacrolimus combined with mycophenolate mofetil (33%), 21 received cyclosporine alone (11.3%), 3 received cyclosporine combined with mycophenolate mofetil (1.7%), 1 received sirolimus (0.6%), and 1 received no immunosuppressive treatment because of postoperative complications.

Of the 176 patients, 74 experienced NCs after surgery (42%). These patients constituted the NC(+) group; the remaining 102 patients constituted the NC(−) group. The mean age of the patients did not differ significantly between the 2 groups (NC(−) vs NC(+) 43.4 ± 13.2 y vs 42.9 ± 14.5 y; P = .811). There was no significant difference between these 2 groups regarding primary liver disease (P = .99) (Table 2) or immunosuppressive treatment (P = .245) (Table 3). Neurologic complications occurred in 54 patients (42.2%) who underwent living-donor transplants and in 20 patients (41.7%) who had deceased-donor transplants. There was no significant difference according to graft type (P = .95).

Neurologic complications occurred within the first month after LT in 55 patients (33.2%), between 1 and 6 months in 11 patients (6.3%), and after 6 months in 8 patients (4.5%). The most common NC was diffuse encephalopathy, which occurred in 39 patients (22.2%). Immunosuppressive treatment-related mental status changes were observed in 16 of these 39 patients (41%). Full recovery was achieved in these 16 patients by switching the drug from one to another. In the other 23 patients (59%), different precipitating factors were detected, such as metabolic imbalance and infection.

Seizures occurred in 25 patients (14.2%), and within 1 month after LT in 16 (64%) of them. Posterior reversible leukoencephalopathy syndrome (PRES) occurred in 3 patients (1.7%). Posterior reversible leukoencephalopathy syndrome was associated with immunosuppressive drug therapy in 2 patients, 1 of whom had been receiving tacrolimus and the other cyclosporine. Peripheral neuropathy developed in 3 patients (1.7%). It was focal in 1 patient and generalized in 2. One of the patients with generalized neuropathy was diagnosed with Guillain-Barré syndrome due to immunosuppressive drug treatment. Two patients (1.1%) experienced cerebrovascular disease; 1 had ischemia, and the other had intracerebral hemorrhage. Central nervous system infection occurred in 2 patients (1.1%); 1 had viral encephalitis, and the other had cryptococcal meningitis. The mortality rates were 47.3% (n = 35) in the NC(+) group and 15.8% (n = 16) in the NC(−) group. The mortality rate was significantly higher in the NC(+) group (P = .000).

Discussion

Neurologic complications are a common problem in patients who undergo LT, and they cause significant morbidity and mortality.5 The incidence of NCs after LT reported in the literature varies.^4-10 Published reports indicate that up to 43% of patients experience severe NCs after the procedure.¹ In our present study, NC frequency was within the limits of previously reported rates.² We considered all NCs that occurred at any time during follow-up. The highest rate was observed in the first month after LT, which is compatible with previous reports in the literature.^11-15

We did not find a significant correlation between primary liver disease and NCs. Some of the results reported in the literature resemble ours; however, Lewis and associates found a higher incidence in patients with alcoholic liver disease and those with primary biliary cirrhosis.^1,4,11 In our study, the incidence of NCs did not differ according to immunosuppressive treatments, as also had been reported elsewhere in the literature.^1,4 The incidence of NCs was previously reported to be lower in patients who underwent living-donor LTs than in patients who had deceased-donor LTs; however, we were unable to detect such a relation.⁵

Diffuse encephalopathy was the most common neurologic manifestation after LT in our study, a finding which is reflected in other studies in the literature.^4,6,11,16 The rate of diffuse encephalopathy reported in the literature varies between 10% and 62%;^1,4,6,11 in our study, 22.2% of our patients (n = 39) experienced different levels of mental status changes.

There are several factors associated with encephalopathy, such as metabolic disturbance, drug neurotoxicity, infection, seizure, and cerebrovascular disease.^3,17 Also, a higher risk of encephalopathy after LT was reported in patients with metabolic liver disease, alcohol abuse-related hepatic failure, and history of severe hepatic encephalopathy.³ The mechanisms underlying encephalopathy are not clear, although the most common finding in neuro­pathologic studies is diffuse anoxic-ischemic changes.⁴

Seizure is the second most common NC after LT.^1,4,6,11 Recently, researchers have reported that the incidence of seizure tends to decrease over time in patients who have undergone LT.^16,18 In most of the patients, seizure occurs in the early period after surgery.² Twenty-five patients (14.2%) in our study experienced seizures, and 64% of the seizures occurred within the first month after LT, which is compatible with previous reports in the literature.² Various factors may precipitate seizures, such as immunosuppressive drug toxicity, metabolic imbalance, infection, and structural brain lesions.² Close monitoring of metabolic parameters and immunosuppressive drug levels is recommended for prevention of seizure occurrence in this setting.²

Posterior reversible leukoencephalopathy syn­drome has been reported in about 5% of patients who undergo LT.^4,5,19 Posterior reversible leuko­encephalopathy syndromes consist of headache, seizure, visual disturbance, focal neurologic deficits, and mental status changes.¹ Diagnosis of PRES is based on neuroimaging features that show bilateral hyperintense lesions caused by vasogenic edema, especially in posterior regions of the brain.^20,21 Several factors can be associated with the development of PRES, but the most prominent factor in patients who have undergone LT is the neurotoxic effect of calcineurin inhibitors.^20,21 We identified postoperative PRES in 1.7% of the patients in our study, but it is hard to establish the true incidence of the syndrome in a retrospective study.

Neuromuscular complications such as peripheral neuropathy and plexus injuries are less common after LT. Peripheral neuropathy and plexopathy frequently occur because of pressure or traction.¹² Peripheral neuropathy was detected in 1.7% of our patients (n = 3).

The incidence of central nervous system infection after LT has been estimated to be 5%; however, it has been reported in fewer than 2% of the patients in recent series.^3,4,8,11 Opportunistic infections due to viruses and fungi are common, and the risk is highest between 1 and 6 months after LT.^2,3 Two of our patients experienced central nervous system infections; 1 had viral encephalitis and the other had cryptococcal meningitis.

Cerebrovascular complications occurred in about 4% of the patients in previously reported clinical series.^3,4,10 In our study, cerebrovascular complications developed in 2 patients (1.1%); an ischemic lesion was detected in 1 patient, and intracranial hemorrhage occurred in the other. In the literature, intracranial hemorrhages have been reported more commonly than ischemic strokes as NCs after LT.^3,5,11

Central pontine myelinolysis is a characteristic NC after LT. It was reported to have occurred in about 2% of the cases in previously published clinical series.^3,4 The incidence of CPM after LT in 1 series was attributed to large amounts of fluid replacement during surgery and rapid correction of hyponatremia.³ The clinical presentation of CPM can vary from asymptomatic to quadriparesis and coma. We did not find that CPM developed in any of our patients. However, neuroimaging studies were not obtained for all patients; therefore, we may not have detected CPM in some patients.

In conclusion, NCs are a common problem after LT. Some of the complications can be prevented by careful assessment of precipitating factors such as metabolic imbalance and immunosuppressive drug toxicity. Physicians who treat these patients should be aware of the high risk for NCs. Early recognition and management of NCs may improve patient morbidity and survival.

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