Liver transplantation is the only curative treatment for patients with end-stage liver disease.1,2 Despite advances in the fields of organ preservation, immunosuppressive therapy, surgery, and perioperative management, the incidence of complications following liver transplantation remains high.2 More specifically, neurological complications are a major cause of morbidity and mortality in these patients.3,4 Approximately one-third of all transplantations are performed in patients younger than 1-year old, and half are performed in patients younger than 2 years of age. Post-transplant survival in children has increased to 90%.5 The main indication for liver transplantation in paediatric patients is primary biliary cirrhosis (65%), caused in most cases by biliary atresia, but also by familial cholestasis, Alagille syndrome, and alpha-1 antitrypsin deficiency. Other frequent indications include metabolic liver disease, unresectable benign or malignant liver tumours (hepatoblastoma, hepatocarcinoma), and acute liver failure (of toxic, infectious, or metabolic aetiology, etc).

Few studies have analysed the incidence of neurological complications in paediatric patients undergoing liver transplantation, with different series reporting rates between 8% and 46%.1–10 One of the first series published on the topic concluded that adults were at higher risk of neurological complications than children (23% vs. 8%).5 Subsequent studies have classified neurological complications as early or late, depending on the moment of onset.6 Early neurological complications include acute encephalopathy, seizures, and cerebrovascular events, whereas the most frequent late neurological complications are headache, poor coordination, tremor, and cognitive alterations (executive and visuospatial dysfunction), in addition to neuropsychiatric disturbances.6,7 Several authors have attempted to determine the risk factors for neurological complications,8–10 finding an association with the following conditions: toxic levels of immunosuppressants (mainly calcineurin inhibitors), poor neurological status prior to the surgery, kidney failure, and transplant rejection.

The main objective of this study is to analyse the incidence of neurological complications in a population of paediatric patients undergoing liver transplantation and to describe the characteristics of these complications. As a secondary objective, we analyse possible risk factors for the development of neurological complications, both before and after transplantation, and compare them to those of the population undergoing liver transplantation and presenting no neurological complications.

We conducted a retrospective study including all paediatric patients (younger than 17 years) undergoing liver transplantation at a tertiary hospital between 2004 and 2016, and analysed those patients presenting neurological complications. We gathered the following information: demographic data, initial diagnosis and reason for liver transplantation, previous neurological alterations, baseline status before the surgery (including need for mechanical ventilation and/or inotropic support, use of extracorporeal blood purification therapy with Molecular Adsorbent Recirculating System [MARS] before transplantation, immunossuppressant treatment received, etc), type of neurological complication, timing of onset, complementary tests, and treatment. We also analysed survival and presence of sequelae. In the statistical analysis, continuous variables are expressed as medians and quartiles 1 and 3, and categorical variables are expressed as absolute frequencies and percentages. We compared the groups of patients with and without neurological complications. Continuous variables in both groups were compared with the Mann–Whitney U test. Contingency tables analysis used the chi-square test and the Fisher exact test. P values < .05 were considered statistically significant. Statistical analysis was conducted with the SPSS software (version 21).

Patient characteristics, clinical status prior to transplantation, type of neurological complications, and complementary tests performed are summarised in Table 1. Fig. 1 shows the most representative cranial CT and brain MR images Table 2 compares the characteristics of patients with and without neurological complications after liver transplantation.

Fig. 1.

A) Non-contrast cranial CT: diffuse parenchymal hypoattenuation, loss of cortico-subcortical differentiation, and collapse of the ventricular system, compatible with diffuse cerebral oedema. B) Brain MRI (T2-weighted, axial plane): oval hyperintensity with a hypointense halo in the right cerebellar hemisphere, compatible with haematoma. C) Brain MRI (T2-weighted, axial plane): hyperintensity affecting nearly the entire central region of the pons, suggestive of central pontine myelinolysis. D) Brain MRI (FLAIR, axial plane): patchy hyperintensities in the juxtacortical and subcortical white matter of the parieto-occipital region of the right hemisphere.

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Paediatric patients undergoing liver transplantation frequently develop neurological complications. Previous studies have analysed the incidence of neurological complications, reporting rates ranging from 8% to 46%.1–10 In our series, 16 patients (34.8% of all transplantations) presented neurological complications. These patients showed a significantly higher median age than patients presenting no neurological complications and this finding is consistent with those reported by other researchers.1–4 Previous studies have reported a higher incidence of neurological complications in patients receiving liver grafts from deceased donors than in those receiving the organ from a living donor.4,5 In our series, few patients received grafts from living donors; therefore we were unable to analyse the potential association between the type of donor and the risk of neurological complications.

Encephalopathy is one of the most frequent neurological complications in the context of hepatocellular dysfunction and liver transplantation. Incidence ranges from 15% to 33% in paediatric patients, and these rates are higher than those reported in some series of adult patients (11%–15%).5 In our series, encephalopathy was more frequent among patients with acute liver failure; similar to previous published studies.6–10

Seizures are another of the most frequently reported neurological complications of liver transplantation, usually classified as acute symptomatic seizures.1–3,5 In the context of liver transplantation, seizures can be secondary to structural causes (e.g., cerebrovascular events, hypoxic–ischaemic encephalopathy), central nervous system infection, and toxic-metabolic causes (e.g., ion imbalance, immunosuppressive therapy).1–3,7–11 In our series, seizures were associated with cerebral oedema, posterior reversible encephalopathy (see below), and toxic levels of tacrolimus.

Regarding the potential association between calcineurin inhibitors (tacrolimus and cyclosporine) and neurological complications, previous studies suggest that these drugs may be neurotoxic.11–15 On the one hand, they inhibit calcineurin in cells, leading to apoptosis of oligodendrocytes and glial cells, which are rich in calcineurin. On the other, these drugs modify the activity of excitatory amino acid receptors (NMDA) and inhibitory amino acid receptors, such as (GABA). However, the neurotoxicity of calcineurin inhibitors does not always occur in the context of toxic levels.14,15

Posterior reversible encephalopathy syndrome (PRES), observed in one of our patients, is a clinico-radiological entity characterised by headache, visual alterations, and seizures, combined with radiological signs of vasogenic oedema predominantly affecting the parieto-occipital white matter.16 This complication has also been associated with the use of calcineurin inhibitors, with poorly controlled arterial hypertension also being a risk factor. These drugs have a potential vascular toxicity secondary to mechanisms of cerebral vasoconstriction and/or cerebrovascular inflammation.15–17 The incidence of PRES in patients receiving calcineurin inhibitors ranges from 1% to 10%.17 In our series, only one patient presented this complication, in association with persistent, poorly controlled arterial hypertension and in absence of toxic levels of tacrolimus. PRES may be underrepresented in our series, as not all patients underwent MRI studies; however none of the remaining patients presented symptoms suggestive of this complication.

Previous studies analysing survival after liver transplantation report contradictory data regarding patients with neurological complications.1–3,5 Therefore, it remains unclear whether this subgroup has a poorer survival prognosis. This is probably explained by the wide variety of possible neurological complications and their varying severity, contributing differently to mortality.18,19 In our series, a longer survival was observed in the group of patients presenting no neurological complications, although the differences were not statistically significant.

One limitation of our study the neuroimaging data available: not all patients underwent brain MRI scans, because it was no technically possible or viable (e.g., in patients receiving MARS therapy). Therefore, some radiological signs that are better assessed with brain MRI may have missed by non-contrast head CT. Furthermore, not all patients undergoing liver transplantation were monitored with video-EEG; as a result, the incidence of encephalopathy may be underestimated, and patients classified as having psychomotor agitation may in fact have presented episodes of encephalopathy that were not detected by conventional EEG. Another limitation of our study is derived from its design. Its retrospective approach and a small sample size may explain the lack of statistically significant differences in some of the potential risk factors analysed. Prospective studies including paediatric patients undergoing liver transplantation should be conducted to identify trigger factors or baseline conditions that may help predict higher risk of developing neurological complications.

In conclusion, neurological complications of liver transplantation are frequent in paediatric patients, and present a highly variable clinical spectrum. Certain pre-existing factors seem to be associated with a higher incidence of complications; these include encephalopathy, MARS therapy, acute liver failure, and circulatory or respiratory support. After transplantation,toxic levels of tacrolimus are associated with an increased risk of neurological complications. To minimise morbidity and mortality in these patients, the management of baseline clinical status should be optimised before the surgery and the patients should be closely monitored during the post-operative period to enable early detection of any complications.

This study has received no funding of any kind.

This study was presented at the 42nd Annual Meeting of the Spanish Society of Paediatric Neurology in Oviedo, Spain (23–25 May 2019) and was awarded one of the prizes for best oral communications.