The Journal of International Medical Research

2011; 39: 1483 – 1489

Neurological Complications after Liver

Transplantation
M YILMAZ1, M CENGIZ1, S SANLI1, A YEGIN1, A MESCI2, A DINCKAN2,
N HADIMIOGLU1, L DOSEMECI3 AND A RAMAZANOGLU1
1
Department of Anaesthesiology and Intensive Care Medicine, and 2Department of Surgery,
School of Medicine, Akdeniz University, Antalya, Turkey; 3Anaesthesiology and ICU,
Medicalpark Hospital Complex, Antalya, Turkey

This was a single-centre, prospective study in level of consciousness (three patients),

to assess the frequency of neurological
complications and their impact on
prolonged hospitalization in 137 liver
transplant patients presenting between
September 1997 and June 2010.
Neurological complications were seen in 22
(16%) patients during their postoperative
stay in the intensive care unit.
Complications included new-onset,
recurrent headache (five patients),
generalized seizures (four patients),
dysarthria (two patients), delirium with
agitation (three patients), persistent
flapping tremor (two patients), alteration
central pontine myelinolysis (one patient),
myopathy (one patient) and visual
hallucinations (one patient). Seizures were
associated with immunosuppressive drug
toxicity (tacrolimus). Myopathy presenting
as quadriplegia was diagnosed by muscle
biopsy. The patient with central pontine
myelinolysis lived in a persistent vegetative
state for 2 years and died of pneumonia. In
conclusion, neurological complications are
frequently encountered after liver
transplantation, and are an important
cause of severe morbidity and prolonged
intensive care unit and hospital stay.

KEY WORDS: LIVER TRANSPLANTATION;NEUROLOGICAL DISORDER; IMMUNOSUPPRESSIVE DRUGS;

INTENSIVE CARE UNIT

Introduction incidence of central nervous system (CNS)

The increasing number of patients waiting complications during the postoperative
for organ donation has led to a greater need period varies widely from 10 to 42%.2 – 5,7 – 9
for organ transplantation. Liver The most common CNS complications are
transplantation is a complex medical– confusion, seizures, posterior leuco-
surgical procedure, accepted as the best encephalopathy syndrome and the
treatment option for patients with terminal neurotoxic side-effects of immuno-
hepatic insufficiency of various aetiologies. suppressive drugs, any of which may require
Surgical techniques and immunosuppressive prolonged intensive care or hospital stays.9,10
drug regimens have improved greatly since In addition, neurological complications are
the first liver transplant was performed in a significant cause of morbidity and
1963,1 although many postoperative mortality in patients who undergo liver
complications are still encountered.2 – 6 The transplantation.9

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 M Yilmaz, M Cengiz, S Sanli et al.
Neurological complications after liver transplantation
This paper reports the findings of a
prospective, single-centre study that
evaluated postoperative neurological
complications following liver
transplantation during the period of stay in
the intensive care unit (ICU).
Patients and methods
PATIENTS
Consecutive patients who underwent liver
transplantation at the Akdeniz University
Hospital, Antalya, Turkey, between
September 1997 and June 2010 were
included in this observational study. Those
who survived the intraoperative or very early
(first 24-h) postoperative period were
followed up for neurological complications
during their ICU stay. Patients who did not
give authorization and written informed
consent to take part in this research, on
admission to the study, were excluded.
The study was approved by the
Institutional Review Board of Akdeniz
University.
POSTOPERATIVE NEUROLOGICAL
ASSESSMENTS
Clinical neurological changes were
evaluated by intensive care physicians and
neurologists. Laboratory studies (including
serum immunosuppressant drug levels),
electromyography (EMG),
electroencephalography (EEG), computed
tomography (CT) and magnetic resonance
imaging (MRI) were performed when
indicated, according to standard hospital
protocols, if the patient showed signs of
neurological impairment.
IMMUNOSUPPRESSION
From the day of operation, tacrolimus was
administered orally twice a day (total daily
dose of 0.1 – 0.15 mg/kg body weight) for 1
year and then reduced. The dosage of
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tacrolimus was titrated based on daily serum
measurements, to achieve therapeutic levels
of 10 – 14 ng/ml. Patients who showed
toxicity to tacrolimus received cyclosporine A
(6 – 8 mg/kg orally twice a day).
Simultaneously, from the day of operation,
methylprednisolone (1 mg/kg per day) was
given intravenously and tapered following
surgery, according to standard hospital
practice.
STATISTICAL ANALYSES
All data are presented as mean ± SD.
Statistical analyses were carried out using
the JMP software package, version 7 (SAS
Institute, Cary, NC, USA). Continuous
variables were compared using the Kruskal–
Wallis or Student’s t-test, and categorical
variables were compared using the χ2-test or
Fisher’s exact test. A P-value < 0.05 was
considered to be statistically significant.
Results
The study initially recruited 172 consecutive
patients who underwent liver
transplantation. Indications for liver
transplantation of those included in the
study are shown in Table 1. The patient
population comprised 107 (62%) males and
65 (38%) females with a mean age of 38.0
years (range 1 – 68 years). The intraoperative
and early postoperative mortality rate was
20% (35 patients), leaving 137 patients in
the study. Only those patients who survived
their stay in the ICU were included in the
analysis. Of the surviving patients, 85 (62%)
were male and 52 (38%) were female, with a
mean age of 37.0 years (range 4 – 65 years).
In all patients, the mean ± SD cold
ischaemia time was 5.09 ± 0.96 h (range 4 –
7 h), the warm ischaemia time was < 2 min
and the mean ± SD operating time was 5.61
± 1.34 h (range 3.3 – 11.50 h). The mean ± SD
length of mechanical ventilation for patients
 M Yilmaz, M Cengiz, S Sanli et al.
Neurological complications after liver transplantation

headaches had normal CT and MRI findings

TABLE 1: and no underlying cause for their headaches
Indications for liver transplantation in the
patients (n = 137) included in the present could be found. Symptoms resolved with
study investigating neurological simple analgesic drug treatment such as
complications post-transplantation paracetamol. No patient required long-term
Aetiology No. of cases analgesic.
Hepatitis B without delta coinfection 71 Serum tacrolimus levels were elevated in
Hepatitis C 28 three of the four patients who had seizures
Hepatitis C + alcohol abuse 7 (25.8, 28.4 and 29.0 ng/ml), but were normal
Alcoholic liver disease 10 in one patient (11.6 ng/ml). Patients who
Drug-related (paracetamol) 1 experienced seizures were initially treated
Hepatitis B + hepatocellular carcinoma 5
with anticonvulsants including phenytoin,
Wilson disease 1
Malignancy 7 phenobarbital and benzodiazepines, at
Cryptogenic cirrhosis 1 standard therapeutic doses. Symptoms
Primary biliary cirrhosis 2 resolved after cessation of tacrolimus
Primary sclerosing cholangitis 1 treatment and MRI findings indicated
Fulminant hepatitis 3
tacrolimus toxicity. In such patients,
cyclosporine A was administered as an
with and without neurological complications alternative to tacrolimus. No patient
was 11.9 ± 9.9 (range 5 – 40 days) and 2.5 ± required long-term anticonvulsant therapy.
1.3 days (range 1 – 5 days) After the onset of seizures, EEG was
(P < 0.001), respectively. The mean ± SD ICU performed. Generalized seizures were
stay of patients with and without recorded and the diagnosis was confirmed by
neurological complications was 16.9 ± 14.8 appropriate seizure patterns on the EEG.
(range 6 – 62 days) and 4.0 ± 1.9 days (range Initial CT examination showed parieto-
1 – 7 days) (P < 0.001), respectively. occipital subcortical white-matter
Percutaneous tracheostomy was performed in hypodensities with cortical involvement in
four patients with neurological complications the posterior parietal lobes (Fig. 1). MRI
due to prolonged mechanical ventilation. studies showed extensive involvement of the
Neurological complications were seen in cortex and white matter in the frontal,
22 of 137 patients (16%), none of whom had parietal, temporal and occipital lobes, which
a history of neurological symptoms before resolved after the cessation of seizures (Fig.
transplantation. Complications included: 2). Prolonged mechanical ventilation of
recurrent headache (five patients); these patients (20, 25, 26 and 40 days)
generalized seizures (four patients); necessitated percutaneous tracheostomy. The
dysarthria (two patients); delirium with durations of ICU stay were 25, 30, 32 and 46
agitation (three patients); persistent flapping days, respectively. All four of these patients
tremor (two patients); alteration in level of were treated successfully; however, long-term
consciousness (three patients); central mechanical ventilation led to critical illness
pontine myelinolysis (one patient); neuropathy in these patients.
myopathy (one patient); and visual Speech disorders in the form of dysarthria
hallucinations (one patient). No patient had occurred in two patients, but CT and MRI
more than one neurological complication. findings were normal and the patients fully
The five patients with recurrent and spontaneously recovered within 2 weeks.

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 M Yilmaz, M Cengiz, S Sanli et al.
Neurological complications after liver transplantation

FIGURE 1: Initial computed tomography image on day 2 postoperatively from a

patient with seizure after liver transplantation, showing parieto-occipital subcortical
white matter hypodensities with cortical involvement in the posterior parietal lobes

Delirium with agitation was seen in three
patients in the early postoperative period
(days 3 – 5) and was treated with
chlorpromazine. Patients recovered
completely within a few days.
Quadriplegia was seen in one patient in
the very early postoperative period (day 2),
in whom a diagnosis of myopathy was
confirmed by EMG and muscle biopsy. EMG
revealed significant diffuse myogenic
findings in the proximal muscles in the legs
and in the arms. No neuromuscular
junction-blocking agent was used
postoperatively and methylprednisolone was
gradually tapered, ending at day 5
postoperatively. Muscle biopsy showed
degeneration, regeneration and changes in
diameter of myosin filaments. Percutaneous
tracheostomy was performed on day 7 after
surgery and the patient was admitted to the
ICU because of the need for prolonged
mechanical ventilation. The patient required
mechanical ventilation for 28 days and was
discharged from the ICU on day 32 and from
the hospital on day 58 after ICU admission.
The single patient with central pontine
myelinolysis remained unconscious at 3 days
postoperatively. Brain CT showed normal
findings. After 7 days, during which the
patient’s clinical status had not improved,
percutaneous tracheostomy was performed.
A T2-weighted MRI revealed hyperintense
areas within the centre of the pons, bilateral
basal ganglia and internal capsule on day

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 M Yilmaz, M Cengiz, S Sanli et al.
Neurological complications after liver transplantation

FIGURE 2: Magnetic resonance image from a patient with seizure after liver
transplantation, performed 1 month after the resolution of neurological symptoms
(same patient as shown in Fig. 1)

10 postoperatively. The patient remained in Discussion

a persistent vegetative state and died of
pneumonia after 2 years. In this patient, the
central pontine myelinolysis was thought to
be associated with a rapid intraoperative
increase in sodium levels (from 124 to 146
mEq/l): levels had been low preoperatively
due to underlying disease.
The onset of visual hallucinations in one
The rate of early neurological complications
following liver transplantation in the present
study (16%) was similar to those found in
previous reports, in which complication rates
ranged from 10 to 42%.2 – 5,7 – 9 The reported
incidence of seizure following liver
transplantation varies widely, with
frequencies ranging from 0 to 42%. 9,11 – 14

patient occurred one week postoperatively.
Hallucinations disappeared spontaneously
within 10 days without any medication. The
serum level of the immunosuppressive agent
cyclosporine A was 195 ng/ml (normal range
100 – 400 ng/ml) in this patient, during this
period.
The incidence of seizure in the present study
was 3% (four patients). The aetiology of post-
transplant seizures has frequently been
ascribed to immunosuppressant drugs.15
Radiological examination of seizure patients
in the present study revealed parieto-
occipital subcortical white-matter

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 M Yilmaz, M Cengiz, S Sanli et al.
Neurological complications after liver transplantation
hypodensities, with cortical involvement in
the posterior parietal lobes, and extensive
involvement of the cortex and white matter
in the frontal, parietal, temporal and
occipital lobes. These findings suggested that
these lesions could have developed due to
cerebral infarctions. After the resolution of
neurological symptoms and improvement in
MRI results it was confirmed that the
neurological pathology was related to
tacrolimus toxicity. Because of this, a
different immunosuppressive drug
(cyclosporine A) was used in these patients.
Mild neurological symptoms including
headache, paraesthesia, tremor, sleep
disturbance, photophobia and dysaesthesia
have been reported in 40 – 60% of patients
treated with tacrolimus;7,12 major
neurological complications such as
confusion, seizures, cortical blindness,
encephalopathy and coma can occur in 5 –
8% of patients receiving tacrolimus.3 Adams
et al.9 found that seizures were the most
common neurological complication reported
after liver transplantation, occurring in 25%
of 52 patients, while Vogt et al.2 reported
seizures in 8 of 19 (42%) patients following
liver transplantation.
Acute myopathy is a condition observed in
critically ill patients with status
asthmaticus.16,17 The use of neuromuscular
junction blocking agents and high-dose
corticosteroids is common in these patients.17
The symptoms of acute myopathy are non-
specific, have sudden onset and prolonged
duration. Acute myopathy has been reported
in 7% of liver transplantation cases and the
only common pathological finding is the
selective loss of thick myosin filaments at
muscle biopsy.18 The patient with acute
myopathy in the present study was treated
intraoperatively with intravenous
vecuronium and 1 g of methylprednisolone.
Central pontine myelinolysis is a
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demyelinating disease of the pons,
occasionally occurring in other areas of the
central nervous system, and is associated with
the rapid correction of hyponatraemia.19
Previous studies have found an association
between central pontine myelinolysis and
hyponatraemia ranging from 30% to 61%,19
although the rapid change in sodium levels
may play a more important role than
hyponatraemia.19,20 A prospective,
multicentre study conducted over a period of
4 years found the incidence of central pontine
myelinolysis among liver transplant patients
to be approximately 0.29%.21 Central pontine
myelinolysis usually occurs within the first 30
days following organ transplantation.21 The
patient with central pontine myelinosis in the
present study developed hyponatraemia
preoperatively, and sodium levels increased
intraoperatively due to aggressive therapy
with sodium bicarbonate, which was required
for the correction of metabolic acidosis.
Headaches in the early postoperative
period may be associated with hypertension,
fever, infection, immunosuppressive agents,
or, uncommonly, intracerebral
haemorrhage.22 Viral or fungal CNS
infections are rare causes of headache in
immunorestricted patients, and usually
occur in the first year after transplantation.22
Chronic headaches are frequently associated
with immunosuppressive therapy.23 Five
patients in the present study had acute
severe headache after transplantation, but
all investigations were normal.
In conclusion, the present study
demonstrated that neurological
complications are frequently encountered
after liver transplantation, being observed in
16% of patients. The mean ICU stay and
length of mechanical ventilation were
significantly higher in patients with, rather
than those without, neurological
complications. The toxic effect of
 M Yilmaz, M Cengiz, S Sanli et al.
Neurological complications after liver transplantation

immunosuppressive drugs should be University Scientific Research Unit, Antalya,

considered as a major factor in the aetiology
of neurological complications.
Acknowledgement
This study was supported by Akdeniz
Turkey.
Conflicts of interest
The authors had no conflicts of interest to
declare in relation to this article.

• Received for publication 17 February 2011 • Accepted subject to revision 22 March 2011
• Revised accepted 5 July 2011
Copyright © 2011 Field House Publishing LLP

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Author’s address for correspondence

Dr Murat Yilmaz
Department of Anaesthesiology and Intensive Care Medicine, Akdeniz University,
Dumlupinar Bulvarı, 07059 Antalya, Turkey.
E-mail: muryigit@yahoo.com

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