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 »  Abstract
 » Methods
 » Patient Population
 » Results
 » Laboratory Data
 » Discussion
 » Conclusion
 » Study Limitations
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Table of Contents    
ORIGINAL ARTICLE
Year : 2020  |  Volume : 68  |  Issue : 1  |  Page : 146-151

Neurological Complications in Recipients after Living Donor Liver Transplantation


1 Department of Internal Medicine, National Research Centre, Giza, Egypt
2 Department of Neurology, Faculty of Medicine, Cairo University, Giza, Egypt

Date of Web Publication28-Feb-2020

Correspondence Address:
Dr. Mohamed Khalil
Assistant Researcher of Neurology, Department of Internal Medicine, National Research Centre, Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.279703

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 » Abstract 


Background and Aim: Liver transplantation (LT) is the only curative treatment for patients with the end-stage liver disease. Amongst the complications post-LT, the neurological complications (NC) are particularly relevant. Our aim is to assess the incidence, risk factors and clinical presentation of NC in recipients after living donor liver transplantation.
Methods: Between November 2011 and December 2013, 149 patients were admitted to ICU in 3 different centres in Egypt after LDLT and were evaluated by full clinical examination, laboratory investigations, neuroimaging and the NC were observed over one month. This study was approved by the ethical committee of the National Research Center.
Results: 46 recipients (30.9%) developed neurological complications. The most common neurological complication was Encephalopathy (14.1%) while the least were both central pontine myelinolysis and meningoencephalitis (0.7%). In addition, 7 patients developed cerebrovascular events (either ischemic or hemorrhagic strokes). Patients were then classified into uncomplicated and complicated subgroups according to the highest percentage of neurological complication symptoms. These were encephalopathy, delirium with agitation, hallucinations, and delusions.
Conclusion: A high incidence of neurological complications (30.9%) after LDLT was recorded, prolonging patient hospital stays. The most common complications were encephalopathy, delirium, hallucinations, delusions, and seizures some of which were drug related.


Keywords: Central pontine myelinolysis, cerebrovascular complications, encephalopathy, liver transplantation, neurological complications
Key Messages: Our study is the largest to date Egyptian multicenter, cross-sectional, retrospective observational study assessing the early neurological disorders in recipients post LDLT. 30.9% of our cohort developed a wide range of neurological signs and symptoms.


How to cite this article:
Khalil M, Elbanhawy I, Elsherbiny A, Amer H, Ahmed S. Neurological Complications in Recipients after Living Donor Liver Transplantation. Neurol India 2020;68:146-51

How to cite this URL:
Khalil M, Elbanhawy I, Elsherbiny A, Amer H, Ahmed S. Neurological Complications in Recipients after Living Donor Liver Transplantation. Neurol India [serial online] 2020 [cited 2020 Apr 4];68:146-51. Available from: http://www.neurologyindia.com/text.asp?2020/68/1/146/279703




Egypt is known to have the highest prevalence of Hepatitis-C Virus (HCV) infection worldwide.[1] Despite a noticed regression in prevalence due to the recently launched national HCV treatment program with the goal of achieving a national chronic infection prevalence of <2% by 2025, the clinical impact is still expected to grow.[2]

Liver transplantation is indicated in patients with liver cirrhosis and with a Model for End-stage Liver Disease score greater than 15.[3] Living donor liver transplant (LDLT) showed better disease-free survival outcome compared to deceased donor liver transplant.[4]

Solid organ have been found to be associated with many neurological complications; opportunistic infections, posterior reversible encephalopathy syndrome, immune reconstitution inflammatory syndrome, lymphoproliferative disorders, etc. Specific complications have been related to organ transplant and certain medications.[5] Neurological complications have been seen in patients who underwent LDLT and these have been directly implicated in the clinical outcomes of some studies.[6] Such complications were mostly related to immunosuppressant neurotoxicity (calcineurin inhibitors (CNI's)) and opportunistic infections.[7]

This study aims to detect the neurological complications in the postoperative period (one month) of living donor liver transplantation patients.


 » Methods Top


Study design

This study was a multicenter, cross-sectional, retrospective observational study conducted at three centers in Egypt on 149 adult Egyptian patients (135 males and 14 females, mean age 50.16 ± 8.38) with end-stage liver disease who underwent living donor liver transplantation starting from November 2011 to December 2013. Patients were recruited from different institutions: Egyptair Hospital, Elsahel Teaching Hospital, and Menoufia Liver Institute.


 » Patient Population Top


Inclusion criteria

The patients included in this study are those who had LDLT with postoperative follow up within one month including:

  • Age >18, no sex predilection;
  • living donor liver transplantation patients; and
  • no record of preoperative neurological signs and symptoms.


Exclusion criteria

Excluded patients from data collection and follow up including:

  • Patients (age < 18 years);
  • incomplete patient records; and
  • patients with previous severe medical condition (e.g., renal failure, neurological disorder).


The approval of the local ethics committee of the National Research Centre was obtained.

The reason for transplantation was registered. Preoperative assessment was done including full general and neurological examination. The transplant was done using standard surgical and anesthesia technique.

Postoperative immunosuppression included: corticosteroids and calcineurin inhibitors (tacrolimus TAC or FK 506, 0.05 mg/Kg/hours or Cyclosporine 5 mg/Kg/12 hours).[8]

Patients' data were collected and included: full history and examination, surgical technique, post-transplant clinical evaluation, and regimen of immunosuppression. The conscious level was assessed using “West Haven Classification System“[9] and “Glasgow Coma Scale.”[10] Any neuropsychiatric symptom otherwise was reported and registered.

Laboratory data registered included daily trough levels of CNI's tacrolimus and cyclosporine, total bilirubin (T.B.), aspartate transaminase (AST), alanine transaminase (ALT), albumin (Alb.), ammonia, urea, creatinine (Cr.), electrolytes (sodium, potassium, calcium, magnesium, phosphorus), complete blood count, coagulation profile (PT, PTT, INR).

Patients who developed neurological complications were subjected to neuroimaging of brain computed tomography (CT) and magnetic resonance imaging (MRI).

Our cohort were subdivided in two groups (complicated and uncomplicated). Patients were considered complicated upon development of any postoperative neurological signs and/or symptoms with or without radiological abnormalities within one month period.

Neurological complications were followed for one-month postoperatively.

Sample size

All the patients who underwent LDLT in the centers mentioned above were included after applying the inclusion and exclusion criteria. Data were retrospectively collected based on chart reviews performed at each center. Patients with previous neurological disorders or severe medical conditions other than liver disorders, children, deaths within 48 hours, and cases with incomplete information were excluded.

Statistical analyses

Results are expressed as mean ± standard deviation (SD) or a percentage. Comparison between mean values of different variables in the two studied groups was performed using the unpaired t-test. Correlation between different variables was performed using Pearson or Spearman correlation tests. Statistical Package for Social Sciences computer program (version 19 windows) was used for data analysis. P value ≤ 0.05 was considered significant, and <0.01 was considered highly significant.


 » Results Top


The baseline demographic characteristics of the 149 recipients who underwent liver transplantation are shown in [Table 1]. The mean age of those patients was 50.16 years ± 8.38 years. They were 135 males (90.6%) and 14 females (9.4%).
Table 1: Demographic features of the studied patients

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The most common indication for transplantation was a liver failure due to HCV infection. Liver failure due to other disorders was significantly much lower [Table 2].
Table 2: Causes of liver failure leading to liver transplantation

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Preoperative morbidity

In addition to their liver disease, 25 patients (16.7%) were diagnosed with diabetes mellitus and 32 patients (21.5%) were having patients had hypertension. These patients were controlled preoperatively with their regular medications.

Neurological complications post-transplant

The most common complications were encephalopathy, delirium, hallucinations, and delusions in a decremental order followed by significantly less frequent yet more severe neurological complications [Table 3].
Table 3: Neurological complications occurring within one month of LDLT

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Among the 149 patients, 46 patients (30.9%) developed neurological complications. Some patients had more than one complication throughout their hospital course. The distribution of the patients whose neurological complications were present is as follows: encephalopathy had the highest percentage [21/149 (14.1%)], followed by delirium with agitation [20/149 (13.4%)], hallucinations [13/149 (8.7%)], delusions [12/149 (8.1%)], altered consciousness [7/149 (4.7%)], focal and generalized seizures [7/149 (4.7%)], evidence of cerebrovascular stroke including cranial nerve affection, speech disorder and limb ataxia with hemiparesis and/or hypothesia [6/149 (4.0%)], headache [6/149 (4.0%)], critical illness neuropathy or myopathy [5/149 (3.4%)], flapping tremors [3/149 (2%)], central pontine myelinolysis, and meningoencephalitis [1/149 (0.7%)]. All neurological complications occurred in a period not exceeding the 2nd week post-operation.

Patients' subgroups

Patients were classified into complicated or uncomplicated subgroups. A patient was considered of the complicated subgroup if he had at least one of the neurological complication symptoms of encephalopathy, delirium with agitation, hallucinations, and delusions [Table 4].
Table 4: Number and percentage of patients in the subgroups

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 » Laboratory Data Top


A comparison between the mean values of different laboratory investigations in the patient subgroups did not show any statistically significant difference except for the hemoglobin levels [Table 5].
Table 5: Comparison between mean values of different laboratory investigations in patient subgroups classified according to neurological complications

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Only hemoglobin level showed a statistically significant lower level in complicated groups when compared to uncomplicated patients. The mean value of hemoglobin was significantly decreased in the complicated group (9.67 ± 1.44) when compared with its corresponding in the uncomplicated one (10.25 ± 1.58) (P = 0.045) [Table 5].

The mean Serum level of Tacrolimus (FK-506) was higher in the complicated subgroup versus the noncomplicated subgroup than the noncomplicated patients, yet both were within the normal therapeutic range with no statistically significant difference.

Comparison between subgroups in the prevalence of hepatic disease

In the uncomplicated patients, the prevalence of liver diseases including HCV, HBV, combined HCV + HBV, HCC, and hepatic diseases were 92.2% (95/103), 1.9% (2/108), 1.9% (2/103), 1.9% (2/103), and 2.9% (3/103), respectively.

In complicated patients, the prevalence of liver diseases including HCV, HBV, combined HCV + HBV, HCC, and hepatic diseases were 80.5% (37/41), 0% (0/41), 4.4% (2/41), 8.7% (4/41), and 6.5% (3/41), respectively. There was no statistically significant difference between both groups (P = 0.126) [Table 6].
Table 6: Association between indications of liver disease and neurological complications in the two studied patient subgroups

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The primary cause for transplantation did not seem to influence the rate of neurological complication occurrence [Table 6].

Correlation between drugs and laboratory parameters in all patients

Among our cohort, there was a positive correlation between FK506 and total bilirubin serum levels (r = 0.226; P = 0.006), [Figure 1]. Also, FK506 was positively correlated with both direct bilirubin (r = 0.160; P = 0.053) and ammonia (r = 0.146; P = 0.078) and inversely correlated with sodium (r = −0.158; P = 0.057) yet still insignificant (borderline insignificant). Otherwise there was no statistically significant correlation between FK506 and the other studied parameters [Table 7].
Figure 1: Correlation between FK506 and total bilirubin in all patients

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Table 7: Correlation between drugs used and different laboratory parameters in patients

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Also, there was no statistically significant correlation between cyclosporine and different studied parameters [Table 7].

[Figure 1] shows the positive correlation between FK506 and total bilirubin serum levels (r = 0.226; P = 0.006).

Correlation between post-transplant neurological complications and age, DM, and HTN in all patients

Neither the age nor the preoperative risk factors (diabetes mellitus, hypertension) had a significant correlation with the early postoperative neurological complications [Table 8].
Table 8: Correlation between final complications and age, DM, and HTN in all patients

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Correlation between drug side effects and neurological complications in patient subgroups

The side effects related to the FK were associated with neurological complications in 30 cases out of the 46 complicated cases (65.2%) [Table 9].
Table 9: Association between FK drug side effects and neurological complications in the two studied patient subgroups

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A highly significant association was found regarding the relation between FK-506 and neurological complications (P = 0.00X).

Association between FK drug side effects and neurological complications in patient subgroups including radiological data

CT or MRI was done for patients who developed any neurological complication (46/149) which occurred only within the first two weeks [Table 10].
Table 10: CT-MRI findings of the studied patients

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These lesions were right parietal infarction, right parietal hematoma, left frontal infarction, left thalamic hematoma, subarachnoid hemorrhage, left parietal subcortical infarction, and central pontine myelinolysis [Table 11].
Table 11: Clinical presentation of the patients with abnormal neuroimaging

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The clinical presentation of these lesions is shown in [Table 11].


 » Discussion Top


The study shows that most common neurological complications following LDLT were mostly transient encephalopathy, delirium, agitation and delusions. Less common, severe complications included stroke, seizures, central myelinolysis, etc.

The primary indication for liver transplantation in our Egyptian patients was the liver failure due to HCV infection (n = 132 out of 149 patients). HCV infection is known to be endemic in Egypt with the highest prevalence among the world. The widespread of the virus was primarily due to mass population antischistosomal treatment involving administration of tartar emetic injections in earlier decades (from the 1950s to 1980s).[11]

Following solid organ transplantation, neurological complications can affect 30%−60% of recipients, including 15%−30% of liver transplant recipients.

The most frequently encountered complication in the postoperative period of our patients was encephalopathy and its related symptoms (agitation, delirium, hallucination, etc.). Saner et al., 2010) found a similar frequency of encephalopathy yet with a higher incidence of seizures compared to our study [Table 12].[6] This difference may be contributed to the higher prevalence of alcoholic cirrhotic patients among his transplanted group.
Table 12: Review of literature regarding the neurological complications following liver transplantation[7]

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Neurotoxicity caused by FK506 together with delayed allograft function is the main precipitators for hepatic encephalopathy. In our study, there was a positive correlation between FK506 and total bilirubin serum levels which also might contribute to the encephalopathy.

Regarding cerebrovascular events, some risk factors were recognized such as coagulation disorders, hypertension, diabetes, and perioperative cerebral hypoperfusion.

Central pontine myelinolysis is a demyelinating lesion occurring at the center of the pons; it was attributed to rapid correction of hyponatremia in a single case in our cohort.

Seizures incidence in our study is 4.7%. Most are generalized clonic seizures. Possible etiologies are neurotoxicity caused by immunosuppressants, acute metabolic derangement, and cerebrovascular insults.

Central nervous system infections are favored by immunosuppression. Regarding the immunosuppression, trough levels of tacrolimus and cyclosporine were within the normal range.[12] Levels of tacrolimus were nearly the same in both complicated and uncomplicated group. Unfortunately, the small sample of patients taking cyclosporine made the statistical analysis underpowered to compare the trough level between the two groups. Calcineurin inhibitors have been related more to chronic complications rather than the acute one. Follow-up of these patients and prospective analysis would probably show different complications related to these drugs such as PRES, opportunistic infections, PML, etc.[13]

Only hemoglobin level showed a statistically significant lower value in the complicated group. Immunosuppressive medications have long been implicated in the pathogenesis of anemia after transplantation due to their bone marrow depressive effects. Controlled trials comparing immunosuppressive regimens have shown an incidence of anemia that ranges from 1% to 53%. In the European FK506 liver study that compared cyclosporine and tacrolimus, the incidence of anemia was 1% in the cyclosporine group and 5% in the tacrolimus.[14]


 » Conclusion Top


Neurological complications were found to be one of the leading causes (30.9%) of morbidity following liver transplantation. The most common neurological complication was encephalopathy followed by a wide range of disorders. All neurological complications occurred within the first two weeks postoperatively. Neurological complications were neither related to the preoperative liver disorder nor other risk factors but were found to be connected to immunosuppressive drugs particularly Tacrolimus (FK506). There was a positive correlation between the levels of FK506 and total bilirubin, direct bilirubin, and ammonia which may help to explain the pathogenesis of some complications. Our study is the largest to date in Egypt to assess the neurological complications following LDLT.

Our study showed that in the short period following LDLT the neurological complications were transient and reversible most of the time.


 » Study Limitations Top


We had some difficulties collecting patients' data due to the poor filing system on some occasions. Furthermore, there was a lack of cooperation from other institutes, which made it difficult to grow the sample size with input from other centers. The absence of a national registry for liver transplant patients around the country was also a significant limitation to our study.

Acknowledgment

I would like to express my cardinal thanks and deepest gratitude to Professor Iman El-Banhawy, Professor of neurology, Cairo University, Professor Ashraf Elsherbiny, Professor of internal medicine, National Research Centre, Professor Hanan Amer, Professor of neurology, Cairo University, Dr. Sandra Ahmed, Lecturer of neurology, Cairo University and Professor Hala Zaki, Professor and Former Head of Internal Medicine department, National Research Centre for their kind guidance, assistance, and encouragement during the progress of this work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Kandeel A, Genedy M, El-Refai S, Funk AL, Fontanet A, Talaat M. The prevalence of hepatitis C virus infection in Egypt 2015: Implications for future policy on prevention and treatment. Liver Int 2017;37:45-53.  Back to cited text no. 1
    
2.
Asmaa G, Naglaa A, Aisha E, Mohamed EK, Imam W. Hepatitis C infection in Egypt: Prevalence, impact, and management strategies. Hepat Med 2017;9:17-25.  Back to cited text no. 2
    
3.
Graziadei I, Zoller H, Fickert P, Schneeberger S, Finkenstedt A, Peck-Radosavljevic M, et al. Indications for liver transplantation in adults: Recommendations of the Austrian Society for Gastroenterology and Hepatology (ÖGGH) in cooperation with the Austrian Society for Transplantation, Transfusion, and Genetics (ATX). Wien Klin Wochenschr 2016;128:679-90.  Back to cited text no. 3
    
4.
Grant RC, Sandhu L, Dixon PR, Greig PD, Grant DR, McGilvray ID. Living vs. deceased donor liver transplantation for hepatocellular carcinoma: A systematic review and meta-analysis. Clin Transplant 2013;27:140-7.  Back to cited text no. 4
    
5.
Pruitt AA, Graus F, Rosenfeld MR. Neurological complications of solid organ transplantation. Neurohospitalist 2013;3:152-66.  Back to cited text no. 5
    
6.
Saner FH, Gensicke J, Olde Damink SW, Pavlaković G, Treckmann J, Dammann M, et al. Neurologic complications in adult living donor liver transplant patients: An underestimated factor? J Neurol 2010;257:253-8.  Back to cited text no. 6
    
7.
Zivković SA. Neurologic complications after liver transplantation. World J Hepatol 2013;5:409-16.  Back to cited text no. 7
    
8.
Elgharably A, Gomaa AI, Crossey MM, Norsworthy PJ, Waked I, Taylor-Robinson SD. Hepatitis C in Egypt - Past, present, and future. Int J Gen Med 2017;10:1-6.  Back to cited text no. 8
    
9.
Wróblewski T, Kobryń K, Kozieł S, Ołdakowska-Jedynak U, Pinkas J, Danielewicz R. Acetaminophen (Paracetamol) induced acute liver failure – A social problem in an era of increasing tendency to self-treatment. Ann Agr Environ Med 2015;22;762-7.  Back to cited text no. 9
    
10.
Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The glasgow coma scale at 40 years: Standing the test of time. Lancet Neurol 2014;13:844-54.  Back to cited text no. 10
    
11.
Moini M, Schilsky ML, Tichy EM. Review on immunosuppression in liver transplantation. World J Hepatol 2015;7:13558.  Back to cited text no. 11
    
12.
Dasari BV, Hodson J, Nassir A, Widmer J, Isaac J, Mergentel H, et al. Variations in practice to therapeutic monitoring of tacrolimus following primary adult liver transplantation. Int J Organ Transplant Med 2016;7:18.  Back to cited text no. 12
    
13.
European FK506 Multicentre Liver Study Group. A randomized trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994;344:423-8.  Back to cited text no. 13
    
14.
Maheshwari A, Mishra R, Thuluvath PJ. Post-liver-transplant anemia: Etiology and management. Liver Transpl 2004;1065-73.  Back to cited text no. 14
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12]



 

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