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Neurological Complications in Recipients after Living Donor Liver Transplantation
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.279703
Keywords: Central pontine myelinolysis, cerebrovascular complications, encephalopathy, liver transplantation, neurological complicationsKey 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.
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.
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.
Inclusion criteria The patients included in this study are those who had LDLT with postoperative follow up within one month including:
Exclusion criteria Excluded patients from data collection and follow up including:
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.
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%).
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].
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].
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].
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].
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].
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].
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].
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].
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].
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].
The clinical presentation of these lesions is shown in [Table 11].
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.
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]
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.
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.
[Figure 1]
[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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