|Year : 2016 | Volume
| Issue : 4 | Page : 225-231
Neuropsychiatric complications after liver transplantation
Mohamed E Elwan1, Rasha A El-Kabany1, Amr S Shalaby1, Ibrahim E Alahmar1, Osama Hegazy2, Mona S Elkholy MD 1
1 Department of Neuropsychiatry, Faculty of Medicine, Menoufya University, Al Minufya, Egypt
2 National Liver Institute, Menoufya University, Al Minufya, Egypt
|Date of Submission||15-Nov-2015|
|Date of Acceptance||03-Feb-2016|
|Date of Web Publication||17-Mar-2017|
Mona S Elkholy
Department of Neuropsychiatry, Faculty of Medicine, Menoufya University, Al Minufya
Source of Support: None, Conflict of Interest: None
Neuropsychiatric complications are responsible for significant mortality and morbidity after liver transplantation (LT).
The aim of this study was to detect the neuropsychiatric complications after LT, and to identify any possible relationship between these complications and certain perioperative risk factors.
Materials and Methods
The study was performed on 35 patients admitted in the National Liver Institute, Menoufiya University, who underwent LT. Patients were assessed 2 weeks preoperatively and followed up for 3 months postoperatively. Preoperatively, clinical assessment, mini mental state examination, Bender–Gestalt test, trail making test, structured clinical interview for DSM-IV axis I disorders scale, assessment using the hospital anxiety depression scale, laboratory tests for hepatic disease and comorbidities, cerebral computerized tomography and/or MRI, carotid duplex and electroencephalography were carried out. Intraoperatively, assessment of warm and cold ischemia time, operative time, and blood transfusion was carried out. Postoperatively, clinical examination, mini mental state examination, Bender–Gestalt test, trail making test, assessment with the structured clinical interview for DSM-IV axis I disorders scale and the hospital anxiety depression scale, brain imaging, electroencephalography, nerve conduction studies, and electromyogram were carried out.
Postoperatively, neurological complications were detected in 13 (37.1%) patients in the form of central complications, such as encephalopathy, seizures, and cerebrovascular strokes, and peripheral neuropathies. However, psychiatric complications were detected in 15 (42.9%) patients in the form of cognitive disorders, maladjustment, anxiety disorders, major depressive disorders, and brief psychotic episode.
This work showed that, in adult patients undergoing living donor LT, there was a relevant variety of neurological and psychiatric complications, which represented significant causes of postoperative morbidity and should be diagnosed and managed early.
Keywords: liver transplantation, neurological, psychiatric
|How to cite this article:|
Elwan ME, El-Kabany RA, Shalaby AS, Alahmar IE, Hegazy O, Elkholy MS. Neuropsychiatric complications after liver transplantation. Egypt J Neurol Psychiatry Neurosurg 2016;53:225-31
|How to cite this URL:|
Elwan ME, El-Kabany RA, Shalaby AS, Alahmar IE, Hegazy O, Elkholy MS. Neuropsychiatric complications after liver transplantation. Egypt J Neurol Psychiatry Neurosurg [serial online] 2016 [cited 2017 Sep 24];53:225-31. Available from: http://www.ejnpn.eg.net/text.asp?2016/53/4/225/202382
| Introduction|| |
Liver transplantation (LT) is the only curative treatment in patients with end-stage liver disease . Clinical series have documented neurological complications in 8.3–47% of all patients receiving LT . Patients with neuropsychiatric complications following LT show a high mortality rate, especially when the complications occur in the first month after transplantation . In addition, patients with neuropsychiatric complications have longer hospitalization, higher need for retransplantation, and social reintegration compared with patients without complications . The emerging evidence of possible persistence of some neuropsychiatric deficits within months after LT raises the question of whether these deficits are completely reversible .
| Materials and Methods|| |
This study was performed on 35 patients between 29 and 50 years of age. There were 20 male and 15 female patients admitted in the Liver Transplant Unit, National Liver Institute, Menoufiya University, who underwent live donor LT from April 2013 to May 2014. Patients were assessed 2 weeks preoperatively and followed up for 3 months postoperatively. The study was ethically approved by the local commitee and Informed consent was taken from each patient.
Patients younger than 18 years, patients with current or past history of psychiatric disorders, and patients with known neurological deficits or having other medical conditions were excluded from the study.
Patients were subjected to the following preoperatively:
- Full history taking and complete physical and neurological examination were carried out using Oxford Neurological Sheet, 2010
- Testing of baseline cognitive functions using:
- Mini mental state examination (MMSE) Crum et al. 
- Bender–Gestalt test (BGT). The test comprised nine figures each on a card, which the participant is asked to copy. Generally, the greater the number of errors, the greater the evidence of brain impairment Reynolds 
- Trail making test (TMT) parts A and B were used to assess executive functioning; the patient connects numbers in ascending order (part A), or alternating between numbers and letters (part B). Longer completion times are indicative of cognitive deficit Lezak et al. 
- Tests for psychiatric disorders were carried out using:
- The structured clinical interview for DSM-IV axis I disorders (SCID-I) scale 
- The hospital anxiety depression (HAD) scale 
- Laboratory tests were carried out for primary cause for hepatic disease and relative comorbidities
- Finally, imaging:
- Cerebral computed tomography (CT) and/or MRI was carried out using Toshiba Scanner Alexion device, (Ōtawara, Tochigi, Japan) 16 channel, model TSX_034A, input 3_300/400/415/460–480 V, 50/60 Hz, maximum input power 50 kVA. All MRI were performed with Titan Excelart vantage series, 1.5 T. Axial T2-weighted spin echo, T1-weighted spin echo, fluid-attenuated inversion recovery, and echo-planar diffusion-weighted sequences were performed
- Carotid duplex was carried out to screen for preoperative vascular risk factors, using Hitachi ultrasonography (gray and colored scales)
- Electroencephalography (EEG) was performed to assess the presence of encephalopathy even subclinically, using conventional scalp EEG, model: EEG-9200K, 2006 (Nihon Kohden Corporation, Shinjuku-ku, Tokyo, Japan).
Intraoperatively, (a) warm and cold ischemia time, (b) operative time, and (c) blood transfusion were recorded.
All recipients were subjected to the following:
- Complete neurological examination (weekly)
- Testing of cognitive functions (3 months postoperatively) using (a) MMSE, (b) BGT, and (c) TMT
- Tests for psychiatric disorders (3 months postoperatively): (a) the SCID-I scale and (b) the HAD scale
- Imaging, including cerebral CT and/or MRI; EEG
- Nerve conduction studies in the upper limb – the median and ulnar nerves (sensory and motor at the wrist, below elbow, and above elbow) – and the lower limb – the common peroneal and posterior tibial nerves (sensory and motor at the ankle, below fibular head, and at the popliteal fossa)
- Electromyography in the upper limb (paraspinal, deltoid, abductor digiti minimi, abductor pollicis brevis, and abductor indices muscles) and the lower limb (paraspinal, quadriceps femoris, gluteii, tibialis anterior, extensor digitorum brevis, and gastrocnemius muscles) using JESPC servo-motor control system with full automatic AC voltage regulator.
The collected data were tabulated and statistically analyzed as described by Armitage et al.  using arithmetic mean, SD, test of significance t-test and the χ2-test. P value was taken at 5% to show significance (<0.05 was determined as moderately significant and < 0.001 was determined as highly significant).
| Results|| |
This study was performed on 35 patients whose ages ranged between 29 and 50 years with a mean age of 41.1 ± 8 years. There were 15 (57.1%) male and 10 (42.9%) female patients ([Table 1]).
Preoperative neurological findings
On performing carotid duplex, one (2.9%) patient had diffuse atherosclerosis with significant occlusion of the right internal carotid artery, two (5.7%) patients had diffuse atherosclerosis not affecting hemodynamics, and 32 (91.4%) patients had free radiological findings. However, CT and MRI of the brain demonstrated brain edema in three (8%) patients, brain atrophy in four (11.4%) patients, and normal findings in 28 (80%) patients. EEG detected diffuse slowing in five (14.3%) patients and no abnormality in 30 (85.7%) patients. In total, 13 (37.1%) patients developed electrolyte disturbance and 16 (45.7%) patients developed encephalopathy. Preoperative psychiatric findings: using the SCID-I scale, the number of patients meeting the criteria for anxiety disorders were four (11.4%), all generalized anxiety disorder, and the number of patients meeting the criteria for major depressive disorder was three (8.6%). The mean HAD score was 6 for anxiety and 6.6 for depression. Cognitive impairments were detected in nine (25.7%) patients.
Postoperative neurological complications
Postoperative neurological complications were detected in 13 (37.1%) patients in the form of central complications, of which encephalopathy was the most common (20%), followed by seizures (17.1%), cerebral hemorrhage (5.7%), and cerebral infarction (2.9%), and peripheral complications, including common peroneal neuropathy (5.7%) and ulnar neuropathy (2.9%), which may be traumatic or compressive ([Table 2] and [Figure 1] and [Figure 2]).
|Figure 1 Unenhanced CT of the brain in a 50-year-old LT patient presenting with altered mental state, left-sided hypotonia, and partial seizures on the left side with secondary generalization 75 days after surgery. It shows a large intraparenchymal hematoma (thick white arrow) in the right and left frontal lobes with contiguous extension into the ipsilateral ventricle (dotted arrow). CT, computed tomography; LT, liver transplantation.|
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|Figure 2 A 50-year-old male patient with right middle cerebral artery.(MCA) infarct presenting with left-sided hemiplegia, irritability and agitation. Axial T2WI (a) and DWI (b) showing acute infarct with diffusion restriction involving the right temporal lobe in the MCA territory.|
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There was a statistically significant association between the presence of preoperative encephalopathy (P = 0.002), preoperative electrolyte imbalance (P = 0.006), and occurrence of postoperative encephalopathy ([Table 3]).
|Table 3 Relation between perioperative data of the patients and development of postoperative encephalopathy|
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Preoperative electrolyte imbalance (P = 0.02) and intraoperative immunosuppressant (P = 0.04) showed a statistically significant association for occurrence of postoperative seizures ([Table 4]).
|Table 4 Relation between perioperative data of the patients and development of postoperative seizures|
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There was a statistically significant association between the presence of preoperative hypertension (P = 0.05) and occurrence of postoperative cerebral hemorrhage.
Age (P = 0.05), atrial fibrillation (P = 0.006), and carotid stenosis up to 50% (P = 0.000) showed a statistically significant association for occurrence of postoperative cerebral infarction.
Postoperative psychiatric complications
Postoperative psychiatric complications were detected in 15 (42.9%) patients. Using the SCID-I scale, the number of patients meeting the criteria for adjustment disorder was four, that for anxiety disorders was three (8.6%) (two generalized anxiety disorder and one post-traumatic), that for major depressive disorder was three (8.6%), and brief psychotic episode was noticed in only one (2.9%) patient, mostly drug induced. The mean HAD score was 7.2 for anxiety and 5.3 for depression. Cognitive impairments were detected in four (11.4%) patients ([Figure 3]).
|Figure 3 Postoperative psychiatric complications. MDD, major depressive disorder.|
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Presence of diabetes mellitus, preoperative electrolyte disturbance, and preoperative encephalopathy showed a statistically significant association for development of postoperative cognitive disorders ([Table 5]).
|Table 5 Relation between perioperative data of the patients and development of postoperative cognitive disorder|
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This study failed to show any difference between the type of immunosuppressant used and the presence of neuropsychiatric complications.
| Discussion|| |
In this study, neurological complications were detected in 13/35 (37.1%) patients in the form of central complications, including encephalopathy in seven (20%) patients, seizures in six (17.1%) patients, cerebral infarction in one (2.9%) patient, and cerebral hemorrhage in two (5.7%) patients, and peripheral complications, including common peroneal neuropathy in two (5.7%) patients and ulnar neuropathy in one (2.9%) patient.
Qiang et al.  studied 516 cases that underwent LT; 83 (16.1%) cases had Neurological complications (NCs). This percent is lower than that reported in our study.
In this study, delirium was the most common, as it occurred in 7/13 (53.8%) patients with neurological complications. On comparing this percent with that preoperatively, it was found that encephalopathy decreased as the liver condition improved after transplant. This coincides with the study by Saner et al. , who found that up to 80% of patients exhibit some degree of encephalopathy during their postoperative course, and this is supported by other studies such as Dhar et al. . In contrast to these studies, Kim et al.  found that peripheral motor disturbance was the most common complication and the encephalopathy rate was only 12.2%.
Preoperative encephalopathy (P = 0.002) and preoperative electrolyte imbalance (P = 0.006) showed a statistically significant association for occurrence of postoperative encephalopathy. This is in agreement with the study of Dhar et al. , who demonstrated that the stronger predictor of postoperative encephalopathy was the presence of active encephalopathy at the time of transplantation, and explained that alterations of the blood–brain barrier due to pre-existing encephalopathy might have made these patients more vulnerable to neurotoxicity compared with other patients.
In this study, it was found that seizures were the second common neurological complication as it occurred in 6/13 (46%) patients with neurological complications and 17.1% of LT patients. This coincides with the study of Colombari et al. , who reported seizures in 12.8% of patients, and explained that the etiology of the seizures in LT patients is usually related to central nervous system lesions – namely, stroke, central pontine myelinolysis or central nervous system infection, neurotoxicity of immunosuppressants, and osmotic disorders.
This study showed a statistically significant association between preoperative electrolyte imbalance (P = 0.02), intraoperative immunosuppressants (P = 0.04), and occurrence of postoperative seizures. This coincides with the study by Tombazzi et al.  in which 128 patients with LTs were studied; seizures were detected in 49 patients. In 43 patients, the etiology was associated with immunosuppressant and this coincides with the study by Guarino et al. .
In this study, three (8.5%) patients developed cerebrovascular complications, two developed cerebral hemorrhage, and one developed ischemic stroke. This percent is higher than that in the study by Ling et al. , who conducted a retrospective study on 337 patients undergoing LT; 10 (3.0%) patients developed in-hospital cerebrovascular complications. They reported that older age and systemic infection might be important risk factors for intracranial hemorrhage following LT.
Age (P = 0.05), preoperative atrial fibrillation (P = 0.006), and carotid stenosis up to 50% (P = 0.000) showed a statistically significant association for occurrence of postoperative infarction and this coincides with the study by Wang et al. .
There was a statistically significant association between presence of preoperative hypertension (P = 0.05) and occurrence of postoperative cerebral hemorrhage, and this coincides with the study by Borg et al. .
This study reported three (8.5%) cases of peripheral neuropathy and this percent is lower than that reported by Tombazzi et al. , who studied 128 LT recipients and reported peripheral neuropathy in 13 (17.3%) patients and explained that peripheral neuropathy is frequently due to pressure or traction of nervous plexuses and, therefore, is more frequent in transplanted patients with a prolonged operative course.
On comparing preoperative and postoperative psychiatric complications using the SCID-I scale, the number of patients having psychiatric diagnosis increased from seven (20%) patients to 11 (31.4%) patients mainly in the form of adjustment disorders. Using cognitive tests (MMSE, BGT, TMT A, and TMT B), the number of patients who showed cognitive impairment dropped from nine (25.7%) patients to four (11.4%) patients.
This coincides with the findings of Fukunishi et al. , who in a follow-up series, using interviews by trained professionals in the post-transplant period, found psychiatric illnesses to be present in 22 of 41 (54%) of adult recipients within 3 months after transplant.
Trzepacz and Levenson  studied 40 LT candidates; half of them could not be given a specific psychiatric diagnosis. Of 20 patients, 60% were found to be delirious and 35% had an adjustment disorder.
On comparing these results with preoperative manifestations, it was found that cognitive dysfunction improved. This is in agreement with the study by Middleton et al. , who indicated that residual cognitive deficits are common and may reflect the extent of pretransplant morbidity.
According to Mattarozzi et al. , cognitive function was restored to a large extent after transplantation, but not completely. Mattarozzi et al.  evaluated neuropsychological performance 6 and 18 months after LT. They observed that cognitive function improved 6 months after LT, continued to improve slightly, but significantly, until an 18-month assessment.
In the present study, on comparing HAD scores preoperatively and postoperatively, it was found that there was no statistically significant difference. This is in disagreement with the study by Russell et al. , who showed that the rates of anxiety and depression decrease significantly when compared with the pretransplant rates.
Telles-Correia et al.  concluded that psychiatric disorders are common in the preoperative period. The prevalence was as follows: 33% for depression, 34% for anxiety, 59% for alcohol dependence/abuse, 24% for delirium, and 28% for alexithymia. Psychiatric disorders are also common in candidates in the postoperative period. During that period the prevalence was as follows: 30% for depression, 26% for anxiety, 30% for delirium, 6.4% for post-traumatic stress disorder, and 7.5% for psychosis. Alcohol relapse occurs in about 29% of the transplanted patients, and this study partly coincides with our study.
The present study showed that there is a close relationship between hepatitis C and depression. This coincides with the study by Tombazzi et al. , which was performed on 128 patients after LT, and found that 11 of 63 patients with hepatitis C (17.4%) and three of 65 patients without hepatitis C (4.6%) developed depression.
This is confirmed by the study of DiMartini et al. , who reported that hepatitis C patients have a higher prevalence of psychiatric disorders, including depression, compared with other patients with different types of liver disease. Psychiatric side effects of interferon occur in more than 20% of patients treated for hepatitis C. In total, 10–12% of patients can develop depression during the treatment and the prevalence of this is greater in patients with previous psychiatric disease, and they also reported that interferon-induced depression carries a substantial risk for suicide.
Dew et al.  explained that the etiology of depression is unknown. Possible etiologies include history of substance abuse, neuroendocrine changes, and direct hepatitis C virus neuroinvasion, whereas Martins et al.  reported that depression is generally underdiagnosed and undertreated by physicians and it may have been even higher than reported in transplantation studies.
The multitude of stresses associated with organ transplantation, coupled with medication side effects, results in rates of anxiety ranging from 17 to 28% .
In this study, only one patient developed brief psychotic disorder, and this is in disagreement with the study by Telles-Correia et al.  in which psychosis was detected to be responsible for 7.5% of psychiatric complications, and reported that it may be due to high doses of cyclosporine after transplantation.
| Conclusion|| |
This study showed that, in adult patients undergoing LT, there was a relevant variety of neurological and psychiatric complications, which represented significant causes of postoperative morbidity and should be diagnosed and managed early.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Surman OS, Cosimi AB, DiMartini A. Psychiatric care of patients undergoing organ transplantation. Transplantation 2009; 87
Tarter RE, Van Thiel DH, Hegedus AM, Schade RR, Gavaler JS, Starzl TE. Neuropsychiatric status after liver transplantation. J Lab Clin Med 1984; 103
Yilmaz M, Cengiz M, Sanli S, Yegin A, Mesci A, Dinckan A, et al.
Neurological complications after liver transplantation. J Int Med Res 2011; 39
Dhar R, Young GB, Marotta P. Perioperative neurological complications after liver transplantation are best predicted by pre-transplant hepatic encephalopathy. Neurocrit Care 2008; 8
Stracciari A, Baldin E, Cretella L, Delaj L, D'Alessandro R, Guarino M. Chronic acquired hepatocerebral degeneration: effects of liver transplantation on neurological manifestations. Neurol Sci 2011; 32
Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA 1993; 269
Reynolds CR. Koppitz-2: The Koppitz Developmental Scoring System for the Bender–Gestalt Test
. Austin, TX: Pro-Ed Inc; 2007.
Lezak MD, Howieson DB, Loring DW. Neuropsychological assessment
. 4th ed. New York, NY: Oxford University Press; 2004.
Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res 2002; 52
First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition (SCID-I/P)
. New York, NY: Biometrics Research, New York State Psychiatric Institute; 2002.
Armitage P, Berry G, Matthews JNS. Statistical methods in medical research. 4th
ed.: Massachusetts, USA: Published by Blackwell Scientific Publication; 2002.
Qiang Yi, Xiao Shun HE, et al.
Prophylaxis and management of neuropsychiatric complications after liver transplantation. Neurology 2009; 12
Saner FH, Nadalin S, Radtke A, Sotiropoulos GC, Kaiser GM, Paul A. Liver transplantation and neurological side effects. Metab Brain Dis 2009; 24
Kim BS, Lee SG, Hwang S, Park KM, Kim KH, Ahn CS, et al.
Neurologic complications in adult living donor liver transplant recipients. Clin Transplant 2007; 21
Colombari RC, de Ataíde EC, Udo EY, Falcão AL, Martins LC, Boin IF. Neurological complications prevalence and long-term survival after liver transplantation. Transplant Proc 2013; 45
Tombazzi CR, Waters B, Shokouh-Amiri MH, Vera SR, Riely CA. Neuropsychiatric complications after liver transplantation: role of immunosuppression and hepatitis C. Dig Dis Sci 2006; 51
Guarino M, Benito-Leon J, Decruyenaere J, Schmutzhard E, Weissenborn K, Stracciari A. Neurological problems in liver transplantation. European handbook of neurological management
. 2nd ed. Oxford, UK: Wiley-Blackwell; 2011; 1
Ling L, He X, Zeng J, Liang Z. In-hospital cerebrovascular complications following orthotopic liver transplantation: a retrospective study. BMC Neurol 2008; 8
Wang WL, Yang ZF, Lo CM, Liu CL, Fan ST. Intracerebral hemorrhage after liver transplantation. Liver Transpl 2000; 6
Borg MA, van der Wouden EJ, Sluiter WJ, Slooff MJ, Haagsma EB, van den Berg AP. Vascular events after liver transplantation: a long-term follow-up study. Transpl Int 2008; 21
Fukunishi I, Sugawara Y, Takayama T, Makuuchi M, Kawarasaki H, Surman OS. Association between pre transplant psychological assessments and post-transplant psychiatric disorders in living related transplantation. Psychosomatics 2002; 43
Trzepacz PT, Levenson J. Textbook of psychosomatic medicine
. Washington, DC: American Psychiatric Publishing. 2005; 91–130.
Middleton PF, Duffield M, Lynch SV, Padbury RT, House T, Stanton P, et al.
Living donor liver transplantation – adult donor outcomes: a systematic review. Liver Transpl 2006; 12
Mattarozzi K, Stracciari A, Vignatelli L, D'Alessandro R, Morelli MC, Guarino M. Minimal hepatic encephalopathy: longitudinal effects of liver transplantation. Arch Neurol 2004; 61
Russell RT, Feurer ID, Wisawatapnimit P, Salomon RM, Pinson CW. The effects of physical quality of life, time, and gender on change in symptoms of anxiety and depression after liver transplantation. J Gastrointest Surg 2008; 12
Telles-Correia D, Barbosa A, Mega I, Monteiro E. Importance of depression and active coping in liver transplant candidates' quality of life. Prog Transplant 2009; 19
DiMartini A, Crone C, Fireman M, Dew MA. Psychiatric aspects of organ transplantation in critical care. Crit Care Clin 2008; 24
Dew MA, Switzer GE, Di Martini AF, Myaskovsky L, Crowley-Matoka M. Psychosocial aspects of living organ donation. In: Tan HP, Marcos A, Shapiro R, editors. Living donor organ transplantation
. Abingdon, UK: Taylor and Francis; 2007. 7–26.
Martins PD, Sankarankutty AK, Silva Ode C, Gorayeb R. Psychological distress in patients listed for liver transplantation. Acta Cir Bras 2006; 21(Suppl 1)
Pelgur H, Atak N, Kose K. Anxiety and depression levels of patients undergoing liver transplantation and their need for training. Transplant Proc 2009; 41
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]