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Central nervous system complications after liver transplantation
Journal of Clinical Neuroscience 22 (2015) 1355–1359
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Central nervous system complications after liver transplantation Jeong-Min Kim b, Keun-Hwa Jung a,⇑, Soon-Tae Lee a, Kon Chu a, Jae-Kyu Roh a,c a
Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, 28, Yongon-dong, Chongro-gu, Seoul 110-744, South Korea Department of Neurology, Chung-Ang University Medical Center, College of Medicine, Chung-Ang University, Seoul, South Korea c Department of Neurology, The Armed Forces Capital Hospital, Gyeunggido, South Korea b
a r t i c l e
i n f o
Article history: Received 24 December 2014 Accepted 1 March 2015
Keywords: Central nervous system Complication Etiology Liver transplantation
a b s t r a c t We investigated the diversity of central nervous system complications after liver transplantation in terms of clinical manifestations and temporal course. Liver transplantation is a lifesaving option for end stage liver disease patients but post-transplantation neurologic complications can hamper recovery. Between 1 January 2001 and 31 December 2010, patients who had undergone liver transplantation at a single tertiary university hospital were included. We reviewed their medical records and brain imaging data and classified central nervous system complications into four categories including vascular, metabolic, infectious and neoplastic. The onset of central nervous system complications was grouped into five post-transplantation intervals including acute (within 1 month), early subacute (1–3 months), late subacute (3–12 months), chronic (1–3 years), and long-term (after 3 years). During follow-up, 65 of 791 patients (8.2%) experienced central nervous system complications, with 30 occurring within 1 month after transplantation. Vascular etiology was the most common (27 patients; 41.5%), followed by metabolic (23; 35.4%), infectious (nine patients; 13.8%), and neoplastic (six patients). Metabolic encephalopathy with altered consciousness was the most common etiology during the acute period, followed by vascular disorders. An initial focal neurologic deficit was detected in vascular and neoplastic complications, whereas metabolic and infectious etiologies presented with non-focal symptoms. Our study shows that the etiology of central nervous system complications after liver transplantation changes over time, and initial symptoms can help to predict etiology. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Liver transplantation is one of the most dynamic fields in modern medicine and is a lifesaving option for patients with end stage liver disease. Since the first successful transplantation in 1967, liver transplantation has been performed in many centers worldwide saving thousands of liver failure patients. However, the post-transplantation clinical course may be associated with neurologic complications that hamper recovery or even lead to death. Several studies have focused on neurological complications after transplantation and revealed variable incidences and grave prognoses [1–3]. The incidence of central nervous system (CNS) complications after liver transplantation is variable among studies, ranging from 10% up to 75% due to different inclusion criteria, definition of CNS complications and observation period [4–6]. Most studies, if not all, have categorized neurological complications simply based on symptomatology such as headache or seizure, not by
⇑ Corresponding author. Tel.: +82 2 2072 3265; fax: +82 2 3672 4949. E-mail address: [email protected] (K.-H. Jung). http://dx.doi.org/10.1016/j.jocn.2015.03.006 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
pathophysiological etiologies, and few studies have focused on disease time course. For prompt and appropriate management, it is desirable to assess etiologic diagnosis based on the initial symptom onset of the CNS complication. One group has previously reported the temporal course of CNS complication after transplantation, revealing that most neurologic complications (80%) took place within 1 month after transplantation [7]. Considering the tremendous improvement in surgical technique and medical management, including intensive care, chemoprophylaxis against infection and immunosuppression, it is necessary to update the etiologic diversity and initial manifestation of CNS complications following liver transplantation.
2. Methods Between 1 January 2001 and 31 December 2010, patients who had undergone liver transplantation and regularly visited the Outpatient Clinic at the Seoul National University Hospital were reviewed. Consecutive patients who had been referred to a neurologist for consultation because of neurologic complications were
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eligible to be included in the study, and we obtained their demographic and clinical information from medical records. Neurological complication was defined when a patient had symptoms or signs due to CNS dysfunction. After reviewing medical records and brain images, we grouped CNS complication etiologies into four categories, including metabolic, vascular, infectious and neoplastic. The onset of CNS complications was categorized into five post-transplantation intervals including acute (within 1 month), early subacute (1–3 months), late subacute (3– 12 months), chronic (1–3 years), and long-term (after 3 years). Their initial manifestation, medication history, underlying liver disease, laboratory tests, as well as brain imaging data were recorded. As vascular complications were the most common etiology of CNS complications, we further evaluated their subtypes and temporal pattern. Ischemic stroke was grouped into four subgroups including large artery disease (when a relevant artery harbors significant stenosis), small vessel occlusion (with typical location and size of lacunar infarction without large artery stenosis or embolic source), embolic infarction (when multiple infarctions are documented beyond a single vascular territory), and venous infarction (when infarction was attributable to cerebral venous thrombosis). Hemorrhagic complications were grouped according to main hematoma location, including intracerebral, subarachnoid and subdural hematoma (SDH). This study was approved by the Institutional Review Board of Seoul National University Hospital, Korea (H-1106-018-364), and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.
3. Results We studied 791 patients who had undergone liver transplantation and maintained follow-up after the procedure. Of these, 65 patients (8.2%) experienced CNS complications. The mean CNS complication onset age of the patients was 57.8 years (standard deviation: 10.2), and the median follow-up period after transplantation was 39 months (interquartile range: 13–72). The underlying liver disease profiles, CNS complication etiology distribution, and initial manifestations are summarized in Table 1. The majority of the patients had either liver cirrhosis with hepatocellular carcinoma following hepatitis B virus infection (33 patients) or liver cirrhosis following other viral hepatitis (24 patients). The most common CNS complication etiology was vascular (27 patients; 41.5%), followed by metabolic (23 patients; 35.4%), infectious (nine patients; 13.8%), and neoplastic (six patients). Representative brain imaging is shown in Figure 1.
3.1. Clinical manifestations Altered consciousness was the most common initial manifestation, which could be due to any of the four etiologies (Table 2). Patients with metabolic encephalopathy presented with non-focal neurological deficits such as altered consciousness or seizure. Three patients who initially presented with altered consciousness were diagnosed with non-convulsive status epilepticus after electroencephalography (EEG) showed a generalized spike and wave complex. The focal neurologic deficits including hemiparesis, visual field defect, and unilateral involuntary movement were common in the vascular etiology. However, despite the absence of focal symptoms, a vascular complication could not be excluded because a considerable number of stroke patients presented with non-focal neurological deficit, especially those patients with multiple embolic infarction or venous infarction who presented with altered consciousness or seizure.
Table 1 Demographic variables, clinical manifestations and etiologic classifications of patients with central nervous system complications after liver transplantation Variables
Patients, n
Age, years, mean ± standard deviation Sex (male: female)
57.8 ± 10.2 47 : 18
Liver disease Hepatocellular carcinoma with liver cirrhosis Liver cirrhosis due to other viral hepatitis Idiopathic liver cirrhosis Wilson disease Acute fulminant hepatitis
33 24 5 2 1
Central neurological complication Cerebrovascular Metabolic/toxic Infectious Neoplastic
27 23 9 6
Neurological manifestation Altered consciousness Focal neurological deficit Seizure Headache Irritability Dizziness
25 15 14 8 2 1
Total patients
65
3.2. Temporal course of neurological complications The etiology of CNS complications changed over time (Fig. 2). Regarding the onset, 30 patients (46.2%) had CNS complications that occurred within 1 month after transplantation. Metabolic complications were the most common in this acute period but this decreased as time elapsed and they were rarely observed after 1 year. Vascular complications frequently occurred within 1 month and remained as a major proportion of the complications throughout the follow-up period. The proportion of CNS neoplasms increased over time and an infectious etiology was only a minor contributor in all time periods. 3.3. Vascular complications The vascular etiologies included both ischemic and hemorrhagic complications, with ischemic complications being more prevalent than hemorrhage (17 versus 10 patients; Table 3). Ischemic stroke within 1 month after surgery was not confined to a single vascular territory in many patients, suggesting embolic infarction and venous thrombosis were predominant during this period. The embolic source was identified in three out of seven patients, including two with atrial fibrillation and the other with infective endocarditis. Venous infarction was diagnosed in five patients, with two dying during hospitalization. The most common type of intracranial hemorrhage was SDH and this had a favorable outcome. The four patients who developed SDH within 1 month recovered completely without neurological deficit. Delayed hemorrhages included subarachnoid or intracerebral hemorrhages, which were associated with a poor functional outcome. Two intracerebral hemorrhage patients died and one of the two subarachnoid hemorrhage patients became bedridden. 3.4. Metabolic and other complications Tacrolimus or cyclosporine induced metabolic encephalopathy was suspected in nine patients, and three of them had brain lesions involving the occipital and parietal lobes which were compatible with posterior reversible encephalopathy syndrome. All of the patients recovered spontaneously after medication adjustment. Altered consciousness due to hyponatremia was observed in six patients, and three of them were diagnosed with central pontine
J.-M. Kim et al. / Journal of Clinical Neuroscience 22 (2015) 1355–1359
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Fig. 1. Representative axial brain images of central nervous system complications after liver transplantation. Acute complications within 1 month after transplantation included (A) tacrolimus encephalopathy with multiple reversible cortical and white matter lesions due to vasogenic edema on a MRI fluid-attenuated inversion recovery (FLAIR) sequence, (B) central pontine myelinolysis with symmetric hyperintensity involving the pons on a MRI FLAIR sequence which developed during treatment for hyponatremia, (C) multiple embolic infarctions with restricted diffusion on diffusion weighted MRI, and (D) venous infarction with a hyperintense lesion involving the right parieto-occipital cortex on a MRI FLAIR sequence which improved after anticoagulation. The complications more than 1 month after transplantation included (E) right cerebellar hemorrhage on a non-contrast brain CT scan, (F) tuberculous meningoencephalitis with hyperintense cerebritis and a left prefrontal tuberculoma on a MRI FLAIR sequence, (G) central nervous system lymphoma with a homogeneous right frontal mass on a MRI FLAIR sequence, and (H) hepatocellular carcinoma brain metastasis with surrounding vasogenic edema on a MRI FLAIR sequence.
Table 2 Initial manifestation of central nervous system complications in liver transplant patients classified by etiology Manifestation, n
Altered consciousness Focal neurologic deficit Seizure Headache Irritability or dizziness Total
Etiologies Vascular
Metabolic
Infectious
Neoplasm
Total
10
9
3
3
25
11
1
1
2
15
3 3 0
10 1 2
1 3 1
0 1 0
14 8 3
27
23
9
6
65
manifestations and symptom onset (Table 4). The presence of a focal neurological deficit excludes CNS complications of metabolic etiology. A vascular etiology should be considered when a patient has a focal neurological deficit within 1 month after transplantation.
myelinolysis. Four patients developed hepatic encephalopathy with graft failure because of acute cellular rejection in three patients, and massive hepatitis C virus reactivation in one patient. Infection involving the CNS occurred in nine patients, including three cases of cryptococcal meningitis, three cases of tuberculous meningitis, two bacterial abscesses and one case of herpes encephalitis. Neoplastic complications included three patients with hepatocellular carcinoma metastases, two with primary CNS lymphoma, and one with a cerebellopontine angle meningioma with fatal tumor bleeding. 3.5. Etiological diagnosis based on initial manifestations and temporal course Overall, the likely etiology of CNS complications after liver transplantation can be predicted based on the initial clinical
Fig. 2. Temporal course of central nervous system complications after liver transplantation. Metabolic encephalopathy was the most common diagnosis during the acute period, followed by vascular disorders. The vascular etiology was consistently represented throughout the follow-up period.
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Table 3 Temporal pattern of central nervous system vascular complication subtypes in liver transplant patients Vascular complications
Stroke subtype Infarction Embolic infarction Venous infarction Large artery disease Small vessel occlusion Hemorrhage Subdural hemorrhage Subarachnoid hemorrhage Intracerebral hemorrhage Transient Ischemic Attack Total
Postoperative complication onset 61 month (n)
>1 month (n)
10 5 4 1 0 4 4 0 0 0 14
5 2 1 1 1 6 1 3 2 2 13
Total (n)
15 7 5 2 1 10 5 3 2 2 27
Table 4 Etiologic classification of central nervous system complications after liver transplantation classified by initial presentation and symptom onset Etiology
Symptom within 1 month post-operative (n)
Symptom after 1 month post-operative (n)
Focal neurologic deficit present Vascular Metabolic Infectious Neoplastic
4
10
4 0 0 0
7 0 1 2
Focal neurologic deficit absent Vascular Metabolic Infectious Neoplastic
26
25
8 16 2 0
8 7 6 4
4. Discussion This retrospective single center study illustrates recent trends in CNS complications after liver transplantation. Almost half of the total CNS complications were concentrated within 1 month after transplantation, and metabolic encephalopathies with altered consciousness were the most common etiology during the acute period, followed by vascular disorders. Vascular disorders frequently presented with non-focal neurological deficit. Consideration of symptom onset and initial manifestation can help predict CNS complication etiology, which will assist prompt diagnostic evaluations and treatment. The critical time for CNS complications was within 1 month after transplantation. Perioperative hemodynamic instabilty, electrolyte and fluid imbalances, adverse medication effects and acute rejection can result in CNS complications [3,8]. Close monitoring of the transplant recipient’s neurological status is necessary as initial presentations can be non-specific. Three patients with non-convulsive status epilepticus might have been misdiagnosed if EEG had not been performed because they presented with altered consciousness without overt convulsive seizures. Four venous infarction patients suffered delayed diagnosis due to non-focal presentation which delayed treatment and had grave outcome. Extensive investigation, including brain imaging and EEG should be considered whenever a recipient’s mental status is altered without discernible cause. The rate of CNS complications was markedly reduced 1 month after transplantation, and vascular disorders remained as the major cause throughout the follow-up period.
Vascular complications occurred in approximately 3% of patients with liver transplantation, comprising the largest portion of CNS complications in our study population. A previous study also reported a 3% incidence of cerebrovascular complications and suggested age and systemic infection as risk factors [9]. Considering that the liver produces virtually all of the coagulation factors, except the Von Willebrand factor, which is mainly produced by endothelium, and that both platelet number and function are altered in liver failure patients, it is reasonable to suggest that patients are susceptible to both hemorrhagic and thromboembolic events [10]. Moreover, perioperative factors including blood loss, tissue ischemia time, sepsis and transfusion may aggravate coagulation disorders [10,11]. Both ischemic and hemorrhagic stroke were observed during the acute period, but ischemia predominated in our study (10 versus four patients, respectively), contrary to previous reports [9,12]. Of interest, stroke mechanisms changed over time. Uncommon stroke subtypes such as venous infarction or multiple embolism predominated during the acute period, suggesting a distinct stroke mechanism related to disturbed coagulation after major surgery. Stroke subtypes presenting beyond 1 month post-transplantation involved more conventional stroke mechanisms, including large artery atherosclerosis and small vessel occlusion. Different strategies are warranted to manage vascular complications according to the time after transplantation. The rate of neurologic complications after liver transplantation varies widely across studies, but a decreasing trend has been shown [2,4,13]. In one study, neuropathologic abnormalities were found on autopsy studies in 60 to 70% of liver transplantation recipients [14]. Previous studies from single hospital cohorts have reported an incidence of neurological complications between 25 and 50% [2,13]. A more recent study in 2007 reported a 15% neurological complication rate among 319 patients, suggesting a decreasing trend [3]. The decline of CNS complications could be due to improvements in perioperative management and immunosuppressive therapies, and the routine use of chemoprophylaxis against opportunistic infections [15,16]. The overall CNS complication rate in this study was 8.2%, which was lower than previously reported. It is also notable that we found the proportion of CNS complications within 1 month decreased from 80 to 46.2%, suggesting improved perioperative management [7]. Electrolyte and fluid imbalances increase the risk of metabolic encephalopathy such as central pontine myelinolysis, which was diagnosed in only three patients in our study. Infections are a leading cause of critical illness, morbidity and mortality after liver transplantation [16–18]. CNS infection reportedly accounts for 20 to 25% of all CNS lesions after liver transplantation, with a high mortality rate exceeding 50% [19,20]. Infectious complications were seen in a small proportion of our study population (13.8%), which could be explained by an advanced routine chemoprophylaxis strategy. This study has several limitations. Although our study population is the largest to date, this study was a retrospective, single center design which might have resulted in selection bias. Some transient complications may have been treated before seeing the consulting neurologist, and the depth of evaluation could vary depending on the consulting neurologist. The most common cause of liver failure in our institution was due to hepatitis B virus-associated liver cirrhosis with or without hepatocellular carcinoma, which might lead to different results from those in populations where major hepatic disease is not due to hepatitis virus. Immunosuppression was maintained with calcineurin inhibition and steroids in most patients but specific regimens and dosages were variable [21]. We could not analyze laboratory data or intraoperative information such as operation time and cold ischemia time, although that information could help in estimating CNS complication risk.
J.-M. Kim et al. / Journal of Clinical Neuroscience 22 (2015) 1355–1359
This study shows the diverse etiologies and distinct temporal patterns of CNS complications after liver transplantation. The most common etiology was vascular, followed by metabolic, and incidences of both were concentrated within the 1 month period following transplantation. Consideration of the initial manifestation and symptom onset can help to predict the etiologic diagnosis, however, prospective studies are warranted. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This work was supported by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology (grant number: 2012R1A1A2002081). The sponsors had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, or preparation, review, or approval of the manuscript. References [1] Adams DH, Ponsford S, Gunson B, et al. Neurological complications following liver transplantation. Lancet 1987;1:949–51. [2] Lewis MB, Howdle PD. Neurological complications of liver transplantation in adults. Neurology 2003;61:1174–8. [3] Kim BS, Lee SG, Hwang S, et al. Neurologic complications in adult living donor liver transplant recipients. Clin Transplant 2007;21:544–7. [4] Saner FH, Gensicke J, Olde Damink SW, et al. Neurologic complications in adult living donor liver transplant patients: an underestimated factor? J Neurol 2010;257:253–8.
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[5] de Groen PC, Aksamit AJ, Rakela J, et al. Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N Eng J Med 1987;317:861–6. [6] Ghaus N, Bohlega S, Rezeig M. Neurological complications in liver transplantation. J Neurol 2001;248:1042–8. [7] Bronster DJ, Emre S, Boccagni P, et al. Central nervous system complications in liver transplant recipients—incidence, timing, and long-term follow-up. Clin Transplant 2000;14:1–7. [8] Saner F, Gu Y, Minouchehr S, et al. Neurological complications after cadaveric and living donor liver transplantation. J Neurol 2006;253:612–7. [9] Ling L, He X, Zeng J, et al. In-hospital cerebrovascular complications following orthotopic liver transplantation: a retrospective study. BMC Neurol 2008;8:52. [10] Senzolo M, Burra P, Cholongitas E, et al. New insights into the coagulopathy of liver disease and liver transplantation. World J Gastroenterol 2006;12:7725–36. [11] Cherian TP, Chiu K, Gunson B, et al. Pulmonary thromboembolism in liver transplantation: a retrospective review of the first 25 years. Transpl Int 2010;23:1113–9. [12] Campagna F, Biancardi A, Cillo U, et al. Neurocognitive-neurological complications of liver transplantation: a review. Metab Brain Dis 2010;25:115–24. [13] Stein DP, Lederman RJ, Vogt DP, et al. Neurological complications following liver transplantation. Ann Neurol 1992;31:644–9. [14] Blanco R, De Girolami U, Jenkins RL, et al. Neuropathology of liver transplantation. Clin Neuropathol 1995;14:109–17. [15] Findlay JY, Fix OK, Paugam-Burtz C, et al. Critical care of the end-stage liver disease patient awaiting liver transplantation. Liver Transpl 2011;17:496–510. [16] Razonable RR, Findlay JY, O’Riordan A, et al. Critical care issues in patients after liver transplantation. Liver Transpl 2011;17:511–27. [17] Blair JE, Kusne S. Bacterial, mycobacterial, and protozoal infections after liver transplantation–part I. Liver Transpl 2005;11:1452–9. [18] Kusne S, Blair JE. Viral and fungal infections after liver transplantation–part II. Liver Transpl 2006;12:2–11. [19] Martinez AJ. The neuropathology of organ transplantation: comparison and contrast in 500 patients. Pathol Res Pract 1998;194:473–86. [20] Feltracco P, Barbieri S, Furnari M, et al. Central nervous system infectious complications early after liver transplantation. Transplant Proc 2010;42:1216–22. [21] Yi NJ, Suh KS, Suh SW, et al. Excellent outcome in 238 consecutive living donor liver transplantations using the right liver graft in a large volume single center. World J Surg 2013;37:1419–29.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Central nervous system complications after liver transplantation Jeong-Min Kim b, Keun-Hwa Jung a,⇑, Soon-Tae Lee a, Kon Chu a, Jae-Kyu Roh a,c a
Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, 28, Yongon-dong, Chongro-gu, Seoul 110-744, South Korea Department of Neurology, Chung-Ang University Medical Center, College of Medicine, Chung-Ang University, Seoul, South Korea c Department of Neurology, The Armed Forces Capital Hospital, Gyeunggido, South Korea b
a r t i c l e
i n f o
Article history: Received 24 December 2014 Accepted 1 March 2015
Keywords: Central nervous system Complication Etiology Liver transplantation
a b s t r a c t We investigated the diversity of central nervous system complications after liver transplantation in terms of clinical manifestations and temporal course. Liver transplantation is a lifesaving option for end stage liver disease patients but post-transplantation neurologic complications can hamper recovery. Between 1 January 2001 and 31 December 2010, patients who had undergone liver transplantation at a single tertiary university hospital were included. We reviewed their medical records and brain imaging data and classified central nervous system complications into four categories including vascular, metabolic, infectious and neoplastic. The onset of central nervous system complications was grouped into five post-transplantation intervals including acute (within 1 month), early subacute (1–3 months), late subacute (3–12 months), chronic (1–3 years), and long-term (after 3 years). During follow-up, 65 of 791 patients (8.2%) experienced central nervous system complications, with 30 occurring within 1 month after transplantation. Vascular etiology was the most common (27 patients; 41.5%), followed by metabolic (23; 35.4%), infectious (nine patients; 13.8%), and neoplastic (six patients). Metabolic encephalopathy with altered consciousness was the most common etiology during the acute period, followed by vascular disorders. An initial focal neurologic deficit was detected in vascular and neoplastic complications, whereas metabolic and infectious etiologies presented with non-focal symptoms. Our study shows that the etiology of central nervous system complications after liver transplantation changes over time, and initial symptoms can help to predict etiology. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Liver transplantation is one of the most dynamic fields in modern medicine and is a lifesaving option for patients with end stage liver disease. Since the first successful transplantation in 1967, liver transplantation has been performed in many centers worldwide saving thousands of liver failure patients. However, the post-transplantation clinical course may be associated with neurologic complications that hamper recovery or even lead to death. Several studies have focused on neurological complications after transplantation and revealed variable incidences and grave prognoses [1–3]. The incidence of central nervous system (CNS) complications after liver transplantation is variable among studies, ranging from 10% up to 75% due to different inclusion criteria, definition of CNS complications and observation period [4–6]. Most studies, if not all, have categorized neurological complications simply based on symptomatology such as headache or seizure, not by
⇑ Corresponding author. Tel.: +82 2 2072 3265; fax: +82 2 3672 4949. E-mail address: [email protected] (K.-H. Jung). http://dx.doi.org/10.1016/j.jocn.2015.03.006 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
pathophysiological etiologies, and few studies have focused on disease time course. For prompt and appropriate management, it is desirable to assess etiologic diagnosis based on the initial symptom onset of the CNS complication. One group has previously reported the temporal course of CNS complication after transplantation, revealing that most neurologic complications (80%) took place within 1 month after transplantation [7]. Considering the tremendous improvement in surgical technique and medical management, including intensive care, chemoprophylaxis against infection and immunosuppression, it is necessary to update the etiologic diversity and initial manifestation of CNS complications following liver transplantation.
2. Methods Between 1 January 2001 and 31 December 2010, patients who had undergone liver transplantation and regularly visited the Outpatient Clinic at the Seoul National University Hospital were reviewed. Consecutive patients who had been referred to a neurologist for consultation because of neurologic complications were
1356
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eligible to be included in the study, and we obtained their demographic and clinical information from medical records. Neurological complication was defined when a patient had symptoms or signs due to CNS dysfunction. After reviewing medical records and brain images, we grouped CNS complication etiologies into four categories, including metabolic, vascular, infectious and neoplastic. The onset of CNS complications was categorized into five post-transplantation intervals including acute (within 1 month), early subacute (1–3 months), late subacute (3– 12 months), chronic (1–3 years), and long-term (after 3 years). Their initial manifestation, medication history, underlying liver disease, laboratory tests, as well as brain imaging data were recorded. As vascular complications were the most common etiology of CNS complications, we further evaluated their subtypes and temporal pattern. Ischemic stroke was grouped into four subgroups including large artery disease (when a relevant artery harbors significant stenosis), small vessel occlusion (with typical location and size of lacunar infarction without large artery stenosis or embolic source), embolic infarction (when multiple infarctions are documented beyond a single vascular territory), and venous infarction (when infarction was attributable to cerebral venous thrombosis). Hemorrhagic complications were grouped according to main hematoma location, including intracerebral, subarachnoid and subdural hematoma (SDH). This study was approved by the Institutional Review Board of Seoul National University Hospital, Korea (H-1106-018-364), and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.
3. Results We studied 791 patients who had undergone liver transplantation and maintained follow-up after the procedure. Of these, 65 patients (8.2%) experienced CNS complications. The mean CNS complication onset age of the patients was 57.8 years (standard deviation: 10.2), and the median follow-up period after transplantation was 39 months (interquartile range: 13–72). The underlying liver disease profiles, CNS complication etiology distribution, and initial manifestations are summarized in Table 1. The majority of the patients had either liver cirrhosis with hepatocellular carcinoma following hepatitis B virus infection (33 patients) or liver cirrhosis following other viral hepatitis (24 patients). The most common CNS complication etiology was vascular (27 patients; 41.5%), followed by metabolic (23 patients; 35.4%), infectious (nine patients; 13.8%), and neoplastic (six patients). Representative brain imaging is shown in Figure 1.
3.1. Clinical manifestations Altered consciousness was the most common initial manifestation, which could be due to any of the four etiologies (Table 2). Patients with metabolic encephalopathy presented with non-focal neurological deficits such as altered consciousness or seizure. Three patients who initially presented with altered consciousness were diagnosed with non-convulsive status epilepticus after electroencephalography (EEG) showed a generalized spike and wave complex. The focal neurologic deficits including hemiparesis, visual field defect, and unilateral involuntary movement were common in the vascular etiology. However, despite the absence of focal symptoms, a vascular complication could not be excluded because a considerable number of stroke patients presented with non-focal neurological deficit, especially those patients with multiple embolic infarction or venous infarction who presented with altered consciousness or seizure.
Table 1 Demographic variables, clinical manifestations and etiologic classifications of patients with central nervous system complications after liver transplantation Variables
Patients, n
Age, years, mean ± standard deviation Sex (male: female)
57.8 ± 10.2 47 : 18
Liver disease Hepatocellular carcinoma with liver cirrhosis Liver cirrhosis due to other viral hepatitis Idiopathic liver cirrhosis Wilson disease Acute fulminant hepatitis
33 24 5 2 1
Central neurological complication Cerebrovascular Metabolic/toxic Infectious Neoplastic
27 23 9 6
Neurological manifestation Altered consciousness Focal neurological deficit Seizure Headache Irritability Dizziness
25 15 14 8 2 1
Total patients
65
3.2. Temporal course of neurological complications The etiology of CNS complications changed over time (Fig. 2). Regarding the onset, 30 patients (46.2%) had CNS complications that occurred within 1 month after transplantation. Metabolic complications were the most common in this acute period but this decreased as time elapsed and they were rarely observed after 1 year. Vascular complications frequently occurred within 1 month and remained as a major proportion of the complications throughout the follow-up period. The proportion of CNS neoplasms increased over time and an infectious etiology was only a minor contributor in all time periods. 3.3. Vascular complications The vascular etiologies included both ischemic and hemorrhagic complications, with ischemic complications being more prevalent than hemorrhage (17 versus 10 patients; Table 3). Ischemic stroke within 1 month after surgery was not confined to a single vascular territory in many patients, suggesting embolic infarction and venous thrombosis were predominant during this period. The embolic source was identified in three out of seven patients, including two with atrial fibrillation and the other with infective endocarditis. Venous infarction was diagnosed in five patients, with two dying during hospitalization. The most common type of intracranial hemorrhage was SDH and this had a favorable outcome. The four patients who developed SDH within 1 month recovered completely without neurological deficit. Delayed hemorrhages included subarachnoid or intracerebral hemorrhages, which were associated with a poor functional outcome. Two intracerebral hemorrhage patients died and one of the two subarachnoid hemorrhage patients became bedridden. 3.4. Metabolic and other complications Tacrolimus or cyclosporine induced metabolic encephalopathy was suspected in nine patients, and three of them had brain lesions involving the occipital and parietal lobes which were compatible with posterior reversible encephalopathy syndrome. All of the patients recovered spontaneously after medication adjustment. Altered consciousness due to hyponatremia was observed in six patients, and three of them were diagnosed with central pontine
J.-M. Kim et al. / Journal of Clinical Neuroscience 22 (2015) 1355–1359
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Fig. 1. Representative axial brain images of central nervous system complications after liver transplantation. Acute complications within 1 month after transplantation included (A) tacrolimus encephalopathy with multiple reversible cortical and white matter lesions due to vasogenic edema on a MRI fluid-attenuated inversion recovery (FLAIR) sequence, (B) central pontine myelinolysis with symmetric hyperintensity involving the pons on a MRI FLAIR sequence which developed during treatment for hyponatremia, (C) multiple embolic infarctions with restricted diffusion on diffusion weighted MRI, and (D) venous infarction with a hyperintense lesion involving the right parieto-occipital cortex on a MRI FLAIR sequence which improved after anticoagulation. The complications more than 1 month after transplantation included (E) right cerebellar hemorrhage on a non-contrast brain CT scan, (F) tuberculous meningoencephalitis with hyperintense cerebritis and a left prefrontal tuberculoma on a MRI FLAIR sequence, (G) central nervous system lymphoma with a homogeneous right frontal mass on a MRI FLAIR sequence, and (H) hepatocellular carcinoma brain metastasis with surrounding vasogenic edema on a MRI FLAIR sequence.
Table 2 Initial manifestation of central nervous system complications in liver transplant patients classified by etiology Manifestation, n
Altered consciousness Focal neurologic deficit Seizure Headache Irritability or dizziness Total
Etiologies Vascular
Metabolic
Infectious
Neoplasm
Total
10
9
3
3
25
11
1
1
2
15
3 3 0
10 1 2
1 3 1
0 1 0
14 8 3
27
23
9
6
65
manifestations and symptom onset (Table 4). The presence of a focal neurological deficit excludes CNS complications of metabolic etiology. A vascular etiology should be considered when a patient has a focal neurological deficit within 1 month after transplantation.
myelinolysis. Four patients developed hepatic encephalopathy with graft failure because of acute cellular rejection in three patients, and massive hepatitis C virus reactivation in one patient. Infection involving the CNS occurred in nine patients, including three cases of cryptococcal meningitis, three cases of tuberculous meningitis, two bacterial abscesses and one case of herpes encephalitis. Neoplastic complications included three patients with hepatocellular carcinoma metastases, two with primary CNS lymphoma, and one with a cerebellopontine angle meningioma with fatal tumor bleeding. 3.5. Etiological diagnosis based on initial manifestations and temporal course Overall, the likely etiology of CNS complications after liver transplantation can be predicted based on the initial clinical
Fig. 2. Temporal course of central nervous system complications after liver transplantation. Metabolic encephalopathy was the most common diagnosis during the acute period, followed by vascular disorders. The vascular etiology was consistently represented throughout the follow-up period.
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Table 3 Temporal pattern of central nervous system vascular complication subtypes in liver transplant patients Vascular complications
Stroke subtype Infarction Embolic infarction Venous infarction Large artery disease Small vessel occlusion Hemorrhage Subdural hemorrhage Subarachnoid hemorrhage Intracerebral hemorrhage Transient Ischemic Attack Total
Postoperative complication onset 61 month (n)
>1 month (n)
10 5 4 1 0 4 4 0 0 0 14
5 2 1 1 1 6 1 3 2 2 13
Total (n)
15 7 5 2 1 10 5 3 2 2 27
Table 4 Etiologic classification of central nervous system complications after liver transplantation classified by initial presentation and symptom onset Etiology
Symptom within 1 month post-operative (n)
Symptom after 1 month post-operative (n)
Focal neurologic deficit present Vascular Metabolic Infectious Neoplastic
4
10
4 0 0 0
7 0 1 2
Focal neurologic deficit absent Vascular Metabolic Infectious Neoplastic
26
25
8 16 2 0
8 7 6 4
4. Discussion This retrospective single center study illustrates recent trends in CNS complications after liver transplantation. Almost half of the total CNS complications were concentrated within 1 month after transplantation, and metabolic encephalopathies with altered consciousness were the most common etiology during the acute period, followed by vascular disorders. Vascular disorders frequently presented with non-focal neurological deficit. Consideration of symptom onset and initial manifestation can help predict CNS complication etiology, which will assist prompt diagnostic evaluations and treatment. The critical time for CNS complications was within 1 month after transplantation. Perioperative hemodynamic instabilty, electrolyte and fluid imbalances, adverse medication effects and acute rejection can result in CNS complications [3,8]. Close monitoring of the transplant recipient’s neurological status is necessary as initial presentations can be non-specific. Three patients with non-convulsive status epilepticus might have been misdiagnosed if EEG had not been performed because they presented with altered consciousness without overt convulsive seizures. Four venous infarction patients suffered delayed diagnosis due to non-focal presentation which delayed treatment and had grave outcome. Extensive investigation, including brain imaging and EEG should be considered whenever a recipient’s mental status is altered without discernible cause. The rate of CNS complications was markedly reduced 1 month after transplantation, and vascular disorders remained as the major cause throughout the follow-up period.
Vascular complications occurred in approximately 3% of patients with liver transplantation, comprising the largest portion of CNS complications in our study population. A previous study also reported a 3% incidence of cerebrovascular complications and suggested age and systemic infection as risk factors [9]. Considering that the liver produces virtually all of the coagulation factors, except the Von Willebrand factor, which is mainly produced by endothelium, and that both platelet number and function are altered in liver failure patients, it is reasonable to suggest that patients are susceptible to both hemorrhagic and thromboembolic events [10]. Moreover, perioperative factors including blood loss, tissue ischemia time, sepsis and transfusion may aggravate coagulation disorders [10,11]. Both ischemic and hemorrhagic stroke were observed during the acute period, but ischemia predominated in our study (10 versus four patients, respectively), contrary to previous reports [9,12]. Of interest, stroke mechanisms changed over time. Uncommon stroke subtypes such as venous infarction or multiple embolism predominated during the acute period, suggesting a distinct stroke mechanism related to disturbed coagulation after major surgery. Stroke subtypes presenting beyond 1 month post-transplantation involved more conventional stroke mechanisms, including large artery atherosclerosis and small vessel occlusion. Different strategies are warranted to manage vascular complications according to the time after transplantation. The rate of neurologic complications after liver transplantation varies widely across studies, but a decreasing trend has been shown [2,4,13]. In one study, neuropathologic abnormalities were found on autopsy studies in 60 to 70% of liver transplantation recipients [14]. Previous studies from single hospital cohorts have reported an incidence of neurological complications between 25 and 50% [2,13]. A more recent study in 2007 reported a 15% neurological complication rate among 319 patients, suggesting a decreasing trend [3]. The decline of CNS complications could be due to improvements in perioperative management and immunosuppressive therapies, and the routine use of chemoprophylaxis against opportunistic infections [15,16]. The overall CNS complication rate in this study was 8.2%, which was lower than previously reported. It is also notable that we found the proportion of CNS complications within 1 month decreased from 80 to 46.2%, suggesting improved perioperative management [7]. Electrolyte and fluid imbalances increase the risk of metabolic encephalopathy such as central pontine myelinolysis, which was diagnosed in only three patients in our study. Infections are a leading cause of critical illness, morbidity and mortality after liver transplantation [16–18]. CNS infection reportedly accounts for 20 to 25% of all CNS lesions after liver transplantation, with a high mortality rate exceeding 50% [19,20]. Infectious complications were seen in a small proportion of our study population (13.8%), which could be explained by an advanced routine chemoprophylaxis strategy. This study has several limitations. Although our study population is the largest to date, this study was a retrospective, single center design which might have resulted in selection bias. Some transient complications may have been treated before seeing the consulting neurologist, and the depth of evaluation could vary depending on the consulting neurologist. The most common cause of liver failure in our institution was due to hepatitis B virus-associated liver cirrhosis with or without hepatocellular carcinoma, which might lead to different results from those in populations where major hepatic disease is not due to hepatitis virus. Immunosuppression was maintained with calcineurin inhibition and steroids in most patients but specific regimens and dosages were variable [21]. We could not analyze laboratory data or intraoperative information such as operation time and cold ischemia time, although that information could help in estimating CNS complication risk.
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This study shows the diverse etiologies and distinct temporal patterns of CNS complications after liver transplantation. The most common etiology was vascular, followed by metabolic, and incidences of both were concentrated within the 1 month period following transplantation. Consideration of the initial manifestation and symptom onset can help to predict the etiologic diagnosis, however, prospective studies are warranted. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This work was supported by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology (grant number: 2012R1A1A2002081). The sponsors had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, or preparation, review, or approval of the manuscript. References [1] Adams DH, Ponsford S, Gunson B, et al. Neurological complications following liver transplantation. Lancet 1987;1:949–51. [2] Lewis MB, Howdle PD. Neurological complications of liver transplantation in adults. Neurology 2003;61:1174–8. [3] Kim BS, Lee SG, Hwang S, et al. Neurologic complications in adult living donor liver transplant recipients. Clin Transplant 2007;21:544–7. [4] Saner FH, Gensicke J, Olde Damink SW, et al. Neurologic complications in adult living donor liver transplant patients: an underestimated factor? J Neurol 2010;257:253–8.
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[5] de Groen PC, Aksamit AJ, Rakela J, et al. Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N Eng J Med 1987;317:861–6. [6] Ghaus N, Bohlega S, Rezeig M. Neurological complications in liver transplantation. J Neurol 2001;248:1042–8. [7] Bronster DJ, Emre S, Boccagni P, et al. Central nervous system complications in liver transplant recipients—incidence, timing, and long-term follow-up. Clin Transplant 2000;14:1–7. [8] Saner F, Gu Y, Minouchehr S, et al. Neurological complications after cadaveric and living donor liver transplantation. J Neurol 2006;253:612–7. [9] Ling L, He X, Zeng J, et al. In-hospital cerebrovascular complications following orthotopic liver transplantation: a retrospective study. BMC Neurol 2008;8:52. [10] Senzolo M, Burra P, Cholongitas E, et al. New insights into the coagulopathy of liver disease and liver transplantation. World J Gastroenterol 2006;12:7725–36. [11] Cherian TP, Chiu K, Gunson B, et al. Pulmonary thromboembolism in liver transplantation: a retrospective review of the first 25 years. Transpl Int 2010;23:1113–9. [12] Campagna F, Biancardi A, Cillo U, et al. Neurocognitive-neurological complications of liver transplantation: a review. Metab Brain Dis 2010;25:115–24. [13] Stein DP, Lederman RJ, Vogt DP, et al. Neurological complications following liver transplantation. Ann Neurol 1992;31:644–9. [14] Blanco R, De Girolami U, Jenkins RL, et al. Neuropathology of liver transplantation. Clin Neuropathol 1995;14:109–17. [15] Findlay JY, Fix OK, Paugam-Burtz C, et al. Critical care of the end-stage liver disease patient awaiting liver transplantation. Liver Transpl 2011;17:496–510. [16] Razonable RR, Findlay JY, O’Riordan A, et al. Critical care issues in patients after liver transplantation. Liver Transpl 2011;17:511–27. [17] Blair JE, Kusne S. Bacterial, mycobacterial, and protozoal infections after liver transplantation–part I. Liver Transpl 2005;11:1452–9. [18] Kusne S, Blair JE. Viral and fungal infections after liver transplantation–part II. Liver Transpl 2006;12:2–11. [19] Martinez AJ. The neuropathology of organ transplantation: comparison and contrast in 500 patients. Pathol Res Pract 1998;194:473–86. [20] Feltracco P, Barbieri S, Furnari M, et al. Central nervous system infectious complications early after liver transplantation. Transplant Proc 2010;42:1216–22. [21] Yi NJ, Suh KS, Suh SW, et al. Excellent outcome in 238 consecutive living donor liver transplantations using the right liver graft in a large volume single center. World J Surg 2013;37:1419–29.