Original Clinical Science
Risk Factors for Central Pontine and Extrapontine Myelinolysis After Liver Transplantation: A Single-Center Study Chiara Crivellin,1 Annachiara Cagnin,2,3 Renzo Manara,4 Patrizia Boccagni,5 Umberto Cillo,5 Paolo Feltracco,6 Stefania Barbieri,6 Alberto Ferrarese,1 Giacomo Germani,1 Francesco Paolo Russo,1 Patrizia Burra,1 and Marco Senzolo1
Background. Central pontine and extrapontine myelinolysis (CPM/EPM) are severe neurologic complications after liver transplantation. Methods. The present work retrospectively evaluated single-center prevalence of CPM/EPM and associated risk factors: cause of liver disease, hepatic encephalopathy, preoperative, intraoperative, and perioperative blood components use, serum levels, and variation of Na+, Cl−, and K+ and immunosuppression were compared between CPM/EPM patients and control group of transplanted patients without neurologic complications. Results. Among 997 transplants, CPM/EPM were diagnosed in 11 patients (1.1%), of whom four were CPM, one was EPM, and six were associated CPM and EPM. Control group consisted of 44 transplanted patients. Central pontine and extrapontine myelinolysis patients experienced higher intraoperative and perioperative serum Na+/24 hr variations compared to controls (16.69±5.17 vs. 9.8±3.4 mEq/L, P = 0.001). Maximum peak of intraoperative or perioperative serum Na+ was significantly higher in patients compared to controls (151.5±3.3 vs. 140.8±6.2 mEq/L, P≤0.001), but no difference in preoperative serum Na+ was detected. Three patients presented hypernatremia as isolated risk factor. Conclusion. Extrapontine myelinolysis can be found isolated or associated with CPM in up to two of three liver transplanted patients with myelinolysis. A marked variation of perioperative serum Na+ remains the main risk factor even in patients without preexisting hyponatremia; however, isolated hypernatremia may be solely responsible in some cases.
(Transplantation 2015;99: 1257–1264)
C
entral pontine myelinolysis (CPM) is a clinical syndrome first reported in 1959 by Adams et al.1 and described as a demyelinating disorder affecting the central pons, typically in malnourished, alcoholic, and chronically debilitated patients. The original clinical description included rapidly evolving quadriplegia, dysarthria, dysphagia, and mutism. The definition of CPM evolved over the years, and the fact that the demyelinating lesions were not confined to the pons, but could also affect basal ganglia, thalamus, lateral Received 30 April 2014. Revision requested 19 May 2014.
geniculate body, and so on, led to the definition in 1962 of extrapontine myelinolysis (EPM). Categories at risk of developing demyelinating disorders also evolved over time, including septic, burn, diabetic, human immunodeficiency virus, and liver transplanted patients. These categories of patients were all linked by the presence of electrolyte imbalances (especially hyponatremia) and a possible too rapid correction thereof. Patients affected by hepatic insufficiency are particularly prone to the development of myelinolysis because of several factors, such as malnutrition, alcohol abuse and frequent
Accepted 2 September 2014. 1
Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua, Italy.
2 Department of Neurosciences, Sciences NPSRR, University Hospital of Padua, Padua, Italy. 3
IRCCS San Camillo Foundation, Venice, Italy.
4
Department of Neuroradiology, University of Salerno, Salerno, Italy.
5
Hepatobiliary Surgery and Liver Transplant Center, University Hospital of Padua, Padua Italy. 6
Operative Unit of Anesthesia and Intensive Care, Department of Medicine, University Hospital of Padua, Padua, Italy. The authors declare no funding or conflicts of interest. C.C. participated in research design, performance of the research, data analysis, and writing of the article. A.C. participated in research design, performance of the research and in data analysis. R.M. participated in research design, performance of the research
Transplantation
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and in data analysis. P.B., U.C., P.F., and S.B. participated in research design and in data analysis. A.F. participated in performance of the research, data analysis, and writing of the article. F.P.R., G.G., and P.B. participated in research design, performance of the research and in data analysis. M.S. participated in research design, performance of the research, data analysis, and writing of the article. All authors have contributed to, read, and approved the article. Correspondence: Marco Senzolo, M.D., Ph.D., Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, Padua, Italy. ([email protected]). Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9906-1257 DOI: 10.1097/TP.0000000000000496
www.transplantjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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chronic hyponatremia. Patients with hepatic encephalopathy present marked depletion of myoinositol, which, together with other organic osmolytes, protects the brain from rapid changes in serum osmolality. Chronic liver disease also leads to a negative nitrogen balance, which reduces the availability of the pool of amino acids necessary for the synthesis of organic osmolytes.2 Moreover, liver dysfunction entails a depletion of glycogen brain reserves: glial cells need glucose to activate the Na+-K+ ATP-ase, thus, in the absence of reserves, even small electrolyte imbalances can lead to energy depletion and cellular death.3 Central pontine myelinolysis was first described after liver transplantation by Starzl et al. in 1978.4 It is one of the most serious neurologic complications after liver transplantation and the incidence varies from 0.94% to 3% in current clinical series5,6 (Fig. 1). Most cases of CPM/EPM (90%) occur within the first week after surgery and in another cohort more than 50% of neurologic symptoms—varying from stupor to locked-in syndrome - appear within the 7th postoperative day.6 Liver transplantation is burdened by frequent osmotic and electrolyte imbalances. Intraoperatively, an abundant infusion of sodium-rich fluids is often necessary to replace blood loss, but the ability of sodium renal excretion is impaired in cirrhotic patients.
www.transplantjournal.com
Since 1978, 163 cases of CPM/EPM developed after liver transplantation in adults have been reported. However, limited data on the risk factors of this condition in liver transplantation have been evaluated.
RESULTS Clinical Characteristics of the CPM/EPM Group
Between November 1990 and June 2011, 997 adult patients underwent liver transplantation at the Padua University Liver Transplant Center. One hundred forty (14%) patients developed postoperative neurologic complications and were evaluated by neurologists. In 11 patients (9 males, 2 females; mean±SD age, 53.6±8.8 years) CPM or EPM (four CPM, one EPM, and six mixed CPM/EPM) were diagnosed after liver transplantation; clinical signs and symptoms of CPM/ EPM occurred in patients after a mean±SD interval time of 6.9±2.5 days after liver transplantation. The incidence of myelinolysis was 1.1%. The control group included 44 liver transplanted patients (26 males, 18 females; mean±SD age, 51.8±9.1 years), without neurologic complications. Patients’ and controls’ clinical findings are summarized in Table 1 (Table S1, SDC, http://links.lww.com/TP/B83).
FIGURE 1. MRI, fluid attenuated inversion recovery axial images of the pons (A) and the corresponding magnification (B). The images showed the symmetric signal alteration in the basis pontis, with a “trident” shape, typical of central pontine myelinolysis. MRI, magnetic resonance imaging.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Crivellin et al
© 2014 Wolters Kluwer
TABLE 1.
Clinical characteristics of transplanted patients with CPM and/or EPM and transplanted controls without neurologic complications CPM/EPM
Controls
P
Number 11 44 Age, yr (mean±SD) 53.64±8.83 51.83±9.15 0.6 Sex (M/F) 9/2 26/18 0.1 Underlying liver disease Alcoholic 2 9 1 Viral 7 25 0.3 Alcoholic + viral 1 5 1 Other 1 5 1 Intraoperative need of inotropic amines 9/2 27/17 0.3 (yes/no) MELD score (mean±SD) 20.89±5.21 23.4±6.8 0.5 MELD Na+ score (mean±SD) 24.11±5.1 26.6±4.39 0.5 Child-Pugh score A 0 2 1 B 5 12 0.3 C 6 30 0.5 Pretransplant hepatic encephalopathy 10/1 26/18 0.07 (yes/no) Immunosuppressive agent (Cya/FK506) 6/5 12/32 0.1 Time in ICU stay, days (mean±SD) 30.8±15.8 11.6±28.6 0.03 Cya, cyclosporine; FK506, tacrolimus; ICU, intensive care unit.
Clinical manifestations were consistent with the classic description of the disease: drowsiness and stupor were reported in six of 11 patients (54.5%) and coma in four of 11 patients
1259
(36.3%); three patients experienced seizures (27.2%), without demonstrated underlying infection or peaks in serum levels of calcineurin inhibitor (CNI). Most patients presented severe muscle strength deficits (especially patients with EPM), which resulted in flaccid hemiplegia and quadriplegia in two patients; in more than half of patients (7/11, 63.6%), dysarthria was reported. Median intensive care unit stay for CPM/EPM patients was 18 days. Risk Factors for CPM/EPM
Risk factors for the development of CPM/EPM were compared between patients and the control group without myelinolysis (Table 2). Central pontine and extrapontine myelinolysis patients experienced a significantly higher perioperative Na+ variations in 24 hr compared to transplanted controls (mean±SD Na+ changes: 16.69±5.17 vs. 9.8±3.4 mEq/L, P = 0.001), but no difference in preoperative Na+ serum values was found between the two groups (132.4±7.6 vs. 134±5.2 mEq/L, P = 0.4). Central pontine and extrapontine myelinolysis patients reached perioperative maximum peak Na+ serum value significantly higher than controls before the onset of neurologic symptoms (151.5±3.3 vs. 140.8±6.2 mEq/L, P =
Risk Factors for Central Pontine and Extrapontine Myelinolysis After Liver Transplantation: A Single-Center Study Chiara Crivellin,1 Annachiara Cagnin,2,3 Renzo Manara,4 Patrizia Boccagni,5 Umberto Cillo,5 Paolo Feltracco,6 Stefania Barbieri,6 Alberto Ferrarese,1 Giacomo Germani,1 Francesco Paolo Russo,1 Patrizia Burra,1 and Marco Senzolo1
Background. Central pontine and extrapontine myelinolysis (CPM/EPM) are severe neurologic complications after liver transplantation. Methods. The present work retrospectively evaluated single-center prevalence of CPM/EPM and associated risk factors: cause of liver disease, hepatic encephalopathy, preoperative, intraoperative, and perioperative blood components use, serum levels, and variation of Na+, Cl−, and K+ and immunosuppression were compared between CPM/EPM patients and control group of transplanted patients without neurologic complications. Results. Among 997 transplants, CPM/EPM were diagnosed in 11 patients (1.1%), of whom four were CPM, one was EPM, and six were associated CPM and EPM. Control group consisted of 44 transplanted patients. Central pontine and extrapontine myelinolysis patients experienced higher intraoperative and perioperative serum Na+/24 hr variations compared to controls (16.69±5.17 vs. 9.8±3.4 mEq/L, P = 0.001). Maximum peak of intraoperative or perioperative serum Na+ was significantly higher in patients compared to controls (151.5±3.3 vs. 140.8±6.2 mEq/L, P≤0.001), but no difference in preoperative serum Na+ was detected. Three patients presented hypernatremia as isolated risk factor. Conclusion. Extrapontine myelinolysis can be found isolated or associated with CPM in up to two of three liver transplanted patients with myelinolysis. A marked variation of perioperative serum Na+ remains the main risk factor even in patients without preexisting hyponatremia; however, isolated hypernatremia may be solely responsible in some cases.
(Transplantation 2015;99: 1257–1264)
C
entral pontine myelinolysis (CPM) is a clinical syndrome first reported in 1959 by Adams et al.1 and described as a demyelinating disorder affecting the central pons, typically in malnourished, alcoholic, and chronically debilitated patients. The original clinical description included rapidly evolving quadriplegia, dysarthria, dysphagia, and mutism. The definition of CPM evolved over the years, and the fact that the demyelinating lesions were not confined to the pons, but could also affect basal ganglia, thalamus, lateral Received 30 April 2014. Revision requested 19 May 2014.
geniculate body, and so on, led to the definition in 1962 of extrapontine myelinolysis (EPM). Categories at risk of developing demyelinating disorders also evolved over time, including septic, burn, diabetic, human immunodeficiency virus, and liver transplanted patients. These categories of patients were all linked by the presence of electrolyte imbalances (especially hyponatremia) and a possible too rapid correction thereof. Patients affected by hepatic insufficiency are particularly prone to the development of myelinolysis because of several factors, such as malnutrition, alcohol abuse and frequent
Accepted 2 September 2014. 1
Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua, Italy.
2 Department of Neurosciences, Sciences NPSRR, University Hospital of Padua, Padua, Italy. 3
IRCCS San Camillo Foundation, Venice, Italy.
4
Department of Neuroradiology, University of Salerno, Salerno, Italy.
5
Hepatobiliary Surgery and Liver Transplant Center, University Hospital of Padua, Padua Italy. 6
Operative Unit of Anesthesia and Intensive Care, Department of Medicine, University Hospital of Padua, Padua, Italy. The authors declare no funding or conflicts of interest. C.C. participated in research design, performance of the research, data analysis, and writing of the article. A.C. participated in research design, performance of the research and in data analysis. R.M. participated in research design, performance of the research
Transplantation
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June 2015
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Volume 99
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Number 6
and in data analysis. P.B., U.C., P.F., and S.B. participated in research design and in data analysis. A.F. participated in performance of the research, data analysis, and writing of the article. F.P.R., G.G., and P.B. participated in research design, performance of the research and in data analysis. M.S. participated in research design, performance of the research, data analysis, and writing of the article. All authors have contributed to, read, and approved the article. Correspondence: Marco Senzolo, M.D., Ph.D., Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, Padua, Italy. ([email protected]). Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9906-1257 DOI: 10.1097/TP.0000000000000496
www.transplantjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Transplantation
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June 2015
■
Volume 99
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Number 6
chronic hyponatremia. Patients with hepatic encephalopathy present marked depletion of myoinositol, which, together with other organic osmolytes, protects the brain from rapid changes in serum osmolality. Chronic liver disease also leads to a negative nitrogen balance, which reduces the availability of the pool of amino acids necessary for the synthesis of organic osmolytes.2 Moreover, liver dysfunction entails a depletion of glycogen brain reserves: glial cells need glucose to activate the Na+-K+ ATP-ase, thus, in the absence of reserves, even small electrolyte imbalances can lead to energy depletion and cellular death.3 Central pontine myelinolysis was first described after liver transplantation by Starzl et al. in 1978.4 It is one of the most serious neurologic complications after liver transplantation and the incidence varies from 0.94% to 3% in current clinical series5,6 (Fig. 1). Most cases of CPM/EPM (90%) occur within the first week after surgery and in another cohort more than 50% of neurologic symptoms—varying from stupor to locked-in syndrome - appear within the 7th postoperative day.6 Liver transplantation is burdened by frequent osmotic and electrolyte imbalances. Intraoperatively, an abundant infusion of sodium-rich fluids is often necessary to replace blood loss, but the ability of sodium renal excretion is impaired in cirrhotic patients.
www.transplantjournal.com
Since 1978, 163 cases of CPM/EPM developed after liver transplantation in adults have been reported. However, limited data on the risk factors of this condition in liver transplantation have been evaluated.
RESULTS Clinical Characteristics of the CPM/EPM Group
Between November 1990 and June 2011, 997 adult patients underwent liver transplantation at the Padua University Liver Transplant Center. One hundred forty (14%) patients developed postoperative neurologic complications and were evaluated by neurologists. In 11 patients (9 males, 2 females; mean±SD age, 53.6±8.8 years) CPM or EPM (four CPM, one EPM, and six mixed CPM/EPM) were diagnosed after liver transplantation; clinical signs and symptoms of CPM/ EPM occurred in patients after a mean±SD interval time of 6.9±2.5 days after liver transplantation. The incidence of myelinolysis was 1.1%. The control group included 44 liver transplanted patients (26 males, 18 females; mean±SD age, 51.8±9.1 years), without neurologic complications. Patients’ and controls’ clinical findings are summarized in Table 1 (Table S1, SDC, http://links.lww.com/TP/B83).
FIGURE 1. MRI, fluid attenuated inversion recovery axial images of the pons (A) and the corresponding magnification (B). The images showed the symmetric signal alteration in the basis pontis, with a “trident” shape, typical of central pontine myelinolysis. MRI, magnetic resonance imaging.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Crivellin et al
© 2014 Wolters Kluwer
TABLE 1.
Clinical characteristics of transplanted patients with CPM and/or EPM and transplanted controls without neurologic complications CPM/EPM
Controls
P
Number 11 44 Age, yr (mean±SD) 53.64±8.83 51.83±9.15 0.6 Sex (M/F) 9/2 26/18 0.1 Underlying liver disease Alcoholic 2 9 1 Viral 7 25 0.3 Alcoholic + viral 1 5 1 Other 1 5 1 Intraoperative need of inotropic amines 9/2 27/17 0.3 (yes/no) MELD score (mean±SD) 20.89±5.21 23.4±6.8 0.5 MELD Na+ score (mean±SD) 24.11±5.1 26.6±4.39 0.5 Child-Pugh score A 0 2 1 B 5 12 0.3 C 6 30 0.5 Pretransplant hepatic encephalopathy 10/1 26/18 0.07 (yes/no) Immunosuppressive agent (Cya/FK506) 6/5 12/32 0.1 Time in ICU stay, days (mean±SD) 30.8±15.8 11.6±28.6 0.03 Cya, cyclosporine; FK506, tacrolimus; ICU, intensive care unit.
Clinical manifestations were consistent with the classic description of the disease: drowsiness and stupor were reported in six of 11 patients (54.5%) and coma in four of 11 patients
1259
(36.3%); three patients experienced seizures (27.2%), without demonstrated underlying infection or peaks in serum levels of calcineurin inhibitor (CNI). Most patients presented severe muscle strength deficits (especially patients with EPM), which resulted in flaccid hemiplegia and quadriplegia in two patients; in more than half of patients (7/11, 63.6%), dysarthria was reported. Median intensive care unit stay for CPM/EPM patients was 18 days. Risk Factors for CPM/EPM
Risk factors for the development of CPM/EPM were compared between patients and the control group without myelinolysis (Table 2). Central pontine and extrapontine myelinolysis patients experienced a significantly higher perioperative Na+ variations in 24 hr compared to transplanted controls (mean±SD Na+ changes: 16.69±5.17 vs. 9.8±3.4 mEq/L, P = 0.001), but no difference in preoperative Na+ serum values was found between the two groups (132.4±7.6 vs. 134±5.2 mEq/L, P = 0.4). Central pontine and extrapontine myelinolysis patients reached perioperative maximum peak Na+ serum value significantly higher than controls before the onset of neurologic symptoms (151.5±3.3 vs. 140.8±6.2 mEq/L, P =
