LIVER TRANSPLANTATION 20:977–986, 2014
ORIGINAL ARTICLE
Cognitive Impairment and Electroencephalographic Alterations Before and After Liver Transplantation: What Is Reversible? Francesca Campagna,1 Sara Montagnese,1,2 Sami Schiff,1,2 Anna Biancardi,1 Daniela Mapelli,2,3 Paolo Angeli,1 Carlo Poci,1 Umberto Cillo,4 Carlo Merkel,1 Angelo Gatta,1,2 and Piero Amodio1,2 1 Department of Medicine, 2Interdepartmental Center of Neuropsychiatric Research in Clinical Medicine, 3 Department of General Psychology, and 4Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy
The influence of liver transplantation (LT) on mental performance is debated, as is the role of pretransplant overt hepatic encephalopathy (OHE). The aim of this study was to evaluate the time course of the neuropsychological and electroencephalogram (EEG) features of patients with cirrhosis before and after LT with respect to prior OHE. The study population included 65 patients with cirrhosis on the transplant waiting list; 23 had a history of OHE. Each patient underwent an extensive psychometric assessment (10 tests, including paper and pencil tests and a computerized test) and an EEG before and 9 to 12 months after LT. For a subgroup of 11 patients, the assessment was also performed 3 and 6 months after LT. EEGs were analyzed spectrally, and the mean dominant frequencies were obtained. Both psychometric tests and EEGs improved 9 to 12 months after LT. Patients with a history of OHE before LT had worse cognitive performances (P < 0.001) and EEG performances in comparison with their counterparts with a negative history. They also showed greater cognitive improvement after LT (P < 0.01); however, their global cognitive performance remained slightly impaired (P < 0.01). After LT, EEGs normalized for 98% of the patients (P < 0.01), regardless of any history of OHE. In the subgroup of patients evaluated every 3 months, psychometric and EEG findings showed deterioration at 3 months and subsequently steady improvements from 6 months onward. In conclusion, both neuropsychological and EEG performances had significantly improved 1 year after LT. Patients with a history of OHE showed greater improvements after LT than patients with a negative history, but their global cognitive function C 2014 AASLD. remained slightly worse; in contrast, EEGs normalized in both groups. Liver Transpl 20:977-986, 2014. V Received December 12, 2013; accepted April 26, 2014.
See Editorial on Page 874 Approximately 30% to 45% of patients with cirrhosis develop at least 1 episode of overt hepatic encephalopathy (OHE) while they are on the waiting list for liver
transplantation (LT).1,2 Patients without OHE may have mild cognitive alterations that qualify as minimal hepatic encephalopathy (MHE). MHE predicts the development of OHE3 and impinges on work and social functioning.4,5 Generally, LT is thought to resolve cognitive deficits due to hepatic encephalopathy (HE), but both new neurological diseases6 and an incomplete reversal
Abbreviations: DZPSI, change in mean Z psychometric index; DS, Digit Span; DSRM, Delayed Story Recall Memory; EEG, electroencephalogram; HE, hepatic encephalopathy; ISRM, Immediate Story Recall Memory; ITM10, Memory with Interference Task at 10 Seconds; ITM30, Memory with Interference Task at 30 Seconds; LT, liver transplantation; MDF, mean dominant frequency; MELD, Model for End-Stage Liver Disease; MHE, minimal hepatic encephalopathy; OHE, overt hepatic encephalopathy; PVF, Phonemic Verbal Fluency; SDT, Symbol Digit Test; TMT, Trail Making Test; ZPSI, mean Z psychometric index. The authors have no conflicts of interest to declare. This study was supported by institutional funding (University of Padua) for Piero Amodio. Address reprint requests to Francesca Campagna, M.D., Department of Medicine, University of Padua, Via Giustiniani 2, 35128 Padua, Italy. Telephone: 139 049 8218675; FAX: 139 049 8218292; E-mail:
[email protected] DOI 10.1002/lt.23909 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
978 CAMPAGNA ET AL.
Figure 1.
LIVER TRANSPLANTATION, August 2014
Study profile. The flow diagram shows screened, included, and excluded patients.
of preexisting dysfunction can occur. It has been suggested that cognitive dysfunction after LT could be related to prior HE, anoxic/ischemic brain damage during surgery, osmotic myelinolysis, immunosuppressant toxicity, liver disease recurrence, comorbidities, and other metabolic alterations.7 Several studies have demonstrated substantial improvements in neuropsychological tests8,9 and quality of life10 after LT. Other studies have demonstrated improvements in cerebral function after LT with proton magnetic resonance imaging spectroscopy,11 positron emission tomography,12 and electroencephalograms (EEGs).1 Neuroimaging studies also support these findings.13 However, a number of studies have documented the persistence of various cognitive deficits within the months after LT.14,15 Only a few studies have analyzed the relationship between neuropsychological alterations and relevant presurgical variables to identify factors that place LT recipients at higher risk for cognitive dysfunction. Sotil et al.15 showed that transplant patients with a history of HE had worse neuropsychological performance as measured by the psychometric HE score and a lower critical flicker frequency in comparison with patients without a history of HE 18 months after LT. Therefore, it seems important to identify MHE in patients awaiting LT for the proper interpretation of disorders occurring after transplantation. Assuming that residual cognitive deficits after LT may reflect the extent of pretransplant morbidity, we performed a prospective study evaluating the time course of the neuropsychological and EEG features of patients with cirrhosis before and after LT with respect to prior episodes of OHE.
PATIENTS AND METHODS Patients The present study consisted of a prospective assessment of neuropsychological and neurophysiological function before and after LT. Two hundred seventyeight consecutive patients with liver cirrhosis were evaluated for HE between September 1998 and October 2006 at the tertiary referral center of Padua University Hospital; 246 were placed on the waiting list for LT. Twenty-eight of these patients died on the waiting list, and 91 successfully underwent transplantation. Ten of these 91 patients died during the first year after LT (including 6 within 1 month because of sepsis and 2 between 6 and 9 months because of cardiovascular events). Nine patients were lost to follow-up, and 7 were excluded (2 for active alcohol misuse, 3 for the recurrence of liver disease, and 2 for cerebrovascular events immediately after LT). Sixty-five patients, including 54 males (mean age 5 51 6 8 years), were finally included (Fig. 1). Before LT, patients were excluded if they had severe renal failure, were on psychoactive drugs, had misused alcohol during the previous 6 months, were not able to perform psychometric tests, or had a current or previous significant neurological comorbidity (except for HE) such as a cerebrovascular event, dementia, or Parkinson’s disease. After LT, patients were excluded for any of the following: recurrence of severe liver disease, relapse into alcohol misuse, use of psychoactive drugs, cerebrovascular events, pontine myelinolysis, and central nervous system infections.
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TABLE 1. Demographic, Clinical, and Biochemical Characteristics of the Total Sample of Patients Studied Before LT and According to the History of Previous Episodes of OHE
Demographics Age (years)* Sex: male/female (%) Etiology of cirrhosis [n (%)] Virus-related Alcohol Mixed Other Child-Pugh class [n (%)] A B C MELD score* Ascites rating [n (%)] None Mild/moderate Severe Aspartate aminotransferase (IU/L)* Total bilirubin (mg/dL)* Albumin (mg/dL)* Prothrombin time (%)* Creatinine (mg/dL)* Glucose (mmol/L)* Sodium (mEq/L)* Previous episodes of OHE (n) 1 2
Total Sample
Prior OHE
No Prior OHE
(n 5 65)
(n 5 23)
(n 5 42)
P Value
51 6 8 83/17
51 6 8 87/13
50 6 9 82/18
0.53 0.64 0.08
38 (58) 13 (20) 9 (14) 5 (8)
11 (48) 4 (17) 7 (30) 1 (5)
27 (64) 9 (21) 2 (5) 4 (10)
4 (6) 55 (85) 6 (9) 11 6 5
2 (9) 18 (78) 3 (13) 11 6 4
2 (5) 37 (88) 3 (7) 11 6 6
37 (57) 20 (31) 8 (12) 80 6 44 4.4 6 4.8 31.2 6 4.7 58 6 17 1 6 0.3 6.6 6 4.5 137 6 6 23 11 12
14 (61) 6 (26) 3 (13) 79 6 47 4.4 6 3.2 31 6 3.9 56 6 17 1 6 0.3 6.8 6 5.6 137 6 5
23 (55) 14 (33) 5 (12) 81 6 42 4.2 6 4.7 31 6 5.8 59 6 15 1 6 0.3 6.5 6 3.8 138 6 4
0.44
0.59 0.57
0.8 0.82 0.83 0.6 0.63 0.87 0.5
*The data are presented as means and standard deviations.
To assess the role of previous HE in the posttransplant cognitive profile, the following variables were collected: the number of OHE episodes and the HE grade according to the West Haven criteria.16 Model for End-Stage Liver Disease (MELD) scores were calculated at the time of neuropsychological and neurophysiological investigations before LT. The indication for LT was end-stage liver disease in 52 patients (80%) and hepatocellular carcinoma in 13 patients (20%). Immunosuppressive therapy at the time of the post-LT assessment was tacrolimus as monotherapy (n 5 34; dose 5 4 6 3 mg/day) or in association with mycophenolate mofetil (n 5 23; dose 5 1000 mg/day) or cyclosporine (n 5 8; dose 5 180 6 47 mg/day). Patients who completed the post-LT evaluation had good liver function (aspartate aminotransferase 5 50.4 6 78 IU/L, total bilirubin 5 0.9 6 0.5 mg/dL, albumin 5 41.3 6 7.3 mg/dL, prothrombin time 5 82% 6 16%) and renal function (creatinine 5 1.2 6 0.3 mg/ dL). The protocol was approved by the hospital ethics committee. All participating subjects provided written, informed consent. The study was conducted according to the Declaration of Helsinki (Hong Kong amendment) and Good Clinical Practice (European) guidelines.
Methods All patients underwent an extensive neuropsychological evaluation and EEG spectral analysis 2 to 8 months before LT and 9 to 12 months after LT. Furthermore, for a subgroup of 11 patients, the measures were also performed 3 and 6 months after LT so that we could evaluate the time course of the psychometric and EEG findings. The demographic and clinical characteristics of the included patients are presented in Table 1.
Neuropsychological Assessment All patients underwent a neuropsychological assessment comprising (1) an extensive paper and pencil psychometric battery and (2) the computerized scan test. Each patient was assessed individually by an experienced neuropsychologist (S.S. or M.D.) for approximately 2 hours. The psychometric test battery comprised the following paper and pencil tests: Trail Making Test A (TMT A), TMT B, Digit Span (DS), Phonemic Verbal Fluency (PVF), Symbol Digit Test (SDT), Memory with Interference Task at 10 Seconds (ITM10), Memory with
Executive function
Memory
NOTE: The data are presented as numbers and percentages of patients with altered tests.
P Value
0.22 0.89
