The reversibility of minimal hepatic encephalopathy (MHE) after successful liver transplantation (LT) has been an object of great interest in the past 10 years. A large body of evidence, derived from different approaches (psychometric tests, psychophysiological measures, and, most recently, magnetic resonance imaging), has consistently indicated that transplantation improves those cognitive functions, which had previously deteriorated during the course of chronic liver disease. These improvements occur notwithstanding the seriousness of the surgery, perioperative complications, and the neurotoxicity of the immunosuppression therapy (1, 3–5). This enhancement is already significantly pronounced in the immediate period after LT, especially for some cognitive functions (e.g., visuospatial attention), whereas it is slower for others (e.g., verbal and visual memory). However, at least in the first 2 years after LT, some cognitive defects seem to persist to some degree, and this is evident especially for supramodal nonverbal neuropsychological functions such as spatial planning intelligence (2, 6) and visuomotor skills (7). Thus, the complete reversibility of MHE still remains an open question. One aspect, which currently remains poorly documented, is the effects of successful LT on cognitive function after more than 5 years since surgery. Several questions remain unaddressed: do the improvements observed in the perioperative period and in the following 2 years fluctuate or remain stable in the long term? Over many years, do the functions that have been found defective also improve? Is the neuropsychological outcome hampered by aging and comorbidities?
To address these questions, more than 5 years (7–10 years) after LT, we decide to recall patients previously included in a prospective study, for which results have been already formerly published (2) for a further neuropsychological evaluation.
Of the 12 patients who completed the T3 follow-up, 2 were women. The mean age of the whole sample at T3 was 52.75±9.31 (range 39–64) years. Ten patients did not show any neurological dysfunction at the time of the psychometric evaluation, two patients (one woman) presented mild bilateral hand tremor, due, most likely, to both metabolic and iatrogenic factors. The immunosuppression therapy was based on cyclosporine (eight patients), tacrolimus (three patients), or sirolimus (one patient).
For concision, most F values of factors not reaching statistical significance were not reported. Scores (mean±standard deviation) and results obtained from pair-wise comparisons regarding each psychometric test are reported in Table 1. To explore differences with the T3 follow-up, we also examined the pair-wise comparison in the single psychometric test that does not reach a significant difference on multivariate or univariate analyses.
A significant effect of time was observed on visuospatial attention, F(12,96) 1.70, P=0.04, ηp2=0.20; selective attention, F(6,66) 3.51, P=0.005, ηp2=0.25; verbal short-term memory, F(3,33) 3.69, P=0.038, ηp2=0.25; visuospatial short-term memory, F(6,64) 2.97, P=0.013, ηp2=0.22; verbal learning, F(12,71) 2.82, P=0.003, ηp2=0.29; visuospatial learning, F(6,66) 5.48, P=0.001, ηp2=0.34; language, F(6,60) 1.98, P=0.082, ηp2=0.17; digit symbol substitution (DSS), F(3,33) 25.07, P=0.001, ηp2=0.69; and spatial planning intelligence (i.e., Elithorn), F(3,33) 7.42; P=0.002, ηp2=0.40.
The Separate Univariate Test showed a significant effect of Time on the following psychometric tests: Visual Matrices (VM), F(3,33) 4.72, P=0.02, ηp2=0.30; Stroop Time, F(3,33) 5.11, P=0.018, ηp2=0.32; Stroop Error, F(3,33) 4.15, P=0.04, ηp2=0.27; Corsi's Test, F(3,33) 3.18, P=0.051, ηp2=0.23; Rey Auditory Verbal Learning Test immediate, F(3,33) 6.37; P=0.004, ηp2=0.39; Rey Auditory Verbal Learning Test 15-min delay recall, F(3,33) 7.25; P=0.003, ηp2=0.42; SupraSpan, F(3,33) 9.93, P=0.001, ηp2=0.47; and FAS, F(3,33) 3.52, P=0.038, ηp2=0.26.
In this study, we examined the long-term effects of successful LT on cognitive functions. Thus doing, we updated previous data already published (2), adding a further assessment 7 to 10 years after LT.
The previous study primarily suggested that the improvement in cognitive performance after LT is not generalized to all cognitive functions. More precisely, in our patients, we found that visuospatial attention and learning ability, as expressed by the DSS test, already showed an improvement in the immediate period after LT and remained stable until the subsequent 18-month follow-up. With regard to selective attention, verbal and visuospatial memory, and verbal fluency, the improvement was slower and noteworthy after 18 months from LT. The results obtained in the extended period follow-up (i.e., this study) primarily suggest that the improvements achieved in the first 2 years after transplantation remain stable during the next 7 to 10 years, especially for visuospatial and selective attention. Furthermore, these findings also seem to suggest an improvement in supramodal cognitive functions, such as spatial planning intelligence (measured by the Elithorn Maze Test), which seemed to persist to some degree during the first 2 years after LT. On the other hand, visuospatial short-term memory and verbal learning, even with a normal score, show a more fluctuating trend over time, probably because of aging-related factors than the persistence of MHE. However, we must be careful not to draw any firm conclusions, because our study does not provide any direct comparison with healthy subjects. Further caution is suggested by the possible immunosuppression-related interactions on cognitive functions. As is known, immunosuppressive agents—especially cyclosporine and tacrolimus—entail a nonnegligible risk of neurotoxicity, which mostly involves the central nervous system. Clinical manifestations often include a diffuse encephalopathy, accompanied by cognitive and behavioral derangement (8). In our sample, we observed favorable early and late effects of LT on cognitive functions, despite the use of cyclosporine or tacrolimus in all but one patient. A recent study by Garcia Martinez et al. (5) reporting a cognitive improvement 9 years after transplantation supports our findings.
Future studies are needed to include a wider sample of patients, possibly with homogeneous immunosuppressive therapy. Keeping these limitations in mind when interpreting the results, these findings seem to suggest that LT, despite the seriousness of the surgery, the perioperative complications, and the neurotoxicity of the immunosuppression therapy, is able to significantly improve patients' cognitive function in the long term.
MATERIALS AND METHODS
We assessed 12 patients from a cohort of 13 patients previously included in a prospective study, the results of which have already been published (2), where patients had undergone clinical and neuropsychological examination before and two times after LT (at 6 and 18 months). One patient was not included because of death after a relapse of hepatitis C, 5 years after surgery. A follow-up addendum was requested and approved by the institutional review board of the LT committee of the Hospital. Once more, patients gave their informed consent to participate. See Figure 1 for the study design and the participants progress through the study.
The assessment took place 7 to10 years after LT (T3). We administered the same psychometric tests used in the previous study (2). Specifically, we investigated the cognitive functions listed below.
- Attention: (a) visuospatial attention was examined by (i) VM (9) and (ii) Cross Out A Test, which are two measures of selective attention based on a visual search task and by (iii) Trail Making A and B (10), which assess spatial planning ability based on a visual motor task; (b) selective attention was assessed by Stroop Test (11), which asses the ability to select relevant information for the task and simultaneously inhibit task-irrelevant automatic response.
- The measures of Stroop Test, Trail Making A and B, and Cross Out A Test are computed on reversed scale, in which low values indicate the best function; in VM tests, a high value is a sign of good functioning.
- Memory: (a) verbal short-term memory was examined by Digit-Span (12), which assesses verbal memory span by means of a number sequence to repeat; (b) Visuospatial Short-Term Memory was evaluated by (i) Corsi's Test (9) and (ii) Immediate Visual Memory Test (9), which assess the amount of visual spatial information that an individual can retain; (c) Verbal Learning was investigated by (i) Rey Auditory Verbal Learning Test, immediate and 15-min delay recall (13), (ii) Brief Story (9), and (iii) Paired Associate Learning (14), which are tests based on learning of verbal stimuli, such as simple words or association of words, and more complex stimuli such as story; and (d) Visuospatial Learning was assessed by (i) Rey-Osterrieth Complex Figure Recall Trial (15) and (ii) Supraspan Learning (9), which are memory tasks based on learning of visual stimuli such as visual sequence to be repeated or complex figures to draw.
- Language was examined by (i) Word Fluency—FAS—(13), which consists of saying as many words as possible beginning with a precise letter and (ii) Phrase Construction (PC) test (13), which consists of constructing phrase meanings with provided words.
- Visuospatial-Constructional Skills were examined by a (i) Copy of Rey-Osterrieth Complex Figure and (ii) Painting Copy and Painting Copy with Facilities (13).
- Motor speed was assessed using DSS (16), which consists of nine digit-symbol pairs followed by a list of digits, requiring patients to write down the corresponding symbol as fast as possible.
- Spatial planning intelligence was investigated by Elithorn's Maze Test (9), which consists of tracing a path as quickly as possible, using a pencil and paper and in accordance with given rules.
All tests are well-validated psychometric instruments. When needed, scores were corrected for age, sex, and education.
Eight separate one-way multivariate analysis of variance (one for each cognitive domain) and two separate analysis of variance (for data derived from DSS Test and Elithorn Maze Test) were performed taking “Time” (T0 vs. T1 vs. T2 vs. T3) as a within-subjects factor. Contrasts were made to characterize the effect of time, with particular attention to the comparison with T3 (i.e., the post 7–10 years follow-up after LT). Bonferroni's confidence interval adjustment (0.05/n) correction was applied when appropriate.
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