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Persistence of Cognitive Impairment After Resolution of Overt Hepatic Encephalopathy

Published:February 22, 2010DOI:https://doi.org/10.1053/j.gastro.2010.02.015

      Background & Aims

      In patients with cirrhosis, hepatic encephalopathy (HE) has acute but reversible as well as chronic components. We investigated the extent of residual cognitive impairment following clinical resolution of overt HE (OHE).

      Methods

      Cognitive function of cirrhotic patients was evaluated using psychometric tests (digit symbol, block design, and number connection [NCT-A and B]) and the inhibitory control test (ICT). Improvement (reduction) in ICT lures and first minus second halves (ΔL1–2) were used to determine learning of response inhibition. Two cross-sectional studies (A and B) compared data from stable cirrhotic patients with or without prior OHE. We then prospectively assessed cognitive performance, before and after the first episode of OHE.

      Results

      In study A (226 cirrhotic patients), 54 had experienced OHE, 120 had minimal HE, and 52 with no minimal HE. Despite normal mental status on lactulose after OHE, cirrhotic patients were cognitively impaired, based on results from all tests. Learning of response inhibition (ΔL1–2 ≥1) was evident in patients with minimal HE and no minimal HE but was lost after OHE. In study B (50 additional patients who developed ≥1 documented OHE episode during follow-up), the number of OHE hospitalizations correlated with severity of residual impairment, indicated by ICT lures (r = 0.5, P = .0001), digit symbol test (r = −0.39, P = .002), and number connection test-B (r = 0.33, P = .04). In the prospective study (59 cirrhotic patients without OHE), 15 developed OHE; ICT lure response worsened significantly after OHE (12 before vs 18 after, P = .0003), and learning of response inhibition was lost. The 44 patients who did not experience OHE did not have deteriorations in cognitive function in serial testing.

      Conclusions

      In cirrhosis, episodes of OHE are associated with persistent and cumulative deficits in working memory, response inhibition, and learning.

      Keywords

      Abbreviations used in this paper:

      ICT (inhibitory control test), ΔL1–2 (lures on the first half of ICT minus those in the second half), HE (hepatic encephalopathy), MELD (Model for End-Stage Liver Disease), SONIC (spectrum of neurocognitive impairment in cirrhosis), TIPS (transjugular intrahepatic portosystemic shunting)
      Minimal and overt hepatic encephalopathy are constituents of the spectrum of neurocognitive impairment in cirrhosis (SONIC).
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      • Wade J.B.
      • Sanyal A.J.
      Spectrum of neurocognitive impairment in cirrhosis: implications for the assessment of hepatic encephalopathy.
      Minimal hepatic encephalopathy (HE) is defined by impaired performance on psychometric or neurophysiologic testing, despite normal mental status.
      • Ortiz M.
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      • Cordoba J.
      Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations.
      In minimal HE, therapy with agents such as lactulose can completely correct the cognitive abnormalities.
      • Prasad S.
      • Dhiman R.K.
      • Duseja A.
      • et al.
      Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy.
      Patients with minimal HE are at increased risk of developing overt HE, characterized by a rostrocaudal progression of symptoms from deficits in attentiveness that may progress to lethargy, asterixis, disorientation, agitation, stupor, and coma. Whereas mental status changes in overt HE improve after treatment, there is some evidence that the metabolic insult associated with overt HE may lead to chronic neurologic injury that is not readily reversible.
      • Sotil E.U.
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      • Ayala E.
      • et al.
      Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.
      Structural “dementia-like” features have been reported in patients with prior overt HE episodes, accompanied by pathologic evidence of neuronal death. Patients with prior overt HE also have a higher risk of persistent neurologic impairment after liver transplantation.
      • Sotil E.U.
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      • et al.
      Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.
      • Butterworth R.F.
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      Ammonia: key factor in the pathogenesis of hepatic encephalopathy.
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      However, it is unclear whether cognitive deficits persist after resolution of mental status changes in patients with overt HE.
      In the current study, we have applied a battery of tests of cognitive function to patients with cirrhosis with and without a prior history of overt HE. We find that, with the advent of overt HE, cognitive function is persistently impaired, despite normalization of mental status on lactulose therapy. In particular, learning of response inhibition, as measured using a novel application of the inhibitory control test, is lost in most individuals following the first episode of overt HE. The severity of the persistent impairment increases with the number of episodes of overt HE. These findings are evidence that episodes of overt HE in cirrhosis lead to neurologic injury that is chronic, cumulative, and not readily reversible.

      Patients and Methods

      Subjects for this study included patients with an established diagnosis of hepatic cirrhosis, based on histology or clinical criteria (physical examination and laboratory and imaging findings), who were seen and evaluated in our outpatient clinics in the Medical College of Wisconsin, Virginia Commonwealth University Medical Center, and McGuire VA Medical Center. Patients with prior overt HE were included only if they were receiving appropriate treatment with lactulose and/or rifaximin, were adherent on medications, and had a normal mental status (defined as a mini-mental status examination score >25). All subjects gave informed consent. Demographic data, etiology, Model for End-Stage Liver Disease (MELD) score, and details of complications of cirrhosis were collected. If a patient had a history of overt HE, the time of first overt HE diagnosis, number of episodes that required hospitalization or emergency room visits, details of therapy, and adherence to therapy were investigated and recorded. Patients receiving psychotropic or sedative medications were excluded, as were individuals with known chronic neurologic conditions (cerebrovascular accidents, dementia, Parkinson's disease, and others). Patients who were nonadherent to therapy, actively abusing alcohol or illicit drugs, or without command of the English language also were excluded.
      The study was divided into cross-sectional and prospective arms. In the cross-sectional arm part A, we enrolled 226 patients with hepatic cirrhosis evaluated at the Medical College of Wisconsin and Virginia Commonwealth University. These patients were categorized according to whether or not they had previously experienced episodes of overt HE. Based on a standard cognitive battery, patients without prior overt HE were further characterized as having minimal HE or no minimal HE (normal). In the cross-sectional arm part B, we studied a separate group of 50 patients with cirrhosis who had been followed longitudinally in our clinics and who had experienced one or more well-documented episodes of overt HE. In these patients, severity of cognitive impairment was analyzed with respect to the number, severity, and duration of prior overt HE episodes.
      In the third, prospective, arm, we included 59 cirrhotic patients without prior overt HE at time of study entry who underwent cognitive testing at least twice between July 1, 2007, and October 1, 2009, at the Medical College of Wisconsin, Virginia Commonwealth University Medical Center, and McGuire VA Medical Center. Of these individuals, 15 experienced a first episode of overt HE during follow-up, whereas 44 remained free of it. The results of cognitive testing were evaluated before and after onset of overt HE and were compared with results of repeat cognitive testing in patients who remained free of it.
      All subjects underwent the following test battery
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      • et al.
      Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease.
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      • et al.
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      • et al.
      Neuropsychological characterization of hepatic encephalopathy.
      :
      • 1
        Number connection test-A: patients are asked to “join the dots” from 1 to 25 in a timed manner; this tests for psychomotor speed. Worse performance is indicated by a longer time for completion.
      • 2
        Number connection test-B: this involves joining the dots while alternating between numbers and letters and tests for psychomotor speed, set shifting, and divided attention. Similar to the number connection test-A, longer time required to complete this indicates worse performance.
      • 3
        Digit symbol test: subjects have to accurately and quickly transcribe nonsense symbols corresponding to numbers looking at a key in a timed manner over 2 minutes; this tests for psychomotor speed, attention, and visual memory. The number of correctly transcribed symbols indicates performance, ie, a low score means poor performance.
      • 4
        Block design test: involves constructing designs made from blocks of increasing complexity in a timed manner. The domains of visuomotor coordination, visuospatial reasoning, praxis, and psychomotor speed are tested. The scores are generated based on accurate construction of designs, and a low score again indicates poor performance.
      • 5
        Inhibitory control test (ICT): in this computer-based test, patients are shown a series of letters and are asked to respond by pressing a mouse key when an X is followed by a Y or a Y is followed by an X (alternating presentation, termed targets). Patients are instructed not to respond to X following X or Y following Y (nonalternating presentation, termed lures
        • Bajaj J.S.
        • Hafeezullah M.
        • Franco J.
        • et al.
        Inhibitory control test for the diagnosis of minimal hepatic encephalopathy.
        • Garavan H.
        • Ross T.J.
        • Stein E.A.
        Right hemispheric dominance of inhibitory control: an event-related functional MRI study.
        ). Cognitive functions required to consistently recognize targets include reaction time,
        • Bajaj J.S.
        • Hafeezullah M.
        • Franco J.
        • et al.
        Inhibitory control test for the diagnosis of minimal hepatic encephalopathy.
        whereas avoidance of lures requires response inhibition, attention, and working memory.
        • Bajaj J.S.
        • Saeian K.
        • Schubert C.M.
        • et al.
        Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.
        High lure and low target response indicate poor psychometric performance. The ICT is administered as a practice test followed by a series of 6 similar 2-minute runs, separated by breaks to allow the subjects to rest. Runs I–III (first half) are identical to runs IV–VI (second half). Improvement (ie, reduction) in performance, particularly lure response, may serve as a measure of learning. In this study, we evaluated a novel ICT parameter, the change in lure response between the first and the second half (ΔL1–2) as a measure of learning of response inhibition.
      The mini-mental status examination was also administered to all patients with a history of overt HE, and only those with a score >25 were included for further testing.
      • Folstein M.F.
      • Folstein S.E.
      • McHugh P.R.
      “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician.
      Based on prior control subjects' performances and as recommended by the Working Group on Hepatic Encephalopathy, minimal HE was diagnosed if 2 of the 4 tests (number connection tests A/B, block design, and digit symbol tests) were impaired 2 standard deviations beyond normative performance.
      • Ferenci P.
      • Lockwood A.
      • Mullen K.
      • et al.
      Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.
      Cirrhotic patients without these impairments did not have minimal HE and were termed normal.

       Statistical Analysis

      In part A of the cross-sectional study, results of the psychometric battery in patients without prior overt HE (normal and minimal HE groups) were compared with those of patients with prior HE, using analysis of variance and unpaired t tests. In part B of the cross-sectional study, the psychometric test battery was performed in individuals with a history of one or more episodes of overt HE. The relationship between psychometric test performance and the number of episodes of overt HE, hospitalizations for overt HE, and the duration of time between the first overt HE episode and the time of psychometric testing were evaluated by Pearson correlation.
      In the prospective arm, the psychometric test battery was administered at least twice at intervals of greater than 3 months to individuals who initially were without prior history of overt HE. Changes in psychometric test performance over time were calculated. Patients who were free of overt HE on enrollment and who developed their first overt HE episode during follow-up were compared with patients who remained free of overt HE throughout the test period. Significance of cognitive change over time in each group was assessed using Student t test for paired samples, whereas differences in quantitative change in cognitive performance between groups were assessed using 1-way analysis of variance. All patients with overt HE were outpatients at the time of the psychometric testing. ΔL1–2 was studied before and after the visits and compared within and between groups who did and did not develop overt HE.
      A subgroup analysis of patients with alcoholic vs nonalcoholic etiology of cirrhosis was also performed. A P value of < .05 was considered significant, and all data are displayed as mean ± standard deviation unless otherwise noted. Studies were performed with the approval of the institutional review boards at the Medical College of Wisconsin, Virginia Commonwealth University, and McGuire Department of Veterans Affairs Medical Center.

      Results

      Cross-sectional study part A: Of the 226 patients included, 54 had prior overt HE and 172 did not. Patients without prior overt HE were divided on the basis of the psychometric tests into normal and minimal HE; 52 were normal, and the remaining 120 were minimal HE. The demographic and cirrhosis details are displayed in Table 1. The 54 patients with prior overt HE were currently adherent on lactulose (defined by mini-mental score >25, corroboration of lactulose use by caregivers, and by at least 2 daily bowel movements) were studied. These patients had first experienced overt HE a mean of 12 ± 5 months prior to this study. Because this was a cross-sectional report, the details of their overt HE hospitalization and precipitating factors were not adequately reflected in their retrospective records, necessitating the inclusion of the second overt HE group (cross-sectional study part B) whose episodes had been documented.
      Table 1Baseline and Psychometric Variables in the 3 Groups of Patients With Cirrhosis in the Cross-sectional Study Part A
      Normal cirrhotic patients (n = 52)Minimal HE (n = 120)Overt HE (n = 54)P value of comparison between normal and overt HEP value of comparison between minimal and overt HE
      Age (y)52 ± 255 ± 155 ± 1.23.28
      Education (y)14 ± 214 ± 213 ± 1.14.17
      Etiology of cirrhosis (HCV/alcohol/both/other)38/5/4/580/21/11/839/7/5/3.5.3
      MELD score (median)8910.10.45
      Number connection-A (s)27 ± 838 ± 1545 ± 32.001.22
      Number connection-B (s)75 ± 41115 ± 60131 ± 72.0001.23
      Digit symbol test (raw score)72 ± 1353 ± 1346 ± 18.0001.03
      Block design test (raw score)37 ± 1227 ± 1126 ± 11.0001.80
      ICT lures (number responded out of 40)5 ± 413 ± 713 ± 9.0001.79
      ICT targets (% correct response)98 ± 392 ± 991 ± 10.0001.66
      NOTE. All comparisons between the normal cirrhotic patients and the 2 impaired groups were significant at a level of P < .001. A high score on number connection-A/B and ICT lures and a low digit symbol, block design, and ICT target number indicate poor psychometric performance. Only digit symbol test was significantly more impaired in overt patients compared with those with minimal HE; the rest of the comparison was statistically similar.
      HCV, chronic hepatitis C virus; overt HE, overt hepatic encephalopathy adequately controlled on treatment.
      Cognitive testing: because this was the basis of division, patients with minimal HE were significantly worse on cognitive testing than the normal cirrhotic patients. On all psychometric tests, patients with overt HE performed significantly worse than normal cirrhotic patients despite being on adequate therapy. There was no significant difference between patients with an alcoholic etiology of cirrhosis compared with those without alcoholic liver disease. When the psychometric performance between minimal and overt HE was compared, the digit symbol test was significantly more impaired in overt HE, and there was a learning deficit demonstrated in the overt HE patients with respect to lures (Table 1). Normal cirrhotic patients, as expected, had significant reduction (improvement) in their lure response when the first half was compared with the second half (3.4 ± 2.1 vs 2.1 ± 2, respectively, P = .0001). Interestingly, minimal HE patients also exhibited a significant learning when the lures of the first half were compared with the second half of the ICT (7.2 ± 3.8 vs 5.7 ± 4, respectively, P = .0001). In sharp contrast, patients with overt HE did not have any significant change when the first half was compared with the second half (6.8 ± 4.4 vs 6.3 ± 4.8, respectively, P = .24), indicating lack of learning (Figure 1).
      Figure thumbnail gr1
      Figure 1Learning impairment in patients with cirrhosis and overt hepatic encephalopathy. The first half of the ICT is identical to the second half; therefore, learning capability and working memory can be tested using ICT performance. There was a significant learning effect in normal cirrhotic patients and those with minimal HE but not in overt HE. This indicates a learning impairment in overt HE despite adequate therapy in these patients. A high number of lures indicates poor psychometric performance on the ICT. 1st, Lures in the first half, 2nd, lures in the second half; overt HE, recent overt hepatic encephalopathy controlled on lactulose therapy.
      Cross-sectional study part B: correlation of the additional overt HE group's cognitive performance with number and duration of overt HE episodes: In the 50 additional patients, detailed information on the overt HE episodes was available. The mean age was 56 ± 6 years, and 39 were men. Of the 50 patients, 38 had hepatitis C, 7 had alcoholic liver disease, 4 had both, and 1 had cryptogenic cirrhosis. The mean follow-up duration was 13 ± 12 months. There were a median of 2 episodes of overt HE (range, 1–13) during this period with a median of 1 hospitalization for overt HE (range, 1–7). The precipitating factors for the first hospitalization were infections in 18 (cellulitis in 9, spontaneous bacterial peritonitis in 5, and respiratory infection in 4), transjugular intrahepatic portosystemic shunting (TIPS) placement in 10, medication use in 7 patients (narcotics in 5 and zolpidem in 3), postsurgical in 2, and spontaneous in the rest. Overall, there were 33 patients with more than 1 admission for overt HE. In these patients, the reason for recurrence was most often nonadherence with lactulose (n = 14), infections (n = 7), and spontaneous in the rest. At the time of psychometric testing, of the 50, 11 were only on rifaximin, 7 were on both rifaximin and lactulose, and the rest (32) were only on lactulose. Rifaximin therapy was only initiated if the patient failed or was nonadherent on lactulose. In between episodes, the patients' mental status was normal, and abdominal imaging did not reveal any large shunts in those with recurrent HE episodes.
      Scores on tests were number connection test-A 48 ± 22 seconds, number connection test-B 149 ± 87 seconds, digit symbol test raw score 41 ± 13, block design test raw score 26 ± 15, ICT lures 15 ± 9, and ICT targets (% correct) were 89% ± 12%. Similar to cross-sectional B, these scores were not statistically different between alcoholic and nonalcoholic patients. Psychometric scores were highly correlated with the number of episodes of and admissions for overt HE and the time from first overt HE episode to the testing (Table 2). This was especially true for ICT lures, ICT targets, digit symbol, and number connection test-B, which were significantly correlated with number of admissions for overt HE, number of overt HE episodes, and duration from the first episode of overt HE until testing. Interestingly, number connection test-A and block design tests were not affected by either the number of hospitalizations or overt HE episodes or the duration of overt HE.
      Table 2Correlations Between Overt HE Episodes and Psychometric Tests: Cross-sectional Study Part B
      N = 50Number of hospitalizations for overt HENumber of episodes of overt HEDuration from first episode to testing
      RP valueRP valueRP value
      Number connection-A (s)0.264.1440.218.2380.166.373
      Number connection-B (s)0.353.0470.354.050.158.396
      Digit symbol test (raw score)−0.387.02−0.461.009−0.364.04
      Block design test (raw score)−0.108.631−0.203.378−0.282.292
      ICT lures (number)0.502.0020.591.0010.483.007
      ICT targets (% correct)−0.433.009−0.442.015−0.2.135
      NOTE. In the 50 patients who were followed prospectively for overt HE development, there was a significant correlation among the number of overt HE episodes, number of overt HE hospitalizations, and duration from the first overt HE episode till the testing. A high score on number connection-A/B and ICT lures and a low digit symbol, block design, and ICT target number indicate poor psychometric performance.
      HCV, chronic hepatitis C virus; overt HE, overt hepatic encephalopathy adequately controlled on treatment; R, correlation coefficient.

       Prospective Study

      Patients in the prospective study arm were enrolled to study the natural history of minimal hepatic encephalopathy. A total of 79 patients were enrolled and underwent their first psychometric evaluation. Fifteen did not return for the second scheduled visit because of withdrawn consent or logistical/transport issues, 3 died because of nonhepatic causes, and 2 patients received a liver transplant. The remaining 59 were followed and retested.

       Change Before and After Development of Overt HE

      A total of 15 patients (age, 54 ± 8 years; 12 men, 11 with chronic hepatitis C, 2 with alcoholic liver disease, and 2 with cryptogenic cirrhosis) developed overt HE during the follow-up period, 8 of them after TIPS placement, 5 spontaneously, and 2 after an infection. Five patients (3 post-TIPS and 2 infection-related overt HE) required hospitalization. The rest were diagnosed and treated with lactulose as outpatients, and none required rifaximin therapy. The repeat testing was performed 36 ± 25 days after the overt HE episode when the patients had been treated with lactulose. Overall, the time between the first and the second testing (after the overt HE episode had been treated) was 4 ± 2 months.
      The mean mini-mental status score post-therapy was 27 ± 2, and all patients scored at least 25 on this examination. All patients were adherent on lactulose by history and by corroboration from their relatives.
      The psychometric tests did not change or improve after development of overt HE compared with their preovert HE baseline despite therapy, apart from an increase in the total ICT lures (Table 2). The pattern of change that was seen in overt HE patients in the cross-sectional arm was again seen in prospective study. Similar to the cross-sectional data, patients prior to overt HE development had a significant learning effect, ie, lures in the first half were much higher than in the second half (7.5 ± 5 vs 4 ± 4.3, respectively, P = .0001, Table 3). After development of overt HE and despite adequate therapy, this learning capability disappeared, and ΔL1–2 reduced significantly. This was demonstrated by the similar response to lures in the first half compared with the second half after they developed overt HE (8.7 ± 5 vs 8.1 ± 5, respectively, P = .69, Figure 2). Also corroborating this, there was no significant difference in lures in the first half before or after overt HE development (P = .12), but there was a significantly higher lure rate in the second half after overt HE development compared with preovert HE testing (P = .012). Fourteen of 15 (93%) reduced their lure response from the first half to the second half before overt HE compared with only 4 of 15 (26%, P = .0001, Figure 2A and B). There was no significant difference in the proportion of patients with alcoholic liver disease who worsened their performance (2 of 2) compared with the ones who did not have alcoholic liver disease (12 of 13, P = .9) after overt HE development.
      Table 3Psychometric Test Results of Patients Tested Before and After Development of Their First Episode of Overt HE
      Patients tested before and after development of the first episode of overt HE (n = 15)
      Pre-overt HEPost-overt HE, first episodePaired t test P values (before and after the episode)
      MELD score (median)910.10
      Number connection test-A (s)40 ± 1248 ± 35.33
      Number connection test-B (s)98 ± 22142 ± 98.11
      Digit symbol test (raw score)51 ± 1447 ± 15.21
      Block design test (raw score)29 ± 1333 ± 20.39
      ICT targets (% correct)93 ± 993 ± 11.96
      ICT lures (number responded to)12 ± 818 ± 10.03
      ICT lures (first half: runs I–III)8 ± 59 ± 5.12
      ICT lures (second half: runs IV–VI)4 ± 4
      P = .00001 in the first half compared with the second half indicating successful learning.
      8 ± 5.012
      ΔL1–23.10.3.01
      NOTE. There was a significant worsening of ICT lures after development of overt HE and the learning effect on the ICT, which was present before overt HE disappeared. A high score on number connection-A/B and ICT lures and a low digit symbol, block design, and ICT target number indicate poor psychometric performance.
      Overt HE, overt hepatic encephalopathy adequately controlled on treatment.
      a P = .00001 in the first half compared with the second half indicating successful learning.
      Figure thumbnail gr2
      Figure 2Change in lure performance on the ICT in patients before and after the development of overt hepatic encephalopathy. (A) There was a significant improvement in lures before overt HE development. (B) After those patients developed overt HE, this learning effect on lures disappeared. Fourteen of 15 (93%) patients were able to learn the ICT before developing overt HE, whereas only 4 (26%) were able to reduce their lures once they developed overt HE (P = .0001). I–III lures, lures in the first half of the ICT; IV–VI lures, lures in the second half of the ICT; OHE, overt hepatic encephalopathy controlled on lactulose therapy.

       Change in Psychometric Tests in Cirrhotic Patients Who Did Not Develop Overt HE

      There were 44 patients who were tested twice 4.2 ± 2 months apart while they remained free of overt HE. These patients were similar in age to the above group and had a mean age of 56 ± 5 years. There were 38 men, and the leading etiology of cirrhosis was chronic hepatitis C infection (n = 30); the rest had alcoholic liver disease (n = 7) and cryptogenic cirrhosis or nonalcoholic steatohepatitis (n = 7). These patients did not have any episodes of overt HE, infections, variceal bleeding, changes in mental status, or initiation of psychotropic medications, TIPS placement, or significant change in MELD score in between the 2 visits. There were no differences in any of the psychometric tests between these 2 visits in any of the patients. The learning effect on lures was maintained in both visits (ie, number of lures in the first half was significantly higher than the second half, Table 4). This indicates that, in patients with no change in clinical status, their psychometric performance remains stable in minimal HE over time. Comparisons between those with alcoholic vs nonalcoholic liver disease regarding all psychometric tests between the 2 visits were not significant. This is in contrast with the patients who develop overt HE, in which there are changes in learning capacity and working memory even after 1 episode of overt HE despite complete resolution of mental status abnormalities.
      Table 4Results of Repeat Testing in Patients Undergoing Psychometric Evaluation Twice Without Interval Development of Overt HE
      Patients tested twice without interval development of overt HE (n = 44)
      BaselineFollow-upPaired t test P value
      MELD score (median)99.76
      Number connection test-A (s)39 ± 1538 ± 18.75
      Number connection test-B (s)110 ± 69105 ± 62.73
      Digit symbol test (raw score)56 ± 1257 ± 20.09
      Block design test (raw score)29 ± 1333 ± 20.39
      ICT targets (% correct)95 ± 594 ± 9.54
      ICT lures (number)11 ± 711 ± 5.97
      ICT lures (first half: runs I–III)7 ± 38 ± 4.23
      ICT lures (second half: runs IV–VI)4 ± 3
      P = .001 in the first half compared with the second half indicating successful learning.
      4 ± 4
      P = .001 in the first half compared with the second half indicating successful learning.
      .45
      ΔL1–22.11.8.52
      NOTE. There was no significant difference in any psychometric test or MELD score in the group that was tested twice without the interval development of overt HE, and the learning effect on the ICT was maintained in both visits. A high score on number connection-A/B and ICT lures and a low digit symbol, block design, and ICT target number indicate poor psychometric performance.
      Overt HE, overt hepatic encephalopathy adequately controlled on treatment.
      a P = .001 in the first half compared with the second half indicating successful learning.
      Comparison of change in psychometric performance between the 2 prospectively studied groups: There were no significant changes in any psychometric test apart from ICT lures between these 2 groups. However, ICT lures increased in those who developed overt HE compared with those who did not; the difference in the total lures was significantly higher in those with overt HE (Table 5). ΔL1–2 was also significantly lower after overt HE development compared with before overt HE, and ΔL1–2 remained unchanged between visits for patients who did not develop overt HE. In addition, when the difference of ΔL1–2 from each visit was compared, there was a significant change in the group that developed overt HE compared with the overt HE-free group.
      Table 5Comparison of ICT Lure Performance Between Patients Who Developed Overt HE and Those Who Remained Overt HE Free
      Developed overt HE (n = 15)Did not develop overt HE (n = 44)P value between groups
      Total lures on visit 1 minus visit 25.20.2.0002
       First visit ΔL1–23.12.1.56
       Second visit ΔL1–20.31.8.0001
       Change in ΔL1–2 between visits2.80.3.0001
      NOTE. There was a significant change over time in total lures in patients who developed their first overt HE episode compared with those who did not. ΔL1–2, lures in runs I–III (first half) minus lures in runs IV−VI (second half): a higher number indicates learning; this was similar between groups at baseline. Once they developed overt HE, ΔL1–2 declined, whereas it remained stable in those who did not develop overt HE and the change in ΔL1–2, ie, extent of change of leaning ability was also significantly different.
      Overt HE, overt hepatic encephalopathy adequately controlled on treatment.

      Discussion

      The SONIC forms a continuum that spans the range from normal cognitive function to minimal HE to overt HE.
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      • Wade J.B.
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      Spectrum of neurocognitive impairment in cirrhosis: implications for the assessment of hepatic encephalopathy.
      • Bajaj J.S.
      • Saeian K.
      • Schubert C.M.
      • et al.
      Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.
      Both minimal and overt hepatic encephalopathy are generally considered to be fully reversible with treatment.
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      • Leong D.K.
      • et al.
      Portacaval anastomosis induces region-selective alterations of the endogenous opioid system in the rat brain.
      • Pomier-Layrargues G.
      • Spahr L.
      • Butterworth R.F.
      Increased manganese concentrations in pallidum of cirrhotic patients.
      • Zieve L.
      • Doizaki W.M.
      • Zieve J.
      Synergism between mercaptans and ammonia or fatty acids in the production of coma: a possible role for mercaptans in the pathogenesis of hepatic coma.
      In autopsy series, brains of patients dying in coma associated with overt HE exhibited definite structural abnormalities.
      • Butterworth R.F.
      • Giguere J.F.
      • Michaud J.
      • et al.
      Ammonia: key factor in the pathogenesis of hepatic encephalopathy.
      • Rose C.
      • Jalan R.
      Is minimal hepatic encephalopathy completely reversible following liver transplantation?.
      • Butterworth R.F.
      Neuronal cell death in hepatic encephalopathy.
      • Kril J.J.
      • Butterworth R.F.
      Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease.
      There may also be residual neurologic findings on physical examination in overt HE patients.
      • Krieger S.
      • Jauss M.
      • Jansen O.
      • et al.
      Neuropsychiatric profile and hyperintense globus pallidus on T1-weighted magnetic resonance images in liver cirrhosis.
      • Mullen K.D.
      • Cole M.
      • Foley J.M.
      Neurological deficits in “awake” cirrhotic patients on hepatic encephalopathy treatment: missed metabolic or mental disorder?.
      Patients with a history of overt HE have an increased likelihood of persistent neurocognitive dysfunction after liver transplantation compared with those without prior overt HE.
      • Sotil E.U.
      • Gottstein J.
      • Ayala E.
      • et al.
      Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.
      Children with chronically elevated ammonia because of hereditary urea cycle disorders can develop irreversible central nervous system damage.
      • Gropman A.L.
      • Batshaw M.L.
      Cognitive outcome in urea cycle disorders.
      The pathogenesis of these durable changes that may persist despite resolution of the mental status is not fully understood.
      In the current study, cognitive impairment in patients with history of overt HE was more severe than in patients without prior overt HE, and severity of impairment increased with the number of previous episodes of overt HE. In patients followed prospectively, we found that a single episode of overt HE was accompanied by acquisition of a defect in learning of response inhibition, as measured by the ICT. In patients with multiple episodes of overt HE, we noted additional defects in reaction times, set shifting, divided attention, response inhibition, and working memory as measured by digit symbol test, number connection test-B, and ICT lures and targets. These tests measure integrity of reaction times, psychomotor speed, set shifting, and divided attention. Poor performance on these cognitive measures was not merely a reflection of generalized psychomotor slowing because we found no relationship between overt HE and performance on number connection test-A (a measure of psychomotor speed) or the block design test (a measure of visuomotor coordination). Our findings indicate that there is cumulative worsening of performance in basic domains of cognitive function following recurrent episodes of overt HE. Working memory and frontal regulatory circuit impairment, measured by ICT lure response, occurs early, whereas loss of other functions such as set shifting, sustained attention, and visual memory indicates a more advanced stage in the SONIC. This is in concordance with the rostrocaudal progression of deficits that has been demonstrated in metabolic encephalopathies through animal studies.
      • Giguere J.F.
      • Butterworth R.F.
      Amino acid changes in regions of the CNS in relation to function in experimental portal-systemic encephalopathy.
      Our data also suggest that decline in working memory and the integrity of frontal regulatory circuits, followed by other forms of cognitive dysfunction may define the neurobehavioral decline in overt HE. It could be argued that the worse cognitive impairment in overt HE may be due to factors such as impaired volition or neuromuscular difficulties. However, this is unlikely because ICT target response, which measures response time, was intact in all patients with overt HE. Therefore, these findings point to a loss of “cognitive reserve” in overt HE patients and may make them increasingly vulnerable to neurobehavioral decline with future changes in brain homeostasis.
      The ICT is a dynamic and fast-paced task that interrogates working memory, learning capacity, and response inhibition.
      • Garavan H.
      • Ross T.J.
      • Stein E.A.
      Right hemispheric dominance of inhibitory control: an event-related functional MRI study.
      In particular, it depends on proper function of the cortical association areas necessary for orienting attentional resources and analysis of critical features for identifying salient stimuli.
      • Garavan H.
      • Ross T.J.
      • Stein E.A.
      Right hemispheric dominance of inhibitory control: an event-related functional MRI study.
      The prefrontal cortex is important for screening distracters and shifting/dividing attention in a task appropriate manner. Furthermore, the prefrontal cortex and angular gyrus are needed for the allocation of attentional resources to achieve target goals in organizing thought/behavior.
      • Derbyshire S.W.
      • Vogt B.A.
      • Jones A.K.
      Pain and Stroop interference tasks activate separate processing modules in anterior cingulate cortex.
      • Passingham R.E.
      Attention to action.
      Successful lure inhibition in the ICT requires the subject to critically evaluate each stimulus presented in a sequence that conforms to the n-back task, which requires the continuous process of building, maintaining, updating, and releasing arbitrary bindings between items in temporal order positions.
      • Cohen J.D.
      • Perlstein W.M.
      • Braver T.S.
      • et al.
      Temporal dynamics of brain activation during a working memory task.
      • Friedman N.P.
      • Miyake A.
      • Corley R.P.
      • et al.
      Not all executive functions are related to intelligence.
      The top-down control of posterior parietal cortex via dorsolateral prefrontal cortex modulation has been proposed to underlie optimal working memory performance during the n-back task. As task difficulty increases, prefrontal excitatory input enhances parietal region activity, thereby increasing memory capacity. Our findings in this study are consistent with those of other studies that have shown impaired activation of the prefrontal cortex in patients with minimal and early overt HE.
      • Zafiris O.
      • Kircheis G.
      • Rood H.A.
      • et al.
      Neural mechanism underlying impaired visual judgement in the dysmetabolic brain: an fMRI study.
      • Zhang L.J.
      • Yang G.
      • Yin J.
      • et al.
      Neural mechanism of cognitive control impairment in patients with hepatic cirrhosis: a functional magnetic resonance imaging study.
      The mechanisms behind the lack of reversibility of the neurocognitive status despite resolution of mental status changes are unclear. It was also interesting to note that, despite therapy with ammonia-lowering strategies, these deficits persisted. This brings up the possibility that toxins other than ammonia, such as accumulation of manganese, inflammatory cytokines, or mercaptans, may be implicated in this persistence.
      • Pomier-Layrargues G.
      • Spahr L.
      • Butterworth R.F.
      Increased manganese concentrations in pallidum of cirrhotic patients.
      • Zieve L.
      • Doizaki W.M.
      • Zieve J.
      Synergism between mercaptans and ammonia or fatty acids in the production of coma: a possible role for mercaptans in the pathogenesis of hepatic coma.
      • Shawcross D.L.
      • Wright G.
      • Olde Damink S.W.
      • et al.
      Role of ammonia and inflammation in minimal hepatic encephalopathy.
      There is also conflicting evidence regarding the molecular mechanisms of these persistent cognitive changes in overt HE. Autopsy and animal studies have implicated changes in neurotransmitter systems, such as neurosteroids, monoamines, and opioids, in the hippocampus and frontal cortex in metabolic encephalopathies such as overt HE.
      • Bergeron M.
      • Reader T.A.
      • Layrargues G.P.
      • et al.
      Monoamines and metabolites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy.
      • de Waele J.P.
      • Audet R.M.
      • Leong D.K.
      • et al.
      Portacaval anastomosis induces region-selective alterations of the endogenous opioid system in the rat brain.
      • Fan P.
      • Lavoie J.
      • Le N.L.
      • et al.
      Neurochemical and electrophysiological studies on the inhibitory effect of ammonium ions on synaptic transmission in slices of rat hippocampus: evidence for a postsynaptic action.
      • Ahboucha S.
      • Layrargues G.P.
      • Mamer O.
      • et al.
      Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy.
      • Butterworth R.F.
      • Le O.
      • Lavoie J.
      • et al.
      Effect of portacaval anastomosis on electrically stimulated release of glutamate from rat hippocampal slices.
      Kril and Butterworth also suggested that thalamic neuronal cell loss in overt HE in patients may contribute to persistent changes in cognition in alcoholic cirrhotic patients
      • Kril J.J.
      • Butterworth R.F.
      Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease.
      ; however there was no specific difference in the cognitive impairment between alcoholic and nonalcoholic patients in our patient population. Therefore, further studies are required to elucidate the underlying mechanisms behind the complex cognitive changes in cirrhosis.
      The finding that episodes of overt HE can lead to persistent cognitive impairment may have important implications in assigning priority for liver transplantation. Previous studies have found that overt HE adversely affects pretransplantation survival independently of the MELD score, and patients with pretransplantation overt HE have a higher incidence of post-transplantation neurologic complications.
      • Sotil E.U.
      • Gottstein J.
      • Ayala E.
      • et al.
      Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.
      • Stewart C.A.
      • Malinchoc M.
      • Kim W.R.
      • et al.
      Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease.
      If brain damage associated with episodes of overt HE is prolonged or permanent, then earlier transplantation may be warranted in patients whose encephalopathy is difficult to control with conventional therapies.
      In conclusion, this study demonstrates that there are residual effects on cognitive function, especially executive functions, that result in learning impairment and working memory problems in patients with overt HE, even after their first episode despite adequate therapy and the attainment of normal mental status. This psychometric performance deterioration continues and expands to the more basic cognitive domains of psychomotor speed, set shifting, and divided attention with increasing numbers of episodes and hospitalizations for overt HE. Further prospective studies are needed to determine the long-term cognitive consequences of overt HE and benefits of expedited transplantation in patients with recurrent overt HE.

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