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  1. 1. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS GASTROENTEROLOGY 2008;xx:xxx Inhibitory Control Test for the Diagnosis of Minimal Hepatic Encephalopathy JASMOHAN S. BAJAJ,* MUHAMMAD HAFEEZULLAH,‡ JOSE FRANCO,‡ RAJIV R. VARMA,‡ RAYMOND G. HOFFMANN,§ JOSHUA F. KNOX,‡ DARRELL HISCHKE,‡ THOMAS A. HAMMEKE, STEVEN D. PINKERTON¶, and KIA SAEIAN *Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia; ‡Division of Gastroenterology and Hepatology, §Department of Population Health/Division of Biostatistics, Division of Neuropsychology, ¶Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin Background & Aims: Minimal hepatic encephalopa- deficits, especially in the domains of attention, vigilance, thy (MHE) is difficult to diagnose. The Inhibitory response inhibition, and executive function.9 –11 Psycho- Control Test (ICT) measures response inhibition and metric tests for MHE diagnosis specifically assess these has diagnosed MHE with 90% sensitivity and speci- cognitive domains.12 The difficulty in applying these psy- ficity in a selected population; high lure and low chometric tests in the United States is the need for target rates indicated poor ICT performance. We psychologic expertise for clinical administration and in- studied the reliability and validity of ICT for MHE terpretation, the expensive and copyrighted testing pro- diagnosis. Methods: ICT was compared with a psy- cedures, and the lack of reimbursement by insurance chometric battery (standard psychometric tests companies. These issues were highlighted in a recent [SPT]) for MHE diagnosis and overt hepatic enceph- survey of the American Association for the Study of Liver alopathy (OHE) prediction. ICT was administered Diseases (AASLD) in which, although most respondents twice for test-retest reliability, before/after trans- believed MHE to be a serious problem that required venous intrahepatic portosystemic shunting (TIPS), testing, only a minority reported doing so.13 Most re- and before/after yogurt treatment. The time taken by spondents believed that a simple test that could be ad- 2 medical assistants (MA) to administer ICT was re- ministered by clinic personnel would increase their test- corded and compared with that of a psychologist for ing rates.13 cost analysis. Results: One hundred thirty-six cir- The Inhibitory Control Test (ICT) is a computerized rhotic patients and 116 age/education-matched con- test of attention and response inhibition that has been trols were studied. ICT (>5 lures) had 88% sensitivity used to characterize attention deficit disorder, schizo- for MHE diagnosis with 0.902 area under the curve phrenia, and traumatic brain injury.10,14 –17 ICT is similar for receiver operating characteristic. MHE-positive to the continuous performance test and consists of pre- patients had significantly higher ICT lures (11 vs 4, sentation of several letters at 500-ms intervals.18 Inter- respectively, P .0001) and lower targets (92% vs 97%, spersed within these letters are the letters X and Y. The respectively, P .0001) compared with MHE-negative subject is instructed to respond to every X and Y during patients. The test/retest reliability for ICT lures (n the initial part of the training run, which establishes the 50, r 0.90, P .0001) was high. ICT and SPT were prepotent response. In the latter part of the training run, equivalent in predicting OHE (21%). ICT lures signif- the subject is instructed only to respond when X and Y icantly worsened after TIPS (n 10; 5 vs 9, respec- are alternating (called targets) and to inhibit from re- tively; P .02) and improved after yogurt supplemen- tation (n 18, 10 vs 5, respectively; P .002). The sponding when X and Y are not alternating (called lures). MAs were successfully trained to administer ICT; the After the training run, 6 test runs, which last approxi- time required for test administration and the associ- mately 2 minutes each, are administered with a total of ated costs were smaller for ICT than for SPT. 40 lures, 212 targets, and 1728 random letters in be- Conclusions: ICT is a sensitive, reliable, and valid tween. At the end of the test, the lure and target response test for MHE diagnosis that can be administered rates, lures, and target reaction times are automatically inexpensively by MAs. calculated. Lower lure response, higher target response, Abbreviations used in this paper: MHE , cirrhotic patients with M inimal hepatic encephalopathy (MHE) is a neuro- cognitive complication of cirrhosis, which has been reported in up to 80% of tested patients.1–3 It is minimal hepatic encephalopathy; MHE , cirrhotic patients without minimal hepatic encephalopathy; OHE, overt hepatic encephalopathy; SPT, standard psychometric tests; ICT, inhibitory control test; NCT-A, associated with increased progression to overt hepatic number connection test; DST, digit symbol; BDT, block design test; TIPS, intrahepatic portosystemic shunting. encephalopathy (OHE), diminished quality of life, and © 2008 by the AGA Institute driving impairment as well as a high risk of traffic acci- 0016-5085/08/$34.00 dents.4 – 8 MHE results in a specific spectrum of cognitive doi:10.1053/j.gastro.2008.07.021FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.
  2. 2. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS 2 BAJAJ ET AL GASTROENTEROLOGY Vol. xx, No. x and shorter lure and target reaction times indicate good cirrhotic patients were included in the study. Age- and psychometric performance. educational status-matched healthy controls were re- ICT has been used for the diagnosis of MHE by our cruited from the community through advertisements. group in 50 nonalcoholic cirrhotic patients compared Written informed consent was obtained from each par- with 50 age- and education-matched controls with 90% ticipant. sensitivity and specificity.19 ICT was similar to the battery of standard psychometric tests (SPT) for prediction of MHE Diagnosis With ICT vs SPT OHE development and had good test-retest reliability. All patients and controls were administered the This was an initial report in highly selected and moti- SPT and ICT during the same sitting under the supervi- vated patients and excluded all patients with an alcoholic sion of a psychologist who was blinded to the nature of etiology of cirrhosis. Furthermore, external validation the participants. Parameters recorded were NCT-A com- was not performed in that initial study.19 pletion time in seconds, raw score of DST and BDT, ICT The aims of this present study were to (1) validate the lure and target response rates, and ICT lure and target ICT for the diagnosis of MHE in cirrhotic patients by reaction times. Control and cirrhotic groups were com- comparing them with age- and education-matched con- pared with respect to demographics and psychometric trols; (2) assess its test-retest reliability; (3) determine its test results. Correlation between age with individual ICT external validity by studying ICT before and after trans- and SPT results were performed for both groups. venous intrahepatic portosystemic shunting (TIPS), be- Cirrhotic patients were divided into those with MHE fore and after yogurt supplementation, and its ability to (MHE ) and those without MHE (MHE ) using SPT as predict onset of OHE; and (4) estimate the time and cost the gold standard. Sensitivity and specificity of diagnosis required for previously untrained medical assistants to of MHE using ICT data were compared using the receiver administer the test in the hepatology clinic. operating characteristic and area under the curve and logistic regression. A subgroup analysis of psychometric Patients and Methods tests was performed within the cirrhotic group for hep- Outpatients with cirrhosis were recruited between atitis C-positive cirrhotic patients, those with alcoholic September 2004 and December 2007 through clinical cirrhosis, and those with both. referral. Patients between ages 18 and 65 years, without Test-Retest Reliability current psychoactive drug use, not on OHE treatments, without history of OHE, and without alcohol use within A randomly selected group of controls and cir- 3 months were included. rhotic patients underwent SPT and ICT twice at least 30 days apart to gauge the test-retest reliability. There was MHE Definition and SPT no change in the clinical status (Child–Pugh score), ad- SPT battery for this study was the Number Con- dition of psychoactive medications, or development of nection Test-A (NCT-A) and 2 subtests of the Wechsler’s new complications of cirrhosis (variceal bleeding, ascites, Adult Intelligence Scale-III: Digit Symbol Test (DST) and and others) in between the 2 testing times. Spearman Block Design (BDT) tests.20 MHE was defined as a per- rank correlation was used to correlate the NCT-A, BDT, formance impaired 2 standard deviations beyond that of DST, and ICT lure and target response of the first and the age/education-matched controls on any test. This is second administration. modified from the Working Group on Hepatic Enceph- alopathy recommendation, which has previously been Follow-Up to Evaluate OHE Development used to diagnose MHE and predict OHE and driving Patients who were enrolled in the cross-sectional impairment in our population.12,19,21 study were followed up as a matter of clinical practice by The study was divided into the following parts: the primary hepatologists for the detection of OHE. OHE (1) Cross-sectional study of SPT vs ICT for MHE diag- was diagnosed when the patient was started on therapy nosis. (2) Test-retest reliability of SPT and ICT. (3) Fol- and the precipitating factor was recorded. Development low-up of cirrhotic patients to detect OHE development. of OHE was compared between patients with MHE ac- (4) External validity: (a) study change in ICT and SPT cording to SPT vs ICT. Patients with discordant or con- after TIPS placement and (b) study change in ICT and SPT cordant results on initial testing were compared. after probiotic yogurt supplementation. (5) Time and cost analysis of ICT administration in hepatology clinics. External Validity For study parts 1, 2, and 3, a total of 256 patients SPT and ICT changes after TIPS placement. Con- without OHE or without current OHE therapy were secutive outpatient cirrhotic patients who underwent considered for recruitment; 65 refused to participate, 33 elective TIPS placement were studied with SPT and ICT had concurrent psychoactive drug use (antianxiety, anti- at least 30 days prior to and 30 days post-TIPS. Patients psychotics, antiepileptics, and interferon), and 23 had already on OHE therapy, those with psychoactive medi- consumed alcohol within 3 months. As a result, 135 cations, and those who underwent emergent TIPS wereFOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.
  3. 3. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS Month 2008 DIAGNOSIS OF MINIMAL HEPATIC ENCEPHALOPATHY 3 excluded from this study. There was no primary prophy- After adequate training of the MAs, the time required laxis protocol against OHE post-TIPS in place. for administration of ICT was recorded for the next 20 Patients were reexamined post-TIPS for OHE develop- patients. The time required for administration of the ment and chart review to evaluate for OHE development standard psychometric battery by the psychologist was before that visit was performed. TIPS stent characteristics also determined for the same patients. Current proce- and reduction in hepatic portal venous pressure gradient dural terminology codes for a MA assessment (E and M were recorded. ICT and SPT parameters before and after 1; 99211) and for neuropsychologic testing by a psychol- TIPS were compared using paired t tests. ogist (96118) were used to estimate third-party charges SPT and ICT changes after probiotic yogurt sup- and Medicare reimbursement.23 Fixed costs for the copy- plementation in a randomized, controlled trial. Consecu- righted Wechsler’s Adult Intelligence Scale-III instrument tive MHE patients were enrolled for a randomized, con- and materials and for computer time for ICT were ex- trolled trial of probiotic yogurt for MHE treatment.22 All cluded from the analyses because these costs are likely to patients fulfilled the overall inclusion and exclusion cri- be negligible when averaged over large numbers of test teria of the cross-sectional study and underwent SPT and administrations. ICT at baseline. Patients were randomized in a 2:1 ratio into the yogurt and the no-treatment group and were Results followed for 60 days, at the end of which SPT and ICT were both repeated at the same sitting by a scorer blinded Cross-Sectional Study of the SPT and ICT for to the randomization scheme. Paired t test within groups Diagnosing MHE and 2 sample t tests were used to compare continuous Within the cirrhotic patients, there were 8 pa- variables, and Fisher exact test was used to compare tients between 18 and 35 years, 67 between 36 and 55 binary variables between groups. years, and 48 patients between 56 and 65 years of age. Of the 116 controls, 23 were between 18 and 35 years, 66 Time and Cost Analysis of ICT between 36 and 55 years, and 27 between 56 and 65 years Administration in the Clinic of age. To assess the time and costs associated with ICT Control and cirrhosis group results and MHE defi- administration in a “real-world” clinic setting, 2 medical nition. There was no significant difference in demo- assistants (MAs; one 31 years old and other 64 years old; graphics (Table 1). The cirrhotic group was significantly both women) were trained to administer ICT on a laptop impaired with respect to SPT performance compared computer in the hepatology clinic. After training on the with controls. A patient with cirrhosis was considered to computer for 30 minutes each, they were asked to ad- be MHE if any of the following conditions were met: minister the test to the principal investigator (J.S.B.) to NCT-A 35 seconds, BDT raw score 28, or DST raw evaluate their ability to administer this test. They then score 66. Similarly, there was a significantly higher ICT administered the test to 10 subjects each (5 cirrhotic lure response, a significantly lower ICT target response, patients and 5 controls) to ensure proficiency in test and a longer target reaction time in the cirrhotic group administration. compared with controls. Table 1. Comparison Between Controls and Patients With Cirrhosis Controls Cirrhotic patients (n 116) (n 135) P values Age (y) 50 8 51 8 .10 Sex (M/F) 63/53 72/63 .88 Education (y) 13 4 12 3 .3 Etiology of cirrhosis (HCV/alcohol/HCV alcohol/others) — 45/19/13/42 — NCT-A (seconds) 23 6 33 11 .0001 DST (raw score) 86 10 63 17 .0001 BDT (raw score) 46 9 34 11 .0001 Response to ICT lures (number out of 40) 3 2 9 7 .0001 Response to ICT targets (percentage responded to) 96 6 94 7 .006 ICT lure reaction time (milliseconds) 535 81 554 69 .13 ICT target reaction time (milliseconds) 490 62 522 57 .001 NOTE. Controls were age- and educational status-matched with cirrhotic patients; sex distribution was similar between the groups. Others within the cirrhotic group included 14 patients with nonalcoholic steatohepatitis, 11 with primary sclerosing cholangitis, 9 with primary biliary cirrhosis, and the remainder with cryptogenic cirrhosis. There was a significantly impaired performance in each SPT test in cirrhotic patients compared with controls. A significantly worse ICT psychometric performance, ie, higher lure response rate, lower target response rate, and higher lure and target response time, was observed. HCV, hepatitis C only; SPT, standard psychometric tests; ICT, Inhibitory Control Test; NCT-A, Number Connection Test; DST, Digit Symbol Test; BDT, Block Design Test.FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.
  4. 4. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS 4 BAJAJ ET AL GASTROENTEROLOGY Vol. xx, No. x Table 2. Comparison Between Patients With Cirrhosis With MHE patients also demonstrated a significantly lower and Without Minimal Hepatic Encephalopathy target response compared with MHE (Table 2) patients. MHE MHE Sensitivity and specificity of ICT using SPT as the (n 87) (n 48) P value gold standard. A cut off of 5 lures per person was used Age (y) 52 8 51 11 .42 to diagnose MHE based on receiver operating character- Sex (M/F) 46/41 26/22 .89 istic analysis and our prior study.19 Of the 87 MHE Education (y) 12 3 13 1 .35 patients by SPT, 76 had 5 lures, and 11 did not. Of the Child–Pugh score distribution 58/26/3 41/7/0 .05 48 MHE patients by SPT, 37 had 5 lures, and 11 had (A/B/C) 5 lures. Sensitivity was 87%, and specificity was 77% for Chronic hepatitis C (%) 41 (47) 17 (35) .19 Alcoholic cirrhosis (%) 22 (25) 10 (21) .56 the diagnosis of MHE using ICT lure threshold of 5 NCT-A (seconds) 37 11 25 6 .0001 lures (Figure 1A). The receiver operating characteristic DST (raw score) 55 13 80 9 .0001 curve had an area under the curve of 0.902 for MHE BDT (raw score) 31 11 41 9 .0001 diagnosis using lures (Figure 1B). Response to ICT lures (number 11 7 4 3 .0001 Correlation between SPT and ICT parameters within out of 40) the cirrhotic group. There was a significant correlation Response to ICT targets 92 8 97 4 .0001 (percentage responded to) between ICT lures and targets with SPT performance. ICT lure reaction time 571 64 520 85 .003 (milliseconds) ICT target reaction time 546 49 486 55 .0001 (milliseconds) NOTE. A cirrhotic patient was considered to be MHE if any of the following conditions were met: NCT-A 35 seconds, BDT raw score 28, or DST raw score 66. There was no significant difference in age, educational status, sex distribution, Child–Pugh score, chronic hepatitis C, and alcoholic cirrhosis prevalence between cirrhotic pa- tients with and without MHE. There was a significantly impaired per- formance in each SPT test in MHE cirrhotic patients compared with MHE cirrhotic patients. A significantly worse ICT psychometric per- formance, ie, higher lure response rate, lower target response rate, and higher lure and target response time, was observed. MHE , cirrhotic patients with minimal hepatic encephalopathy; MHE , cirrhotic patients without minimal hepatic encephalopathy; SPT, standard psychometric tests; ICT, Inhibitory Control Test; NCT-A, Number Connection Test; DST, Digit Symbol Test; BDT, Block Design Test. Comparison within the cirrhotic group. Using the a priori definition, 87 patients were considered to be MHE , and the remaining 48 were MHE (Table 2). Therefore, 48 patients were not impaired in any test. Of the 87 MHE patients, 25 were impaired on all 3 tests, 24 patients on 2 tests, and 38 patients on 1 psychometric test. A significant positive correlation between number of impaired tests on the SPT and lure response (r 0.51, P .0001) and a significant negative correlation of tar- gets with number of impaired tests on SPT (r 0.39, P .0001) was observed. There was also a significant negative correlation between ICT lures and targets (r 0.37, P .0001). Figure 1. (A) The individual value plot of lures in cirrhotic patients with and without MHE shows 88% sensitivity and 77% specificity for the There was no significant difference in demographics, diagnosis of MHE using a cut off of 5 lures and above. SPT was used as prevalence of hepatitis C, or alcoholic etiology of cirrho- the gold standard for the diagnosis of MHE. The total number of lures in sis between MHE and MHE groups. A borderline the ICT is 40. MHE, minimal hepatic encephalopathy; SPT, standard statistically significant predominance of Child–Pugh B psychometric battery. (B) The receiver operating characteristic curve for and C class cirrhotic patients in the MHE group was the ICT lure response for the diagnosis of MHE using SPT as a gold standard showed that an area under the curve was 0.902. There was no observed (P .05). significant contribution of ICT targets, lure, and target reaction time to The MHE group had a significantly higher rate of this area under the curve on logistic regression. MHE, minimal hepatic lure response and longer lure and target reaction times. encephalopathy; SPT, standard psychometric battery.FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.
  5. 5. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS Month 2008 DIAGNOSIS OF MINIMAL HEPATIC ENCEPHALOPATHY 5 Table 3. Comparison Between Patients With Cirrhosis With and age in cirrhotic patients. However, there was no and Without Chronic Hepatitis C as the Etiology of significant correlation in the cirrhotic group between Cirrhosis NCT-A (r 0.204, P .79) and DST (r 0.13, P .15) HCV positive HCV negative scores and age. ICT lures continued to demonstrate no (n 58) (n 77) P value significant correlation with age in the cirrhotic patients Age (y) 52 7 52 10 .89 (r 0.06, P .51). Because some of the metrics showed age NCT-A (seconds) 34 10 32 11 .17 effects, cirrhotic patients were age matched to controls. DST (raw score) 60 15 64 17 .06 Hepatitis C, alcoholic cirrhosis, and both sub- BDT (raw score) 35 11 34 11 .54 group analysis. Within the cirrhotic patients, 58 pa- Response to ICT lures 8 7 9 6 .41 tients had chronic hepatitis C, and 77 did not. There was (number out of 40) Response to ICT 93 8 94 7 .19 no statistically significant difference in SPT or ICT pa- targets (%) rameters between those with or without hepatitis C ICT lure reaction time 547 55 555.3 88 .57 groups (Table 3). Similarly, no significant difference in (milliseconds) ICT or SPT parameters was observed between those with ICT target reaction time 523 8 523 64 .98 an alcoholic etiology of cirrhosis compared with cirrhotic (milliseconds) patients without alcohol as the etiology (Table 4). Thir- NOTE. There was no significant difference in age, individual SPT teen patients had both alcohol- and chronic hepatitis performance, and all aspects of ICT performance, ie, lure response C-associated cirrhosis; the performance on SPT (NCT-A: rate, target response rate, and lure and target reaction times, be- tween cirrhotic patients with and without HCV infection (included 13 36 8 seconds, BDT: 33 9, DST: 57 12) and ICT patients with HCV and alcohol). (targets 92 7 and lures 7 7) were statistically similar SPT, standard psychometric tests; ICT, Inhibitory Control Test; NCT-A, to patients with chronic hepatitis C and those with alco- Number Connection Test; DST, Digit Symbol Test; BDT, Block Design holic cirrhosis. Test. Test-Retest Reliability Results ICT lures were positively correlated with NCT-A perfor- A randomly selected group of 20 controls and 30 mance (r 0.41, P .0001) and negatively correlated cirrhotic patients from the patients enrolled above were with BDT (r 0.40, P .0001) and DST (r 0.36, administered the SPT and ICT 86 45 days apart. No P .0001). ICT targets were significantly negatively cor- change in the clinical status of the patients and controls related with NCT-A (r 0.29, P .001) and positively was observed in the interim. The 30 cirrhotic patients correlated with BDT (r 0.29, P .001) and DST (r included 21 with hepatitis C, 5 with alcoholic cirrhosis, 3 0.41, P .001). with cryptogenic cirrhosis, and 1 with primary biliary Correlation of age with SPT and ICT results. There cirrhosis; all were Child–Pugh class A. Both ICT and SPT was a significant positive correlation between age and parameters had a strong test-retest correlation in cir- NCT-A (r 0.425, P .0001) in controls. BDT (r rhotic patients as well as controls (Table 5). None of the 0.437, P .0001) and DST (r 0.417, P .0001) test-retest correlations differed significantly between the demonstrated a corresponding significant negative corre- controls and the cirrhotic patients. lation with age in controls. ICT lures were not signifi- cantly correlated with age in controls (r 0.121, P .23). OHE Development Similar to the control group, there was a significant All patients (apart from 15 who refused) were negative correlation between BDT (r 0.231, P .01) followed up for a mean of 36 30 months since first Table 4. Comparison Between Patients With Cirrhosis With and Without Alcohol as the Etiology of Cirrhosis Alcoholic etiology Nonalcoholic etiology (n 32) (n 103) P value Age (y) 52 8 52 9 .68 NCT-A (seconds) 31 9 33 11 .14 DST (raw score) 59 15 64 18 .11 BDT (raw score) 31 10 35 15 .06 Response to ICT lures (number out of 40) 8 6 8 7 .67 Response to ICT targets (%) 93 8 93 7 .99 ICT lure reaction time (milliseconds) 565 51 547 84 .12 ICT target reaction time (milliseconds) 536 51 519 61 .16 NOTE. All included patients had not consumed alcohol within 3 months before the study. There was no significant difference in age, individual SPT performance, and all aspects of ICT performance, ie, lure response rate, target response rate, and lure and target reaction times between cirrhotic patients with and without history of alcoholic liver disease (included 13 patients with both HCV and alcoholic etiology of cirrhosis). SPT, standard psychometric tests; ICT, Inhibitory Control Test; NCT-A, Number Connection Test; DST, Digit Symbol Test; BDT, Block Design Test.FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.
  6. 6. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS 6 BAJAJ ET AL GASTROENTEROLOGY Vol. xx, No. x Table 5. Test-Retest Reliability of ICT and SPT Performance patients underwent TIPS for refractory ascites (n 6), Controls Cirrhotic patients hepatic hydrothorax (n 2), and for control of chronic (n 20) (n 30) hemorrhage from rectal and stomal varices (n 2). Covered TIPS (Viatorr stent, Flagstaff, AZ) placement Correlation Correlation was successful in all patients, and a mean hepatic portal coefficient P value coefficient P value venous pressure gradient reduction of 8.4 2.6 mm Hg NCT-A (seconds) 0.67 .02 0.77 .0001 post-TIPS was achieved. All were discharged home in a DST (raw score) 0.76 .011 0.93 .0001 BDT (raw score) 0.89 .0001 0.78 .0001 satisfactory condition. Three patients (2 underwent TIPS Response to ICT 0.90 .0001 0.90 .0001 for refractory ascites and 1 for chronic bleeding) were lures noted to have developed OHE by clinical examination by Response to ICT 0.78 .0001 0.83 .0001 their primary hepatologist. All 3 were started on lactulose targets and underwent the second visit testing while they were NOTE. There was a significant correlation between the first and sec- on lactulose treatment. ond administration of SPT components and ICT performance in con- The second visit with SPT and ICT testing occurred trols and cirrhotic patients. SPT, standard psychometric tests; ICT, Inhibitory Control Test; NCT-A, 35 8 days post-TIPS. There was a significant increase in Number Connection Test; DST, Digit Symbol Test; BDT, Block Design lure response on the ICT post-TIPS with or without Test. inclusion of the 3 post-TIPS OHE patients (see supple- mentary Figure 1 online at and Table 6). ICT target response rate significantly worsened enrollment for OHE development. Nineteen patients post-TIPS only when all patients were included. Similarly were diagnosed to have OHE; OHE was diagnosed 9 6 NCT-A performance was significantly affected only when months after enrollment. Of the 19 patients, 6 developed all patients were considered. BDT and DST scores were OHE after acute variceal bleeding, 7 after infections re- impaired after TIPS placement, but this did not reach quiring hospital admission, 3 after TIPS, and the remain- statistical significance (Table 6). ing 3 diagnosed after undergoing an operation. Probiotic yogurt trial ICT results. Twenty-five pa- All 19 patients had been diagnosed with MHE using tients were enrolled: 17 were randomized into the yogurt both ICT and SPT. None of the 22 patients with discor- group and 8 into the no-treatment group. Three yogurt dant test results (11 who were positive for MHE using group patients did not complete the study (2 stopped it SPT but not ICT and 11 who were positive for MHE because of palatability issues, and 1 died of an unrelated using ICT but not SPT) developed OHE on follow-up. There was no statistically significant difference in the Pseudomonas aeruginosa septicemia after spending time in SPT or ICT parameters of MHE patients who developed a public hot tub). Two patients in the no-treatment OHE compared with those who did not. group developed OHE in the 60-day study period. There- fore, 14 yogurt-assigned and 6 no-treatment-assigned pa- External Validity Study Results tients completed the study.22 Testing before and after TIPS. Fifteen consecu- There was significant improvement in psychometric tive patients undergoing elective TIPS placement within test performance across all SPT tests in the yogurt group February 2007 and December 2007 were approached, of (Table 7).22 Paralleling this was a statistically significant which 3 were on psychoactive medications and 2 refused improvement in ICT lure and ICT target performance to participate. The remaining 10 patients were initially within the yogurt group (see supplementary Figure 2 tested 26 5 days prior to the TIPS placement. The online at In contrast, there was Table 6. Psychometric Performance Before and After Tips Paired t test of pre- and post-TIPS Paired t test of pre- and Before TIPS Post-TIPS including Post-TIPS without patients (including OHE) post-TIPS (excluding OHE) (n 10) OHE (n 10) OHE (n 7) (n 10) (n 7) NCT-A (seconds) 31 8 39 11 34 8 .012 .098 DST (raw score) 55 19 48 19 51 21 .081 .459 BDT (raw score) 37 14 36 17 40 18 .759 .747 ICT lures 5.2 3.8 9.4 4.6 8.5 4.6 .02 .02 ICT targets 98.8 1.1 93.4 4.7 94.7 4.7 .007 .08 NOTE. Three patients developed OHE after TIPS and were tested while they were on lactulose therapy. There was a trend toward significant impairment of tests of the SPT after TIPS. ICT lure response rate increased and ICT target response rate decreased significantly after TIPS, indicating an impairment of ICT performance compared with before TIPS. TIPS, transvenous intrahepatic portosystemic shunting; SPT, standard psychometric tests; ICT, Inhibitory Control Test; NCT-A, Number Connec- tion Test; DST, Digit Symbol Test; BDT, Block Design Test.FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.
  7. 7. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS Month 2008 DIAGNOSIS OF MINIMAL HEPATIC ENCEPHALOPATHY 7 Table 7. Psychometric Performance Before and After Probiotic Yogurt in a Randomized Controlled Trial Yogurt baseline No-Rx baseline Yogurt end No-Rx end Yogurt within group, No-Rx within group, (n 17) (n 8) (n 14) (n 6) P values P values NCT-A (seconds) 43 10 48 17 31 4 48 10 .0001 .21 DST (raw score) 60 8 48 14 69 8 54 18 .0001 .13 BDT (raw score) 36 3 25 8 41 5 28 10 .008 .43 ICT lures 10 5 14 10 5 3 17 10 .002 .74 ICT targets 92 4 91 7 95 3 91 5 .05 .97 NOTE. Probiotic yogurt therapy resulted in significant improvement in psychometric function in all SPT components in the probiotic yogurt- randomized group only. Similarly there was a significant improvement in ICT performance (increased ICT lure response and decreased ICT target response rates). There was no significant change in SPT or ICT in the no-treatment randomized group. No-Rx, no treatment; SPT, standard psychometric tests; ICT, Inhibitory Control Test; NCT-A, Number Connection Test; DST, Digit Symbol Test; BDT, Block Design Test. no improvement in SPT or ICT parameters within the inhibition underlies each action that is performed by the no-treatment group.22 subject, and its impairment can be inherently responsible for potentiating wrong decisions in psychometric testing Time and Cost Analysis of ICT and in daily life, such as during driving. Administration in the Clinic On the ICT, errors of omission produce a significantly The average time required for the medical assis- lower target detection rate in MHE patients compared tants to administer the ICT in the clinic was 14 3 with controls and patients without MHE. These errors minutes compared with 32 7 minutes for SPT admin- are considered primary errors of attention in that they istration by a trained psychologist. Medicare reimburse- represent a lapse in focus. Errors of omission along with ment for more than 30 and less than 60 minutes of a longer lure and target reaction times are commonly as- psychologist’s time to administer the SPT is $112, and sociated with diminished processing speed and impair- the third-party billing charge is $348. In contrast, for ments in visuomotor function.16 It is likely that MHE ICT, an MA’s time would cost $18 for Medicare and $41 affects attention circuits that lead to functional impair- for third-party insurance. ments in these patients.26 In addition, ICT lures response The Institutional Review Board at the Medical College was also negatively correlated with ICT target perfor- of Wisconsin approved this protocol. mances, indicating that both these aspects of attention deficits coexist. Undoubtedly, the effects of these atten- Discussion tion deficits on MHE patients’ performance in daily life The current study demonstrates that the ICT is are compounded when combined with impaired response simple to administer and has a high sensitivity, area inhibition. under the curve for diagnosis, and test-retest reliability The standard battery used for the diagnosis for MHE for the diagnosis of MHE compared with SPT. ICT has in this study consists of 3 tests that evaluate the atten- external validity for MHE because it predicts OHE devel- tion and visuomotor coordination. Previous studies have opment, improves after successful MHE therapy, and demonstrated a significantly worse performance of MHE worsens after TIPS placement. This study also demon- patients on similar batteries and have recommended strates that ICT can be administered in clinics by MAs these tests for MHE diagnosis.12 NCT-A or trail-making after a single training session, which makes ICT a less expensive method for MHE diagnosis than SPT. test involves connecting numbers from 1 to 25 accurately ICT measures response inhibition and attention, 2 while being timed; it is a test of visual scanning speed, basic cognitive domains that are affected in MHE.24 The visual attention, and psychomotor tracking. DST, in outcomes of ICT (lures, targets, and reaction times) pro- which a subject has to transcribe nonsense symbols vide measures of separate but complementary aspects of paired with numbers after referring to a key, is a test of impairment in MHE. Lure response is an act of commis- mental speed and visuomotor coordination and memory. sion, signifying a defect in response inhibition.18 Re- BDT is a test of visuospatial reasoning that requires sponse inhibition is an essential aspect of executive func- spatial orientation, manipulation, and problem solving tion in the brain, which controls an individual’s ability to to rapidly reproduce designs shown to them using inhibit a response that is perhaps prepotent but incorrect blocks. ICT impairment, for both lures and targets, were in a circumstance.11,25 In the current study, all subjects significantly correlated with impairment in NCT-A, DST, were instructed to avoid responding to lures in the train- and BDT and also with the number of tests that were ing session. Despite this, patients with MHE responded impaired. Because all SPT tests rely on accurate visual to a significantly higher number of lures compared with and attention processing, therefore, it is to be expected patients without MHE and healthy controls. Response that the ICT, which is also a test of attention and pro-FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.
  8. 8. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS 8 BAJAJ ET AL GASTROENTEROLOGY Vol. xx, No. x cessing speed, would correlate with performances on ICT lures or SPT individual performance between the these tests. patients who develop OHE and those who did not. As shown in prior studies, performances on NCT-A, TIPS is an excellent model for testing external validity BDT, and DST significantly worsen with increasing age, a of ICT because it can adversely affect psychometric func- finding also demonstrated in our study.9,27 To account tion.30 –32 It has been hypothesized that patients with for this, cirrhotic patients were matched on age to con- TIPS have a combination of portal hypoperfusion and trols. In sharp contrast, ICT lure response rates do not increased availability of nitrogenous compounds because significantly change with increasing age. This is an im- of the shunting. This results in worsening psychometric portant distinction between SPT and ICT because the function and possibly OHE in 5%–35% of patients.32,33 In norms of SPT in most populations are age dependent, this study, there was a significant worsening of SPT whereas ICT performance in controls and cirrhotic pa- performance 1 month after TIPS placement compared tients are not related to age. This potentially broadens with the pre-TIPS performance. Importantly, ICT lures and simplifies the applicability of ICT in the clinic set- worsened after TIPS placement in all but 1 patient. When ting. the 3 patients without OHE after TIPS were excluded, There are several confounding variables that can affect ICT lures were the only psychometric test that was sig- the diagnosis of MHE. Chronic hepatitis C infection has nificantly impaired after TIPS placement. Although the been proposed to result in neurocognitive deficits even number of patients was limited, this finding demon- before the development of cirrhosis.28 In this study, there strates that ICT performance worsens after TIPS. This is was no significant difference in SPT or ICT parameters an important facet of external validity for ICT in patients patients with or without chronic hepatitis C infection. with cirrhosis. This has been similar to our prior published experience Treatment for MHE is an attainable goal because gut- with ICT and shows that, in our population, the effect of based therapy with lactulose, probiotics, and prebiotics cirrhosis probably outweighs the effect of chronic hepa- has demonstrated improvement in psychometric func- tioning and quality of life.34,35 Our group performed a titis C infection. Similarly, there was no significant dif- randomized controlled trial of a probiotic yogurt vs no ference in the psychometric performance on SPT and ICT treatment in nonalcoholic cirrhotic patients over 60 in patients with alcoholic vs nonalcoholic etiology of days.22 There was a significant improvement in individual cirrhosis. This is important to establish because the ini- tests of SPT in the yogurt group but not in the no- tial ICT study specifically excluded those with alcoholic treatment group. Patients who were randomized to yo- cirrhosis, even those with proven alcohol abstinence. gurt in parallel to SPT improvement also had improve- These findings further increase the applicability of the ment in ICT lure response rate. In the no-treatment ICT across a broad range of prevalent chronic liver dis- group, similar to the SPT, ICT lure response did not eases. change.22 This finding further establishes the external Both inter-/intraobserver reliability and test-retest re- validity of ICT as a test that changes with change in the liability are important components of the overall valida- clinical status. tion for a diagnostic test. ICT is a patient-administered The AASLD survey highlighted that a simple test that instrument that has an automated, computerized analy- can be administered by clinic personnel would increase sis system. Therefore inter-/intraobserver reliability is not the chances of MHE testing in clinic.13 In the present important. There was a high correlation of ICT lures and study, 2 previously untrained MAs were trained to ad- targets between repeated administrations, indicating ex- minister the ICT in the hepatology clinic, and the time cellent test-retest reliability. This is essential because psy- required to administer the test was compared with the chometric performance is an end point of MHE trials, SPT. Both administration time and associated costs were and differentiating between learning and therapeutic ef- much smaller for ICT than for SPT. In contrast to SPT, fect of an MHE intervention is important.5,29 The good which requires an additional appointment with a psy- test-retest reliability of ICT lures would make it a good chology specialist, ICT can be administered in the clinic test for application in trials. by MAs while patients await their appointment with the This study also addressed the external validity of the hepatologist. Because of the high sensitivity and ease of ICT by evaluating the ability of ICT to predict OHE and administration, ICT would be useful as a screening test in define post-TIPS and post-MHE therapy alterations in clinics, which will aid in the decision of whether to treat psychometric performance. Patients with MHE have a or to send the patient for further testing. A modified significantly higher rate of developing OHE, the detec- version of the ICT will be made freely available to be tion of which is part of routine care.4 Sixteen percent of downloaded after the trial has been published, which can included patients developed OHE in this study. Extend- increase the availability of MHE testing. In addition, ing our previous experience with ICT, all OHE patients because ICT involves recognizing specific letters, it can had been diagnosed with MHE using both ICT and potentially be administered to non-English-speaking sub- SPT.19 However, there was no significant difference in jects with minimal modifications.FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.
  9. 9. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS Month 2008 DIAGNOSIS OF MINIMAL HEPATIC ENCEPHALOPATHY 9 This study has several limitations. The educational 9. Weissenborn K, Ennen JC, Schomerus H, et al. Neuropsycholog- status of the cirrhotic patients is high compared with the ical characterization of hepatic encephalopathy. J Hepatol 2001; 34:768 –773. general population; however, despite this, cirrhotic pa- 10. Ford JM, Gray M, Whitfield SL, et al. Acquiring and inhibiting tients as a whole and MHE patients in particular per- prepotent responses in schizophrenia: event-related brain poten- formed significantly worse on ICT and SPT compared tials and functional magnetic resonance imaging. Arch Gen Psy- with education-matched controls. Similar to our previ- chiatry 2004;61:119 –129. ous experience, most cirrhotic patients were Child–Pugh 11. Schiff S, Vallesi A, Mapelli D, et al. Impairment of response class A or B. This is probably due to the high likelihood inhibition precedes motor alteration in the early stage of liver of Child–Pugh class C patients being on OHE therapy, cirrhosis: a behavioral and electrophysiological study. Metab Brain Dis 2005;20:381–392. which was an exclusion criterion for this study. There is 12. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy— no current “gold standard” for MHE diagnosis, and this definition, nomenclature, diagnosis, and quantification: final report study used a modification of a recommended SPT bat- of the working party at the 11th World Congresses of Gastroenter- tery; however, this study as well as our prior experience ology, Vienna, 1998. Hepatology 2002;35:716 –721. has found this method of MHE diagnosis to successfully 13. Bajaj JS, Etemadian A, Hafeezullah M, et al. Testing for minimal predict OHE and driving impairment.19,21 In addition, hepatic encephalopathy in the United States: an AASLD survey. Hepatology 2007;45:833– 834. there was a good correlation between the number of 14. Epstein JN, Johnson DE, Varia IM, et al. Neuropsychological impaired SPT and ICT results. The sample size for the assessment of response inhibition in adults with ADHD. J Clin TIPS and yogurt trial aspect were limited, but they did Exp Neuropsychol 2001;23:362–371. demonstrate a significant change in ICT that was similar 15. Konrad K, Gauggel S, Manz A, et al. Inhibitory control in children with to the change in SPT that was expected after TIPS and traumatic brain injury (TBI) and children with attention deficit/ therapy. hyperactivity disorder (ADHD). Brain Inj 2000;14:859 – 875. In summary, ICT is a sensitive test for the diagnosis of 16. Garavan H, Ross TJ, Stein EA. Right hemispheric dominance of inhibitory control: an event-related functional MRI study. Proc Natl MHE, which can also predict OHE similar to SPT and Acad Sci U S A 1999;96:8301– 8306. has good external validity and test-retest reliability. ICT 17. Pliszka SR, Liotti M, Woldorff MG. Inhibitory control in children can be administered by clinic personnel without the need with attention-deficit/hyperactivity disorder: event-related po- for psychologic expertise, which makes it an inexpensive tentials identify the processing component and timing of an option for MHE diagnosis. impaired right-frontal response-inhibition mechanism. Biol Psy- chiatry 2000;48:238 –246. 18. Ballard JC. Assessing attention: comparison of response-inhibi- Supplementary Data tion and traditional continuous performance tests. J Clin Exp Note: To access the supplementary material ac- Neuropsychol 2001;23:331–350. companying this article, visit the online version of Gas- 19. Bajaj JS, Saeian K, Verber MD, et al. Inhibitory control test is a troenterology at, and at doi:10. simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy. Am J Gas- 1053/j.gastro.2008.07.021. troenterol 2007;102:754 –760. 20. Wechsler D. Wechsler Adult Intelligence Scale-III. San Antonio, References TX; Psychological Corp, 1999. 1. Mullen K, Ferenci P, Bass NM, et al. An algorithm for the 21. Bajaj JS, Hafeezullah M, Hoffmann RG, et al. Navigation skill management of hepatic encephalopathy. Semin Liv Dis 2007; impairment: another dimension of the driving difficulties in 27:32– 48. minimal hepatic encephalopathy. Hepatology 2008;47:596 – 2. Li YY, Nie YQ, Sha WH, et al. Prevalence of subclinical hepatic 604. encephalopathy in cirrhotic patients in China. World J Gastroen- 22. Bajaj JS, Saeian K, Christensen K, et al. Probiotic yogurt for terol 2004;10:2397–2401. the treatment of minimal hepatic encephalopathy. Am J Gas- 3. Das A, Dhiman RK, Saraswat VA, et al. Prevalence and natural troenterol 2008;103:1707–1715. history of subclinical hepatic encephalopathy in cirrhosis. J Gas- 23. AMA. Current Procedural Terminology. Chicago, IL; American troenterol Hepatol 2001;16:531–535. Medical Association, 2007. 4. Romero-Gomez M, Boza F, Garcia-Valdecasas MS, et al. Subclin- 24. Weissenborn K, Giewekemeyer K, Heidenreich S, et al. Attention, ical hepatic encephalopathy predicts the development of overt memory, and cognitive function in hepatic encephalopathy. hepatic encephalopathy. Am J Gastroenterol 2001;96:2718 – Metab Brain Dis 2005;20:359 –367. 2723. 25. Walker AJ, Shores EA, Trollor JN, et al. Neuropsychological func- 5. Prasad S, Dhiman RK, Duseja A, et al. Lactulose improves cog- nitive functions and health-related quality of life in patients with tioning of adults with attention deficit hyperactivity disorder. J Clin cirrhosis who have minimal hepatic encephalopathy. Hepatology Exp Neuropsychol 2000;22:115–124. 2007;45:549 –559. 26. Ortiz M, Cordoba J, Jacas C, et al. Neuropsychological abnormal- 6. Wein C, Koch H, Popp B, et al. Minimal hepatic encephalopathy ities in cirrhosis include learning impairment. J Hepatol 2006; impairs fitness to drive. Hepatology 2004;39:739 –745. 44:104 –110. 7. Bajaj JS, Hafeezullah M, Hoffmann RG, et al. Minimal hepatic 27. Ortiz M, Jacas C, Cordoba J. Minimal hepatic encephalopathy: encephalopathy: a vehicle for accidents and traffic violations. diagnosis, clinical significance and recommendations. J Hepatol Am J Gastroenterol 2007;102:1903–1909. 2005;42(Suppl):S45–S53. 8. Groeneweg M, Quero JC, De Bruijn I, et al. Subclinical hepatic 28. Perry W, Hilsabeck RC, Hassanein TI. Cognitive dysfunction encephalopathy impairs daily functioning. Hepatology 1998;28: in chronic hepatitis C: a review. Dig Dis Sci 2008;53:307– 45– 49. 321.FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.
  10. 10. FOR HKMA CME MEMBERARTICLE DO NOT REPRODUCE OR DISTRIBUTE. USE ONLY. IN PRESS 10 BAJAJ ET AL GASTROENTEROLOGY Vol. xx, No. x 29. Watanabe A, Sakai T, Sato S, et al. Clinical efficacy of lactulose 34. Liu Q, Duan ZP, Ha da K, et al. Synbiotic modulation of gut flora: in cirrhotic patients with and without subclinical hepatic enceph- effect on minimal hepatic encephalopathy in patients with cirrho- alopathy. Hepatology 1997;26:1410 –1414. sis. Hepatology 2004;39:1441–1449. 30. Sanyal AJ, Freedman AM, Shiffman ML, et al. Portosystemic 35. Malaguarnera M, Greco F, Barone G, et al. Bifidobacterium encephalopathy after transjugular intrahepatic portosystemic longum with fructo-oligosaccharide (FOS) treatment in minimal shunt: results of a prospective controlled study. Hepatology hepatic encephalopathy: a randomized, double-blind, placebo- 1994;20:46 –55. controlled study. Dig Dis Sci 2007;52:3259 –3265. 31. Jalan R, Elton RA, Redhead DN, et al. Analysis of prognostic variables in the prediction of mortality, shunt failure, variceal rebleeding and encephalopathy following the transjugular intra- Received April 8, 2008. Accepted July 17, 2008. hepatic portosystemic stent-shunt for variceal haemorrhage. Address requests for reprints to: Jasmohan S Bajaj, MD, MS, Division J Hepatol 1995;23:123–128. of Gastroenterology, Hepatology and Nutrition, Virginia Common- 32. Riggio O, Masini A, Efrati C, et al. Pharmacological prophylaxis of wealth University and McGuire VA Medical Center, 1201 Broad Rock hepatic encephalopathy after transjugular intrahepatic portosys- Blvd, Richmond, VA. e-mail:; fax: (804) 675 temic shunt: a randomized controlled study. J Hepatol 2005;42: 5816. 674 – 679. Supported in part by GCRC grant number M01-RR00058 and by the 33. Mullen KD, Ghanta RK, Putka BS. Prevention of first overt epi- New Investigator Research Affairs Committee grant at the Medical sode of hepatic encephalopathy after TIPS: no easy task. Hepa- College of Wisconsin (to J.S.B.). tology 2006;43:1155–1156. Financial interest and disclosure: None relevant to this study.FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE.