Diagnosis of Minimal Hepatic Encephalopathy Using Stroop EncephalApp

A Multicenter US-Based, Norm-Based Study

Sanath Allampati, MD; Andres Duarte-Rojo, MD; Leroy R. Thacker, PhD; Kavish R. Patidar, MD; Melanie B. White, RN; Jagpal S. Klair, MD; Binu John, MD; Douglas M. Heuman, MD; James B. Wade, PhD; Christopher Flud, MD; Robert O'Shea, MD; Edith A. Gavis, RN; Ariel B. Unser, BS; Jasmohan S. Bajaj, MD


Am J Gastroenterol. 2016;111(1):78-86. 

In This Article


Outpatients with cirrhosis and healthy controls between 21 and 65 years of age were prospectively recruited from three centers (Virginia Commonwealth University and McGuire VA Medical Center, Cleveland Clinic, and University of Arkansas) between December 2012 and June 2014. Cirrhotic patients were diagnosed either by biopsy, radiologic evidence of cirrhosis, endoscopic evidence of varices in a patient with chronic liver disease, or those with frank decompensation (history of variceal bleeding, ascites, or prior OHE). We included patients with a history of prior episodes of OHE provided they were controlled on medications (lactulose and/or rifaximin) at the time of testing. All patients were able to give informed consent as judged by a mini-mental status score of ≥25, and frank dementia was excluded by family interview, chart review, and evaluation of concurrent medications. We excluded subjects who were not able to give informed consent, had red–green color blindness, had abused alcohol/illicit drugs over the last 3 months, and were on psychoactive medications apart from chronic antidepressants, as these were not associated with cognitive impairment in prior studies.[11] All healthy controls were free from chronic diseases and did not have red–green color blindness. The investigators underwent one training meeting before study initiation and one during the study. The results were communicated and issues discussed at least once a month as the study progressed. The protocol was approved in the institutional review boards of all the sites.

The study was carried out in two phases: (A) cross-sectional; and (B) prospective.

Cross-sectional Study

Cirrhotics and controls were enrolled prospectively and screened for eligibility issues. Those eligible then underwent the three testing strategies at the same sitting in this order: PHES; ICT; and then EncephalApp.

Creation of Norms for EncephalApp, PHES, and ICT in the US Population

Healthy controls from the three sites were used to create norms for all three testing methodologies, EncephalApp, PHES, and ICT, that were adjusted with respect to age, gender, and years of education for all three tests to normal and abnormal values.

PHES. This consists of five tests—number connection test-A (NCT-A; time to join the dots with only numbers), number connection test-B (NCT-B; time to join the dots with numbers and letters), digit symbol test (DST; number of correctly marked symbols in 120 s), serial dotting test (SDT; time to dot individual circles), and line tracing test (LTT; time to complete a maze without touching the sides; we used errors+time as the outcome).[12] S.d.'s according to healthy control performance in the three centers, adjusted for age, gender, and years of education, were created, and a performance below −4 points based on composite s.d. scores was considered MHE by PHES.[12]

ICT. ICT is a computerized test with two outcomes, lures, which are stimuli, which subjects should inhibit their response, and targets, which subjects should respond to. Lure outcomes were used in this study given the prior US-based experience.[9] Unlike the prior experience, these results were adjusted to age, gender, and education and abnormal performance was defined as MHE by ICT.

EncephalApp. The EncephalApp was administered using standard iPod screens. The task has two components: "off" and "on" state depending on the discordance or concordance of the stimuli. Both components were administered after two training runs. In the easier "off" state, the subject views a neutral stimulus, pound signs (###) presented in red, green, or blue, one at a time and has to respond as quickly as possible by touching the matching color of the stimulus to the colors displayed at the bottom of the screen. The colors at the bottom of the screen are also randomized and not fixed to their respective positions. This continues until a total of 10 presentations are completed correctly, which is one run. Outcome values include the total time taken for the run as well as the individual responses. If the subject makes a mistake, i.e., presses a wrong color, the run stops and has to start again. Therefore, the number of runs required to make five correct runs also indicates the number of mistakes. We continued the off state till the subject had achieved five correct runs. The "on" state is more challenging from a cognitive standpoint in that incongruent stimuli are presented in nine of the ten stimuli. In this portion, the subject has to accurately touch the color of the word presented, which is actually the name of the color in discordant coloring, i.e., the word "RED" is displayed in blue color and the correct response is blue not red. Similar to the "off" state, we gave two training runs and then continued the task till five correct runs were achieved. The specific outcomes at the end of the EncephalApp app were: (a) total time for five correct runs in the "off" state (OffTime); (b) number of runs needed to complete the five correct "off" runs; (c) total time for five correct runs in the "on" state (OnTime); and (d) number of runs needed to complete the five correct "on" runs. The test of cognitive processes controlling for psychomotor speed was obtained by subtracting the OffTime from the OnTime, and this was performed for all groups. OffTime+OnTime has been found in prior EncephalApp studies to be the best discriminator between subjects with and without MHE.[6,7] This outcome was the ultimate measure used to define EncephalApp performance in controls, which was adjusted by age, educational attainment, and gender. MHE was defined as an abnormal threshold based on these adjusted norms.

Comparison of EncephalApp Based on PHES and ICT Values

In addition to developing norms based on the healthy controls, we also developed specific unadjusted cutoff points based on control performance (−4 composite points and worse for PHES and lures >1 s.d. for ICT) to define EncephalApp MHE based on PHES and EncephalApp MHE based on ICT. The EncephalApp OffTime+OnTime cutoffs generated through the Youden index calculation of the area under the curve using receiver operating characteristic analysis were used to define MHE according to EncephalApp.

Therefore, we had three methods to validate and develop clinical norms for EncephalApp: (1) based on direct population norms; (2) based on PHES; and (3) based on ICT.

Comparison of Concordance and Inter-site Variability of PHES, ICT, and EncephalApp Results

Using the adjusted norms, we defined the concordance between the three testing methodologies. Also, we determined the inter-site variability between the three sites using phi coefficients.

Prospective Study (Prediction of the Development of OHE)

Patients who were included in the cross-sectional arm were followed for a minimum of 6 months after testing for the development of OHE, which was defined as the presence of disorientation and asterixis that required hospitalization and initiation/change in therapy. Cox regression analyses with time to OHE as the outcome were created. This was performed using three models in the entire group and patients without prior OHE.

In the entire group, all three models contained age, gender, alcoholic etiology, model for end-stage liver disease (MELD) score, and OHE status at the time of testing, all of which can impact cognitive testing and OHE development; model 1 had MHE on EncephalApp based on direct adjusted US population norms, model 2 had with MHE on EncephalApp based on PHES, and model 3 had MHE on EncephalApp based on ICT. In the population without prior OHE, similar three models were created without the prior OHE at baseline variable. Cox regression analyses were performed as well for the development of OHE in all groups using the different MHE definitions and following covariates; age, gender, education, MELD score, prior OHE (in models that included all patients), and alcoholic etiology.

Validation Cohort Testing

A separate cohort of cirrhotic patients was recruited from Virginia with the identical eligibility criteria as the cross-sectional cohort. Using the cutoffs generated through the combined data with direct norms for EncephalApp and EncephalApp based on PHES and ICT, the area under the curve (AUC) of the receiver operating characteristic curves for EncephalApp was created and concordances with the initial cohort combined values and Virginia (VA)-specific values were compared.