The continuous reaction time test for minimal hepatic encephalopathy validated by a randomized controlled multi-modal intervention-A pilot study

Abstract

Background: Minimal hepatic encephalopathy (MHE) is clinically undetectable and the diagnosis requires psychometric tests. However, a lack of clarity exists as to whether the tests are in fact able to detect changes in cognition.

Aim: To examine if the continuous reaction time test (CRT) can detect changes in cognition with anti-HE intervention in patients with cirrhosis and without clinically manifest hepatic encephalopathy (HE).

Methods: Firstly, we conducted a reproducibility analysis and secondly measured change in CRT induced by anti-HE treatment in a randomized controlled pilot study: We stratified 44 patients with liver cirrhosis and without clinically manifest HE according to a normal (n = 22) or abnormal (n = 22) CRT. Each stratum was then block randomized to receive multimodal anti-HE intervention (lactulose+branched-chain amino acids+rifaximin) or triple placebos for 3 months in a double-blinded fashion. The CRT is a simple PC-based test and the test result, the CRT index (normal threshold > 1.9), describes the patient's stability of alertness during the 10-minute test. Our study outcome was the change in CRT index in each group at study exit. The portosystemic encephalopathy (PSE) test, a paper-and-pencil test battery (normal threshold above -5), was used as a comparator test according to international guidelines.

Results: The patients with an abnormal CRT index who were randomized to receive the active intervention normalized or improved their CRT index (mean change 0.92 ± 0.29, p = 0.01). Additionally, their PSE improved (change 3.85 ± 1.83, p = 0.03). There was no such effect in any of the other study groups.

Conclusion: In this cohort of patients with liver cirrhosis and no manifest HE, the CRT identified a group in whom cognition improved with intensive anti-HE intervention. This finding infers that the CRT can detect a response to treatment and might help in selecting patients for treatment.

Fig 1. Patient flow through the study.

A total of 44 patients were prospectively included and stratified according to a CRT index below or at 1.9 (abnormal) or above (normal). Patients were then block randomized into groups to receive either triple-active anti-HE intervention or triple placebo. We followed them for 3 months.

Fig 2. Data from 22 patients with liver cirrhosis who all underwent 8 repeated continuous reaction time (CRT) measurements: 4 measurements on to consecutive days.