Measurement of continuous reaction times (CRT) was applied to 105 hospitalized controls, 65 patients with brain damage and 47 patients with hepatic encephalopathy. One hundred and fifty reaction times were measured in every patient. The best discrimination between controls and patients with organic brain damage was obtained with the 10 percentile of the reaction time distribution (86% correct classification). The 90 percentile discriminated best between controls and patients with hepatic encephalopathy (86% correct classification). Furthermore, the ratio between the 50 percentile and the difference between the 10 and 90 percentile made it possible to discriminate between the two groups of patients (91% correct classification), which indicates that the CRT test is suitable as a screening device for discrimination between organic brain damage and hepatic encephalopathy.

Liver. 1985 Feb;5(1):29-34.

Existing tests for minimal/covert hepatic encephalopathy (m/cHE) are time- and expertise consuming and primarily useable for research purposes. An easy-to-use, fast and reliable diagnostic and grading tool is needed. We here report on the background, experience, and ongoing research regarding the continuous reaction times (CRT) method. The method has been in clinical use for decades in Denmark for the stated purpose. The method is a 10-minutes, computerised registration of a series of motor reaction times to an auditory stimulus, with results reported as the CRTindex (50 percentile/(90-10) percentile) as a parameter of reaction time variability. The index is a measure of alertness stability and is used to assess attention and cognition deficits. The CRTindex identifies half of patients in a Danish cohort with chronic liver disease, as having m/cHE, a normal value safely precludes HE, it has a broad outcome span reflecting the degree of brain impairment, it shows no learning effect, and it is independent on age and gender. The CRTindex is, therefore, a candidate tool for routine screening, detecting, grading, and monitoring m/cHE. Still, however, further methodological and clinical validation trials are required and are currently being conducted.

Metab Brain Dis. 2013 Jun;28(2):231-4. doi: 10.1007/s11011-012-9373-z. Epub 2013 Jan 10.

Number Connection Test (NCT) and Continuous Reaction Times (CRT) have been used for assessment of encephalopathy in groups of 105 controls, 65 brain damaged patients and 22 patients with hepatic encephalopathy. With the use of NCT, 65% of the patients with cerebral damage could be correctly classified with regard to presence versus absence of brain disease, whereas the use of CRT gave 85% correct classification. With regard to hepatic encephalopathy the CRT was better for classification than NCT; respectively 86% and 64% were correctly classified. The NCT could not separate the patient with brain damage from the patients with hepatic encephalopathy, whereas CRT could classify respectively 95% and 86% correctly. When the tests were performed on five successive days, the NCT scores showed a learning effect, whereas the CRT gave stable measures. This means that the CRT was superior to the NCT for classification purposes.

Acta Pharmacol Toxicol (Copenh). 1984 Feb;54(2):115-9.

These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic; (2) guideline policies covered by the American Association for the Study of Liver Diseases/European Association for the Study of the Liver (AASLD/EASL) Policy on the Joint Development and Use of Practice Guidelines; and (3) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD/EASL Practice Guidelines Subcommittee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup, with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the quality of evidence designated by high (A), moderate (B), or low quality (C); and the strength of recommendations classified as strong (1) or weak (2).

Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver

Minimal hepatic encephalopathy (MHE) is intermittently present in up to 2/3 of patients with chronic liver disease. It impairs their daily living and can be treated. However, there is no consensus on diagnostic criteria except that psychometric methods are required. We compared two easy-to-perform reproducible bedside methods: the critical flicker frequency (CFF) and continuous reaction times (CRT) tests. A CFF <39 Hz and CRT-index <1.9 (index: the ratio 50/(90 minus 10) percentiles of reaction times) indicates cerebral dysfunction. 154 patients with acute or chronic liver disease with out overt hepatic encephalopathy (HE) underwent both tests at the same occasion. Both tests were abnormal in 20% of the patients and both tests were normal in 40% of the patients. In more than 1/3 the two tests were not in agreement as CFF classified 32% and CRT-index classified 48% of the patients as having MHE (p < 0.005). The two tests were weakly linearly correlated (r(2) = 0.14, p < 0.001) and neither test correlated with the metabolic liver function measured by the Galactose Elimination Capacity (GEC), nor with the blood ammonia concentration. Both tests identified a large fraction of the patients as having MHE and cleared only 40%. The two tests did not show concordant results, likely because they describe different aspects of MHE: the CFF gives a measure of astrocytic metabolic state and hence pathogenic aspects of MHE, whereas the CRT measures a composite key performance, viz. the ability of reacting appropriately to a sensory stimulus. The choice of test depends on the information needed in the clinical and scientific care and study of the patients.

Metab Brain Dis. 2011 Jun;26(2):135-9. doi: 10.1007/s11011-011-9242-1. Epub 2011 Apr 12.

Minimal hepatic encephalopathy (MHE) is a metabolic brain disorder occurring in patients with liver cirrhosis. MHE lessens a patient’s quality of life, but is treatable when identified. The continuous reaction times (CRT) method is used in screening for MHE. Gender and age effects on the CRT method are unknown and may confound the results. The aim of this study was to standardise the CRT method outcomes for age and gender effects. We studied 121 volunteers without known disease and 181 patients with cirrhosis by a CRT test. Reaction time to an auditory signal was measured 100 times, the 10th, 50th, and 90th reaction time percentiles were recorded, and the CRT index was calculated as the 50th percentile/(90th percentile-10th percentile), as a measure of intra-individual stability in reaction times. In volunteers, men reacted faster than women and their reaction times slowed with age. However, neither the gender nor the age effect was present regarding the CRT index. The patients with cirrhosis reacted slower and with a higher degree of instability than volunteers. Male patients reacted faster than female patients, and reaction times tended to slow with age. As among the volunteers, there was no gender or age effect on CRT index for the patients with cirrhosis. Age and gender influenced reaction times of both volunteers and patients with cirrhosis. The CRT index, however, was independent of age and gender in both groups. Screening of patients with cirrhosis using the CRT index, therefore, identifies brain dysfunction rather than effects of gender and age.

Metab Brain Dis. 2012 Dec;27(4):559-65. doi: 10.1007/s11011-012-9318-6. Epub 2012 May 22.

While it is consensus that minimal hepatic encephalopathy (mHE) has significant impact on a patient’s daily living, and thus should be diagnosed and treated, there is no consensus about the optimal diagnostic tools. At present the most frequently used psychometric methods for diagnosing minimal hepatic encephalopathy are the Inhibitory Control Test and the Psychometric Hepatic Encephalopathy Score PHES. Another frequently used method is Critical Flicker Frequency. The PHES and the Repeatable Battery for the Assessment of Neuropsychological Status have been recommended for diagnosing mHE by a working party commissioned by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism. Recently the Continuous Reaction Time Test, which has been used in the 1980ies, has gained new interest. Today, no data are available that allow to decide which of these methods is the most appropriate. In fact, even basic information such as dependence on age, sex and education or influence of diseases that frequently accompany liver cirrhosis upon test results is missing for most of them. Future studies must address these questions to improve diagnosis of mHE.

Metab Brain Dis. 2013 Jun;28(2):227-9. doi: 10.1007/s11011-012-9336-4. Epub 2012 Sep 21.