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      Prediction of overt hepatic encephalopathy by the continuous reaction time method and the portosystemic encephalopathy syndrome test in clinically mentally unimpaired patients with cirrhosis

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          Abstract

          Background and aim

          Predicting overt hepatic encephalopathy (OHE) is important because the condition is frequent, often requires hospitalization and is potentially preventable. The risk of OHE is related to pre-existing discrete cognitive defects, and for clinical practice it is recommended to apply two different psychometric tests to detect such deficits. We used the continuous reaction time test (CRT) and the portosystemic encephalopathy (PSE) syndrome test and examined their single and combined value for OHE prediction in cirrhosis patients.

          Patients and methods

          We studied 130 clinically mentally unimpaired cirrhosis patients by the two tests and followed them for an average of 38.5 months. The CRT measures velocity and stability of motor reaction times to 150 repeated auditory signals. The PSE is a five sub-set paper-and-pencil test battery evaluating cognitive and psychomotor processing, speed and vision-motor coordination. We collected data on episodes of OHE during follow-up. The clinical course was analysed in patient groups according to the outcome of each test and of both tests together. No anti-HE treatment was initiated except for cases with OHE.

          Results

          At baseline, the CRT test was abnormal in 74 patients and the PSE in 47. During follow-up 35 patients (27%) experienced 74 OHE events. 23 patients with abnormal CRT experienced OHE (prediction sensitivity 65%). The PSE predicted OHE in 14 patients (prediction sensitivity 40%). One or both tests were abnormal in 87/130 (67%) and this predicted OHE in 27 patients (21%) (prediction sensitivity 77%).

          Conclusion

          The CRT test was clinically useful in identifying two-thirds of clinically mentally unimpaired cirrhosis patients who later experienced OHE, and the use of both the CRT and PSE showed satisfactory prediction by identifying three-fourths of later OHE cases.

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          Most cited references22

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          The clinical course of cirrhosis: The importance of multistate models and competing risks analysis.

          Multistate models are models of disease progression that, for a patient group, define multiple outcome events, each of which may affect the time to develop another outcome event. Multistate models are highly relevant for studies of patients with cirrhosis; both the classical perception of cirrhosis as either compensated or decompensated and the recent, more complex models of cirrhosis progression are multistate models. Therefore, researchers who conduct clinical studies of patients with cirrhosis must realize that most of their research questions assume a multistate disease model. Failure to do so can result in severely biased results and bad clinical decisions. The analyses that can be used to study disease progression in a multistate disease model may be called competing risks analysis, named after the competing risks disease model, which is the simplest multistate disease model. In this review article, we introduce multistate disease models and competing risks analysis and explain why the standard armamentarium of Kaplan-Meier survival estimates and Cox regression sometimes gives bad answers to good questions. We also use real data to answer typical research questions about the course of cirrhosis and illustrate biases resulting from inadequate methods. Finally, we suggest statistical software packages that are helpful and accessible to the clinician-researcher.
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            Diagnosis of minimal hepatic encephalopathy.

            Minimal hepatic encephalopathy (mHE) has significant impact upon a liver patient's daily living and health related quality of life. Therefore a majority of clinicians agree that mHE should be diagnosed and treated. The optimal means for diagnosing mHE, however, is controversial. This paper describes the currently most frequently used methods-EEG, critical flicker frequency, Continuous Reaction time Test, Inhibitory Control Test, computerized test batteries such as the Cognitive Drug Research test battery, the psychometric hepatic encephalopathy score (PHES) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)-and their pros and cons.
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              The continuous reaction times method for diagnosing, grading, and monitoring minimal/covert hepatic encephalopathy.

              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.
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                Author and article information

                Contributors
                Role: Formal analysisRole: MethodologyRole: Project administrationRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 December 2019
                2019
                : 14
                : 12
                : e0226283
                Affiliations
                [1 ] Department of Gastroenterology, Hospital of Southwest Jutland, Esbjerg, Region of Southwest of Denmark, Denmark
                [2 ] Department for Medical Gastrointestinal Diseases, Odense University Hospital, Odense, Region of Southwest of Denmark, Denmark
                [3 ] Department of Hepatology and Gastroenterology, Aarhus University Hospital, Central Denmark Region, Denmark
                Medizinische Fakultat der RWTH Aachen, GERMANY
                Author notes

                Competing Interests: MM Lauridsen has given lectures paid by Norgine, MM Lauridsen has a consultant agreement with Umecrine Cognition, MM Lauridsen is on the steering committee in the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0001-8964-0650
                http://orcid.org/0000-0003-0586-8549
                Article
                PONE-D-19-25609
                10.1371/journal.pone.0226283
                6907801
                31830113
                4951914d-4cee-4f3c-ac1e-53c57d095687
                © 2019 Wernberg et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 September 2019
                : 22 November 2019
                Page count
                Figures: 2, Tables: 2, Pages: 12
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Biology and Life Sciences
                Psychology
                Psychometrics
                Social Sciences
                Psychology
                Psychometrics
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Cirrhosis
                Biology and Life Sciences
                Neuroscience
                Cognitive Science
                Cognitive Neuroscience
                Cognitive Neurology
                Cognitive Impairment
                Biology and Life Sciences
                Neuroscience
                Cognitive Neuroscience
                Cognitive Neurology
                Cognitive Impairment
                Medicine and Health Sciences
                Neurology
                Cognitive Neurology
                Cognitive Impairment
                Biology and Life Sciences
                Neuroscience
                Cognitive Science
                Cognitive Neuroscience
                Reaction Time
                Biology and Life Sciences
                Neuroscience
                Cognitive Neuroscience
                Reaction Time
                Biology and Life Sciences
                Neuroscience
                Cognitive Science
                Cognitive Psychology
                Biology and Life Sciences
                Psychology
                Cognitive Psychology
                Social Sciences
                Psychology
                Cognitive Psychology
                Biology and Life Sciences
                Neuroscience
                Cognitive Science
                Cognition
                Biology and Life Sciences
                Nutrition
                Diet
                Alcohol Consumption
                Medicine and Health Sciences
                Nutrition
                Diet
                Alcohol Consumption
                People and places
                Geographical locations
                Europe
                European Union
                Denmark
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information file. In order to secure all participants’ privacy, identifying information (birthdate, age, gender, rare devices, admission- and death-dates) as well as some pseudo-identifying information has been removed. The Supporting information is therefore considered highly anonymous and there is no risk of potential identifiable material and we have therefore not obtained informed consent on open data from participants.

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