---
title: "Eye movement analysis identifies early cognitive impairment in cirrhosis missed by PHES"
id: "plos-one-12-eye-movement-analysis-detects-early-neurological-alterations-in-cirrhotic"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-12-eye-movement-analysis-detects-early-neurological-alterations-in-cirrhotic"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358353"
published_at: "2026-09-15T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Eye movement analysis identifies early cognitive impairment in cirrhosis missed by PHES
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-12-eye-movement-analysis-detects-early-neurological-alterations-in-cirrhotic
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358353)
- **Published At:** 2026-09-15T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Cirrhotic patients classified as without **minimal hepatic encephalopathy (MHE)** by the Psychometric Hepatic Encephalopathy Score (**PHES**) can nonetheless have subtle cognitive deficits detectable with other tests and eye movement analysis. - The study enrolled 118 cirrhotic patients (32 with MHE by PHES, 86 without MHE) and 35 healthy controls; eye movements were recorded with video-oculography and psychometric testing performed. - Using a novel score derived from historical cohorts (519 cirrhotic patients and 74 age-matched healthy controls), the most discriminatory psychometric variables were from the **d2**, Oral Symbol Digit Modalities Test (SDMT), and **Stroop** tests. - Among the 86 patients labeled as without MHE by PHES, 46 (53.5%) showed impaired cognitive performance on the new score and were classified as having early cognitive impairment (early-MHE). - Early-MHE patients had worse psychometric performance and measurable alterations in **eye movement** tests, especially in **antisaccade** and fixation tasks; abnormalities were more marked in patients with overt MHE by PHES, suggesting a continuum of dysfunction. - Eye movement variables with highest predictive value for combined mild impairment (early-MHE + MHE) came from horizontal and vertical antisaccade tasks and fixation tests. - A multivariate model using horizontal antisaccade variables achieved the best predictive performance: **AUROC** 0.803 (95% CI: 0.711–0.896; p < 0.0001), with 66.7% sensitivity and 90.6% specificity at a relative-risk cutoff of 65.66%. - The authors conclude that **eye movement analysis** is a rapid, objective, non-invasive method that can detect subtle neurological alterations in cirrhotic patients and may enable earlier identification and intervention. - Data supporting the findings, including eye movement variables, are available on Zenodo as reported in the article.
## Clinical Analysis & Structured Key Points
Eye movement analysis detects early neurological alterations in cirrhotic patients classified as not having minimal hepatic encephalopathy by the Psychometric Hepatic Encephalopathy Score | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Reader Comments Figures Figures Abstract Cirrhotic patients classified by the Psychometric Hepatic Encephalopathy Score (PHES) as without minimal hepatic encephalopathy (MHE) may present subtle cognitive alterations which could be detected by eye movement analysis. The aims were to develop a score for detecting early cognitive alterations in cirrhotic patients using specific psychometric tests and to identify which eye movement parameters could be used to detect them. A total of 118 cirrhotic patients (32 with MHE and 86 without MHE, according to PHES) and 35 healthy controls underwent psychometric assessment and eye movement testing by video-oculography. Forty-six patients without MHE (53.5%) showed impaired cognitive performance and were classified as having early cognitive impairment (early-MHE) using a novel score based on the most affected variables from several psychometric tests. This score was developed using historical cohorts of 519 cirrhotic patients and 74 age-matched healthy controls, and the optimal set of parameters included were from d2, Oral Symbol Digit Modalities, and Stroop tests. Early-MHE patients showed poorer cognitive performance and alterations in eye movement tests, particularly in antisaccade and fixation tasks. These abnormalities were more pronounced in MHE patients, suggesting a continuum of cognitive dysfunction from patients without detectable impairment by PHES to those with MHE. Eye movement variables with the highest predictive value for detecting mild cognitive alterations (early-MHE + MHE) were obtained from horizontal and vertical antisaccade tasks and fixation tests. Multivariate analysis grouping by eye movement task showed that a model including variables from the horizontal antisaccade test achieved the best predictive performance, with AUROC of 0.803 (95% CI: 0.711–0.896; p < 0.0001), 66.7% sensitivity, and 90.6% specificity at a relative-risk cutoff of 65.66%. Eye movement analysis is a rapid, objective, and non-invasive tool for detecting subtle neurological alterations in cirrhotic patients. This approach may facilitate earlier identification of cognitive impairment and support timely clinical intervention. Citation: Gallego J-J, Casanova-Ferrer F, Fiorillo A, López-Gramaje A, Campos D, Urios A, et al. (2026) Eye movement analysis detects early neurological alterations in cirrhotic patients classified as not having minimal hepatic encephalopathy by the Psychometric Hepatic Encephalopathy Score. PLoS One 21(9): e0358353. https://doi.org/10.1371/journal.pone.0358353 Editor: Sharon DeMorrow, THe University of Texas in Austin, UNITED STATES OF AMERICA Received: November 18, 2025; Accepted: August 31, 2026; Published: September 15, 2026 Copyright: © 2026 Gallego 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. Data Availability: The data generated and analyzed during this study are included within this article, and its Supporting Information . Data of eye movement variables are available from the Zenodo.org repository https://doi.org/10.5281/zenodo.20638131 (accessed on 11 June 2026). Funding: This work was supported by Agencia Valenciana de Innovación, Generalitat Valenciana (Consolidacio Cadena Valor) to CM; Generalitat Valenciana (CIPROM2021/082, co-funded ERDF funds to CM; CIAICO/2026/6 to CM; CIACIF/2022/444 to ALG; CIGRIS/2024/058 to DC); Instituto de Salud Carlos III (PI23/00062), co-funded ERDF funds to CM; Donation from Fundación Raminatrans (president of Foundation, Larissa Milla) to CM. F. Sarabia Donation (PRV00225) to CM. This study has been conducted in accordance with the theme 075-00224-26-02 ITEB RAS assigned to E.K. for the year 2026 and the 2027–2028 planning period. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Competing interests: The authors have declared that no competing interests exist. Introduction Minimal hepatic encephalopathy (MHE) is characterized by cognitive and motor impairments, including alterations in cognitive and executive functions such as selective and sustained attention, visuospatial perception and motor speed [ 1 – 3 ]. These impairments negatively affect daily functioning, reduce quality of life and survival, and increase the risk of falls and hospitalizations [ 4 – 6 ]. MHE represents the earliest clinically recognized stage of hepatic encephalopathy (HE) and is considered the main risk factor for the development of overt HE [ 7 – 9 ]. Early identification and treatment of MHE would improve the quality of life, prevent progression to overt HE, reduce healthcare costs, and improve clinical outcomes [ 10 , 11 ]. Since the 11th World Congress of Gastroenterology (1998), the Psychometric Hepatic Encephalopathy Score (PHES) has been widely accepted as the reference standard for the diagnosis of MHE [ 12 , 13 ]. However, over the last decade, several studies have shown that PHES lacks sufficient sensitivity to identify all patients with mild cognitive and motor impairment [ 14 – 17 ]. Butz et al [ 16 ] showed that ataxia and some motor abnormalities may represent early markers of cerebral dysfunction in a subgroup of cirrhotic patients before deficits become detectable by conventional psychometric testing. Similarly, several studies have shown that a proportion of patients classified as “without MHE” according to PHES already exhibit impairments in specific neurological functions [ 3 , 14 – 17 ]. Felipo et al. [ 3 , 17 ] demonstrated that some patients without MHE according to PHES showed deficits in attention assessed by the Stroop test as well as impairments in bimanual coordination. In a more detailed study, Giménez-Garzó et al [ 14 ], found that 42% of patients classified as without MHE by PHES exhibited alterations in attention and coordination that were not detected by PHES. In that study, the oral Symbol Digit Modalities Test (SDMT), d2 and bimanual and visuo-motor coordination tests were more sensitive than PHES in detecting these subtle alterations [ 14 ]. Moreover, patients classified as without MHE by PHES but presenting these early cognitive alterations showed an increased risk of developing clinical complications, including overt HE [ 14 ]. Together, these findings indicate that reliance on PHES alone may leave a substantial proportion of patients with early neurological impairment undetected. The diagnosis of MHE using psychometric tests also presents practical limitations. These tests are time consuming, require trained personnel, and must be adjusted for age and education level. Consequently, their implementation in routine clinical practice remains limited, and many patients with MHE remain undiagnosed and untreated worldwide. Therefore, there is a need for objective, rapid, reproducible and sensitive tools that facilitate the early detection of cognitive impairment in cirrhotic patients. Alterations in cognitive processing are often reflected in abnormalities of saccadic eye movements [ 18 ]. Accordingly, the analysis of eye movement parameters has been proposed as a valuable approach for the early detection of cognitive and motor dysfunction in several neurological disorders, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease [ 18 – 21 ]. Several studies have demonstrated the presence of eye movement abnormalities in patients with cirrhosis and highlighted their potential utility for the diagnosis of MHE and HE [ 22 – 24 ]. These studies reported impairments in smooth pursuit performance and increased saccadic latency, both of which correlated with psychometric performance and the severity of encephalopathy [ 22 – 24 ]. Previously, our group evaluated eye movement alterations in cirrhotic patients with and without MHE using a gaze tracker, based on video-oculography [ 25 , 26 ]. This technique allows to evaluate and analyze with high precision oculomotor responses during a variety of visual tasks [ 25 , 26 ], which are involved in some neurological diseases and their progression. Furthermore, the tasks are simple to perform and well tolerated by patients. In our previous study, we analyzed a large set of eye movement variables and found that patients with MHE exhibited abnormalities in 56 out of 177 measured parameters compared to patients without MHE. These alterations were associated with deficits in attention and mental processing speed [ 26 ]. As noted above, the PHES does not detect all cirrhotic patients with early subtle cognitive alterations [ 14 – 17 ]. We therefore performed, in addition to PHES, other psychometric tests assessing different cognitive domains, which are more sensitive to detect these subtle impairments: d2 test (for selective and sustained attention and concentration), oral SDMT (mental processing speed) and Stroop test (cognitive flexibility, selective attention, inhibition) [ 3 , 14 ]. It would be useful to have a score that allows for the quantification of these alterations and the classification of patients for the subsequent evaluation of eye movement parameters. The first aim of this study was to develop a score that allowed us to identify and stratify cirrhotic patients with early cognitive alterations who are not classified as having MHE by PHES. We refer to this subgroup as early-MHE. A second aim was to perform a comprehensive analysis of 164 eye movements parameters obtained from a set of visual tests (visually-guided saccades, memory-guided saccades, antisaccades, smooth pursuit eye movements and fixation test) recorded by video-oculography, in order to identify a set of parameters capable of detect early neurological alterations in cirrhotic patients that are not detectable using PHES. Patients and methods Subjects This cross-sectional study included 118 patients with liver cirrhosis, who were consecutively recruited between 26 April 2018–12 July 2024 at the outpatient clinics at the Hospital Clínico and Hospital Arnau de Vilanova (Valencia, Spain). Inclusion criteria were patients older than 18 years and a diagnosis of liver cirrhosis of any etiology established by liver histology or a combination of clinical, biochemical, and imaging features. Exclusion criteria were current or previous overt HE, alcohol consumption within the previous 6 months, infection, recent antibiotic use (over 6 weeks), gastrointestinal bleeding, use of drugs that affect cognitive function, hepatocellular carcinoma and the presence of neurological or psychiatric disorders. Patients included in the study did not show fever or any clinical or biological sign of recent infection. Thirty-five healthy volunteers were also recruited as a control group. Patients and controls underwent clinical evaluation, psychometric assessment, and blood analyses to determine ammonia levels and routine biochemical parameters on the same day. The study protocols were approved by the Scientific and Ethical Committees of Hospital Clínico Universitario and Arnau de Vilanova Hospital of Valencia, Spain (approval code: 2018.051; approval date: 27 February 2018; approval code: 2023/130; approval date: 29 February 2024) and were in accordance with the principles of the World Medical Association’s Declaration of Helsinki, the Council of Europe Convention regarding human rights and the requirements established in Spanish legislation in the field of Biomedical research, personal data protection and bioethics. Written informed consent was obtained from all participants prior to enrollment. Diagnosis of MHE and psychometric assessment Thirty-two patients were diagnosed with MHE using the Psychometric Hepatic Encephalopathy Score battery (PHES) [ 12 ]. PHES scores were adjusted for age and education level using Spanish normative data ( www.redeh.org/TEST_phes.htm ). Patients with a PHES score ≤ −4 were classified as having MHE. Healthy volunteers also completed the PHES battery to exclude cognitive impairment according to this criterion. To assess specific cognitive and motor domains, participants additionally underwent the Stroop test (selective attention, cognitive flexibility and inhibitory mental control), the oral Symbol Digit Modalities test (Oral SDMT; mental processing speed and selective attention); d2 test (selective and sustained attention and concentration), Digit Span and letter-number sequencing tests (working memory), and bimanual and visuomotor coordination tests. All psychometric tests were administered and scored as previously described in Giménez-Garzó et al [ 14 ]. Analysis of eye movements Eye movement analysis was performed using a gaze tracker system (OSCANN desk100, AURA Innovative Robotics) based on the video-oculography, and analyzed with OSCANN software [ 25 , 26 ]. Eye movement assessment was performed after psychometric testing. Ten eye movement tasks were evaluated in the following order: visually-guided saccades, memory-guided saccades, antisaccades, and smooth pursuit, each in horizontal and vertical versions; sinusoidal smooth pursuit and fixation tests were also included. A detailed description of the procedure has been reported previously [ 26 ]. Briefly, during the visually guided saccade task, a target was presented at the center of the screen for 1500 ms and then moved to a randomly selected position on either side of the screen before returning to the center. Participants were instructed to follow the target as quickly and accurately as possible. Each horizontal and vertical task lasted 36 s. In the memory guided saccade task, participants were required to remember the position of the stimulus. After presentation of the peripheral target, it disappeared for 1500 ms, and participants were instructed to direct their gaze to the remembered target position. Each task lasted 72 s. During the anti-saccade task, the target followed the same movement pattern as in the visually guided saccade task. However, participants were instructed to direct their gaze towards the position of the screen opposite of the stimulus. Each task lasted 36 s. In the smooth pursuit task, the target moved continuously across the screen with a period of 8 s, and participants were instructed to follow the stimulus all time. The task duration was 32 s. An additional horizontal smooth pursuit condition using sinusoidal velocity changes was also included. In the fixation task, participants were instructed to maintain their gaze on the immobile stimulus, presented at the center of the screen for 20 s. The eye movement variables obtained from each task are summarized in Table 1 . For several eye-movement parameters, a corresponding variability measure (standard deviation) was also calculated (e.g., latency and SD of latency). Download: PNG larger image TIFF original image Table 1. Main variables measured in eye-movement tests performed. https://doi.org/10.1371/journal.pone.0358353.t001 Development of a methodology for identifying early cognitive impairment in patients with liver cirrhosis Results from a historical cohort of 74 age-matched healthy controls were used to establish reference values for cognitive performance in the psychometric tests employed in this study. Cognitive impairment was defined using the mean ± 2 standard deviations (SD) of the control population as the normality criterion. This criterion was subsequently applied to a historical cohort of 519 patients with cirrhosis. The proportion of patients showing impairment in each psychometric variable was calculated, and the tests with the highest frequency of abnormalities were selected. Based on these variables, and following the methodology described by Adam and Foley [ 27 ], a composite score was developed to identify early cognitive impairment in patients with liver cirrhosis. Statistical analyses Values are given as mean ± standard error of the mean (SEM) for parametric variables; in case of nonparametric variables, values are given as median and interquartile range (IQR) unless otherwise stated. Results were analyzed using one of three options: one-way ANOVA followed by post-hoc Tukey’s multiple comparison test for variables both parametric and homoscedastic, Welch’s ANOVA followed by Games-Howell’s multiple comparison test for variables parametric but not homoscedastic, and Kruskal–Wallis’ test followed by Dunn’s test for nonparametric variables. Due to the number of variables analyzed in this study, p values obtained were corrected using the false discovery rate (FDR) method [ 28 ]. FDR values < 0.05 were considered significant. For all statistical analyses and receiver operating characteristic (ROC) curves, data were processed and analyzed using the software R version 4.1.1. Finally, to test the discriminant capabilities of the parameters from the eye-movements tests that showed the best individual results during the analysis of their ROC curves, several multivariate generalized linear models were created using the glm function included in the stats package (version 3.6.2) for R. Internal validation using bootstrap resampling with 1,000 iterations and optimism correction was performed as recommend the TRIPOD statement [ 29 ]. Results Classification of early-MHE patients Previous studies have shown that a substantial proportion of cirrhotic patients classified as not having MHE according to PHES exhibit subtle cognitive alterations that are not detected by this test battery [ 14 ]. To identify these patients, referred to here as early-MHE, we developed a psychometric score based on the cognitive tests included in the present study. Reference values were established using a cohort of healthy controls (n = 74) by applying the mean ± 2 standard deviations (SD) criterion to each psychometric variable. The resulting cutoff values are shown in Table 2 . Participants with values outside these limits were considered to have impairment in the cognitive or motor function assessed by the corresponding parameter. Download: PNG larger image TIFF original image Table 2. Proportion of cirrhotic patients showing cognitive impairment for each parameter, and formulas of early-MHE score. https://doi.org/10.1371/journal.pone.0358353.t002 These cutoffs were subsequently applied to a historical cohort of 519 patients with cirrhosis to determine the proportion of patients showing impairment in each psychometric variable. To construct the early-MHE score, we selected variables according to two criteria: (i) a high prevalence of impairment among cirrhotic patients and (ii) assessment of distinct cognitive domains. The variables showing the highest frequency of impairment were the concentration index (CON) of d2 test (40.7%), the total performance score (TOT) of the d2 test (34.9%), the number of correct responses in the Oral SDMT (29.1%), and incongruent task score of Stroop test (18.2%) ( Table 2 ). These variables assess complementary cognitive functions, including concentration, selective and sustained attention, and mental processing speed. Using the Adam and Foley method [ 27 ], individual scores were calculated for each patient and each psychometric parameter, as the number of standard deviations by which the patient’s value deviated from the mean of healthy controls, according to the formulas shown in Table 2 . These standardized values were summed to obtain a composite score for each participant. Patients without MHE were classified as h
## Related Clinical Research

- [8-hour time-restricted eating yields greater weight loss but not consistent blood pressure benefits](https://medichelpline.com/clinical-feed/medical-news-today-0-16-8-intermittent-fasting-best-for-weight-loss-but-not-for-blood-pressure.md)
- [Comparing Melatonin and Magnesium: Which is Better for Sleep?](https://medichelpline.com/clinical-feed/medical-news-today-0-should-you-take-melatonin-or-magnesium-for-sleep-experts-weigh-in.md)
- [Climate change worsens health for people with chronic illness](https://medichelpline.com/clinical-feed/stat-news-1-opinion-climate-change-is-making-people-with-chronic-illness-even-sicker.md)
- [Integrated multi-omics detection of m6A‑SNP–related diagnostic biomarkers for ALS](https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-integrated-multi-omics-identification-of-m6a-snp-related-diagnostic-biomarkers.md)
- [Metabolomics identifies lipid and amino acid signatures linked to disease severity in multiple scl](https://medichelpline.com/clinical-feed/biorxiv-3-metabolomics-reveals-lipid-and-amino-acid-signatures-of-disease-severity-in.md)

## Navigation
- [← Back to General Feed](https://medichelpline.com/clinical-feed/general.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.