Hepatic Encephalopathy Is Associated with Persistent Learning Impairments Despite Adequate Medical Treatment: A Multicenter, International Study

Nardelli, Silvia; Allampati, Sanath; Riggio, Oliviero; Mullen, Kevin D.; Prakash, Ravi; Gioia, Stefania; Unser, Ariel; White, Melanie B.; Fagan, Andrew; Wade, James B.; Farcomeni, Alessio; Gavis, Edith; Bajaj, Jasmohan S.

doi:10.1007/s10620-016-4425-6

Cited by 21 publications

(19 citation statements)

References 33 publications

(49 reference statements)

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“…Prior studies have demonstrated that response inhibition is impaired in patients with prior OHE using the ICT(4, 6). Additional studies demonstrated that this impaired learning was found over time using the PHES in HE patients(5, 6). This is the first experience using EncephalApp, which extends these findings into a separate, larger population with longitudinal confirmation.…”

Section: Discussionmentioning

confidence: 99%

Overt hepatic encephalopathy impairs learning on the EncephalApp stroop which is reversible after liver transplantation

Acharya¹,

Wade

Fagan³

et al. 2017

Liver Transpl

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After an initial exposure, subjects can develop test-taking/learning strategies called the “test sophistication effect. Cirrhotics wth prior overt hepatic encephalopathy (OHE) could have persistent learning impairments. Aim To define learning/test-sophistication on EncephalApp (downloadable Application) in OHE patients compared to no-OHE patients and controls cross-sectionally and longitudinally. Methods The EncephalApp Stroop App consists of 2 sections; the easier “Off” run assesses psychomotor speed while the difficult “On” run assesses cognitive flexibility. Cross-sectional Analysis: Cirrhotic outpatients with/without controlled OHE and healthy controls underwent EncephalApp testing, which requires 5 “off” and 5 “on” runs. We studied the difference in time required between completing trial 1 compared with trial 5 (delta 1–5) in the both the “On” and “Off” runs in controls, all cirrhotics; and between prior OHE/no-OHE cirrhotics. Longitudinal Analyses: Two groups of cirrhotics were studied; one was administered EncephalApp, ≥ 2 weeks apart and the second before, and 6 months post-liver transplantation. Results 89 controls and 230 cirrhotics (85 prior OHE, MELD 11) with similar age (64 vs 61, p=0.9) were included. Cirrhotic patients had impaired EncephalApp total times and impaired learning on the On runs compared to controls. OHE patients had worse EncephalApp times and learning with the On runs compared to no-OHE patients, which persisted in the longitudinal cohort. No differences in learning were seen in the Off runs. After transplant there was restoration of learning capability with the On runs in the OHE patients. Conclusion Cognitive flexibility tested by the EncephalApp On runs improves over time in healthy controls and no-OHE but not prior OHE. Psychomotor speed remains similar over time. The learning Impairment manifested by cirrhotics with OHE is restored post-transplant.

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Section: Discussionmentioning

confidence: 99%

Overt hepatic encephalopathy impairs learning on the EncephalApp stroop which is reversible after liver transplantation

Acharya¹,

Wade

Fagan³

et al. 2017

Liver Transpl

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“…Learning ability has been suggested to be impaired in patients with cirrhosis after at least one episode of OHE. Such impairment seems to be detectable on tests performed twice on the same day and also on tests repeated over varying time intervals …”

Section: Discussionmentioning

confidence: 99%

“…Different studies on this topic have utilized different tests and different times between repeated assessments. Some of them have tested learning by comparing performance on the first and second half of a test . For example, both Bajaj et al and Nardelli et al showed that only patients with no history of OHE had better performance on the second half of the inhibitory control test (ICT) compared to the first half.…”

Section: Introductionmentioning

confidence: 99%

“…Some of them have tested learning by comparing performance on the first and second half of a test . For example, both Bajaj et al and Nardelli et al showed that only patients with no history of OHE had better performance on the second half of the inhibitory control test (ICT) compared to the first half. Other studies have investigated learning by comparing scores obtained on two different assessments: patients with no OHE history showed improvement in the Psychometric Hepatic Encephalopathy Score (PHES) and ICT scores, while those with a positive history showed improvement only in a few subtests of the PHES battery …”

Section: Introductionmentioning

confidence: 99%

“…19,22 Learning ability also seems to be impaired in patients with a history of one or more episodes of OHE. 23 More specifically, while the performance of healthy elderly adults benefits from the repetition of a test, 24,25 that of patients with cirrhosis and a history of HE does not. 23,[26][27][28] Different studies on this topic have utilized different tests and different times between repeated assessments.…”

Section: Introductionmentioning

confidence: 99%

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The influence of HE history, HE status and neuropsychological test type on learning ability in patients with cirrhosis

Zarantonello

Turco

Formentin

et al. 2019

Liver International

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Background & Aims Learning ability may be impaired in patients with a history of overt hepatic encephalopathy (OHE). The aim of this study was to compare performance on the first/second attempt at a series of tests. Methods Two hundred and fourteen patients with cirrhosis were enrolled. On the day of study, 41% were classed as unimpaired, 38% as having minimal HE and 21% as having mild OHE; 58% had a history of OHE. Performance was compared between two versions of the trail‐making test A (TMT‐A), and between the first/second half of a simple/choice reaction time (sRT and cRT), and a working memory test (ScanRT). Results Both patients with and without OHE history improved in TMT‐A, sRT and ScanRT. Only patients with no OHE history improved in cRT. All patients, regardless of their HE status on the day of study, improved in TMT‐A and sRT. Only patients with mild OHE on the day of study improved in cRT. Only unimpaired patients improved in ScanRT. When OHE history and HE status on the day of study were tested together, only HE status had an effect. The same held true when age, the Model for End Stage Liver Disease (MELD) and educational attainment were adjusted for. Conclusions HE status on the day of study and the type of neuropsychological test had an effect on learning ability in a well‐characterized group of patients with cirrhosis.

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Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo‐Controlled Trial

et al. 2019

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Hepatic encephalopathy (HE) can cause major morbidity despite standard of care (SOC; rifaximin/lactulose). Fecal microbial transplant (FMT) enemas postantibiotics are safe, but the effect of FMT without antibiotics using the capsular route requires investigation. The aim of this work was to determine the safety, tolerability, and impact on mucosal/stool microbiota and brain function in HE after capsular FMT in a randomized, single-blind, placebocontrolled clinical trial in Virginia. Patients with cirrhosis with recurrent HE with MELD (Model for End-Stage Liver Disease) <17 on SOC were randomized 1:1 into receiving 15 FMT capsules versus placebo from a single donor enriched in Lachnospiraceae and Ruminococcaceae. Endoscopies with duodenal and sigmoid biopsies, stool analysis, cognition, serum lipopolysaccharide-binding protein (LBP), and duodenal antimicrobial peptide (AMP) expression at baseline were used. Clinical follow-up with SOC maintenance was performed until 5 months. FMTassigned patients underwent repeat endoscopies 4 weeks postenrollment. Twenty subjects on lactulose/rifaximin were randomized 1:1. MELD score was similar at baseline (9.6 vs. 10.2) and study end (10.2 vs. 10.5). Six patients in the placebo group required hospitalizations compared to 1 in FMT, which was deemed unrelated to FMT. Infection/ HE episodes were similar between groups. Baseline microbial diversity was similar in all tissues between groups. Post-FMT, duodenal mucosal diversity (P = 0.01) increased with higher Ruminococcaceae and Bifidobacteriaceae and lower Streptococcaceae and Veillonellaceae. Reduction in Veillonellaceae were noted post-FMT in sigmoid (P = 0.04) and stool (P = 0.05). Duodenal E-cadherin (P = 0.03) and defensin alpha 5 (P = 0.03) increased whereas interleukin-6 (P = 0.02) and serum LBP (P = 0.009) reduced post-FMT. EncephalApp performance improved post-FMT only (P = 0.02). Conclusion: In this phase 1 study, oral FMT capsules are safe and well tolerated in patients with cirrhosis and recurrent HE. FMT was associated with improved duodenal mucosal diversity, dysbiosis, and AMP expression, reduced LBP, and improved EncephalApp performance. Further studies are needed to prove efficacy.

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Hepatic Encephalopathy Is Associated with Persistent Learning Impairments Despite Adequate Medical Treatment: A Multicenter, International Study

Abstract: In this multicenter study, prior HE patients showed persistent significant learning impairment compared to those without prior HE, despite adequate medical therapy. This persistent change should increase efforts to reduce the first HE episode.

Cited by 21 publications

References 33 publications

Overt hepatic encephalopathy impairs learning on the EncephalApp stroop which is reversible after liver transplantation

Overt hepatic encephalopathy impairs learning on the EncephalApp stroop which is reversible after liver transplantation

The influence of HE history, HE status and neuropsychological test type on learning ability in patients with cirrhosis

Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo‐Controlled Trial

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