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Matthews AJ, Starkie FE, Staniaszek LE, Kane NM. The Role of Electroencephalography Following CAR-T Cell Therapy in Clinical Practice. Clin EEG Neurosci 2025:15500594241312451. [PMID: 39773224 DOI: 10.1177/15500594241312451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Objectives:Neurotoxicity, encephalopathy, and seizures can occur following chimeric antigen receptor (CAR)-T cell therapy. Our aim was to assess what value electroencephalography (EEG) offers for people undergoing CAR-T treatment in clinical practice, including possible diagnostic, management, and prognostic roles. Methods: All patients developing CAR-T related neurotoxicity referred for EEG were eligible for inclusion. Reasons for EEG referral and qualitative EEG findings were analysed and reported. The relationship between objective quantitative EEG (QEEG) encephalopathy grade and clinical neurotoxicity (immune effector cell-associated neurotoxicity syndrome; ICANS) grade was determined. The prognostic ability of QEEG grade was assessed for survival and functional status. Results: Twenty-eight patients with 53 EEG recordings were included. Common reasons given on EEG referrals were possible seizure diagnosis (n = 38), reduced consciousness (n = 8), and superimposed cerebral infection (n = 4). Four focal seizures were detected on three (3/53; 5.7%) EEGs. There was a moderately positive correlation between QEEG grade and ICANS grade (r = + 0.41, p = .030). QEEG grade could not predict survival at 3 months (Area Under Curve; AUC = 0.673) or 6 months (AUC = 0.578), nor could it predict functional status at 1 month (r = + 0.40; p = .080), 3 months (r = + 0.19; p = .439), or time to return to baseline (r = + 0.32; p = .156). Conclusions: EEG was useful in seizure diagnosis. QEEG has a possible role as a specific biomarker of encephalopathy/neurotoxicity. EEG generated no tangible changes in patient management. QEEG was unable to prognosticate survival or functional status.
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Affiliation(s)
- Alexander J Matthews
- Neurophysiology Department, University Hospitals Bristol and Weston NHS Foundation Trust, Upper Maudlin Street, Bristol, BS2 8BJ, UK
| | - Fiona E Starkie
- Bristol Haematology and Oncology Centre, University Hospitals Bristol and Weston NHS Foundation Trust, Horfield Road, Bristol, BS2 8ED, UK
| | - Lydia E Staniaszek
- Neurophysiology Department, University Hospitals Bristol and Weston NHS Foundation Trust, Upper Maudlin Street, Bristol, BS2 8BJ, UK
| | - Nicholas M Kane
- Neurophysiology Department, University Hospitals Bristol and Weston NHS Foundation Trust, Upper Maudlin Street, Bristol, BS2 8BJ, UK
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Özgör B, Gungor S, Aladağ M, Varol FI, Aslan M, Yilmaz S, Gungor S. The Value of Electroencephalogram (EEG) Findings in the Evaluation and Treatment Management of Pediatric Acute Liver Failure. Cureus 2024; 16:e54300. [PMID: 38496192 PMCID: PMC10944321 DOI: 10.7759/cureus.54300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2024] [Indexed: 03/19/2024] Open
Abstract
Background Pediatric acute liver failure (PALF) is still life-threatening and requires urgent care. The presence of encephalopathy is a clinical diagnosis, but it is more difficult to diagnose in children than in adults, and an electroencephalogram (EEG) can be invaluable. The role of EEG in managing the treatment of patients with PALF, other than the identification of encephalopathy, is unknown. This study aimed to investigate patients' EEGs, which may guide in choosing the most appropriate treatment in encephalopathy children. A further aim was to investigate a new score method, based on the laboratory results, which might indicate the presence of encephalopathy in cases with PALF. Methods Medical data of 33 PALF patients followed in our clinic were reviewed retrospectively. This study included 33 patients, whose EEG recording was taken on the first day of supportive treatment due to liver failure in the pediatric intensive care unit (PICU). The EEG findings were categorized into three classes: normal, epileptic and non-epileptic paroxysmal, and background encephalopathic patterns including widespread slowing and voltage suppression. Result This retrospective study included 13 male and 20 female patients with a mean age at presentation of 4.82±4.81 months whose EEG was performed on the first day of supportive therapy for liver failure in the PICU. The EEG findings were categorized into three groups: normal, epileptic and non-epileptic paroxysms, and encephalopathic patterns including diffuse background slowing and voltage suppression. Comparing EEG findings and treatments, we found that the normal EEG group responded well to liver-supporting therapy and the rate of plasmapheresis treatment was significantly higher in the diffuse slowing group. Patients with diffuse slowing of the EEG were 9.6 times more likely to receive plasmapheresis. We found that above a cut-off of ≥7.5 for the TAI (total bilirubin, albumin, and international normalized ratio (INR)) score used in our study, the risk of developing encephalopathy increased 14.4-fold. Conclusions In PALF, EEG findings can provide findings that will help clinicians in determining treatment selection and prognosis, as well as detecting epileptic focus and encephalopathy. The TAI score can be used to assess the risk of encephalopathy in cases of PALF, when it is challenging to identify encephalopathy or when an EEG is not possible.
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Affiliation(s)
- Bilge Özgör
- Pediatric Neurology, İnönü University, Malatya, TUR
| | - Sukru Gungor
- Pediatric Gastroenterology, İnönü University, Malatya, TUR
| | - Merve Aladağ
- Pediatric Medicine, Nurdağı State Hospital, Gaziantep, TUR
| | - Fatma I Varol
- Pediatric Gastroenterology, İnönü University, Malatya, TUR
| | - Mahmut Aslan
- Pediatric Neurology, Mersin City Hospital, Mersin, TUR
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Mangini C, Zarantonello L, Formentin C, Giusti G, Angeli P, Montagnese S. Evolution of hepatic encephalopathy over time: ecological data from a tertiary referral centre for hepatology. Dig Liver Dis 2023; 55:93-98. [PMID: 35725551 DOI: 10.1016/j.dld.2022.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/27/2022] [Accepted: 06/01/2022] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Few data on hepatic encephalopathy (HE) over time are available, thus our aim was to study its evolution in patients with varying degree of HE on first assessment. METHODS Eighty-six patients with cirrhosis (age = 58 ± 11 years; males = 72) were evaluated 2-10 times for liver transplantation selection purposes, differential diagnosis or treatment optimization. The presence/severity of HE was assessed by clinical and neuropsychiatric indices [ Psychometric Hepatic Encephalopathy Score (PHES) and electroencephalography (EEG)] and the severity of liver disease by the Model for End-Stage Liver Disease (MELD) score. Treatment was instituted/modified after each evaluation. RESULTS Amongst 23 unimpaired patients, 56/6% remained unimpaired, 35/3% developed covert HE, 9/0% developed overt HE on second/third evaluation. Amongst 32 patients with covert HE, 25/10% became unimpaired, 44/19% remained covert, 31/13% developed overt HE. Finally, amongst 32 patients with overt HE, 19/16% became unimpaired, 25/13 % became covert and 56/25% remained overt. PHES results improved in patients with overt HE and EEG worsened over time (despite remaining normal) in unimpaired patients. In patients with multiple evaluations, HE evolution was manifold and difficult to predict. CONCLUSIONS HE evolution over time is variable and largely dependent on HE history/management. These data support the concept that HE is an essentially reversible condition.
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Affiliation(s)
- C Mangini
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - L Zarantonello
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - C Formentin
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - G Giusti
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - P Angeli
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - S Montagnese
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy.
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Montagnese S, Lauridsen M, Vilstrup H, Zarantonello L, Lakner G, Fitilev S, Zupanets I, Kozlova I, Bunkova E, Tomasiewicz K, Berglund JE, Rorsman F, Hagström H, Kechagias S, Ocklind CE, Mauney J, Thunarf F, Mokhatarani M, Bäckström T, Doverskog M, Lins LE, Månsson M, Samuelson P, Nilsson D, Schalling M, Johansson M, Arlander E, Scharschmidt BF. A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy. J Hepatol 2021; 75:98-107. [PMID: 33894327 DOI: 10.1016/j.jhep.2021.03.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 03/07/2021] [Accepted: 03/09/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis. METHODS Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. RESULTS Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. CONCLUSION Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone. LAY SUMMARY Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug. CLINICAL TRIAL REGISTRATION NUMBER EudraCT 2016-003651-30.
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Affiliation(s)
| | | | | | | | | | - Sergey Fitilev
- State Budgetary Healthcare Institution "City Polyclinic №2", Moscow, Russia
| | - Igor Zupanets
- Clinical and Diagnostics Center, National University of Pharmacy, Kharkiv, Ukraine
| | - Irina Kozlova
- State Healthcare Institution "Saratov Clinical Hospital #5", Saratov, Russia
| | | | - Krzysztof Tomasiewicz
- Department of Infectious Diseases and Hepatology, Medical University of Lublin, Poland
| | | | - Fredrik Rorsman
- Dept of Gastroenterology and Hepatology, University Hospital Uppsala, Sweden
| | - Hannes Hagström
- Unit of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Stergios Kechagias
- Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | | | - Joe Mauney
- Array Biostatistics, Wilmington, NC, USA
| | | | | | - Torbjörn Bäckström
- Umecrine Cognition AB, Stockholm, Sweden; Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, SE-901 87 Umeå, Sweden
| | | | | | | | | | | | - Martin Schalling
- Umecrine Cognition AB, Stockholm, Sweden; Department of Molecular Medicine and Surgery and the Center for Molecular Medicine at Karolinska Institutet., Sweden
| | - Maja Johansson
- Umecrine Cognition AB, Stockholm, Sweden; Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, SE-901 87 Umeå, Sweden
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Formentin C, Zarantonello L, Mangini C, Frigo AC, Montagnese S, Merkel C. Clinical, neuropsychological and neurophysiological indices and predictors of hepatic encephalopathy (HE). Liver Int 2021; 41:1070-1082. [PMID: 33411388 DOI: 10.1111/liv.14785] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/30/2020] [Accepted: 01/01/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were to: 1) describe a large cohort of patients with cirrhosis in terms of neuropsychological or neurophysiological HE indices, and 2) test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort. METHOD Four hundred and sixty-one patients with cirrhosis (59 ± 10 years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow-up information on mortality/HE-related hospitalization in 134/127 respectively. Information on previous overt HE episodes and both mortality and HE-related hospitalization over the follow-up in 124. RESULTS Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow-up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Among patients without a history of overt HE, those with worse PHES had higher HE risk. Among patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk. CONCLUSIONS In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction.
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Affiliation(s)
- Chiara Formentin
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Lisa Zarantonello
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Chiara Mangini
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Anna C Frigo
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Sara Montagnese
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Carlo Merkel
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
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Smith SK, Nguyen T, Labonte AK, Kafashan M, Hyche O, Guay CS, Wilson E, Chan CW, Luong A, Hickman LB, Fritz BA, Emmert D, Graetz TJ, Melby SJ, Lucey BP, Ju YES, Wildes TS, Avidan MS, Palanca BJA. Protocol for the Prognosticating Delirium Recovery Outcomes Using Wakefulness and Sleep Electroencephalography (P-DROWS-E) study: a prospective observational study of delirium in elderly cardiac surgical patients. BMJ Open 2020; 10:e044295. [PMID: 33318123 PMCID: PMC7737109 DOI: 10.1136/bmjopen-2020-044295] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Delirium is a potentially preventable disorder characterised by acute disturbances in attention and cognition with fluctuating severity. Postoperative delirium is associated with prolonged intensive care unit and hospital stay, cognitive decline and mortality. The development of biomarkers for tracking delirium could potentially aid in the early detection, mitigation and assessment of response to interventions. Because sleep disruption has been posited as a contributor to the development of this syndrome, expression of abnormal electroencephalography (EEG) patterns during sleep and wakefulness may be informative. Here we hypothesise that abnormal EEG patterns of sleep and wakefulness may serve as predictive and diagnostic markers for postoperative delirium. Such abnormal EEG patterns would mechanistically link disrupted thalamocortical connectivity to this important clinical syndrome. METHODS AND ANALYSIS P-DROWS-E (Prognosticating Delirium Recovery Outcomes Using Wakefulness and Sleep Electroencephalography) is a 220-patient prospective observational study. Patient eligibility criteria include those who are English-speaking, age 60 years or older and undergoing elective cardiac surgery requiring cardiopulmonary bypass. EEG acquisition will occur 1-2 nights preoperatively, intraoperatively, and up to 7 days postoperatively. Concurrent with EEG recordings, two times per day postoperative Confusion Assessment Method (CAM) evaluations will quantify the presence and severity of delirium. EEG slow wave activity, sleep spindle density and peak frequency of the posterior dominant rhythm will be quantified. Linear mixed-effects models will be used to evaluate the relationships between delirium severity/duration and EEG measures as a function of time. ETHICS AND DISSEMINATION P-DROWS-E is approved by the ethics board at Washington University in St. Louis. Recruitment began in October 2018. Dissemination plans include presentations at scientific conferences, scientific publications and mass media. TRIAL REGISTRATION NUMBER NCT03291626.
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Affiliation(s)
- S Kendall Smith
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Thomas Nguyen
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Alyssa K Labonte
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - MohammadMehdi Kafashan
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Orlandrea Hyche
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Christian S Guay
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Elizabeth Wilson
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Courtney W Chan
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Anhthi Luong
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - L Brian Hickman
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Bradley A Fritz
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Daniel Emmert
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Thomas J Graetz
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Spencer J Melby
- Department of Surgery, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Brendan P Lucey
- Department of Neurology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Yo-El S Ju
- Department of Neurology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Troy S Wildes
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Michael S Avidan
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Ben J A Palanca
- Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University in St Louis, Saint Louis, Missouri, USA
- Division of Biology and Biomedical Sciences, Washington University in St Louis, Saint Louis, Missouri, USA
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Karanfilian BV, Cheung M, Dellatore P, Park T, Rustgi VK. Laboratory Abnormalities of Hepatic Encephalopathy. Clin Liver Dis 2020; 24:197-208. [PMID: 32245527 DOI: 10.1016/j.cld.2020.01.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Currently, there is no gold standard serologic or imaging modality to detect hepatic encephalopathy (HE). It is a clinical diagnosis gathered from the history and physical. Imaging is nonspecific; however, PET and MRI have shown areas of utility, but are not widely available, cost-efficient, or necessary for diagnosis. Electroencephalogram has shown promise as it can be used in conjunction with the Portal Systemic Hepatic Encephalopathy Score test to diagnose minimal HE. Further research on these techniques would need to be performed to identify strict criteria and cutoffs for diagnosing HE as well as associated sensitivities and specificities.
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Affiliation(s)
- Briette Verken Karanfilian
- Department of Internal Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, 125 Paterson Street, New Brunswick, NJ 08901, USA
| | - Maggie Cheung
- Department of Internal Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, 125 Paterson Street, New Brunswick, NJ 08901, USA
| | - Peter Dellatore
- Department of Internal Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, 125 Paterson Street, New Brunswick, NJ 08901, USA
| | - Taeyang Park
- Department of Internal Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, 125 Paterson Street, New Brunswick, NJ 08901, USA
| | - Vinod K Rustgi
- Department Gastroenterology and Hepatology, Rutgers-Robert Wood Johnson Medical School, 125 Paterson Street, Suite 5100B, New Brunswick, NJ 08901, USA.
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KASL clinical practice guidelines for liver cirrhosis: Varices, hepatic encephalopathy, and related complications. Clin Mol Hepatol 2020; 26:83-127. [PMID: 31918536 PMCID: PMC7160350 DOI: 10.3350/cmh.2019.0010n] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023] Open
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Senzolo M, Zarantonello L, Formentin C, Orlando C, Beltrame R, Vuerich A, Angeli P, Burra P, Montagnese S. Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy. Metab Brain Dis 2019; 34:1803-1812. [PMID: 31506797 DOI: 10.1007/s11011-019-00490-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/03/2019] [Indexed: 01/16/2023]
Abstract
Hepatic encephalopathy (HE) occurs in 20-50% of patients after transjugular intrahepatic portosystemic shunt (TIPS) placement. Older age, HE history and severe liver failure have all been associated with post-TIPS HE but it remains difficult to identify patients at risk. The aim of the present pathophysiological, pilot study was to assess the role of induced hyperammonaemia and associated neuropsychological and neurophysiological changes as predictors of post-TIPS HE. Eighteen TIPS candidates with no overt HE history (56 ± 8 yrs., MELD 11 ± 3) underwent neurophysiological [Electroencephalography (EEG)], neuropsychological [Psychometric Hepatic Encephalopathy Score (PHES) and Scan tests], ammonia and sleepiness assessment at baseline and after the induction of hyperammonaemia by an oral amino acid challenge (AAC). Pre-AAC, 17% of patients had abnormal EEG, 5% abnormal PHES, and 33% abnormal Scan performance. Post-AAC, 17% had abnormal EEG, 0% abnormal PHES, and 17% abnormal Scan performance. Pre-AAC, ammonia concentrations were 201 ± 73 μg/dL and subjective sleepiness 2.5 ± 1.2 (1-9 scale). Post-AAC, patients exhibited the expected increase in ammonia/sleepiness. Six months post-TIPS, 3 patients developed an episode of HE requiring hospitalization; these showed significantly lower pre-AAC fasting ammonia concentrations compared to patients who did not develop HE (117 ± 63 vs. 227 ± 57 μg/dL p = 0.015). They also showed worse PHES/Scan performance pre-AAC, and worse Scan performance post-AAC. Findings at 12 months follow-up (n = 5 HE episodes) were comparable. In conclusion, baseline ammonia levels and both pre- and post-AAC neuropsychiatric indices hold promise in defining HE risk in TIPS candidates with no HE history.
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Affiliation(s)
- Marco Senzolo
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | | | | | - Costanza Orlando
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Raffaello Beltrame
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Anna Vuerich
- Department of Medicine, University of Padova, Padova, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padova, Padova, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Sara Montagnese
- Department of Medicine, University of Padova, Padova, Italy.
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Zarantonello L, Turco M, Formentin C, Izquierdo-Altarejos P, Vuerich A, Barcenas Jimenez MJ, Montoliu C, Felipo V, Angeli P, Amodio P, Montagnese S. The influence of HE history, HE status and neuropsychological test type on learning ability in patients with cirrhosis. Liver Int 2019; 39:861-870. [PMID: 30658006 DOI: 10.1111/liv.14046] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/06/2018] [Accepted: 01/11/2019] [Indexed: 12/25/2022]
Abstract
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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Affiliation(s)
| | - Matteo Turco
- Department of Medicine, University of Padova, Padova, Italy
| | | | - Paula Izquierdo-Altarejos
- Department of Medicine, University of Padova, Padova, Italy.,Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Anna Vuerich
- Department of Medicine, University of Padova, Padova, Italy
| | | | - Carmina Montoliu
- Fundación Investigación Hospital Clínico, Instituto Investigación Sanitaria-INCLIVA, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Paolo Angeli
- Department of Medicine, University of Padova, Padova, Italy
| | - Piero Amodio
- Department of Medicine, University of Padova, Padova, Italy
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11
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Formentin C, De Rui M, Zoncapè M, Ceccato S, Zarantonello L, Senzolo M, Burra P, Angeli P, Amodio P, Montagnese S. The psychomotor vigilance task: Role in the diagnosis of hepatic encephalopathy and relationship with driving ability. J Hepatol 2019; 70:648-657. [PMID: 30633946 DOI: 10.1016/j.jhep.2018.12.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/14/2018] [Accepted: 12/16/2018] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Hepatic encephalopathy (HE) is a syndrome of decreased vigilance and has been associated with impaired driving ability. The aim of this study was to evaluate the psychomotor vigilance task (PVT), which is used to assess both vigilance and driving ability, in a group of patients with cirrhosis and varying degrees of HE. METHODS A total of 145 patients (120 males, 59 ± 10 years, model for end-stage liver disease [MELD] score 13 ± 5) underwent the PVT; a subgroup of 117 completed a driving questionnaire and a subgroup of 106 underwent the psychometric hepatic encephalopathy score (PHES) and an electroencephalogram (EEG), based on which, plus a clinical evaluation, they were classed as being unimpaired (n = 51), or as having minimal (n = 35), or mild overt HE (n = 20). All patients were followed up for an average of 13 ± 5 months in relation to the occurrence of accidents and/or traffic offences, HE-related hospitalisations and death. Sixty-six healthy volunteers evenly distributed by sex, age and education served as a reference cohort for the PVT. RESULTS Patients showed worse PVT performance compared with healthy volunteers, and PVT indices significantly correlated with MELD, ammonia levels, PHES and the EEG results. Significant associations were observed between neuropsychiatric performance/PVT indices and licence/driving status. PVT, PHES and EEG results all predicted HE-related hospitalisations and/or death over the follow-up period; none predicted accidents or traffic offences. However, individuals with the slowest reaction times and most lapses on the PVT were often not driving despite having a licence. When patients who had stopped driving for HE-related reasons (n = 6) were modelled as having an accident or fine over the subsequent 6 and 12 months, PVT was a predictor of accidents and traffic offences, even after correction for MELD and age. CONCLUSIONS The PVT is worthy of further study for the purposes of both HE and driving ability assessment. LAY SUMMARY Hepatic encephalopathy (HE) is a complication of advanced liver disease that can manifest as excessive sleepiness. Some patients with HE have been shown to have difficulty driving. Herein, we used a test called the Psychomotor Vigilance Task (PVT), which measures sleepiness and can also be used to assess driving competence. We showed that PVT performance is fairly stable in healthy individuals. We also showed that PVT performance parallels performance in tests which are commonly used in cirrhotic patients to measure HE. We suggest that this test is helpful in quantifying HE and identifying dangerous drivers among patients with cirrhosis.
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Affiliation(s)
| | - Michele De Rui
- Department of Medicine, University of Padova, Padova, Italy
| | - Mirko Zoncapè
- Department of Medicine, University of Padova, Padova, Italy
| | - Silvia Ceccato
- Department of Medicine, University of Padova, Padova, Italy
| | | | - Marco Senzolo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padova, Padova, Italy
| | - Piero Amodio
- Department of Medicine, University of Padova, Padova, Italy
| | - Sara Montagnese
- Department of Medicine, University of Padova, Padova, Italy.
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12
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Palanca BJA, Wildes TS, Ju YS, Ching S, Avidan MS. Electroencephalography and delirium in the postoperative period. Br J Anaesth 2018; 119:294-307. [PMID: 28854540 DOI: 10.1093/bja/aew475] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Delirium commonly manifests in the postoperative period as a clinical syndrome resulting from acute brain dysfunction or encephalopathy. Delirium is characterized by acute and often fluctuating changes in attention and cognition. Emergence delirium typically presents and resolves within minutes to hours after termination of general anaesthesia. Postoperative delirium hours to days after an invasive procedure can herald poor outcomes. Easily recognized when patients are hyperactive or agitated, delirium often evades diagnosis as it most frequently presents with hypoactivity and somnolence. EEG offers objective measurements to complement clinical assessment of this complex fluctuating disorder. Although EEG features of delirium in the postoperative period remain incompletely characterized, a shift of EEG power into low frequencies is a typical finding shared among encephalopathies that manifest with delirium. In aggregate, existing data suggest that serial or continuous EEG in the postoperative period facilitates monitoring of delirium development and severity and assists in detecting epileptic aetiologies. Future studies are needed to clarify the precise EEG features that can reliably predict or diagnose delirium in the postoperative period, and to provide mechanistic insights into this pathologically diverse neurological disorder.
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Affiliation(s)
| | | | | | - S Ching
- Department of Electrical and Systems Engineering.,Department of Biomedical Engineering
| | - M S Avidan
- Department of Anesthesiology.,Department of Surgery, Division of Cardiothoracic Surgery, Washington University School of Medicine in St Louis, St Louis, MO, USA
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13
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Baumgarten TJ, Neugebauer J, Oeltzschner G, Füllenbach ND, Kircheis G, Häussinger D, Lange J, Wittsack HJ, Butz M, Schnitzler A. Connecting occipital alpha band peak frequency, visual temporal resolution, and occipital GABA levels in healthy participants and hepatic encephalopathy patients. Neuroimage Clin 2018; 20:347-356. [PMID: 30109194 PMCID: PMC6090010 DOI: 10.1016/j.nicl.2018.08.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 07/24/2018] [Accepted: 08/08/2018] [Indexed: 12/12/2022]
Abstract
Recent studies have proposed a connection between the individual alpha band peak frequency and the temporal resolution of visual perception in healthy human participants. This connection rests on animal studies describing oscillations in the alpha band as a mode of phasic thalamocortical information transfer for low-level visual stimuli, which critically relies on GABAergic interneurons. Here, we investigated the interplay of these parameters by measuring occipital alpha band peak frequency by means of magnetoencephalography, visual temporal resolution by means of behavioral testing, and occipital GABA levels by means of magnetic resonance spectroscopy. Importantly, we investigated a sample of healthy participants and patients with varying grades of hepatic encephalopathy, which are known to exhibit decreases in the investigated parameters, thus providing an increased parameter space. We found that occipital alpha band peak frequency and visual temporal resolution were positively correlated, i.e., higher occipital alpha band peak frequencies were on average related to a higher temporal resolution. Likewise, occipital alpha band peak frequency correlated positively with occipital GABA levels. However, correlations were significant only when both healthy participants and patients were included in the analysis, thereby indicating a connection of the measures on group level (instead of the individual level). These findings provide new insights into neurophysiological and neurochemical underpinnings of visual perception.
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Key Words
- Alpha oscillations
- CFF, Critical flicker frequency
- CSD, Cross-spectral density
- EC, Eyes-closed
- ECG, Electro-cardiogram
- EO, Eyes-open
- EOG, Electro-oculogram
- GABA
- GABA+/Cr, GABA-to creatine -ratio
- GABA, γ-aminobutyric acid
- HE, Hepatic encephalopathy
- HE1, Clinically manifest HE grade 1
- HPI, Head position indication
- Hepatic encephalopathy
- ICA, Independent component analysis
- MEG, Magnetoencephalography
- MNI, Montreal Neurological Institute
- MRS, Magnetic resonance spectroscopy
- Magnetic resonance spectroscopy
- Magnetoencephalography
- Peak frequency
- mHE, Minimal HE
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Affiliation(s)
- Thomas J Baumgarten
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany; Neuroscience Institute, New York University Langone Medical Center, New York, NY, USA.
| | - Julia Neugebauer
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Georg Oeltzschner
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; F.M. Kirby Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
| | - Nur-Deniz Füllenbach
- Department of Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Gerald Kircheis
- Department of Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Joachim Lange
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Hans-Jörg Wittsack
- Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Markus Butz
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Alfons Schnitzler
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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14
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Volpato S, Montagnese S, Zanetto A, Turco M, De Rui M, Ferrarese A, Amodio P, Germani G, Senzolo M, Gambato M, Russo FP, Burra P. Neuropsychiatric performance and treatment of hepatitis C with direct-acting antivirals: a prospective study. BMJ Open Gastroenterol 2017; 4:e000183. [PMID: 29333276 PMCID: PMC5759705 DOI: 10.1136/bmjgast-2017-000183] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/28/2017] [Accepted: 11/29/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Since direct-acting antivirals (DAAs) have been approved for the treatment of hepatitis C virus (HCV) infection, a small series of patients with new-onset neuropsychiatric alterations have been referred to us. We therefore set out to study neuropsychiatric function in relation to DAAs prospectively. METHODS Ten patients with cirrhosis and 12 post-liver transplant (post-LT) patients were enrolled. All underwent wake electroencephalography (EEG) and a neuropsychological evaluation (paper and pencil battery, simple/choice reaction times, working memory task) at baseline, at the end of treatment with DAAs and after 6 months. At the same time points, full blood count, liver/kidney function tests, quantitative HCV RNA, ammonia and immunosuppressant drug levels were obtained, as appropriate. RESULTS Patients with cirrhosis were significantly older than post-LT patients (65±12 vs 55±7 years; P<0.05). Neuropsychological performance and wake EEG were comparable in the two groups at baseline. At the end of a course of treatment with DAAs, a significant slowing in choice reaction times and in the EEG (increased relative delta power) was observed in patients with cirrhosis, which resolved after 6 months. In contrast, no significant changes over time were observed in the neuropsychiatric performance of post-LT patients. No significant associations were observed between neuropsychiatric performance and stand-alone/combined laboratory variables. CONCLUSION Some degree of neuropsychiatric impairment was observed in relation to treatment with DAAs in patients with cirrhosis, but not in post-LT patients, suggesting that the former may be sensitive to mild DAA neurotoxicity.
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Affiliation(s)
- Sofia Volpato
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Sara Montagnese
- Department of Medicine, Padova University Hospital, Padova, Italy
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Matteo Turco
- Department of Medicine, Padova University Hospital, Padova, Italy
| | - Michele De Rui
- Department of Medicine, Padova University Hospital, Padova, Italy
| | - Alberto Ferrarese
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Piero Amodio
- Department of Medicine, Padova University Hospital, Padova, Italy
| | - Giacomo Germani
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Martina Gambato
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
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15
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Feltracco P, Cagnin A, Carollo C, Barbieri S, Ori C. Neurological disorders in liver transplant candidates: Pathophysiology and clinical assessment. Transplant Rev (Orlando) 2017; 31:193-206. [DOI: 10.1016/j.trre.2017.02.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 12/29/2016] [Accepted: 02/20/2017] [Indexed: 12/14/2022]
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16
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Montagnese S, De Rui M, Angeli P, Amodio P. Reply to: "Tools and tactics for improving diagnosis of hepatic encephalopathy". J Hepatol 2017; 66:1328-1329. [PMID: 28215599 DOI: 10.1016/j.jhep.2017.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 02/09/2017] [Indexed: 12/04/2022]
Affiliation(s)
| | - Michele De Rui
- Department of Medicine, University of Padua, Padua, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padua, Padua, Italy
| | - Piero Amodio
- Department of Medicine, University of Padua, Padua, Italy
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17
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Surjan RC, Dos Santos ES, Basseres T, Makdissi FF, Machado MA. A Proposed Physiopathological Pathway to Hyperammonemic Encephalopathy in a Non-Cirrhotic Patient with Fibrolamellar Hepatocellular Carcinoma without Ornithine Transcarbamylase (OTC) Mutation. AMERICAN JOURNAL OF CASE REPORTS 2017; 18:234-241. [PMID: 28270654 PMCID: PMC5358858 DOI: 10.12659/ajcr.901682] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Patient: Male, 31 Final Diagnosis: Fibrolamellar hepatocellular carcinoma Symptoms: Encephalopathy Medication:— Clinical Procedure: — Specialty: Gastroenterology and Hepatology
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Affiliation(s)
- Rodrigo C Surjan
- Department of Surgery, University of São Paulo, São Paulo, SP, Brazil
| | | | - Tiago Basseres
- Department of Surgery, University of São Paulo, São Paulo, SP, Brazil
| | - Fabio F Makdissi
- Department of Gastroenterology, University of São Paulo, São Paulo, SP, Brazil
| | - Marcel A Machado
- Department of Surgery, University of São Paulo, São Paulo, SP, Brazil
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18
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Morgan MY, Amodio P, Cook NA, Jackson CD, Kircheis G, Lauridsen MM, Montagnese S, Schiff S, Weissenborn K. Qualifying and quantifying minimal hepatic encephalopathy. Metab Brain Dis 2016; 31:1217-1229. [PMID: 26412229 DOI: 10.1007/s11011-015-9726-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 09/01/2015] [Indexed: 12/11/2022]
Abstract
Minimal hepatic encephalopathy is the term applied to the neuropsychiatric status of patients with cirrhosis who are unimpaired on clinical examination but show alterations in neuropsychological tests exploring psychomotor speed/executive function and/or in neurophysiological variables. There is no gold standard for the diagnosis of this syndrome. As these patients have, by definition, no recognizable clinical features of brain dysfunction, the primary prerequisite for the diagnosis is careful exclusion of clinical symptoms and signs. A large number of psychometric tests/test systems have been evaluated in this patient group. Of these the best known and validated is the Portal Systemic Hepatic Encephalopathy Score (PHES) derived from a test battery of five paper and pencil tests; normative reference data are available in several countries. The electroencephalogram (EEG) has been used to diagnose hepatic encephalopathy since the 1950s but, once popular, the technology is not as accessible now as it once was. The performance characteristics of the EEG are critically dependent on the type of analysis undertaken; spectral analysis has better performance characteristics than visual analysis; evolving analytical techniques may provide better diagnostic information while the advent of portable wireless headsets may facilitate more widespread use. A large number of other diagnostic tools have been validated for the diagnosis of minimal hepatic encephalopathy including Critical Flicker Frequency, the Inhibitory Control Test, the Stroop test, the Scan package and the Continuous Reaction Time; each has its pros and cons; strengths and weaknesses; protagonists and detractors. Recent AASLD/EASL Practice Guidelines suggest that the diagnosis of minimal hepatic encephalopathy should be based on the PHES test together with one of the validated alternative techniques or the EEG. Minimal hepatic encephalopathy has a detrimental effect on the well-being of patients and their care-givers. It responds well to treatment with resolution of test abnormalities and the associated detrimental effects on quality of life, liver-related mortality and morbidity. Patients will only benefit in this way if they can be effectively diagnosed. Corporate efforts and consensus agreements are needed to develop effective diagnostic algorithms.
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Affiliation(s)
- Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, Rowland Hill Street, London, NW32PF, UK.
| | - Piero Amodio
- Department of Medicine, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Nicola A Cook
- Department of Medicine, St Mary's Hospital Campus, Imperial College, London, W2 1NY, UK
| | - Clive D Jackson
- Department of Neurophysiology, Royal Free Hospital, Royal Free London NHS Foundation Trust, Pond Street, London, Hampstead, NW3 2QG, UK
| | - Gerald Kircheis
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Mette M Lauridsen
- Department of Gastroenterology, Hospital of South West Jutland, Finsensgade 35, 6700, Esbjerg, Denmark
| | - Sara Montagnese
- Department of Medicine, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Sami Schiff
- Department of Medicine, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Karin Weissenborn
- Department of Neurology, Hannover Medical School, 30623, Hannover, Germany
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19
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Olesen SS, Gram M, Jackson CD, Halliday E, Sandberg TH, Drewes AM, Morgan MY. Electroencephalogram variability in patients with cirrhosis associates with the presence and severity of hepatic encephalopathy. J Hepatol 2016; 65:517-23. [PMID: 27184531 DOI: 10.1016/j.jhep.2016.05.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 04/19/2016] [Accepted: 05/07/2016] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS The outputs of physiological systems fluctuate in a complex manner even under resting conditions. Decreased variability or increased regularity of these outputs is documented in several disease states. Changes are observed in the spatial and temporal configuration of the electroencephalogram (EEG) in patients with hepatic encephalopathy (HE), but there is no information on the variability of the EEG signal in this condition. The aim of this study was to measure and characterize EEG variability in patients with cirrhosis and to determine its relationship to neuropsychiatric status. METHODS Eyes-closed, awake EEGs were obtained from 226 patients with cirrhosis, classified, using clinical and psychometric criteria, as neuropsychiatrically unimpaired (n=127) or as having minimal (n=21) or overt (n=78) HE, and from a reference population of 137 healthy controls. Analysis of EEG signal variability was undertaken using continuous wavelet transform and sample entropy. RESULTS EEG variability was reduced in the patients with cirrhosis compared with the reference population (coefficient of variation: 21.2% [19.3-23.4] vs. 22.4% [20.8-24.5]; p<0.001). A significant association was observed between EEG variability and neuropsychiatric status; thus, variability was increased in the patients with minimal HE compared with their neuropsychiatrically unimpaired counterparts (sample entropy: 0.98 [0.87-1.14] vs. 0.83 [0.75-0.95]; p=0.02), and compared with the patients with overt HE (sample entropy: 0.98 [0.87-1.14] vs. 0.82 [0.71-1.01]; p=0.01). CONCLUSIONS Variability of the EEG is associated with both the presence and severity of HE. This novel finding may provide new insights into the pathophysiology of HE and provide a means for monitoring patients over time. LAY SUMMARY Decreased variability or increased regularity of physiological systems is documented in several disease states. Variability of the electroencephalogram was found to be associated with both the presence and severity of brain dysfunction in patients with chronic liver disease.
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Affiliation(s)
- Søren Schou Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark.
| | - Mikkel Gram
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark
| | - Clive Douglas Jackson
- Department of Neurophysiology, Royal Free Hospital, Royal Free London NHS Foundation Trust, Hampstead, London, UK
| | - Edwin Halliday
- UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, Hampstead, London, UK
| | - Thomas Holm Sandberg
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Marsha Yvonne Morgan
- UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, Hampstead, London, UK
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20
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Jepsen P, Christensen J, Weissenborn K, Watson H, Vilstrup H. Epilepsy as a risk factor for hepatic encephalopathy in patients with cirrhosis: a cohort study. BMC Gastroenterol 2016; 16:77. [PMID: 27457247 PMCID: PMC4960784 DOI: 10.1186/s12876-016-0487-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 07/06/2016] [Indexed: 01/03/2023] Open
Abstract
Background Epilepsy is associated with an increased mortality among cirrhosis patients, but the reasons are unknown. We aimed to determine whether epilepsy is a risk factor for developing hepatic encephalopathy (HE), which is a strong predictor of mortality. Methods We used data from three randomized 1-year trials of satavaptan in cirrhosis patients with ascites. With Cox regression, we compared the hazard rates of HE grade 1–4 between those cirrhosis patients who did or did not have epilepsy. We adjusted for confounding by gender, age, cirrhosis etiology, diabetes, history of HE, Model for Endstage Liver Disease (MELD) score, serum sodium, albumin, lactulose use, rifaximin use, and benzodiazepine/barbiturate sedation. In a supplementary analysis we examined the association between epilepsy and the hazard rate of HE grade 2–4. Results Of the 1120 cirrhosis patients with ascites, 21 (1.9 %) were diagnosed with epilepsy. These patients had better liver function at inclusion than the patients without epilepsy (median MELD score 7.9 vs. 11.4), and only one died during the trials. Nevertheless, seven patients with epilepsy had an HE episode during the follow-up, and the adjusted hazard ratio of HE grade 1–4 for patients with epilepsy vs. controls was 2.12 (95 % CI 0.99–4.55). The corresponding hazard ratio of HE grade 2–4 was 3.83 (95 % CI 1.65–8.87). Conclusions Our findings suggest that epilepsy is associated with an increased risk of HE in patients with cirrhosis.
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Affiliation(s)
- Peter Jepsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Nørrebrogade 44, DK-8000, Aarhus, Denmark. .,Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
| | - Jakob Christensen
- Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Nørrebrogade 44, DK-8000, Aarhus, Denmark
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21
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Singh J, Sharma BC, Maharshi S, Puri V, Srivastava S. Spectral electroencephalogram in liver cirrhosis with minimal hepatic encephalopathy before and after lactulose therapy. J Gastroenterol Hepatol 2016; 31:1203-9. [PMID: 26716736 DOI: 10.1111/jgh.13283] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 12/07/2015] [Accepted: 12/21/2015] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIM Minimal hepatic encephalopathy (MHE) represents the mildest form of hepatic encephalopathy. Spectral electroencephalogram (sEEG) analysis improves the recognition of MHE by decreasing inter-operator variability and providing quantitative parameters of brain dysfunction. We compared sEEG in patients with cirrhosis with and without MHE and the effects of lactulose on sEEG in patients with MHE. METHODS One hundred patients with cirrhosis (50 with and 50 without MHE) were enrolled. Diagnosis of MHE was based on psychometric hepatic encephalopathy score (PHES) of ≤ -5. Critical flicker frequency, model of end-stage liver disease score, and sEEG were performed at baseline in all patients. The spectral variables considered were the mean dominant frequency (MDF) and relative power in beta, alpha, theta, and delta bands. Patients with MHE were given 3 months of lactulose, and all parameters were repeated. RESULTS Spectral electroencephalogram analysis showed lower MDF (7.8 ± 1.7 vs 8.7 ± 1.3 Hz, P < 0.05) and higher theta relative power (34.29 ± 4.8 vs 24 ± 6.7%, P = 001) while lower alpha relative power (28.6 ± 4.0 vs 33.5 ± 5.3%, P = .001) in patients with MHE than in patients without MHE. With theta relative power, sensitivity 96%, specificity 84%, and accuracy of 90% were obtained for diagnosis of MHE. After lactulose treatment, MHE improved in 21 patients, and significant changes were seen in MDF (7.8 ± 0.5 vs 8.5 ± 0.6), theta (34.2 ± 4.8 vs 23.3 ± 4.1%), alpha (28.6 ± 4.0 vs 35.5 ± 4.5%), and delta relative power (13.7 ± 3.5 vs 17.0 ± 3.3%) after treatment (P ≤ 0.05). CONCLUSIONS Spectral EEG is a useful objective and quantitative tool for diagnosis and to assess the response to treatment in patients with cirrhosis with MHE.
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Affiliation(s)
- Jatinderpal Singh
- Department of Gastroenterology, G. B. Pant Hospital, New Delhi, India
| | | | - Sudhir Maharshi
- Department of Gastroenterology, G. B. Pant Hospital, New Delhi, India
| | - Vinod Puri
- Department of Neurology, G. B. Pant Hospital, New Delhi, India
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Schiff S, Casa M, Di Caro V, Aprile D, Spinelli G, De Rui M, Angeli P, Amodio P, Montagnese S. A low-cost, user-friendly electroencephalographic recording system for the assessment of hepatic encephalopathy. Hepatology 2016; 63:1651-9. [PMID: 26833704 DOI: 10.1002/hep.28477] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 01/24/2016] [Indexed: 12/22/2022]
Abstract
UNLABELLED Electroencephalography (EEG) is useful to objectively diagnose/grade hepatic encephalopathy (HE) across its spectrum of severity. However, it requires expensive equipment, and hepatogastroenterologists are generally unfamiliar with its acquisition/interpretation. Recent technological advances have led to the development of low-cost, user-friendly EEG systems, allowing EEG acquisition also in settings with limited neurophysiological experience. The aim of this study was to assess the relationship between EEG parameters obtained from a standard-EEG system and from a commercial, low-cost wireless headset (light-EEG) in patients with cirrhosis and varying degrees of HE. Seventy-two patients (58 males, 61 ± 9 years) underwent clinical evaluation, the Psychometric Hepatic Encephalopathy Score (PHES), and EEG recording with both systems. Automated EEG parameters were calculated on two derivations. Strong correlations were observed between automated parameters obtained from the two EEG systems. Bland and Altman analysis indicated that the two systems provided comparable automated parameters, and agreement between classifications (normal versus abnormal EEG) based on standard-EEG and light-EEG was good (0.6 < κ < 0.8). Automated parameters such as the mean dominant frequency obtained from the light-EEG correlated significantly with the Model for End-Stage Liver Disease score (r = -0.39, P < 0.05), fasting venous ammonia levels (r = -0.41, P < 0.01), and PHES (r = -0.49, P < 0.001). Finally, significant differences in light-EEG parameters were observed in patients with varying degrees of HE. CONCLUSION Reliable EEG parameters for HE diagnosing/grading can be obtained from a cheap, commercial, wireless headset; this may lead to more widespread use of this patient-independent tool both in routine liver practice and in the research setting. (
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Affiliation(s)
- Sami Schiff
- Department of Medicine, University of Padua, Padua, Italy
| | - Mariella Casa
- Department of Medicine, University of Padua, Padua, Italy
| | | | - Daniele Aprile
- Department of Medicine, University of Padua, Padua, Italy
| | | | - Michele De Rui
- Department of Medicine, University of Padua, Padua, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padua, Padua, Italy
| | - Piero Amodio
- Department of Medicine, University of Padua, Padua, Italy
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Jackson CD, Gram M, Halliday E, Olesen SS, Sandberg TH, Drewes AM, Morgan MY. New spectral thresholds improve the utility of the electroencephalogram for the diagnosis of hepatic encephalopathy. Clin Neurophysiol 2016; 127:2933-2941. [PMID: 27236607 DOI: 10.1016/j.clinph.2016.03.027] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 02/19/2016] [Accepted: 03/14/2016] [Indexed: 01/06/2023]
Abstract
OBJECTIVE The utility of the electroencephalogram (EEG) for the diagnosis of hepatic encephalopathy, using conventional spectral thresholds, is open to question. The aim of this study was to optimise its diagnostic performance by defining new spectral thresholds. METHODS EEGs were recorded in 69 healthy controls and 113 patients with cirrhosis whose neuropsychiatric status was classified using clinical and psychometric criteria. New EEG spectral thresholds were calculated, on the parietal P3-P4 lead derivation, using an extended multivariable receiver operating characteristic curve analysis. Thresholds were validated in a separate cohort of 68 healthy controls and 113 patients with cirrhosis. The diagnostic performance of the newly derived spectral thresholds was further validated using a machine learning technique. RESULTS The diagnostic performance of the new thresholds (sensitivity 75.0%; specificity 77.4%) was better balanced than that of the conventional thresholds (58.3%; 93.2%) and comparable to the performance of a machine learning technique (72.9%; 76.8%). The diagnostic utility of the new thresholds was confirmed in the validation cohort. CONCLUSIONS Adoption of the new spectral thresholds would significantly improve the utility of the EEG for the diagnosis of hepatic encephalopathy. SIGNIFICANCE These new spectral EEG thresholds optimise the performance of the EEG for the diagnosis of hepatic encephalopathy and can be adopted without the need to alter data recording or the initial processing of traces.
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Affiliation(s)
- Clive D Jackson
- Department of Neurophysiology, Royal Free Hospital, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, UK.
| | - Mikkel Gram
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark.
| | - Edwin Halliday
- Department of Neurophysiology, Royal Free Hospital, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, UK.
| | - Søren Schou Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark.
| | - Thomas Holm Sandberg
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
| | - Marsha Y Morgan
- UCL Institute for Liver and Digestive Health, Department of Medicine, Royal Free Campus, University College London, Hampstead, London NW3 2PF, UK.
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Thomsen KL, Macnaughtan J, Tritto G, Mookerjee RP, Jalan R. Clinical and Pathophysiological Characteristics of Cirrhotic Patients with Grade 1 and Minimal Hepatic Encephalopathy. PLoS One 2016; 11:e0146076. [PMID: 26745876 PMCID: PMC4706303 DOI: 10.1371/journal.pone.0146076] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Background and Aims EASL/AASLD hepatic encephalopathy (HE) guidelines proposed the alternative use of the term ‘Covert HE’ combining minimal HE (mHE) and Grade 1 HE into a single entity. However, longitudinal data to indicate that these are indeed a single entity are lacking. The aims of this study were to determine whether the occurrence of complications of cirrhosis requiring hospital admission and mortality were similar in these sub-groups of patients. Methods Clinically-stable cirrhotic patients (n = 106) with no previous history of ‘Overt HE’ were included over a 2-year period and classified as having no HE (n = 23), mHE (n = 39) or Grade 1 HE (n = 44). Standard biochemistry, venous ammonia, bacterial DNA and neutrophil function were measured at inclusion and the patients were followed for a mean of 230±95 days. Results Patients with Grade 1 HE had significantly more complications requiring hospitalisation (infection 9/18/34%; HE 4/8/18%; other 13/10/11%; P = 0.02) and significantly greater mortality (4/5/20%; P = 0.04) compared to patients with no HE or mHE respectively. Patients with mHE and grade 1 HE had similar ammonia levels, but higher than the no HE group (P<0.001). MELD score was similar between groups but Grade 1 HE patients had increased frequency of bacterial translocation (P = 0.06) and neutrophil spontaneous respiratory burst (P = 0.02) compared to patients with mHE. Conclusions The results of this study show for the first time that ‘Covert HE’ is a heterogeneous entity with significantly greater hospitalisations and mortality in the Grade 1 HE patients compared with mHE. Further prospective longer-term studies are required before EASL/AASLD guidance is fully implemented.
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Affiliation(s)
- Karen Louise Thomsen
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
| | - Jane Macnaughtan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
| | - Giovanni Tritto
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
| | - Rajeshwar P. Mookerjee
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
- * E-mail:
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Jindal A, Sharma BC, Sachdeva S, Chawla R, Srivastava S, Maharshi S. Bispectral index monitoring for diagnosis and assessment of severity of hepatic encephalopathy in cirrhotic patients. Dig Liver Dis 2015; 47:769-74. [PMID: 26022229 DOI: 10.1016/j.dld.2015.04.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 02/25/2015] [Accepted: 04/28/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recent evidence suggests that bispectral index may aid in the diagnosis of hepatic encephalopathy. We evaluated its utility to diagnose, grade and monitor clinical course of hepatic encephalopathy in patients with cirrhosis. METHODS 200 patients (70.5% males, mean age 39.5±9.1 years) with cirrhosis and 20 healthy controls were enrolled prospectively. Cirrhotic patients were divided into groups based on encephalopathy grades I-IV assessed by West Haven criteria; minimal encephalopathy was assessed by psychometric tests. Bispectral index was measured at baseline and after one week of lactulose therapy in patients with overt encephalopathy, and after 3 months in patients with minimal encephalopathy. RESULTS Bispectral index scores were significantly different in patients with different grades of encephalopathy; 79.5±4.2, 67.5±4.3, 56.4±3.5, 44.8±3.9 and 85.0±4.3 respectively for grade I, II, III, IV overt and minimal hepatic encephalopathy, but similar (92.6±3.7 vs 93.75±2.8) in cirrhotics without encephalopathy and healthy controls. Bispectral scores' cut off values for minimal and overt encephalopathy grade I, II, III, IV were 90.5 and 77.5, 70.5, 60.5, 50.5, respectively. Changes in bispectral index after treatment corresponded to cut-off scores for grades of overt and minimal hepatic encephalopathy. CONCLUSIONS Bispectral index was found to be useful in diagnosis, grading and monitoring of treatment response in cirrhotic patients with hepatic encephalopathy.
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Affiliation(s)
- Amit Jindal
- Department of Gastroenterology and Anaesthesiology, G.B. Pant Hospital, New Delhi, India
| | - Barjesh Chander Sharma
- Department of Gastroenterology and Anaesthesiology, G.B. Pant Hospital, New Delhi, India.
| | - Sanjeev Sachdeva
- Department of Gastroenterology and Anaesthesiology, G.B. Pant Hospital, New Delhi, India
| | - Rajiv Chawla
- Department of Gastroenterology and Anaesthesiology, G.B. Pant Hospital, New Delhi, India
| | - Siddharth Srivastava
- Department of Gastroenterology and Anaesthesiology, G.B. Pant Hospital, New Delhi, India
| | - Sudhir Maharshi
- Department of Gastroenterology and Anaesthesiology, G.B. Pant Hospital, New Delhi, India
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Amodio P, Montagnese S. Clinical neurophysiology of hepatic encephalopathy. J Clin Exp Hepatol 2015; 5:S60-8. [PMID: 26041960 PMCID: PMC4442865 DOI: 10.1016/j.jceh.2014.06.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 06/05/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVES Hepatic encephalopathy (HE) has relevant impact on the quality of life of patients and their caregivers and causes relevant costs because of hospitalizations and work days lost. Its quantification is important to perform adequate clinical trials on this relevant complication of cirrhosis and portal-systemic shunting. Clinical neurophysiology, which detects functional alterations of the nervous system, has been applied to the study of HE for over 60 years. This review aims at summarizing and clarifying the role of neurophysiologic techniques in the study of HE. METHODS A narrative review was performed aiming at interpreting the cited papers and the techniques on the basis of their physiological and pathophysiological meaning. RESULTS The potential role of EEG, quantified EEG, evoked potentials-both exogenous, endogenous and motor-have been clarified to the reader that may be unfamiliar with neurophysiology. CONCLUSIONS The EEG, reflecting the oscillatory changes of neural network is the preferable tool to detect and monitor HE, with the exception of its most severe stage, when EEG flattens. SSEP and MEP have indication to detect and monitor transmission alterations that are likely related to myelin changes and microedema.
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Key Words
- BAEPs, brainstem acoustic evoked potentials
- EEG
- EEG, electroencephalogram
- EPs, evoked potentials
- ERPs, event related potentials
- HE, hepatic encephalopathy
- MEG, magnetoencephalogram
- MEPs, motor evoked potentials
- SSEPs, somatosensory evoked potential
- VEPs, visual evoked potentials
- cirrhosis
- evoked potentials
- fVPS, flash visual evoked potentials
- hepatic encephalopathy
- neurophysiology
- pVEPs, pattern reversal visual evoked potentials
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Affiliation(s)
- Piero Amodio
- Address for correspondence: Piero Amodio, Department of Medicine, DIMED, University of Padua, via Giustiniani, 2; 35128 Padova, Italy. Fax: +39 049 7960903.
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Weissenborn K. Diagnosis of minimal hepatic encephalopathy. J Clin Exp Hepatol 2015; 5:S54-9. [PMID: 26041959 PMCID: PMC4442856 DOI: 10.1016/j.jceh.2014.06.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Accepted: 06/05/2014] [Indexed: 12/12/2022] Open
Abstract
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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Key Words
- CDR, cognitive drug research
- CFF, critical flicker frequency
- CRT, continuous reaction time test
- EEG, electroencephalography
- ICT, inhibitory control test
- PHES, psychometric hepatic encephalopathy score
- PSE, portosystemic encephalopathy
- RBANS, repeatable battery for the assessment of neuropsychological status
- TA, target accuracy
- WL, weighted lures
- diagnostic means
- diagnostic use
- mHE, minimal hepatic encephalopathy
- minimal hepatic encephalopathy
- sensitivity
- specificity
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Affiliation(s)
- Karin Weissenborn
- Address for correspondence: Karin Weissenborn, Department of Neurology, Hannover Medical School, 30623 Hannover, Germany. Tel.: +49 511 532 2339; fax: +49 511 532 3115.
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Montagnese S, De Rui M, Schiff S, Ceranto E, Valenti P, Angeli P, Cillo U, Zanus G, Gatta A, Amodio P, Merkel C. Prognostic benefit of the addition of a quantitative index of hepatic encephalopathy to the MELD score: the MELD-EEG. Liver Int 2015; 35:58-64. [PMID: 24517387 DOI: 10.1111/liv.12490] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 02/03/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS A slowed electroencephalogram (EEG) is indicative of the presence of hepatic encephalopathy (HE). Since HE is not reflected in the MELD score and is an important prognostic parameter, we assess the prognostic benefit of the addition of an EEG-based HE index to the MELD. METHODS Three hundred and ninety-two patients with cirrhosis underwent EEG and automated determination of its mean dominant frequency (MDF). MELD was calculated at the time of EEG recording. Patients were monitored for up to 18 months in relation to the occurrence of death/transplantation. The prognostic value of the stand-alone/combined MELD and MDF was calculated using standard survival analysis techniques. Patients transplanted for hepatic decompensation were considered dead on the day of transplantation, those transplanted for hepatocellular carcinoma were censored. The findings were validated using a split-sample technique (reference group: n = 256; test group: n = 136). During the follow-up period, 107 patients died/were transplanted for hepatic decompensation. RESULTS Both MELD and MDF predicted mortality on Kaplan-Meier analysis, and both were independent predictors of mortality on a Cox model. Based on Cox regression parameters, a novel prognostic index was devised, as follows: MELD-EEG = 0.087*MELD-0.306*MDF. On ROC curve analysis, MELD-EEG had higher prognostic accuracy in predicting 12- and 18-month mortality compared to MELD (P = 0.016 and P = 0.018, respectively). In addition, it had better sensitivity and reduced the misclassification rate for given levels of specificity. On validation, no significant differences were observed between the reference/test groups. CONCLUSIONS The addition of an automatically obtained EEG-based index improves the prognostic accuracy of the MELD score.
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Computer-aided diagnosis of alcoholism-related EEG signals. Epilepsy Behav 2014; 41:257-63. [PMID: 25461226 DOI: 10.1016/j.yebeh.2014.10.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2014] [Revised: 09/28/2014] [Accepted: 10/03/2014] [Indexed: 02/05/2023]
Abstract
Alcoholism is a severe disorder that affects the functionality of neurons in the central nervous system (CNS) and alters the behavior of the affected person. Electroencephalogram (EEG) signals can be used as a diagnostic tool in the evaluation of subjects with alcoholism. The neurophysiological interpretation of EEG signals in persons with alcoholism (PWA) is based on observation and interpretation of the frequency and power in their EEGs compared to EEG signals from persons without alcoholism. This paper presents a review of the known features of EEGs obtained from PWA and proposes that the impact of alcoholism on the brain can be determined by computer-aided analysis of EEGs through extracting the minute variations in the EEG signals that can differentiate the EEGs of PWA from those of nonaffected persons. The authors advance the idea of automated computer-aided diagnosis (CAD) of alcoholism by employing the EEG signals. This is achieved through judicious combination of signal processing techniques such as wavelet, nonlinear dynamics, and chaos theory and pattern recognition and classification techniques. A CAD system is cost-effective and efficient and can be used as a decision support system by physicians in the diagnosis and treatment of alcoholism especially those who do not specialize in alcoholism or neurophysiology. It can also be of great value to rehabilitation centers to assess PWA over time and to monitor the impact of treatment aimed at minimizing or reversing the effects of the disease on the brain. A CAD system can be used to determine the extent of alcoholism-related changes in EEG signals (low, medium, high) and the effectiveness of therapeutic plans.
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Challenges in diagnosing hepatic encephalopathy. Neurochem Res 2014; 40:265-73. [PMID: 25142937 DOI: 10.1007/s11064-014-1416-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 08/08/2014] [Accepted: 08/12/2014] [Indexed: 02/07/2023]
Abstract
The term "hepatic encephalopathy" (HE) covers the neuropsychiatric syndrome associated with acute, chronic and acute-on-chronic liver disease (CLD). This paper deals with clinical features and diagnosis of HE in patients with liver cirrhosis and portal hypertension or porto-systemic shunts. The possible impact of concomitant disorders and the cirrhosis underlying liver disease upon brain function is described emphasizing the need of a detailed diagnostic work up of every individual case before diagnosing HE. Currently used methods for diagnosing minimal or covert hepatic encephalopathy are compared with regard to their sensitivity and specificity for diagnosing HE against the background of a multitude of concomitant disorders and diseases that could contribute to brain dysfunction.
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Brain oscillatory activity during sleep shows unknown dysfunctions in early encephalopathy. J Physiol Biochem 2014; 70:821-35. [PMID: 25074827 DOI: 10.1007/s13105-014-0351-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 07/21/2014] [Indexed: 12/12/2022]
Abstract
Electroencephalographic recordings in cirrhotic patients without overt hepatic encephalopathy (HE) have mainly been performed during wakefulness. Our aim was to quantify their alterations in nocturnal sleep electroencephalogram (EEG). In 20 patients and 20 healthy volunteers, we recorded a nocturnal digital polysomnography. Different sleep parameters were measured. Besides, we performed quantitative analysis of EEG (qEEG) as follows: spectral power in the different sleep stages was calculated in the frequency bands low δ, δ, θ, α, and σ. Also, the mean dominant frequency and Sleep Indexes were obtained. In comparison with controls, the group of patients showed (1) different alterations in both the microstructure and the macrostructure of sleep; (2) an increase in, both, θ band power and the average mean dominant frequency during rapid eye movement (REM); (3) in all sleep stages, a decrease of sleep electroencephalogram spectral power in low δ band and an increase in δ band: and (4) in stages N3 and REM, significant increases in the minimum of mean dominant frequency and in the respective sleep indexes. Therefore, in cirrhotic patients without overt HE, and likely having minimal hepatic encephalopathy, we found different alterations in both the microstructure and the macrostructure of nocturnal sleep. Also, sleep qEEG showed a brain dysfunction in slow oscillatory mechanisms intrinsic of sleep stages, with an increase in the frequency of its maximal electroencephalogram synchronization, from low δ to δ band. These alterations may reflect the onset of encephalopathy; sleep qEEG may, thus, be an adequate tool for its brain functional evaluation and follow-up.
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Abstract
AbstractHepatic encephalopathy is a neuropsychiatric disorder usually associated with severe hepatic insufficiency. It may however be divided into clinical and subclinical groupings. Psychometric testing, serial EEG's, EEG spectral analysis and event related potentials are all presently being used to quantify and differentiate between the various stages of hepatic encephalopathy. We review the use of psychometrics in hepatic encephalopathy and discuss evidence that these findings are comparable with the more objective data of electrophysiological studies. An adequate, simple and inexpensive assessment may be carried out using a battery of psychometric tests which include number connection tests and five pointed star construction.
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Corrias M, Turco M, Rui MD, Gatta A, Angeli P, Merkel C, Amodio P, Schiff S, Montagnese S. Covert hepatic encephalopathy: does the mini-mental state examination help? J Clin Exp Hepatol 2014; 4:89-93. [PMID: 25755545 PMCID: PMC4116703 DOI: 10.1016/j.jceh.2013.12.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 12/31/2013] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVES The Mini-Mental State Examination (MMSE) has been utilized for the diagnosis of hepatic encephalopathy (HE). However, its threshold of abnormality has not been formally tested in patients with cirrhosis and its diagnostic/prognostic validity remains unknown. The aim of this study was to assess it in a large group of well-characterized outpatients with cirrhosis and no overt HE. METHODS One-hundred-and-ninety-one patients underwent clinical assessment, MMSE, electroencephalography (EEG) and paper-and-pencil psychometry (PHES); 117 were followed up for 8 ± 5 months in relation to the occurrence of HE-related hospitalizations. RESULTS On the day of study, 81 patients (42%) had abnormal EEG and 67 (35%) abnormal PHES; 103 (60%) had a history of HE. Average MMSE was 26.6 ± 3.5; 22 (19%) patients had abnormal MMSE based on the standard threshold of 24. Patients with abnormal EEG/PHES/history of HE had worse MMSE performance than their counterparts with normal tests/negative history (25.7 ± 4.2 vs. 27.3 ± 2.7; P < 0.01; 25.5 ± 3.2 vs. 27.9 ± 1.8, P < 0.0001; 26.3 ± 3.7 vs. 27.4 ± 2.6, P < 0.05, respectively). Based on the above results, MMSE thresholds of 26 and 27 were tested against abnormalities in clinical/EEG/PHES indices and significant associations were observed. An MMSE threshold of 26 was also a predictor of HE-related hospitalization (Cox-Mantel: P = 0.001); patients with MMSE <26 were significantly older than those with MMSE ≥26 but comparable in terms of liver dysfunction and ammonia levels. When MMSE items were considered separately, those which correlated most significantly with standard HE indices where spatial orientation and writing. CONCLUSION In conclusion, an MMSE <26 identifies older patients with cirrhosis who are more prone to manifest HE signs.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Sara Montagnese
- Address for correspondence: Sara Montagnese, Dipartimento di Medicina, University of Padova, Via Giustiniani, 2, Padova 35128, Italy. Tel.: +39 (0) 49 8218675; fax: +39 (0) 49 7960903.
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Abstract
EEG patterns in pediatric encephalopathy are largely nonspecific and may be seen in a wide variety of pathologies. However, EEG can play a valuable role in helping to assess the severity and ultimate prognosis in pediatric encephalopathies. This review article considers three of the most common forms of pediatric encephalopathy encountered in pediatric critically care units, including hypoxic ischemic encephalopathy, central nervous system infections, and metabolic encephalopathies. Because EEG is being used with increasing frequency in critically ill children, the value of EEG monitoring in encephalopathic patients continues to evolve.
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EEG abnormalities are associated with increased risk of transplant or poor outcome in children with acute liver failure. J Pediatr Gastroenterol Nutr 2014; 58:449-56. [PMID: 24345828 DOI: 10.1097/mpg.0000000000000271] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES There are limited data on the incidence of seizures and utility of brain imaging and electroencephalogram (EEG) to predict outcome of children with acute liver failure (ALF). We investigated the association between hepatic encephalopathy (HE) scores, abnormal EEG or neuroimaging, and short-term outcome. METHODS Single-center retrospective observational study of infants and children with ALF who underwent continuous EEG monitoring and brain imaging within 24 hours of admission to the intensive care unit (ICU). RESULTS A total of 19 patients with ALF with a mean age of 6.8 ± 1.5 years were evaluated. The majority of cases (74%) were indeterminate. Of the total, 10 patients (53%) survived to discharge without liver transplant (LT), 5 (26%) received LT, and 4 (21%) died without LT. Seizures occurred in only 2 cases (19%). Patients who had an abnormal EEG on admission (n = 7) were significantly more likely to die or require LT (P < 0.05, Fisher exact test). Patients with either an admission HE score ≤ 2, or liver injury unit score <222, combined with a normal or mildly abnormal EEG were more likely to survive without LT. Neuroimaging was normal in the majority of cases (87%) and was not associated with outcome. CONCLUSIONS Children with a moderate or severe abnormality of EEG background on admission were significantly more likely to require LT or to die. Children with an HE score ≤ 2, and a normal or only mildly abnormal EEG, were significantly more likely to survive without needing LT. These findings are an initial step toward distinguishing patients with ALF who may recover spontaneously from those who will require LT.
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Butz M, May ES, Häussinger D, Schnitzler A. The slowed brain: Cortical oscillatory activity in hepatic encephalopathy. Arch Biochem Biophys 2013; 536:197-203. [DOI: 10.1016/j.abb.2013.04.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 04/04/2013] [Accepted: 04/08/2013] [Indexed: 12/12/2022]
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Mladenović D, Hrnčić D, Rašić-Marković A, Puškaš N, Petrovich S, Stanojlović O. Spectral analysis of thioacetamide-induced electroencephalographic changes in rats. Hum Exp Toxicol 2012; 32:90-100. [DOI: 10.1177/0960327112456312] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Thioacetamide (TAA) is widely used as a model of hepatic encephalopathy (HE). The aim of our study was to investigate the effects of TAA on electroencephalographic (EEG) changes in rats and to compare them with human HE. Male Wistar rats were divided into groups: (1) saline-treated group and (2) TAA-treated groups: TAA300 (300 mg/kg), TAA600 (600 mg/kg), and TAA900 (900 mg/kg). Daily dose of TAA (300 mg/kg) was administered intraperitoneally once (TAA300), twice (TAA600), or thrice (TAA900) in subsequent days. EEG changes were recorded about 24 h after the last dose of TAA. Absolute and relative power density in alpha bands were significantly higher in TAA300 versus control group. In TAA300, absolute beta power density was higher and relative beta power density was lower versus control group. Absolute alpha, theta, delta, and relative theta power were significantly lower, while relative power in delta band was significantly higher in TAA900 versus control group ( p < 0.01). In conclusion, decrease in EEG voltage with an increase in delta relative power, which correspond to the EEG manifestations of severe HE in humans, was observed in TAA900 group. Electrical activity in TAA300 group correlates with mild HE in humans.
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Affiliation(s)
- D Mladenović
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 9 Belgrade, Serbia
| | - D Hrnčić
- Institute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, Višegradska 26/II, Belgrade, Serbia
| | - A Rašić-Marković
- Institute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, Višegradska 26/II, Belgrade, Serbia
| | - N Puškaš
- Institute of Histology and Embryology, Faculty of Medicine, University of Belgrade, Višegradska 26, Belgrade, Serbia
| | - S Petrovich
- Laboratory of Molecular Biology and Endocrinology, Vinča Institute of Nuclear Sciences, University of Belgrade, Serbia
| | - O Stanojlović
- Institute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, Višegradska 26/II, Belgrade, Serbia
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Kahlbrock N, Butz M, May ES, Brenner M, Kircheis G, Häussinger D, Schnitzler A. Lowered frequency and impaired modulation of gamma band oscillations in a bimodal attention task are associated with reduced critical flicker frequency. Neuroimage 2012; 61:216-27. [DOI: 10.1016/j.neuroimage.2012.02.063] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Revised: 01/31/2012] [Accepted: 02/21/2012] [Indexed: 10/28/2022] Open
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Abstract
Kinnier Wilson coined the term metabolic encephalopathy to describe a clinical state of global cerebral dysfunction induced by systemic stress that can vary in clinical presentation from mild executive dysfunction to deep coma with decerebrate posturing; the causes are numerous. Some mechanisms by which cerebral dysfunction occurs in metabolic encephalopathies include focal or global cerebral edema, alterations in transmitter function, the accumulation of uncleared toxic metabolites, postcapillary venule vasogenic edema, and energy failure. This article focuses on common causes of metabolic encephalopathy, and reviews common causes, clinical presentations and, where relevant, management.
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Affiliation(s)
- Michael J Angel
- Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
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Sakamoto M, Perry W, Hilsabeck RC, Barakat F, Hassanein T. Assessment and usefulness of clinical scales for semiquantification of overt hepatic encephalopathy. Clin Liver Dis 2012; 16:27-42. [PMID: 22321463 DOI: 10.1016/j.cld.2011.12.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic encephalopathy (HE) represents the effects of liver dysfunction on the brain. When HE is clinically obvious (eg, confusion, poor judgment, personality change), it is termed overt HE. The severity of HE is measured by different methods. Assessing the severity of HE is important for determining patient prognosis and effectiveness of therapy. This article discusses the different methods for grading HE, including clinical rating scales, neuropsychological tests, and neurophysiologic measures.
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Affiliation(s)
- Maiko Sakamoto
- Department of Psychiatry, University of California, San Diego, 220 Dickinson Street, Suite B (MC: 8231), San Diego, CA 92103, USA
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Kappus MR, Bajaj JS. Assessment of minimal hepatic encephalopathy (with emphasis on computerized psychometric tests). Clin Liver Dis 2012; 16:43-55. [PMID: 22321464 PMCID: PMC3312030 DOI: 10.1016/j.cld.2011.12.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Minimal hepatic encephalopathy (MHE) is associated with a high risk of development of overt hepatic encephalopathy, impaired quality of life, and driving accidents. The detection of MHE requires specialized testing because it cannot, by definition, be diagnosed on standard clinical examination. Psychometric and neurophysiologic techniques are often used to test for MHE. Paper-pencil psychometric batteries and computerized tests have proved useful in diagnosing MHE and predicting its outcomes. Neurophysiologic tests also provide useful information. The diagnosis of MHE is an important issue for clinicians and patients alike. Testing strategies depend on the normative data available, patient comfort, and local expertise.
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Affiliation(s)
- Matthew R Kappus
- Division of Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center, Virginia Commonwealth University, 1201 Broad Rock Boulevard, Richmond, VA 23249, USA
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Marchetti P, D'Avanzo C, Orsato R, Montagnese S, Schiff S, Kaplan PW, Piccione F, Merkel C, Gatta A, Sparacino G, Toffolo GM, Amodio P. Electroencephalography in patients with cirrhosis. Gastroenterology 2011; 141:1680-9.e1-2. [PMID: 21763244 DOI: 10.1053/j.gastro.2011.06.085] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Revised: 06/04/2011] [Accepted: 06/28/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Electroencephalography has not been completely quantified in patients with cirrhosis. We investigated the electroencephalogram (EEG) dynamics in patients with cirrhosis. METHODS We performed closed-eye EEGs on 175 patients with cirrhosis (age, 55 ± 11 years; 24% Child-Pugh class A, 48% class B, and 285 class C), conducted clinical and psychometric assessments for hepatic encephalopathy (HE), and followed the patients for 1 year. EEG characteristics were assessed in the frequency domain, in the frontal (F3-F4) and parietal (P3-P4) derivations. Intrahemispheric (frontoparietal, right, and left) and interhemispheric (F3-F4 and P3-P4) coherence were computed. The EEGs of 50 healthy volunteers (age, 56 ± 17 years) served as controls. RESULTS Compared with controls, the EEGs of patients with cirrhosis had a reduced frequency in the posterior derivations (P3/P4 mean dominant frequency, 9.1 ± 1.8 and 8.9 ± 1.7 Hz vs 10.4 ± 1.3 and 10.2 ± 1.3 Hz, respectively; P < .01) and an increase in interhemispheric parietal relative coherence within the theta band (22.3% ± 5.5% vs 18.9% ± 3.5%; P < .01). These features were more prominent in patients with Child class C and in patients with a history of overt HE; they correlated with hyperammonemia and hyponatremia. The decrease in EEG frequency, along with the increase in interhemispheric theta coherence in the posterior derivations, was inversely associated with survival and the occurrence of overt HE during the follow-up period. CONCLUSIONS In patients with cirrhosis, alterations in the EEG were significantly associated with the severity of liver disease and HE; the EEG might be used in determining prognosis.
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Malaguarnera M, Bella R, Vacante M, Giordano M, Malaguarnera G, Gargante MP, Motta M, Mistretta A, Rampello L, Pennisi G. Acetyl-L-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy. Scand J Gastroenterol 2011; 46:750-9. [PMID: 21443422 DOI: 10.3109/00365521.2011.565067] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Minimal hepatic encephalopathy (MHE) represents a common complication present in well-compensated cirrhotic patients that impairs patients' daily functioning and health-related quality of life (HRQL). Acetyl-L-carnitine (ALC) has been shown to be useful in improving blood ammonia and cognitive functions in cirrhotic patients with MHE. OBJECTIVE This study evaluated the effects of ALC treatment on HRQL and depression in patients with MHE. STUDY DESIGN This was a randomized, double-blind, placebo-controlled study. Sixty-seven patients with MHE were recruited to the study. They were randomly assigned to two groups and received either 2 g acetyl-L-carnitine twice a day (n = 33) or placebo (n = 34) for 90 days. The primary efficacy measures were changes in aspartate aminotransferase, alanine aminotransferase, γ-glutamyl-transpeptidase, albumin, alkaline phosphatase, prothrombin time, and ammonia. Clinical and laboratory assessments, psychometric tests and automated electroencephalogram (EEG) analysis were performed for all patients. RESULTS At the end of the study period, between the two groups, we observed a significant difference in physical function (p < 0.001), role physical (p < 0.001), general health (p < 0.001), social function (p < 0.05), role emotional (p < 0.05), mental health (p < 0.05), Beck Depression Inventory (p < 0.001), TMT-B s (p < 0.001), State Trait Inventory (p < 0.001), urea (p < 0.05), NH(4)(+) (p < 0.001), and bilirubin (p < 0.001). CONCLUSIONS This study shows that ALC treatment is associated with significant improvement in patient energy levels, general functioning and well-being. The improvement of quality of life is associated with reduction of anxiety and depression.
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Affiliation(s)
- Mariano Malaguarnera
- Department of Senescence, Urological and Neurological Sciences, University of Catania, Ospedale Cannizzaro, Catania, Italy.
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Malaguarnera M, Vacante M, Giordano M, Pennisi G, Bella R, Rampello L, Malaguarnera M, Li Volti G, Galvano F. Oral acetyl-L-carnitine therapy reduces fatigue in overt hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr 2011; 93:799-808. [PMID: 21310833 DOI: 10.3945/ajcn.110.007393] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Fatigue is frequently reported in hepatic encephalopathy (HE) and may be related to hyperammonemia. Acetyl-L-carnitine (ALC) offers neuroprotective benefits and improves mitochondrial energetics and function. OBJECTIVE This study evaluated the effect of exogenous ALC on physical and mental fatigue, fatigue severity, and physical activity in patients with mild and moderate hepatoencephalopathy (HE1 and HE2, respectively). DESIGN A total of 121 patients with overt HE were recruited to the study and were subdivided into 2 groups according to their initial HE grade [HE1 (n = 61) or HE2 (n = 60)]. Thirty-one patients with HE1 and 30 with HE2 received 2 g ALC, and 30 patients with HE1 and 30 patients with HE2 received placebo twice a day for 90 d. All patients underwent clinical and laboratory assessments and automated electroencephalogram analysis. RESULTS At the end of the study period, the ALC-treated patients in the HE1 group showed significantly better improvement than did the placebo group in mental fatigue score (-1.7 compared with -0.3; P < 0.05), the fatigue severity scale (-6.4 compared with 2.3; P < 0.001), 7-d Physical Activity Recall questionnaire score (17.1 compared with -2.5; P < 0.001), and Short Physical Performance Battery (2.1 compared with 0.2; P < 0.001); the HE2 group showed significantly better improvement in the fatigue severity scale (-8.1 compared with -5.1; P < 0.001) and 6-min walk test (19.9 compared with 2.3; P < 0.05). Significant decreases in NH(4)(+) were observed in both groups (P < 0.001). CONCLUSION Patients with HE treated with ALC showed a decrease in the severity of both mental and physical fatigue and an increase in physical activity. This trial was registered at clinicaltrials.gov as NCT01223742.
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Affiliation(s)
- Michele Malaguarnera
- Department of Biological Chemistry, Medical Chemistry, and Molecular Biology, University of Catania, Italy.
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Montagnese S, Biancardi A, Schiff S, Carraro P, Carlà V, Mannaioni G, Moroni F, Tono N, Angeli P, Gatta A, Amodio P. Different biochemical correlates for different neuropsychiatric abnormalities in patients with cirrhosis. Hepatology 2011; 53:558-66. [PMID: 21274876 DOI: 10.1002/hep.24043] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Accepted: 09/28/2010] [Indexed: 12/13/2022]
Abstract
UNLABELLED The diagnosis of hepatic encephalopathy (HE) relies on clinical, neurophysiological, psychometric and laboratory variables. The relationships between such tests remain debated. The aim of this study was to determine the laboratory correlates/prognostic value of neurophysiological/psychometric abnormalities in patients with cirrhosis. Seventy-two patients and 14 healthy volunteers underwent EEG and paper-and-pencil psychometry (PHES). Blood was obtained for C reactive protein (CRP), interleukin 6 (IL6), tumor necrosis factor (TNF)α, ammonia and indole/oxindole. Patients were followed prospectively for a median of 22 months in relation to the occurrence of death, transplantation and HE-related hospitalizations. Thirty-three patients had normal PHES and EEG, 6 had abnormal PHES, 18 abnormal EEG and 13 abnormal PHES and EEG. Patients with abnormal PHES had higher CRP (17 ± 22 vs 7 ± 6, P < 0.01), IL6 (32 ± 54 vs 12 ± 13, P < 0.05) and TNFα (17 ± 8 vs 11 ± 7, P < 0.001) levels than those with normal PHES. Patients with abnormal EEG had higher indole (430 ± 270 vs 258 ± 255, P < 0.01) and ammonia (66 ± 35 vs 45 ± 27, P < 0.05) levels than those with normal EEG. Psychometric test scores showed significant correlations with CRP, TNFα and IL6; EEG indices with ammonia and IL6. CRP and TNFα concentrations were independent predictors of abnormal PHES, ammonia and indole of abnormal EEG on multivariate analysis. Seven patients were lost to follow-up; of the remaining 65, 20 died and 14 underwent transplantation; 15 developed HE requiring hospitalization. PHES and EEG performance were independent predictors of HE and death (P < 0.05). CONCLUSION PHES and EEG abnormalities in patients with cirrhosis have partially different biochemical correlates and independently predict outcome.
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Affiliation(s)
- Sara Montagnese
- Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
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Angel MJ, Chen R, Bryan Young G. Metabolic encephalopathies. HANDBOOK OF CLINICAL NEUROLOGY 2010; 90:115-66. [PMID: 18631820 DOI: 10.1016/s0072-9752(07)01707-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Michael J Angel
- University of Toronto, Division of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada.
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Abstract
Practice guidelines for hepatic encephalopathy were developed and published in 2001 for overall management in adults. Hepatic encephalopathy is caused by nitrogenous substances from the gastrointestinal tract that adversely affect brain function. Hepatic encephalopathy is a diagnosis of exclusion. The West Haven criteria are recommended for staging the disease. Treatment goals are providing supportive care, identifying and removing precipitating factors, reducing nitrogenous load, and assessing long-term therapy needs. Data from some trials published before 2001 are not included in the guidelines. In addition, since the publication of the guidelines, new data have become available regarding treatment interventions and outcomes. Newer, nonabsorbed agents, such as rifaximin, alone or in conjunction with lactulose, may enhance compliance and adherence with therapy, and provide better treatment outcomes. New updated practice guidelines need to be developed for hepatic encephalopathy, along with treatment algorithms for patients with both minimal hepatic encephalopathy and overt hepatic encephalopathy.
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Affiliation(s)
- J Richard Thompson
- Department of Pharmacy Practice, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204-3951, USA.
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Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy. Eur J Gastroenterol Hepatol 2010; 22:199-206. [PMID: 19730107 DOI: 10.1097/meg.0b013e328330a8d3] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome in patients with liver disease. It was suggested that Bifidobacterium+fructo-oligosaccharides (FOS) may decrease blood and brain ammonia levels. AIM The study was conducted to compare the efficacy of Bifidobacterium+FOS and lactulose in patients with HE. METHODS One hundred and twenty-five patients (35 hepatitis B virus infected, 70 hepatitis C virus infected and 20 cryptogenetic cirrhosis) were enrolled in the study. Patients were randomized either to a treatment for 60 days with Bifidobacterium and FOS (group A) or into-group receiving lactulose (group B) in double-blind. RESULTS After 30 days of the study period, the Bifidobacterium+FOS-treated patients compared with lactulose-treated patients showed a significant decrease of Trail Making Test B (TMT B) (P<0.005), and a significant increase of Symbol Digit Modalities Test (P<0.001) and Block Design Test (P<0.001).After 60 days of the study period, the Bifidobacterium+FOS-treated patients compared with lactulose-treated patients showed a significant decrease of NH4 fasting HE1 (P<0.001), TMT A (P<0.05), TMT B (P<0.001), and a significant increase of Symbol Digit Modalities Test (P<0.001) and Block Design Test (P<0.001). CONCLUSION The treatment with Bifidobacterium+FOS is an alternative to the use of lactulose in patients with cirrhosis, for its usefulness in reducing blood ammonia levels and improvement of psychometric tests.
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Forget P, Wittebole X, Laterre PF. Therapeutic dose of acetaminophen may induce fulminant hepatitis in the presence of risk factors: a report of two cases. Br J Anaesth 2009; 103:899-900. [DOI: 10.1093/bja/aep322] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy. Hepatology 2009; 50:2014-21. [PMID: 19787808 DOI: 10.1002/hep.23216] [Citation(s) in RCA: 248] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA 23249, USA.
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