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Abstract

By studying neuronal activity through neuronal electrogenesis, neurophysiological investigations provide a functional assessment of the nervous system and, therefore, has been used for quantitative assessment and follow-up of hepatic encephalopathy (HE). The different clinical neurophysiological approaches can be classified depending on the function to explore and their sensitivity to HE. The reliable techniques are those that reflect cortical function, i.e., cognitive-evoked potentials (EPs) (P300 paradigm), electroencephalogram (EEG), visual EPs (latency>100 ms) and somatosensory EPs (SEPs) (latency between 25 and 100 ms). Short-latency EPs (brainstem acoustic EPs, SEPs of a latency<25 ms) are in principle insensitive to HE, but can disclose brainstem conduction deficits due to oedema. SEPs and motor EPs can disclose myelopathies. Because of its parallelism to the clinical examination, clinical neurophysiology can complement the neurological examination: (i) to provide evidence of HE in patients who have normal consciousness; (ii) to rule out, at least under some conditions, disturbances of consciousness due to other causes (e.g. drug-induced disturbances, non-convulsive status epilepticus) with the reservation that the mildest degrees of encephalopathy might be associated with an EEG pattern similar to that induced by drugs; and (iii) to demonstrate the worsening or, conversely improvement, of HE in the follow-up period.

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... The PHES is a validated assessment tool specifically designed for HE trials to test cognitive and psychomotor processing speed and visuomotor coordination (copyright by Hanover Medical School). [14][15][16] Prior work has demonstrated no learning effect or improving scores when tests are 14 days apart in patients with cirrhosis and a history of overt HE. [17] Any potential learning effect was mitigated by using four different PHES versions. A secondary efficacy outcome was assessed by change in the EncephalApp Stroop test, also validated in HE. [17] Short form health survey 36 (SF-36) was performed to assess quality of life. ...
... The median age was 61 years (range, 53-72), six (60%) were men, four (40%) had alcohol-associated cirrhosis, three (30%) had nonalcoholic steatohepatitis cirrhosis, and four (40%) had undergone transjugular intrahepatic portosystemic shunt (TIPS) ( Table 1). Median MELD at screening was 14 (range, [9][10][11][12][13][14][15][16][17][18]. Figure S1). ...
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Early data suggest fecal microbiota transplant (FMT) may treat hepatic encephalopathy (HE). Optimal FMT donor and recipient characteristics are unknown. We assessed the safety and efficacy of FMT in patients with prior overt HE, comparing five FMT donors. We performed an open‐label study of FMT capsules, administered 5 times over 3 weeks. Primary outcomes were change in psychometric HE score (PHES) and serious adverse events (SAEs). Serial stool samples underwent shallow shotgun metagenomic sequencing. Ten patients completed FMT administration and 6‐month follow‐up. Model for End‐Stage Liver Disease (MELD) score did not change after FMT (14 versus 14, p = 0.51). Thirteen minor adverse events and three serious adverse events (two unrelated to FMT) were reported. One SAE was extended‐spectrum beta‐lactamase Escherichia coli bacteremia. The PHES improved after three doses of FMT (+2.1, p < 0.05), after five doses of FMT (+2.9, p = 0.007), and 4 weeks after the fifth dose of FMT (+3.1, p = 0.02). Mean change in the PHES ranged from −1 to +6 by donor. Two taxa were identified by random forest analysis and confirmed by linear regression to predict the PHES— Bifidobacterium adolescentis (adjusted R2 = 0.27) and B. angulatum (adjusted R2 = 0.25)—both short‐chain fatty acid (SCFA) producers. Patients who responded to FMT had higher levels of Bifidobacterium as well as other known beneficial taxa at baseline and throughout the study. The FMT donor with poorest cognitive outcomes in recipients had the lowest fecal SCFA levels. Conclusion: FMT capsules improved cognition in HE, with an effect varying by donor and recipient factors (NCT03420482). In this trial, fecal microbiota transplant (FMT) from multiple different donors were used to treat hepatic encephalopathy. To our knowledge, this is the first study to evaluate FMT donor and recipient characteristics that influence response to therapy.
... Among various applications, P300 was thus proposed as a sensitive cognitive index in HCV patients (Kramer et al. 2002). Though not formally indicated for clinical use (Amodio and Montagnese 2015), it may "provide an insight into the cognitive processes in research settings" (Guerit et al. 2009). Recently, its usefulness was strongly revived (Fath-Elbab et al. 2018). ...
... Later studies questioned the P300 practical value in the clinical assessment of hepatic encephalopathy, since routine or quantitative EEG was found superior (Amodio et al. 2005). The International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) still preserved some role for the P300 in the research setting (Guerit et al. 2009). Most recently, the P300 validity has been strongly revived by Fath-Elbab et al. (2018), since this index could disclose "minimal and subclinical impairment of cognitive function at early stages of chronic hepatitis with accuracy". ...
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Cognition was assessed in hepatitis C virus (HCV) patients, who did not meet the criteria for a minimal hepatic encephalopathy. Their liver function was compensated. We then disentangled potential cognitive changes associated with a sustained virologic response at 12 weeks (SVR-12), following treatment with direct antiviral agents (DAAs). We studied 23 selected HCV patients with a battery of standard neuropsychological tests, and with recordings of the P300 wave, a cerebral potential of "cognitive" significance. There was a baseline evaluation (T0) and a second one 6 months later (T1). We had 2 control groups of comparable age and sex, i.e., 15 patients suffering from non-alcoholic fatty liver disease (NAFLD) and 15 healthy subjects. At T0, we detected a significant (p < 0.05) cognitive impairment in the HCV group, which involved episodic and working memory, attention, visuospatial and verbal abilities, executive functions, and logic reasoning. The P300 latency was significantly (p < 0.05) delayed in the group. At T1, we observed some significant (p < 0.05) HCV recovery in given test domains, e.g., memory, executive functions, and reasoning. Accordingly, the P300 latency shortened significantly (p < 0.05). HCV patients exhibited subtle cognitive defects, somehow independent of their liver condition, possibly linked to direct or indirect brain involvement by the virus. These defects partly recovered following the SVR-12, as achieved through DAAs. The P300 wave was a valid neurophysiologic counterpart of these changes. DAAs can have a role in the early preservation of cognition in HCVs.
... The term 'covert' includes minimal and Grade 1 HE. The testing strategies can be divided into two major types: psychometric and neurophysiological [68,69]. Since the condition affects several components of cognitive functioning, which may not be impaired to the same degree, the ISHEN suggests the use of at least two tests depending on the local population norms and availability, and preferably with one of the tests being more widely accepted so as to serve as a comparator. ...
... Further studies are underway to evaluate its potential for screening for minimal/covert HE. vi. Electroencephalograph (EEG) examination can detect changes in cortical cerebral activity across the spectrum of HE without patient cooperation or risk of a learning effect [68]. It is, however, nonspecific and may be influenced by accompanying metabolic disturbances such as hyponatremia as well as drugs. ...
Article
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Hepatic encephalopathy (HE) is a reversible syndrome of impaired brain function occurring in patients with advanced liver diseases. The precise pathophysiology of HE is still under discussion; the leading hypothesis focus on the role of neurotoxins, impaired neurotransmission due to metabolic changes in liver failure, changes in brain energy metabolism, systemic inflammatory response and alterations of the blood brain barrier. HE produces a wide spectrum of nonspecific neurological and psychiatric manifestations. Minimal HE is diagnosed by abnormal psychometric tests. Clinically overt HE includes personality changes, alterations in consciousness progressive disorientation in time and space, somnolence, stupor and, finally, coma. Except for clinical studies, no specific tests are required for diagnosis. HE is classified according to the underlying disease, the severity of manifestations, its time course and the existence of precipitating factors. Treatment of overt HE includes supportive therapies, treatment of precipitating factors, lactulose and/or rifaximin. Routine treatment for minimal HE is only recommended for selected patients.
... TAA induces hepatocellular necrosis, as well as lymphocyte infiltration in the absence of cholestasis. Additionally, the TAA model has been used to explain alterations in the central nervous system (CNS) functioning in HE (Guerit et al., 2009). Hyperammonemia is considered one of the most severe pathophysiologic mechanisms promoting cerebral edema in HE. ...
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NM (2022) Astrocytes profiling in acute hepatic encephalopathy: Possible enrolling of glial fibrillary acidic protein, tumor necrosis factor-alpha, inwardly rectifying potassium channel (Kir 4.1) and aquaporin-4 in rat cerebral cortex.
... TAA induces hepatocellular necrosis, as well as lymphocyte infiltration in the absence of cholestasis. Additionally, the TAA model has been used to explain alterations in the central nervous system (CNS) functioning in HE (Guerit et al., 2009). Hyperammonemia is considered one of the most severe pathophysiologic mechanisms promoting cerebral edema in HE. ...
Article
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Hepatic encephalopathy (HE) is a neurological disarray manifested as a sequel to chronic and acute liver failure (ALF). A potentially fatal consequence of ALF is brain edema with concomitant astrocyte enlargement. This study aims to outline the role of astrocytes in acute HE and shed light on the most critical mechanisms driving this role. Rats were allocated into two groups. Group 1, the control group, received the vehicle. Group 2, the TAA group, received TAA (300 mg/kg) for 3 days. Serum AST, ALT, and ammonia were determined. Liver and cerebral cortical sections were processed for hematoxylin and eosin staining. Additionally, mRNA expression and immunohistochemical staining of cortical GFAP, TNFα, Kir4.1, and AQP4 were performed. Cortical sections from the TAA group demonstrated neuropil vacuolation and astrocytes enlargement with focal gliosis. GFAP, TNFα, and AQP4 revealed increased mRNA expression, positive immunoreactivity, and a positive correlation to brain water content. In contrast, Kir 4.1 showed decreased mRNA expression and immunoreactivity and a negative correlation to brain water content. In conclusion, our findings revealed altered levels of TNFα, Kir 4.1, GFAP, and AQP4 in HE-associated brain edema. A more significant dysregulation of Kir 4.1 and TNFα was observed compared to AQP4 and GFAP.
... VEPs are influenced by optic nerve diseases, demyelinating processes, disorders of either subcortical or cortical neurons of brain hemispheres, metabolic abnormalities, traumatic brain injury and the use of psychoactive medications. Several researches have been done to investigate the role of VEPs in the detection of cortical affection among cirrhotic patients (Guerit et al., 2009;Amodio & Montagnese, 2015). El-Sherif et al. 2018, studied VEP and psychometric test in thirty patients with liver cirrhosis and no clinical evidence of HE . ...
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Background: Cirrhosis is a dynamic process starts after sustained inflammation, followed by necrosis of liver cells and fibrosis that occur as a normal wound healing response then nodular formation that eventually lead to hepatic dysfunction. Aim and objectives: Study the effect of hepatic cirrhosis on cerebral cortex and subcortical pathways using VEP, and Comparison between different VEP check sizes in detection of early encephalopathy among cirrhotics. Subjects and methods: This was a case/control study carried out on 45 cirrhotic patients, and 45 matched normal controls. All subjects underwent full opthalmological assesment prio to the conduction of the PVEP, after the approval of the ethical committee. Results: the studied cases had significantly more delayed latency and lower amplitude than the studied controls on both sides at both 1 degree and 15 minutes check sizes (P-value<0.05), however 13 patiebts were detected by the 15 min check size to be abnormal on he contrary of the 1 degree chech size that detected changes only in 6 patients. Conclusion: Vep 15 min is more sensitive in detecting early changes in cirrhotic patients. denoting that most of the hepatic encephalopathy changes are affecting the central visual field.
... MHE does not show cognitive signs or other clinical signs and should be tested with psychometric and neurophysiological approaches [59]. MHE may cause socioeconomic difficulties due to a decrease in the patient's quality of life [60,61]. ...
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Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome and disease can be positively utilized not only in the diagnosis area of HE but also in the treatment area. Probiotics and prebiotics aim to resolve gut dysbiosis and increase beneficial microbial taxa, while fecal microbiota transplantation aims to address gut dysbiosis through transplantation (FMT) of the gut microbiome from healthy donors. Antibiotics, such as rifaximin, aim to improve cognitive function and hyperammonemia by targeting harmful taxa. Current treatment regimens for HE have achieved some success in treatment by targeting the gut microbiota, however, are still accompanied by limitations and problems. A focused approach should be placed on the establishment of personalized trial designs and therapies for the improvement of future care. This narrative review identifies factors negatively influencing the gut–hepatic–brain axis leading to HE in cirrhosis and explores their relationship with the gut microbiome. We also focused on the evaluation of reported clinical studies on the management and improvement of HE patients with a particular focus on microbiome-targeted therapy.
... Изменения ЭЭГ, наблюдаемые у данных пациентов, отражают наличие минимальной ПЭ в отсутствие других причин и коррелируют со степенью тяжести дисфункции печени. Данная методика требует специализированного программного обеспечения и навыков, поэтому для диагностики МПЭ в клинической практике обычно не используется [23]. ...
Article
Hepatic encephalopathy (HE) is one of the most common and dangerous complications of cirrhosis. HE is considered a predictor of death within the first year after onset in more than 60% of patients. Recently, studies have focused on minimal HE (MHE) which is characterized by medical, social, and clinical relevance. MHE patients are a risk group for cirrhosis complications and hospital admission. This demonstrates the need for early therapeutic and preventive measures for MHE. This paper provides information on current diagnostic and treatment tools for MHE in cirrhosis and illustrates the efficacy of various therapies on the outcomes and quality of life in these patients. The authors conclude that one should rely on studies establishing the efficacy of rifaximin-α to regress MHE, improve the quality of life and reduce the risks of complications and decompensation in cirrhosis compared to other medications. Meanwhile, further studies are needed to reveal favorable and unfavorable predictors of disease course and to optimize therapeutic and preventive measures in these patients. KEYWORDS: cirrhosis, hepatic encephalopathy, minimal hepatic encephalopathy, psychometric tests, lactulose, L-ornithine-L-aspartate, rifaximin-α FOR CITATION: Bakulin I.G., Ivanova K.N. Up-to-date diagnostic and treatment approaches to minimal hepatic encephalopathy in cirrhosis. Russian Medical Inquiry. 2022;6(5):272–277 (in Russ.). DOI: 10.32364/2587-6821-2022-6-5-272-277
... Food & Function hepatic disorders with highly defined cerebral alterations. [37][38][39] The results of the present work clearly show that TAA in a dose of 100 mg kg −1 three times weekly for two weeks was efficient to induce typical symptoms of acute HE, including progressive liver damage as indicated by the increased serum activities of ALT and AST, hyperammonaemia, as well as neurocognitive deficits evidenced by decreased locomotor activity and depressive emotion. 40 TAA is metabolized within the liver cytochrome 2E1 (CYP2E1) enzyme into a toxic by-product that triggers ROS production, particularly superoxide free radicals, promoting lipid peroxidation and oxidative liver damage. ...
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In the present study, we aimed to delineate the neuroprotective potential of thymol (THY) against neurotoxicity and cognitive deterioration induced by thioacetamide (TAA) in an experimental model of hepatic encephalopathy (HE). Rats received TAA (100 mg kg-1, intraperitoneally injected, three times per week) for two weeks. THY (30 and 60 mg kg-1), and Vit E (100 mg k-1) were administered daily by oral gavage for 30 days after HE induction. Supplementation with THY significantly improved liver function, reduced serum ammonia level, and ameliorated the locomotor and cognitive deficits. THY effectively modulated the alteration in oxidative stress markers, neurotransmitters, and brain ATP content. Histopathology of liver and brain tissues showed that THY had ameliorated TAA-induced damage, astrocyte swelling and brain edema. Furthermore, THY downregulated NF-kB and upregulated GFAP protein expression. In addition, THY significantly promoted CREB and BDNF expression at both mRNA and protein levels, together with enhancing brain cAMP level. In conclusion, THY exerted hepato- and neuroprotective effects against HE by mitigating hepatotoxicity, hyperammonemia and brain ATP depletion via its antioxidant, anti-inflammatory effects in addition to activation of the CREB/BDNF signaling pathway.
... It is an available examination that does not require the patient's cooperation, but its results may be influenced by metabolic disorders, other CNS diseases, and the drugs used. Due to the dependence of the result on the evaluating investigator, it is recommended to use spectral, computer-assisted EEG analysis [18]. In some studies, EEG abnormalities were found in patients with MHE in as many as 85% of patients without clinical symptoms of encephalopathy. ...
Article
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Hepatic encephalopathy is a dysfunction of the central nervous system caused by chronic and acute liver disease. It presents a wide spectrum of symptoms from undetectable in a standard clinical examination to hepatic coma. The mildest form of hepatic encephalopathy is minimal hepatic encephalopathy. It significantly influences the quality of life, prognosis, and the incidence of complications. A wide range of psychometric and neurophysiological tests are used in the diagnostics. Treatment is based on the same principles as in overt encephalopathy. The most commonly used drugs include rifaximin, ornithine aspartate, and LOLA.
... Although the grading of severity of EEG alterations in HE can be evaluated based on visual pattern recognition, this method has shown to have limited reliability [36] semi-quantitative analysis for base frequency [27] or quantitative spectral analysis [37,38] with or without brain mapping needs to be included in protocols [39,40]. ...
Article
Background and aim: Hepatic encephalopathy is a serious complication that entails liver cirrhosis with a high mortality rate. The Child- Turcotte-Pugh class (CTP class) and model for end-stage liver disease (MELD) score are two important prognostic indicators for cirrhosis, while sequential organ failure assessment (SOFA) is a dynamic score for the assessment of critically ill patients. Patients with liver disease with advanced CTP class and higher MELD scores have poor prognosis. The aim of this study was to evaluate the role of electroencephalography (EEG) in cirrhotic patients requiring ventilator support for hepatic encephalopathy Grade III-IV. Methods: A retrospective study was conducted on patients admitted to the liver intensive care unit (ICU) of a tertiary teaching institute. EEG records of 92 patients with Grade III-IV hepatic encephalopathy who were admitted between April 2015 and May 2017 to the liver ICU were analyzed. The correlation between EEG findings and 28-day mortality, ICU length of stay, and the number of days on mechanical ventilation was determined. Results: Seventy-eight of 92 patients (85%) exhibited bilateral slowing EEG pattern, suggestive of encephalopathy. A triphasic pattern was the most common EEG abnormality in 40% (31 of 78) of the patients. Patients with abnormal EEG had a significantly higher MELD score compared to those with a normal EEG (P=0.02). There were no significant differences in length of mechanical ventilation between both groups, but an increasing trend was observed in those with abnormal EEG (P=0.09). Conclusion: EEG findings correlate well with severity of disease in critically ill patients with liver disease. Relevance for patients: EEG has a role in monitoring and prognostication of hepatic encephalopathy in critically ill patients with liver disease.
... La EHM puede ser definida como la presencia de defectos cognitivos medibles en pacientes con enfermedad hepática, shunts portosistémicos o ambos, que no son identificados a través de una historia clínica detallada y un examen neurológico completo, que incluye la entrevista a familiares cercanos, pero que sí son detectados por anormalidades en pruebas neuropsicométricas o neurofisiológicas que se pueden realizar en la cabecera del paciente y en el contexto ambulatorio, en ausencia de otras causas conocidas de anormalidades en las pruebas cognitivas. Entre el 60-80% de los pacientes con cirrosis presentan evidencias de EHM [2][3][4][5] . ...
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Hacer ciencia es un esfuerzo gratificante, aunque no por ello exento de dificultades. La sabiduría popular señala, “Todo lo que tenemos es prestado”; con mucho acierto y es que dentro este contexto es importante reconocer que en cada momento quienes se involucran en hacer ciencia producen nuevos conocimientos sobre las experiencias de los que nos antecedieron en este quehacer y tuvieron el cuidado de dejar para los nuevos científicos un bagaje de conocimiento logrados, durante su vida académica, conscientes de que “todo lo que tenemos es prestado”. Quienes nos antecedieron en este quehacer científico, supieron enfrentar el desafío de hacer ciencia con capacidad y ante todo generosidad para compartir sus experiencias con los nuevos científicos a fin de que estos puedan contar con la solvencia adecuada para enfrentar el desafío de hacer ciencia y en el futuro lo seguirán haciendo otros que tomen la posta. Los conocimientos logrados fruto de ese esfuerzo colectivo intergeneracional, representa para los nuevos científicos un primer capital para futuros logros científicos. Al presente, la comunidad científica boliviana asiste de manera especial, a una realidad con diferentes oportunidades y diferentes vivencias esperimentadas de diferente manera pero con la meta común de beneficiar a la sociedad.
... (Olesen et al. 2016)). Both EEG and MEG recordings are suggested to support the study and diagnosis of HE (Guerit et al. 2009;Hari et al. 2018;Schiff et al. 2016). ...
Article
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Hepatic encephalopathy (HE) is a frequent neuropsychiatric complication in patients with acute or chronic liver failure. Symptoms of HE in particular include disturbances of sensory and motor functions and cognition. HE is triggered by heterogeneous factors such as ammonia being a main toxin, benzodiazepines, proinflammatory cytokines and hyponatremia. HE in patients with liver cirrhosis is triggered by a low-grade cerebral edema and cerebral oxidative/nitrosative stress which bring about a number of functionally relevant alterations including posttranslational protein modifications, oxidation of RNA, gene expression changes and senescence. These alterations are suggested to impair astrocyte/neuronal functions and communication. On the system level, a global slowing of oscillatory brain activity and networks can be observed paralleling behavioral perceptual and motor impairments. Moreover, these changes are related to increased cerebral ammonia, alterations in neurometabolite and neurotransmitter concentrations and cortical excitability in HE patients.
... Neurophysiological tests measure physiological function, often using electroencephalograms to analyze brain function. Cerebral magnetic resonance is also applied to determine the hyperactivity of both the basal ganglia and white matter and to establish whether the changes observed in these brain regions are associated with the oedema occurring in HE and the level of hyperammonemia (Guerit et al., 2009;Su et al., 2015). Cerebral spectroscopy is used to analyze cerebral mass in relation to ammonium, glutamate, or glutamine exposure, as well as the presence of cerebral/brain water. ...
Article
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Glutamate fulfils many vital functions both at a peripheral level and in the central nervous system (CNS). However, hyperammonemia and hepatic failure induce alterations in glutamatergic neurotransmission, which may be the main cause of hepatic encephalopathy (HE), an imbalance which may explain damage to both learning and memory. Cognitive and motor alterations in hyperammonemia may be caused by a deregulation of the glutamate-glutamine cycle, particularly in astrocytes, due to the blocking of the glutamate excitatory amino-acid transporters 1 and 2 (EAAT1, EAAT2). Excess extracellular glutamate triggers mechanisms involving astrocyte-mediated inflammation, including the release of Ca2+-dependent glutamate from astrocytes, the appearance of excitotoxicity, the formation of reactive oxygen species (ROS), and cell damage. Glutamate re-uptake not only prevents excitotoxicity, but also acts as a vital component in synaptic plasticity and function. The present review outlines the evidence of the relationship between hepatic damage, such as that occurring in HE and hyperammonemia, and changes in glutamine synthetase function, which increase glutamate concentrations in the CNS. These conditions produce dysfunction in neuronal communication. The present review also includes data indicating that hyperammonemia is related to the release of a high level of pro-inflammatory factors, such as interleukin-6, by astrocytes. This neuroinflammatory condition alters the function of the membrane receptors, such as N-methyl-D-aspartate (NMDA), (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AMPA, and γ-aminobutyric acid (GABA), thus affecting learning and spatial memory. Data indicates that learning and spatial memory, as well as discriminatory or other information acquisition processes in the CNS, are damaged by the appearance of hyperammonemia and, moreover, are associated with a reduction in the production of cyclic guanosine monophosphate (cGMP). Therefore, increased levels of pharmacologically controlled cGMP may be used as a therapeutic tool for improving learning and memory in patients with HE, hyperammonemia, cerebral oedema, or reduced intellectual capacity.
... These changes correlate with indices of hepatic dysfunction and predict OHE development and liver-related death. [37] EEG study during sleep may be helpful in cirrhotic patients because changes in MDF during sleep represent an early marker of brain dysfunction in a subject with MHE. In this situation, q-EEG shows alterations in slow oscillatory activity, with an increase in frequency of dominant delta-rhythm. ...
Article
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Type C hepatic encephalopathy (HE) is a brain dysfunction caused by severe hepatocellular failure or presence of portal-systemic shunts in patients with liver cirrhosis. In its subclinical form, called “minimal hepatic encephalopathy (MHE), only psychometric tests or electrophysiological evaluation can reveal alterations in attention, working memory, psychomotor speed and visuospatial ability, while clinical neurological signs are lacking. The term “covert” (CHE) has been recently used to unify MHE and Grade I HE in order to refer to a condition that is not unapparent but also non overt. “Overt” HE (OHE) is characterized by personality changes, progressive disorientation in time and space, acute confusional state, stupor and coma. Based on its time course, OHE can be divided in Episodic, Recurrent or Persistent. Episodic HE is generally triggered by one or more precipitant factors that should be found and treated. Unlike MHE, clinical examination and clinical decision are crucial for OHE diagnosis and West Haven criteria are widely used to assess the severity of neurological dysfunction. Primary prophylaxis of OHE is indicated only in the patient with gastrointestinal bleeding using non-absorbable antibiotics (Rifaximin) or non-absorbable disaccharides (Lactulose). Treatment of OHE is based on the identification and correction of precipitating factors and starting empirical ammonia-lowering treatment with Rifaximin and Lactulose (per os and enemas). The latter should be used for secondary prophylaxis, adding Rifaximin if HE becomes recurrent. In recurrent/persistent HE, the treatment options include fecal transplantation, TIPS revision and closure of eventual splenorenal shunts. Treatment of MHE should be individualized on a case-by-case basis.
... observed in other forms of metabolic encephalopathies), and changes in EEG background occur already with very mild degree of HE [29]. Moreover, somato-sensory evoked potentials may reveal signs of brainstem dysfunction or myelopathy in cirrhotic patients, but their use is quite limited in many ICUs [30]. High Pulsatility Index (PI) values from trans-cranial Doppler has been investigated in patients with HE as a reflect of increased cerebrovascular resistance or intracranial hypertension [11,31]; however, most of cirrhotic patients have normal PI values even in severe HE. ...
Article
Purpose: To evaluate whether pupillary abnormalities would correlate with the severity of encephalopathy in critically ill cirrhotic patients. Methods: In this retrospective study, we enrolled adult cirrhotic patients admitted to the Intensive Care Unit undergoing automated pupillometry assessment within the first 72 h since ICU admission. Encephalopathy was assessed with West-Haven classification and GlasgowComa Scale. Pupillometry-derived variableswere also correlatedwith biological variables, includingammonium, renal function or inflammatory parameters,measured on the day of pupillary assessment. Results: A total of 62 critically ill cirrhotic patients (Age 61 [52–68] years; 69% male) were included.Median GCS andWest-Haven classification were 14 [11–15] and 1 [0–3], respectively. There was a significant although weak correlation between GCS and constriction velocity (CV; R2=0.1; p=0.017).Weobserved significant differences in CV and DV values among different levels ofWest-Haven classification.When only patients with encephalopathy (n = 42) or severe HE (n = 18) were considered, a weak correlation between GCS and worst CV was observed. When patients receiving sedatives or opioids were excluded, no significant correlation between pupillometry and clinical variables was observed. Conclusions: Pupillary function assessed by the automated pupillometrywas poorly associatedwith encephalopathy scales in cirrhotic patients.
... 11 Testing strategies can be psychometric and neurophysiological. 12 Patients with subtle problems are advised to be tested. 13 Porto-systemic encephalopathy (PSE) syndrome tests are commonly used because of easy administration and good external validity. ...
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Introduction: Among patients with Hepatic Encephalopathy, prevalence of Minimal HE varies between 30-50%. Identifying patients with MHE has been shown to improve with medications and delay development of Overt HE, however only limited clinicians screen for MHE in patients due to time consuming neuropsychological and neurophysiological tests. The Number Connection Test is an easy way to evaluate patients to diagnose MHE. The aim of this study is to find out the prevalence of covert hepatic encephalopathy. Methods: The descriptive cross-sectional study was done to find out the prevalence of covert hepatic encephalopathy among patients with chronic liver disease. To diagnose Covert HE which included MHE as well, NCT was used in Devanagari script. Results: The prevalence of covert hepatic encephalopathy is found to be 56 (58.3%) at 90% confidence interval (58.23-58.37%). A total of 96 patients (71.9% male) were diagnosed as HE, with mean age of 49.6+11.8 years. The cause of CLD in 85 (88.5%) of these patients was alcohol, of which 76 (79.2%) consumed locally brewed alcohol. Of these 96 patients with HE, only 40 (41.7%) had overt HE. Among all these, maximum patients had MHE (37.5%). Conclusions: Our study showed that although the prevalence of minimal HE is quite high among cirrhotics, they are usually missed in clinical practice due to absence of symptoms. Active screening with easy-to-administer tests, like Number Connection tests, can help identify patients with minimal HE and hence treat them early.
... TAA causes hepatocellular and bridging necrosis as well as lymphocytic infiltration without cholestasis. This model has been used to clarify changes in the functions of the central nervous system (CNS) in HE (Guerit et al. 2009;Butterworth 2001). Studies related to the changes in cerebral chemistry during overt end-stage HE suggest overactivation of NMDA receptor followed by alterations in a number of biochemical events in the brain (Felipo and Butterworth 2002), including induction of nitrosative and oxidative stress as important factors in the pathogenesis of HE (Norenberg et al. 2007;Singh and Trigun 2010). ...
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Brain affection is a common symptom of liver insufficiency. This study aimed to evaluate the role of low-dose γ irradiation (LDR) as a potential therapeutic agent in thioacetamide (TAA)-induced hepatic encephalopathy (HE) in rats. Effects of local and whole-body irradiation (0.5 Gy) on rat brain/liver were evaluated following the induction of HE by TAA (200 mg/kg/day/for 3 successive days). Serum activities of aspartate transaminase (AST) and alanine transaminase (ALT) and ammonia level were assessed. The effect of HE on brain was evaluated through the determination of brain contents of malondialdehyde (MDA), reduced glutathione (GSH), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β) and glutathione peroxidase (GPx) activity. Moreover, apoptotic and inflammatory changes in brain and liver tissues were assessed together with alpha-smooth muscle actin (α-SMA); fibrosis marker. Results showed correction of the biochemical parameters which was supported by the results of the immunohistochemical examinations. LDR is a promising hepato- and neurotherapy against HE.
... Testing approaches can be divided into two major types: psychometric and neurophysiological [70,71]. As MHE affects many elements of cognitive functioning, which may not be impaired to identical degrees, the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) recommends the use of at least two tests, based on the local population norms and availability, and if possible, with one of the tests being more widely accepted to serve as a comparator [72]. ...
... The tests can be categorized into neuropsychological and psychometric tests. 20,21 The ISHEN also recommends that a minimum of two tests should be utilized as HE can impact numerous aspects of cognition. 17 The evaluation for minimal and covert hepatic encephalopathy is important as it can assess for the high risk patients. ...
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Hepatic encephalopathy is a well-recognized complication of decompensated cirrhosis. It is a reversible state of neurocognitive decline, the etiology of which is multifactorial. Diagnosis is predominantly clinical and usually a diagnosis of exclusion. The identification of precipitating factors and their correction is an essential part of the management along with medical therapies such as lactulose and rifaxmin.
... The testing options of covert HE is based on psychometric neurophysiological tests (the term "covert" comprises minimal and Grade 1 HE) [27]. In the absence of clear physical examination signs of HE, neuropsychometric tests may be used to distinguish disruption in concentration, working memory, visuospatial abilities and normal motor skills [28]. ...
... 38 The neurophysiological tests include the critical flicker frequency (CFF) test 39,40 and the electroencephalogram (EEG). The EEG is independent of cognitive stimulation and patient cooperation and demonstrates a characteristic, but not specific, shift in electric activity in patients with HE. 41,42 In clinical routine, liver centers can use the tests they are familiar with, given that normative reference data are available. However, none of the tests is specific for HE, and the correlation between them is poor, likely due to the multidimensional dysfunctionality in HE. 31 Thus, already the diagnosis of MHE presents unsolved difficulties, and when it comes to the diagnosis of RHE it must be kept in mind that the features of RHE are not well characterized. ...
Article
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Liver transplantation (LT) represents the definitive treatment for end-stage liver disease. Cognitive impairment following LT is frequent, referred to as postliver transplant encephalopathy (PLTE). LT removes the underlying chronic liver disease, and until recently hepatic encephalopathy (HE) was assumed to be fully reversible after LT. However, increasing evidence indicates that some degree of cognitive impairment may be present after LT. To which extent PLTE reflects cognitive impairment caused by residual HE (RHE) or the combined effect of other factors affecting brain function before, during, and after LT is not clarified. None of the available psychometric and neurophysiological tests used for detecting HE is shown to be able to distinguish between etiologies. The available, mostly retrospective, clinical studies indicate a high prevalence of abnormal psychometric tests after LT, and not all seem to recover completely. The patients with earlier HE show the most marked improvements, suggesting that the clinical picture of the early PLTE, in fact, represents RHE. Other early post-LT etiologies for PLTE comprise cerebral ischemia, critical illness encephalopathy, and immunosuppressive therapy. Late-onset etiologies comprise diabetes and hypertension, among others. PLTE regardless of etiology is a worrying issue and needs more attention in the form of mechanistic research, development of diagnostic/discriminative tools, and standardized prospective clinical studies.
... The recording procedure does not require patient co-operation and is not subject to learning effects-problems which beset other assessment methods. 59 The main EEG characteristic of this condition is progressive slowing of the mean frequency but this is not specific as similar changes can be observed in other metabolic and drug-induced encephalopathies. 60 In interventional trials in hepatic encephalopathy, spectral analysis of the recordings is likely to be more informative. ...
Article
Randomised clinical trials and systematic reviews of research findings can provide high-quality evidence for decision-making in the management of patients with hepatic encephalopathy. A large number of clinical trials have been undertaken, over the last 50 years, relative to the prevention and treatment of this condition. However, changes have been made, during this time, in the classification of hepatic encephalopathy, diagnostic criteria and assessment measures. These temporally based changes and the consequent lack of standardisation make it difficult to compare interventions and to evaluate their comparative efficacy and safety. While some consensus has been reached in relation to the diagnostic evaluation, classification and monitoring of patients in clinical trials, there is less surety about the choice of clinical endpoints. These outcome measures should be universally applicable, easily measured and clinically relevant. This article reviews the current recommendations regarding outcome selection and outlines some of the potential problems and pitfalls inherent in clinical trial evaluating interventions for the management of hepatic encephalopathy.
... La EHM puede ser definida como la presencia de defectos cognitivos medibles o shunts portosistémicos (en pacientes con enfermedad hepática) que no son identificados a través de una historia clínica detallada y un examen neurológico completo que incluya la entrevista a familiares cercanos, pero que sí son detectados debido a anormalidades en pruebas neuropsicométricas o neurofisiológicas que se pueden realizar en la cabecera del paciente y en el contexto ambulatorio, en ausencia de otras causas conocidas de anormalidades en las pruebas cognitivas. Entre el 60%-80% de los pacientes con cirrosis presentan evidencias de EHM (2)(3)(4)(5). ...
Article
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Objetivos: la encefalopatía hepática mínima constituye el estadio subclínico previo al desarrollo de encefalopa- tía hepática clínica en el paciente cirrótico, además de asociarse con un deterioro de la calidad de vida de estos pacientes y con un riesgo incrementado de accidentes laborales e incapacidad de conducción de vehículos. El Psychometric Hepatic Encephalopathy Score es considerado actualmente el método diagnóstico de elección en el diagnóstico de la EHM. El objetivo de este trabajo fue diseñar las tablas de normalidad del PHES para la población cubana. Población y métodos: se estudió una muestra conformada por 520 personas sanas de las provincias de Villa Clara, Sancti Spíritus y Cienfuegos. Las mismas realizaron las 5 pruebas incluidas en el PHES. Se analizaron las variables edad, sexo, años de escolarización, procedencia y consumo diario de alcohol. Mediante la prueba de la t de Student, ANOVA y el coeficiente de correlación de Pearson, se realizó el análisis univariante. Se efectuó un análisis de regresión lineal múltiple para cada prueba, y se construyeron las tablas de normalidad. Resultados: en el análisis multivariante (regresión lineal múltiple) la edad y los años de escolarización fueron las 2 variables independientes relacionadas con el rendimiento en cada una de las cinco pruebas. Conclusión: la disponibilidad de las tablas de normalidad del PHES permitirá contar con un método diagnóstico de referencia aplicable a los pacientes cubanos con cirrosis hepática, sin la necesidad de configurar grupos controlados por la edad y el nivel de escolaridad regionalmente.
... EEG is used to detect changes in cortical cerebral activity across the wide spectrum of HE without patient cooperation or risk of a learning effect. The reliability of EEG analysis can increase with quantitative analysis (including the background frequency with mean dominant frequency or spectral band analysis) [79]. However, it is nonspecific and may be influenced by accompanying metabolic disturbances, such as hyponatremia as well as drugs. ...
Article
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Minimal hepatic encephalopathy (MHE) is the mildest form of hepatic encephalopathy (HE). It affects the performance of psychometric tests focused on attention, working memory, psychomotor speed, and visuospatial ability, as well as electrophysiological and other functional brain measures. MHE is a frequent complication of liver disease, affecting up to 80% of tested patients. By being related to falls, an impairment in fitness to drive and the development of overt HE, MHE severely affects the lives of patients and caregivers by altering their quality of life and their socioeconomic status. MHE is detected in clinically asymptomatic patients using appropriate psychometric tests and neurophysiological methods that highlight neuropsychological alterations, such as video-spatial orientation deficits, attention disorders, memory, reaction times, electroencephalogram slowing, prolongation of latency-evoked cognitive potentials, and reduction in the critical flicker frequency. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics such as rifaximin, probiotics and branched-chain amino acids. However, because of the multiple diagnosis methods, the various endpoints of treatment trials and the variety of agents used in trials, the treatment of MHE is not currently recommended as routine, but only on a case-by-case basis.
... Діагностика когнітивних порушень при мінімальній ПЕ та ПЕ 1 ступеня можлива лише на підставі психометричних тестів [10], орієнтованих на оцінку уваги, робочої пам'яті, швидкості психомоторної та зоровопросторової орієнтації, нейрофізіологічних (електрофізіологічних та ін.) функціональних тестів оцінки діяльності мозку [11,12]. ...
Article
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Актуальність. Печінкова енцефалопатія — патологічні зміни функцій головного мозку незапального генезу, що проявляються синдромом вторинних неврологічних і когнітивних розладів, спричинених комплексом глибоких метаболічних порушень, в результаті гострої печінкової недостатності, хронічних захворювань печінки або портосистемного шунтування крові. Початкова стадія енцефалопатії не має клінічних неврологічних симптомів, але визначається у 20–80 % хворих на цироз печінки і на відміну від кінцевих стадій є оборотною. Мета дослідження: оцінити ефективність тесту зв’язку чисел, флікер-тесту та електроенцефалографії в діагностиці енцефалопатії у хворих з печінковою та позапечінковою формою портальної гіпертензії. Матеріали та методи. Синдром печінкової енцефалопатії вивчено у 50 хворих з печінковою формою портальної гіпертензії, 30 хворих з позапечінковою формою портальної гіпертензії та 25 осіб без ознак портальної гіпертензії. Для діагностики використовували тест зв’язку чисел, флікер-тест та електроенцефалографію. Результати. Тест зв’язку чисел дозволив встановити ознаки печінкової енцефалопатії майже в усіх хворих незалежно від наявності та форми портальної гіпертензії. Однак прояви печінкової енцефалопатії за частотою і за вираженістю переважали у хворих з печінковою портальною гіпертензією. Проведення флікер-тесту дозволило діагностувати мінімальну печінкову енцефалопатію у 96 % хворих з печінковою портальною гіпертензією та 60 % хворих з позапечінковою портальною гіпертензією. Виконання електроенцефалографії визначило наявність печінкової енцефалопатії у 60 % хворих з печінковою портальною гіпертензією, 50 % хворих з позапечінковою портальною гіпертензією та 12 % хворих без портальної гіпертензії. Висновки. Зіставлення ефективності діагностичних тестів показало, що простий у виконанні і доступний тест зв’язку чисел є найбільш ефективним, однак і інші тести мають свої позитивні сторони в клінічній оцінці печінкової енцефалопатії у хворих з портальною гіпертензією.
... Numerous neurological and neurocognitive domains are affected, which have protean manifestations including extrapyramidal dysfunction, asterixis, myelopathy, progressive memory impairment, disorientation for time and space, acute confusion and coma. 2 Conversely, in minimal HE (mHE), there is none of the clinical or obvious cognitive dysfunctions of OHE and it is only detectable by psychometric testing of psychomotor speed, executive functions or neurophysical alterations. 3 Even though mHE is blanketed by its subclinical presentation, it may have a significant impact on activities of daily living, such as impairment of the ability to drive or operate machinery safely, owing to impaired cognitive and locomotive function. 4 Psychometric testing to identify early HE development is crucial for initiating treatment and halting disease progression to OHE, reducing the overall burden of disease to the local health care system. ...
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Background Psychometric testing is used to identify patients with cirrhosis who have developed hepatic encephalopathy (HE). Most batteries consist of a series of paper-and-pencil tests, which are cumbersome for most clinicians. A modern, easy-to-use, computer-based battery would be a helpful clinical tool, given that in its minimal form, HE has an impact on both patients’ quality of life and the ability to drive and operate machinery (with societal consequences). Aim We compared the Cogstate™ computer battery testing with the Psychometric Hepatic Encephalopathy Score (PHES) tests, with a view to simplify the diagnosis. Methods This was a prospective study of 27 patients with histologically proven cirrhosis. An analysis of psychometric testing was performed using accuracy of task performance and speed of completion as primary variables to create a correlation matrix. A stepwise linear regression analysis was performed with backward elimination, using analysis of variance. Results Strong correlations were found between the international shopping list, international shopping list delayed recall of Cogstate and the PHES digit symbol test. The Shopping List Tasks were the only tasks that consistently had P values of <0.05 in the linear regression analysis. Conclusion Subtests of the Cogstate battery correlated very strongly with the digit symbol component of PHES in discriminating severity of HE. These findings would indicate that components of the current PHES battery with the international shopping list tasks of Cogstate would be discriminant and have the potential to be used easily in clinical practice.
... The high protein meal was used to predict the likelihood of HE developing following a shunt procedure [23] . To test for covert HE, the "number connection test" (NCT) [24] was performed in all patients and an electroencephalogram [25] was recorded in Child- Table 1. ...
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AIM To investigate the plasma amino acid response and tolerance to normal or high protein meals in patients with cirrhosis. METHODS The plasma amino acid response to a 20 g mixed protein meal was compared in 8 biopsy-proven compensated cirrhotic patients and 6 healthy subjects. In addition the response to a high protein meal (1 g/kg body weight) was studied in 6 decompensated biopsy-proven cirrhotics in order to evaluate their protein tolerance and the likelihood of developing hepatic encephalopathy (HE) following a porto-caval shunt procedure. To test for covert HE, the “number connection test” (NCT) was done on all patients, and an electroencephalogram was recorded in patients considered to be at Child-Pugh C stage. RESULTS The changes in plasma amino acids after a 20 g protein meal were similar in healthy subjects and in cirrhotics except for a significantly greater increase (P < 0.05) in isoleucine, leucine and tyrosine concentrations in the cirrhotics. The baseline branched chain amino acids/aromatic amino acids (BCAA/AAA) ratio was higher in the healthy persons and remained stable-but it decreased significantly after the meal in the cirrhotic group. After the high protein meal there was a marked increase in the levels of most amino acids, but only small changes occurred in the levels of taurine, citrulline, cysteine and histidine.The BCAA/AAA ratio was significantly higher 180 and 240 min after the meal. Slightly elevated basal plasma ammonia levels showed no particular pattern. Overt HE was not observed in any patients. CONCLUSION Patients with stable liver disease tolerate natural mixed meals with a standard protein content. The response to a high protein meal in decompensated cirrhotics suggests accumulation of some amino acids but it did not precipitate HE. These results support current nutritional guidelines that recommend a protein intake of 1.2-1.5 g/kg body weight/day for patients with cirrhosis.
... Moreover, with P300 testing, damage of cognitive functions resulting from taking different medicines, especially antiepileptic drugs, can also be monitored (61)(62)(63). Additionally, P300 characteristics help diagnosing cognitive damage resulting from systemic diseases, such as anaemia, uremia (renal insufficiency), hepatic encephalopathy, systemic lupus erythematosus, diabetes mellitus, hypothyreosis, as well as COPD (64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76). Moreover, cognitive function damage in patients with HIV-1 neurologically asymptomatic seropositive can be assessed with P300 testing (78). ...
... This case was type B of HE according to International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) practice guidelines. 2 We did not examine blood citrulline in the present case, but type D of HE (urea-cycle disorders) could be ruled out because of elder age and clinical 2 Japanese Clinical Medicine finding. 3 Precipitating factors of HE (eg, excess protein, infection, diuretics, hyponatremia, acidosis, gastrointestinal bleeding, trauma, sedatives) worsen the relevant components (hyperammonemia, hyponatremia, inflammatory cytokines, benzodiazepines) and oxidative stress-derived brain damages. ...
Article
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We report an elderly male patient with hyperammonemia induced by intrahepatic portal-systemic shunt without cirrhosis (IPSSwoC). The occasional emergence of his erratic behaviors was misdiagnosed as a psychiatric disorder. Regardless of his uneven symptoms, IPSSwoC was suspected due to his hyperammonemia. The contrast computed tomography of the abdomen revealed a congenital type of IPSSwoC. As blood ammonia levels are inconstant, repeated blood tests are recommended when this disease is suspected in elderly patients with psychiatric symptoms.
... However, test scores have to be normalized for a number of confounding variables and, at present, normative databases are only available in Germany, Italy, Spain, and Great Britain. A number of neurophysiological abnormalities are observed in patients with hepatic encephalopathy [15,20]. The electroencephalogram (EEG), which primarily reflects cortical neuronal activity, may show progressive slowing of the background activity and abnormal wave morphology. ...
Article
Hepatic encephalopathy (HE) is a severe complication of cirrhosis. The prevalence of overt HE (OHE) ranges from 30% to 45%, whereas the prevalence of minimal HE (MHE) is as high as 85% in some case series. Widespread use of transjugular intrahepatic portosystemic shunt to control complications related to portal hypertension is associated with an increase in HE incidence. If the diagnosis of OHE remains simple in most cases, then the diagnosis of MHE is less codified because of many differential diagnoses with different therapeutic implications. This review analyzes current knowledge about the pathophysiology, diagnosis, and different therapeutic options of HE.
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To evaluate the effects of l-carnitine on impaired brain function in patients with liver cirrhosis. We conducted a retrospective cohort study that included sequential 80 liver cirrhosis patients with impaired brain function evaluated using near-infrared spectroscopy (NIRS). Among them, l-carnitine was administered to 48 patients. The NIRS data and blood ammonia level at baseline and after 8 weeks of treatment were compared between patients administered with l-carnitine (l-carnitine group) and those who were not (control group). The NIRS data at baseline were similar between the l-carnitine and control groups (0.04 ± 0.04 vs. 0.04 ± 0.05 mMmm, p = n.s), whereas those in the l-carnitine group (n = 48) were significantly better than that of the control group at 8 weeks of treatment (n = 32) (0.103 ± 0.081 vs. 0.040 ± 0.048 mMmm, p < 0.001). In the l-carnitine group, 35.4% (17/48) of patients had hyperammonemia. The NIRS data of the l-carnitine group at 8 weeks of treatment were significantly improved than that of the control group, irrespective of baseline ammonia levels (0.11 ± 0.09 vs. 0.04 ± 0.05 mMmm, p = 0.005, and 0.10 ± 0.06 vs. 0.02 ± 0.03 mMmm, p = 0.003, for normal baseline ammonia and elevated ammonia levels, respectively). In the multivariate analysis, l-carnitine administration (odds ratio [OR] 3.51, 95% confidence interval [CI] 1.23–9.99, p = 0.019) and baseline NIRS data of ≤ 0.07 mMmm (OR 5.21, 95% CI 1.69–16.0, p = 0.0041) were found as independent significant factors. l-carnitine improves impaired brain function in patients with liver cirrhosis.
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La encefalopatía hepática (EH) es un término que engloba un amplio espectro de alteraciones neuropsiquiátricas, secundarias al daño hepático crónico. En México se dispone de escasos datos epidemiológicos sobre cirrosis, por lo que se desconoce su prevalencia. En el año 2000 era la quinta causa de muerte y en 2011 el INEGI reportó que las enfermedades digestivas eran la quinta causa más frecuente de mortalidad; en 2013, la cirrosis fue la cuarta causa de muerte. Se ha estimado que para el año 2020 habrá 1,496,000 pacientes con cirrosis y hacia 2050 la cifra alcanzará 1,866,000. Por ello, se realizó el presente análisis de la nueva clasificación para proponerla como instrumento para el cálculo de la epidemiología de la EH y de la cirrosis en México, y para analizar su impacto en la calidad de vida. A partir de las descripciones históricas de la EH, se revisó la historia natural de este trastorno con enfoque en las clasificaciones. En los resultados se observó que la EH mínima requiere, al igual que la EH subclínica, una revisión clínica acuciosa. En cuanto a la calidad de vida, diversos investigadores han relacionado la mejoría con el tratamiento de la EH. En conclusión, la EH debe categorizarse en función de la etiología subyacente, la gravedad clínica, el transcurso del tiempo y los factores desencadenantes analizados en las más recientes guías clínicas internacionales. Citation: Abdo Francis JM, de Ariño Suárez M, Castro Narro GE, Malé Velázquez R, Ramos Gómez VR, Rizo Robles MT, et al. Encefalopatía hepática: historia natural de la enfermedad, nueva clasificación e impacto en la calidad de vida. Lat Am J Clin Sci Med Technol. 2019 Aug; 1: 50-58.
Article
The Chinese Society of Hepatology developed the current guidelines on the management of hepatic encephalopathy in cirrhosis based on the published evidence and the panelists' consensus. The guidelines provided recommendations for the diagnosis and management of hepatic encephalopathy (HE) including minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy, emphasizing the importance on screening MHE in patients with end-stage liver diseases. The guidelines emphasized that early identification and timely treatment are the key to improve the prognosis of HE. The principles of treatment include prompt removal of the cause, recovery of acute neuropsychiatric abnormalities to baseline status, primary prevention, and secondary prevention as soon as possible.
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Background: Hepatic encephalopathy is a common complication of cirrhosis, with high related morbidity and mortality. Its presence is associated with a wide spectrum of change ranging from clinically obvious neuropsychiatric features, known as 'overt' hepatic encephalopathy, to abnormalities manifest only on psychometric or electrophysiological testing, 'minimal' hepatic encephalopathy. The exact pathogenesis of the syndrome is unknown but ammonia plays a key role. Drugs that specifically target ammonia include sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST-120 (spherical carbon adsorbent), and polyethylene glycol. Objectives: To evaluate the beneficial and harmful effects of pharmacotherapies that specifically target ammonia versus placebo, no intervention, or other active interventions, for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Search methods: We searched the Cochrane Hepato-Biliary Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three other databases to March 2019. We also searched online trials registries such as ClinicalTrials.gov, European Medicines Agency, WHO International Clinical Trial Registry Platform, and the Food and Drug Administration for ongoing or unpublished trials. In addition, we searched conference proceedings, checked bibliographies, and corresponded with investigators. Selection criteria: We included randomised clinical trials comparing sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST-120, and polyethylene glycol versus placebo or non-absorbable disaccharides, irrespective of blinding, language, or publication status. We included participants with minimal or overt hepatic encephalopathy or participants who were at risk of developing hepatic encephalopathy. Data collection and analysis: Two review authors independently extracted data from the included reports. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 statistic values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the certainty of the evidence using GRADE. Main results: We identified 11 randomised clinical trials that fulfilled our inclusion criteria. Two trials evaluated the prevention of hepatic encephalopathy while nine evaluated the treatment of hepatic encephalopathy. The trials assessed sodium benzoate (three trials), glycerol phenylbutyrate (one trial), ornithine phenylacetate (two trials), AST-120 (two trials), and polyethylene glycol (three trials). Overall, 499 participants received these pharmacotherapies while 444 participants received a placebo preparation or a non-absorbable disaccharide. We classified eight of the 11 trials as at 'high risk of bias' and downgraded the certainty of the evidence to very low for all outcomes.Eleven trials, involving 943 participants, reported mortality data, although there were no events in five trials. Our analyses found no beneficial or harmful effects of sodium benzoate versus non-absorbable disaccharides (RR 1.26, 95% CI 0.49 to 3.28; 101 participants; 2 trials; I2 = 0%), glycerol phenylbutyrate versus placebo (RR 0.65, 95% CI 0.11 to 3.81; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.73, 95% CI 0.35 to 1.51; 269 participants; 2 trials; I2 = 0%), AST-120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial), or polyethylene glycol versus lactulose (RR 0.50, 95% CI 0.09 to 2.64; 190 participants; 3 trials; I2 = 0%).Seven trials involving 521 participants reported data on hepatic encephalopathy. Our analyses showed a beneficial effect of glycerol phenylbutyrate versus placebo (RR 0.57, 95% CI 0.36 to 0.90; 178 participants; 1 trial; number needed to treat for an additional beneficial outcome (NNTB) 6), and of polyethylene glycol versus lactulose (RR 0.19, 95% CI 0.08 to 0.44; 190 participants; 3 trials; NNTB 4). We did not observe beneficial effects in the remaining three trials with extractable data: sodium benzoate versus non-absorbable disaccharides (RR 1.22, 95% CI 0.51 to 2.93; 74 participants; 1 trial); ornithine phenylacetate versus placebo (RR 2.71, 95% CI 0.12 to 62.70; 38 participants; 1 trial); or AST-120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial).Ten trials, involving 790 participants, reported a total of 130 serious adverse events. Our analyses found no evidence of beneficial or harmful effects of sodium benzoate versus non-absorbable disaccharides (RR 1.08, 95% CI 0.44 to 2.68; 101 participants; 2 trials), glycerol phenylbutyrate versus placebo (RR 1.63, 95% CI 0.85 to 3.13; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.92, 95% CI 0.62 to 1.36; 264 participants; 2 trials; I2 = 0%), or polyethylene glycol versus lactulose (RR 0.57, 95% CI 0.18 to 1.82; 190 participants; 3 trials; I2 = 0%). Likewise, eight trials, involving 782 participants, reported a total of 374 non-serious adverse events and again our analyses found no beneficial or harmful effects of the pharmacotherapies under review when compared to placebo or to lactulose/lactitol.Nine trials, involving 733 participants, reported data on blood ammonia. We observed significant reductions in blood ammonia in placebo-controlled trials evaluating sodium benzoate (MD -32.00, 95% CI -46.85 to -17.15; 16 participants; 1 trial), glycerol phenylbutyrate (MD -12.00, 95% CI -23.37 to -0.63; 178 participants; 1 trial), ornithine phenylacetate (MD -27.10, 95% CI -48.55 to -5.65; 231 participants; 1 trial), and AST-120 (MD -22.00, 95% CI -26.75 to -17.25; 98 participants; 1 trial). However, there were no significant differences in blood ammonia concentrations in comparison with lactulose/lactitol with sodium benzoate (MD 9.00, 95% CI -1.10 to 19.11; 85 participants; 2 trials; I2 = 0%), AST-120 (MD 5.20, 95% CI -2.75 to 13.15; 35 participants; 1 trial), and polyethylene glycol (MD -29.28, 95% CI -95.96 to 37.39; 90 participants; 2 trials; I2 = 88%). Funding: Five trials received support from pharmaceutical companies while four did not; two did not provide this information. Authors' conclusions: There is insufficient evidence to determine the effects of these pharmacotherapies on the prevention and treatment of hepatic encephalopathy in adults with cirrhosis. They have the potential to reduce blood ammonia concentrations when compared to placebo, but their overall effects on clinical outcomes of interest and the potential harms associated with their use remain uncertain. Further evidence is needed to evaluate the potential beneficial and harmful effects of these pharmacotherapies in this clinical setting.
Chapter
Several systemic or metabolic disorders may cause an impairment of cerebral functions. Neuroimaging investigations are often not sensitive enough to appropriately evaluate these clinical conditions. The EEG represents therefore a useful method for assessing brain functional activity, to support clinical diagnosis and to monitor follow-up (neuromonitoring). In systemic and metabolic disorders, EEG changes reflect the diffuse cerebral impairment and may detect negative prognostic factors. Widespread EEG slowing sometimes associated with epileptiform activity is a typical pattern encountered in these conditions; however it is neither pathognomonic nor specific of a certain etiology. EEG can also demonstrate the improvement of cerebral function following therapy of the underlying disorder.
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Zusammenfassung Die Leitlinie Komplikationen der Leberzirrhose der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) ersetzt die Leitlinie aus dem Jahr 2011. Sie basiert auf den Empfehlungen der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) für eine evidenzbasierte Konsensus-Leitlinie der Entwicklungsstufe S2k und wurde interdisziplinär unter Beteiligung aller relevanten Fachgesellschaften und der Patientenvertretung erstellt. Neben den in der Vorgängerversion behandelten Kapiteln Aszites, spontan bakterielle Peritonitis, hepatorenales Syndrom, hepatischer Hydrothorax und hepatopulmonales Syndrom wurden die Kapitel Diagnostik und Therapie der Hepatischen Enzephalopathie neu aufgenommen.
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This is a protocol for a Cochrane Review (Intervention). The objective isas to assess the beneficial and harmful effects of medical interventions for the prevention and treatment of hepatic encephalopathy in adults with cirrhosis
Article
Background Parkinsonism like features can be seen in cirrhotics, possibly related to alterations in brain dopamine metabolism, transport and receptor integrity at basal ganglia. Hepatic parkinsonism [HP] is often not suspected and only ammonia reducing therapies are given to such patients. We investigated the efficacy and safety of bromocriptine, a dopaminergic agent, in patients with HP. Patients and Methods Cirrhotics were screened for presence of extrapyramidal symptoms and were diagnosed as HP if any two of tremor, bradykinesia and/or rigidity were present, supported by MRI brain showing T1 hyperintensities in basal ganglia and substantia nigra. Patients were randomized to receive placebo (Gr A, n=22) or bromocriptine (Gr B, n=24) for 12 weeks. Complete, partial and non‐response were defined as 30%, 10%‐30% and <10% reduction respectively in Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Results Of 1016 cirrhotics, 50 (4.9%) had HP. Patients in two treatment groups were comparable for MELD score, arterial NH3 and frequency of porto‐systemic shunts. Bromocriptine therapy for 12 weeks resulted in improvement in rigidity, tremors, bradykinesia and gait compared to placebo with complete and partial response in 7 versus none (29.1%, 0%, p<0.01) and 12 versus one (50%, 4.5%, p<0.01) patients. Prolonged and more severe motor symptoms were associated with non‐response to bromocriptine therapy. There were no major side‐effects in either treatment group. Conclusions Hepatic parkinsonism is seen in ~5% cirrhotics. Bromocriptine is a safe and effective therapy for these patients and is more effective in mild to moderate hepatic parkinsonism. This article is protected by copyright. All rights reserved.
Chapter
Hepatic encephalopathy is a common complication of cirrhosis. It comprises a spectrum of neuropsychiatric abnormalities ranging from subtle changes in cognition to clinically obvious changes in intellect, behaviour, motor function and consciousness. Hepatic encephalopathy has a detrimental effect on health-related quality of life, safety and survival. Ammonia plays a key role in the pathogenesis of the syndrome via induction of astrocyte swelling and the development of low-grade cerebral oedema. Oxidative stress, disrupted glial-neuronal communication and neuronal dysfunction ensue. There is no diagnostic gold standard; a combination of clinical examination, psychometric testing and electroencephalography is recommended. Nevertheless, the condition is often undiagnosed and patients are often left untreated. Newer diagnostic approaches need further validation. Treatment is directed at reducing circulating ammonia, mainly through use of non-absorbable disaccharides/non-absorbable antibiotics, and is generally effective. Newer treatment approaches, based on recent insights into the pathogenesis, need further appraisal.
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Background: Hepatic encephalopathy is a common complication of cirrhosis and has high associated morbidity and mortality. The condition is classified as overt if it is clinically apparent or minimal if only evident though psychometric testing. The exact pathogenesis of this syndrome is unknown although ammonia is thought to play a key role. L-ornithine L-aspartate has ammonia-lowering properties and may, therefore, benefit people with cirrhosis and hepatic encephalopathy. Objectives: To evaluate the beneficial and harmful effects of L-ornithine L-aspartate versus placebo, no intervention, or other active interventions in people with cirrhosis and hepatic encephalopathy. Search methods: We undertook electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS and Science Citation Index Expanded to December 2017 and manual searches of meetings and conference proceedings; checks of bibliographies; and corresponded with investigators and pharmaceutical companies. Selection criteria: We included randomised clinical trials, irrespective of publication status, language, or blinding. We included participants with cirrhosis who had minimal or overt hepatic encephalopathy or who were at risk for developing hepatic encephalopathy. We compared: L-ornithine L-aspartate versus placebo or no intervention; and L-ornithine L-aspartate versus other active agents such as non-absorbable disaccharides, antibiotics, probiotics, or branched-chain amino acids. Data collection and analysis: Two review authors, working independently, retrieved data from published reports and correspondence with investigators and pharmaceutical companies. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented the results as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed bias control using the Cochrane Hepato-Biliary Group domains; we evaluated the risk of publication bias and other small trial effects in regression analyses; conducted subgroup and sensitivity analyses; and performed Trial Sequential Analyses. We determined the quality of the evidence using GRADE. Main results: We identified 36 randomised clinical trials, involving at least 2377 registered participants, which fulfilled our inclusion criteria including 10 unpublished randomised clinical trials. However, we were only able to access outcome data from 29 trials involving 1891 participants. Five of the included trials assessed prevention, while 31 trials assessed treatment. Five trials were at low risk of bias in the overall assessment of mortality; one trial was at low risk of bias in the assessment of the remaining outcomes.L-ornithine L-aspartate had a beneficial effect on mortality compared with placebo or no intervention when including all trials (RR 0.42, 95% CI 0.24 to 0.72; I2 = 0%; 19 trials; 1489 participants; very low quality evidence), but not when the analysis was restricted to the trials at low risk of bias (RR 0.47, 95% CI 0.06 to 3.58; 4 trials; 244 participants). It had a beneficial effect on hepatic encephalopathy compared with placebo or no intervention when including all trials (RR 0.70, 95% CI 0.59 to 0.83; 22 trials; 1375 participants; I2 = 62%; very low quality evidence), but not in the one trial at low risk of bias (RR 0.96, 95% CI 0.85 to 1.07; 63 participants). The analysis of serious adverse events showed a potential benefit of L-ornithine L-aspartate when including all randomised clinical trials (RR 0.63, 95% CI 0.45 to 0.90; 1 trial; 1489 participants; I2 = 0%; very low quality evidence), but not in the one trial at low risk of bias for this outcome (RR 0.83, 95% CI 0.15 to 4.65; 63 participants). The Trial Sequential Analyses of mortality, hepatic encephalopathy, and serious adverse events found insufficient evidence to support or refute beneficial effects. Subgroup analyses showed no difference in outcomes in the trials evaluating evaluating the prevention or treatment of either overt or minimal hepatic encephalopathy or trials evaluating oral versus intravenous administration We were unable to undertake a meta-analysis of the three trials involving 288 participants evaluating health-related quality of life. Overall, we found no difference between L-ornithine L-aspartate and placebo or no intervention in non-serious adverse events (RR 1.15, 95% CI 0.75 to 1.77; 14 trials; 1076 participants; I2 = 40%). In comparison with lactulose, L-ornithine L-aspartate had no effect on mortality (RR 0.68, 95% CI 0.11 to 4.17; 4 trials; 175 participants; I2 = 0%); hepatic encephalopathy (RR 1.13, 95% CI 0.81 to 1.57); serious adverse events (RR 0.69, 95% CI 0.22 to 2.11); or non-serious adverse events (RR 0.05, 95% CI 0.01 to 0.18). In comparison with probiotics, L-ornithine L-aspartate had no effect on mortality (RR 1.01, 95% CI 0.11 to 9.51); serious adverse events (RR 1.07, 95% CI 0.23 to 4.88); or changes in blood ammonia concentrations from baseline (RR -2.30 95% CI -6.08 to 1.48), but it had a possible beneficial effect on hepatic encephalopathy (RR 0.71, 95% CI 0.56 to 0.90). Finally, in comparison with rifaximin, L-ornithine L-aspartate had no effect on mortality (RR 0.33, 95% CI 0.04 to 3.03; 2 trials; 105 participants); hepatic encephalopathy (RR 1.06, 95% CI 0.57 to 1.96); serious adverse events (RR 0.32, 95% CI 0.01 to 7.42), or non-serious adverse events (RR 0.32, 95% CI 0.01 to 7.42). Authors' conclusions: The results of this review suggest a possible beneficial effect of L-ornithine L-aspartate on mortality, hepatic encephalopathy, and serious adverse events in comparisons with placebo or no-intervention, but, because the quality of the evidence is very low, we are very uncertain about these findings. There was very low quality evidence of a possible beneficial effect of L-ornithine L-aspartate on hepatic encephalopathy, when compared with probiotics, but no other benefits were demonstrated in comparison with other active agents. Additional access to data from completed, but unpublished trials, and new randomised placebo-controlled, double-blind clinical trials are needed.
Article
Overt and covert hepatic encephalopathy (HE) are debilitating complications of cirrhosis. HE results in a poor quality of life for patients and their caregivers and, unless there is access to liver transplantation, the prognosis is poor. The development of overt HE is often unpredictable, and its management, particularly in the ward, remains challenging. There is an urgent need for novel approaches to treat HE. Until recently, therapies for this complication were disappointing, with frequently intolerable side effects such as diarrhoea and faecal incontinence. However, a non-absorbable antibiotic, rifaximin, * has been approved for the prevention of recurrent overt HE. It aims to reduce hospitalisation and resource use, as well as improve patients' quality of life. This article describes the practical aspects of diagnosing, classifying and managing HE. It reviews the pharmacological options for the treatment and prophylaxis of overt HE, and explores the evidence base demonstrating that rifaximin reduces the recurrence of overt HE.
Article
Objectives: Minimal hepatic encephalopathy (MHE) is the subclinical stage prior to the development of clinical hepatic encephalopathy in cirrhotic patients. For these patients, it is associated with impaired quality of life, increased risk of accidents, and incapacity for driving vehicles. The Psychometric Hepatic Encephalopathy Score (PHES) is currently considered to be the diagnostic method of choice for diagnosis of MHE. The aim of this work was to design PHES normality tables for the Cuban population. Population and Methods: The study sample consisted of 520 healthy people from the provinces of Villa Clara, Sancti Spiritus and Cienfuegos who all took the 5 tests included in the PHES. Variables of age, sex, years of schooling, place of origin, and daily alcohol consumption were analyzed. Univariate analysis with the Student’s t test, ANOVA and Pearson correlation coefficient was performed. Multivariable linear regression for each test was performed and normality tables were constructed. Results: Multivariate analysis used multiple linear regression with age and years of schooling as the independent variables related to performance for each of the 5 tests. Conclusions: The availability of normality tables provides a diagnostic reference method for PHES which is applicable to Cuban patients with liver cirrhosis without requiring control groups for age and regional education level
Article
Background: Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function. The previous version of this review, which included 13 randomised clinical trials, found no effect of flumazenil on all-cause mortality, based on an analysis of 10 randomised clinical trials, but found a beneficial effect on hepatic encephalopathy, based on an analysis of eight randomised clinical trials. Objectives: To evaluate the beneficial and harmful effects of flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. Search methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and LILACS; meeting and conference proceedings; and bibliographies in May 2017. Selection criteria: We included randomised clinical trials regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms. Data collection and analysis: Two review authors extracted data independently. We undertook meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CI) and I(2) values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains; determined the quality of the evidence using GRADE; evaluated the risk of small-study effects in regression analyses; and conducted trial sequential, subgroup, and sensitivity analyses. Main results: We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from two randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials.In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; nine randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events. Authors' conclusions: We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy.
Article
Background: Neurological complications in liver failure are common. Often under-recognized neurological complications are seizures and status epilepticus. These may go unrecognized without continuous electroencephalography (CEEG). We highlight the observed electro-radiological changes in patients with grade III/IV hepatic encephalopathy (HE) found to have seizures and/or status epilepticus on CEEG and the associated neuroimaging. Methods: This study was a retrospective review of patients with West Haven grade III/IV HE and seizures/status epilepticus on CEEG. Results: Eleven patients were included. Alcohol was the most common cause of HE (54.5%). All patients were either stuporous/comatose. The most common CEEG pattern was diffuse slowing (100%) followed by generalized periodic discharges (GPDs; 36.4%) and lateralized periodic discharges (LPDs, 36.4%). The subtype of GPDs with triphasic morphology was only seen in 27.3%. All seizures and/or status epilepticus were without clinical signs. Magnetic resonance imaging (MRI) was available in six patients. Cortical hyperintensities on diffusion weighted imaging sequence were seen in all six patients. One patient had CEEG seizure concomitantly with the MRI. Seven patients died prior to discharge. Conclusion: Seizures or status epilepticus in the setting of HE were without clinical findings and could go unrecognized without CEEG. The finding of cortical hyperintensity on MRI should lead to further evaluation for unrecognized seizure or status epilepticus.
Article
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Hepatic encephalopathy (HE) remains a Diagnosis of exclusion due to the lack of specific signs and symptoms. Refractory HE is an uncommon but serious conDition that requires the search of hidden precipitating events (i.e. , portosystemic shunt) and alternative Diagnosis. HypothyroiDism shares clinical manifestations with HE and is usually considered within the Differential Diagnosis of HE. Here, we describe a patient with refractory HE who presented a large portosystemic shunt and post-ablative hypothyroiDism. Her cognitive impairment, hyperammonaemia, electroencephalograph alterations, impaired neuropsychological performance, and magnetic resonance imaging and spectroscopy Disturbances were highly suggestive of HE, paralleled the course of hypothyroiDism and normalized after thyroid hormone replacement. There was no need for intervention over the portosystemic shunt. The case finDings support that hypothyroiDism may precipitate HE in cirrhotic patients by inducing hyperammonaemia and/or enhancing ammonia brain toxicity. This case led us to consider hypothyroiDism not only in the Differential Diagnosis but also as a precipitating factor of HE.
Article
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Background: Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function. The previous version of this review, which included 13 randomised clinical trials, found no effect of flumazenil on all-cause mortality, based on an analysis of 10 randomised clinical trials, but found a beneficial effect on hepatic encephalopathy, based on an analysis of eight randomised clinical trials. Objectives: To evaluate the beneficial and harmful effects of flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. Search methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and LILACS; meeting and conference proceedings; and bibliographies in May 2017. Selection criteria: We included randomised clinical trials regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms. Data collection and analysis: Two review authors extracted data independently. We undertook meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CI) and I(2) values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains; determined the quality of the evidence using GRADE; evaluated the risk of small-study effects in regression analyses; and conducted trial sequential, subgroup, and sensitivity analyses. Main results: We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from 2 randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials.In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; 9 randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events. Authors' conclusions: We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy.
Article
Background: Hepatic encephalopathy is a brain dysfunction with neurological and psychiatric changes associated with liver insufficiency or portal-systemic shunting. The severity ranges from minor symptoms to coma. A Cochrane systematic review including 11 randomised clinical trials on branched-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy. Objectives: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy. Search methods: We identified trials through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, and LILACS (May 2017). Selection criteria: We included randomised clinical trials, irrespective of the bias control, language, or publication status. Data collection and analysis: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The analyses included random-effects and fixed-effect meta-analyses. We performed subgroup, sensitivity, regression, and trial sequential analyses to evaluate sources of heterogeneity (including intervention, and participant and trial characteristics), bias (using The Cochrane Hepato-Biliary Group method), small-study effects, and the robustness of the results after adjusting for sparse data and multiplicity. We graded the quality of the evidence using the GRADE approach. Main results: We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. We classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30). Authors' conclusions: In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.
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Object The early pathophysiological features of traumatic brain injury observed in the intensive care unit (ICU) have been described in terms of altered cerebral blood flow, altered brain metabolism, and neurochemical excitotoxicity. Seizures occur in animal models of brain injury and in human brain injury. Previous studies of posttraumatic seizures in humans have been based principally on clinical observations without a systematic approach to electroencephalographic (EEG) recording of seizures. The purpose of this study was to determine prospectively the incidence of convulsive and nonconvulsive seizures by using continuous EEG monitoring in patients in the ICU during the initial 14 days postinjury. Methods Ninety-four patients with moderate-to-severe brain injuries underwent continuous EEG monitoring beginning at admission to the ICU (mean delay 9.6 ± 5.4 hours) and extending up to 14 days postinjury. Convulsive and nonconvulsive seizures occurred in 21 (22%) of the 94 patients, with six of them displaying status epilepticus. In more than half of the patients (52%) the seizures were nonconvulsive and were diagnosed on the basis of EEG studies alone. All six patients with status epilepticus died, compared with a mortality rate of 18 (24%) of 73 in the nonseizure group (p < 0.001). The patients with status epilepticus had a shorter mean length of stay (9.14 ± 5.9 days compared with 14 ± 9 days (t-test, p < 0.03). Seizures occurred despite initiation of prophylactic phenytoin on admission to the emergency room, with maintenance at mean levels of 16.6 ± 2.8 mg/dl. No differences in key prognostic factors (such as the Glasgow Coma Scale score, early hypoxemia, early hypotension, or 1-month Glasgow Outcome Scale score) were found between the patients with seizures and those without. Conclusions Seizures occur in more than one in five patients during the 1st week after moderate-to-severe brain injury and may play a role in the pathobiological conditions associated with brain injury.
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  FLF is a life-threatening disease. Hepatic coma exerts dramatic impact on patient survival. At present, LTx is the treatment modality of choice that provides significant improvement in outcome of most patients with FLF. Multiple attempts have been made to reduce mortality and improve the patient's condition. One of the new options is AD – MARS. We present the case of a 11-yr-old boy with FLF and hepatic coma who avoided the scheduled LTx because of rapid neurological and biochemical improvement immediately after three MARS sessions.
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Automated analysis of the electroencephalogram as an objective measurement of hepatic encephalopathy for the individual patient was investigated. The mean dominant frequency of patients with grades 0 and 1 hepatic encephalopathy was in the normal range (greater than or equal to 6.4 Hz); grade 1 hepatic encephalopathy, however, was characterized by abnormal relative power of theta activity of more than 35%. Twelve out of 34 patients with clinical grade 0 hepatic encephalopathy also had an elevated power of theta activity and probably therefore latent hepatic encephalopathy. Patients with grades 2, 3 and 4 hepatic encephalopathy had a low mean dominant frequency (less than 6.4 Hz) and could be identified by a biphasic power spectrum (theta and delta peaks, grade 2) or by a high power of delta activity (greater than or equal to 70%, grade 3-4). We conclude that automated EEG analysis based on the parameters mean dominant frequency and the relative powers of the delta and theta band is very suitable for objective classification of hepatic encephalopathy in individual patients.
Article
Normal development and functioning of the nervous system represents the proper integration of information received and acted upon in an integrated manner. Concern is raised upon disruptions of these processes whether due to structural or functional changes induced by endogenous disease process such as, genetic based metabolic disorders or from exposure to exogenous agents in the environment. These effects can be either clinically remarkable or represent very subtle alterations that, over time, can lead to adverse health effects. This chapter presents examples of known environmental neurotoxicants and metabolic disorders and briefly discusses how one might examine and evaluate toxicological data to assess potential adverse health effects and incorporate this information into a diagnostic process.
Article
OBJECTIVES:In patients with compensated liver cirrhosis the clinical repercussions of detecting subclinical hepatic encephalopathy (SHE) are unclear. We present a long-term follow-up study in cirrhotic patients to examine the relationship between SHE and subsequent episodes of overt hepatic encephalopathy.METHODS:A total of 63 cirrhotic patients were studied by Number Connection Test and auditory evoked potentials. We determined glutamine, ammonia, zinc, glutamate, urea, and ratio of branched chain amino acids to aromatic amino acids, and Child-Pugh classification.RESULTS:Of 63 patients, 34 (53%) exhibited SHE. Nineteen out of 63 (30%) developed overt hepatic encephalopathy during follow-up. Hepatic encephalopathy in follow-up was related to alcoholic etiology, ammonia, glutamine, zinc, ratio of branched chain amino acids to aromatic amino acids, liver function, presence of esophageal varices, and detection of SHE (84% of patients who exhibited hepatic encephalopathy in follow-up showed SHE). In Cox-regression, glutamine levels, SHE, esophageal varices, and Child-Pugh class were the independent variables related to hepatic encephalopathy in follow-up.CONCLUSIONS:SHE (defined on the basis of number connection test or auditory evoked potentials alteration) could predict a subsequent episode of overt hepatic encephalopathy. Lower glutamine levels, presence of esophageal varices, and liver dysfunction were also related to the development of overt hepatic encephalopathy.
Article
Neuropsychological tests used for the assessment of subclinical hepatic encephalopathy (SHE) may overdiagnose SHE because scores are usually not corrected for age. The aim of this study was to estimate the prevalence of SHE using two easy administrable psychometric tests (Number Connection Test part A [NCT-A], Symbol Digit Test [SDT]) with age-related normal values. In addition, spectral electroencephalogram (EEG) was used, which is the in-house electrophysiological method for quantifying encephalopathy. One hundred and thirty-seven consecutive patients (mean age 49 years, range 17-77) with cirrhosis without any clinical signs of encephalopathy, were screened for SHE. In addition, the Child-Pugh score and the arterial blood ammonia were determined. Patients with concurrent use of alcohol, benzodiazepines or anti-epileptics were excluded. Fifty percent of the patients had an abnormal NCT according to the standard recommended procedure, in contrast only 7% of the patients had an abnormal NCT when scores corrected for age were used. Combining the results of the spectral EEG and the psychometric tests corrected for age yielded a higher prevalence of SHE (23%) than when each test method was used alone (17% vs. 10% abnormal, respectively). Severity of liver disease correlated with the presence of SHE, because the prevalence of abnormal tests increased from 14% in Child-Pugh grade A to 45% in Child-Pugh grade B or C. Age above 40 years and an elevated blood ammonia level were significant determinants related to an abnormal EEG. We conclude that the NCT uncorrected for age markedly overdiagnoses SHE and, therefore, should not be used as a test for the screening of SHE. Using a combination of spectral EEG and two psychometric tests with age-corrected normal values a low prevalence of SHE in patients with Child A liver cirrhosis is found. Older patients with an elevated arterial ammonia are more prone to develop SHE than younger patients with an equal arterial ammonia concentration. (Hepatology 1996 Sep;24(3):556-60)
Article
OBJECTIVES:We aimed to test the hypothesis that subclinical cognitive brain dysfunction in cirrhotic patients would deteriorate after a transjugular intrahepatic portosystemic shunt (TIPS) in the absence of clinically detectable hepatic encephalopathy.METHODS:Out of 49 consecutive cirrhotic patients receiving elective TIPS for recurrent variceal hemorrhage, we identified 22 patients who were not encephalopathic and had not undergone liver transplantation at 6-month follow-up and confirmed TIPS patency by Doppler ultrasound. Patients were tested before and 6 months after TIPS implantation using event-related (P300) cognitive evoked potentials, late somatosensory median nerve (N70) potentials, and standard psychometric tests (Mini-Mental State and trailmaking test A). Twenty-two age-matched healthy subjects served as controls.RESULTS:Relative to controls, patients showed significantly impaired P300 and N70 latencies and abnormal psychometric test results at baseline. Six months after the TIPS, a further impairment of P300 latency was observed (p = 0.005), whereas no relevant changes in N70 latency and psychometric test results occurred.CONCLUSIONS:In cirrhotic patients with portal hypertension, neurophysiological signs of cognitive brain dysfunction are detectable in the absence of hepatic encephalopathy. A further subclinical deterioration of cognitive processing was observed 6 months after the TIPS. These findings demonstrate an aggravation of subclinical hepatic encephalopathy after a TIPS.
Article
Individual monitoring of EEG and evoked potentials is gradually becoming standard in neurosurgery: compressed power spectra during carotid endarterectomy, brainstem auditory evoked potentials (BAEP) during posterior fossa surgery, and somatosensory evoked potentials (SEP) mainly during spinal cord surgery. In this paper, a new technique is described in which EEG, BAEP, and SEP are recorded and evaluated simultaneously and continuously. This allows a better survey of different neuronal structures and systems in the brain and brainstem. First results from intraoperative and intensive care patient monitoring are reported.
Article
We review the principal aspects of EEG and evoked potential (EP) neuromonitoring in the intensive care unit. The electrophysiological methods allow functional assessment of comatose patients and can be used (a) as a help to diagnose the origin of coma, (b) as a means to predict outcome, and (c) for monitoring purposes. The combination of the EEG and long-, middle-, and short-latency EPs allows widespread assessment of the cerebral cortex, the brain-stem, and the spinal cord. The EEG and the EP interpretation first requires taking into account non-neurological factors that may interfere with the recorded activities (sensory pathologies, toxic or metabolic problems, body temperature). The sensitivity and the specificity of any neurophysiological technique depend on the etiology of coma. Anoxic comas are associated with a predominantly cortical involvement, while the cortical and brain-stem functions are to be taken into account to interpret the EEG and the EPs in head trauma. The EEG and the EPs can be used to differentiate the comas due to structural lesions from those of metabolic origin, to confirm brain death and help to diagnose psychogenic unresponsiveness or a de-efferented state. While the prognostic value of the EEG is markedly hampered by the widespread use of sedative drugs, it has been possible to design efficient systems based on early- and middle-latency multimodality evoked potentials in anoxic and traumatic comas and, more generally, in all comas associated with an increase of the intracranial pressure. Continuous neuromonitoring techniques are currently under development. They have already been proven useful for the early detection and for the prevention of subclinical seizures, transtentorial herniation, vasospasm, and other causes of brain or spinal-cord ischemia.
Article
We monitored the effect of 7 intermittent machine hemofiltration treatments in 4 patients with fulminant hepatic failure who had progressed to grade IV coma and developed acute oliguric renal failure. Prior to treatment the processed EEG showed excess slow wave activity, and the latency of the later visual evoked potentials (N2 and P2) was delayed. Following treatment there was a further increase in both EEG slow wave activity and latency of the N1,N2, and P2 potentials. Intrac-ranial pressure increased from a median of 8 mm Hg (2–12, range) to 14 (8–28) following treatment, p < 0.05. There was a correlation between intracranialpressure and all of the later visual evoked potentials, for N3r = 0.71, for Pl r = 0.39, and P2 r = 0.74, all p < 0.05. Although there appeared to be a good correlation between intracranial pressure and the noninvasive electrophysiological recordings, there were major changes in intracranial pressure, cerebral perfusion pressure, and cerebrospinal fluid pH during the first hour of treatment, during which time there were no discernable changes in EEG or evoked potentials. In this study, non-invasive neurophysiological methods were not found to be reliable as invasive methods in assessing acute, minute-by-minute changes in cerebral metabolism but these methods may have a role in the longer term in assessing patient prognosis.
Article
We studied the median nerve stimulated somatosensory evoked potentials (SEP) of 23 patients with hepatic encephalopathy (HE) resulting from severe acute hepatitis and 22 healthy volunteers. Ten patients who improved and survived more than 60 days were classified as Group 1 and the remaining 13 patients who died shortly after the SEP studies were classified as Group 2. The mean N9-N13 interpeak latencies (IPL) were not different among control and two patient groups. The mean N13-N20 IPL of Group 2 was significantly prolonged when compared with normal controls (P < 0.001) and Group 1 (P < 0.001). Five of the six patients with abnormal N13-N20 IPL died of hepatic failure within 24 h after SEP testing. The occurrence of abnormal subcortical conduction together with cortical dysfunction suggested that brain damage in terminal hepatic encephalopathy was diffuse. The presentation of abnormal prolongation of N13–N20 IPL of SEP during the course of severe acute hepatitis indicated a poor prognosis. Peripheral somatosensory conduction is unaffected even in terminal HE.
Article
The guideline on the management of chronic hepatitis B (CHB) was first developed in 2004 and revised in 2007 by the Korean Association for the Study of the Liver (KASL). Since then there have been many developments, including the introduction of new antiviral agents and the publications of many novel research results from both Korea and other countries. In particular, a large amount of knowledge on antiviral resistance--which is a serious issue in Korea--has accumulated, which has led to new strategies being suggested. This prompted the new guideline discussed herein to be developed based on recent evidence and expert opinion. Target population: The main targets of this guideline comprise patients who are newly diagnosed with CHB and those who are followed or treated for known CHB. This guideline is also intended to provide guidance for the management of patients under the following special circumstances: malignancy, transplantation, dialysis, coinfection with other viruses, pregnancy, and children.
Article
A randomized double blind clinical comparison of neomycin and lactulose was performed in 33 cirrhotic patients with chronic portal-systemic encephalopathy (PSE) at seven cooperating hospitals. In order to maintain double blindness, sorbitol syrup was used as a control solution along with neomycin and was compared with lactulose syrup and placebo tablets in a double drug protocol. Twenty-nine patients were studied in a crossover investigation in which each received both therapeutic regimens preceded and followed by control periods. Four additional patients received one or the other agent, but did not receive both. Serial, semiquantitative assessments were made in all patients of mental status, asterixis, and the trailmaking test (TMT) and electroencephalograms (EEG) and arterial ammonia levels. Both neomycin-sorbitol and lactulose were effective in the majority of patients (83 and 90%, respectively). Each of these parameters (mental state, asterixis, TMT, EEG, and NH3) was improved significantly by neomycin-sorbitol and lactulose. The post-treatment levels for each of these measures were similar in the neomycin and lactulose-treated groups. Mean stool pH was reduced by neomycinsorbitol to 6.1 and by lactulose to 5.5. This difference was highly significant statistically. Bowel activity was similar in the two groups. Both drugs were free of toxicity. These investigations demonstrate that both lactulose and neomycin-sorbitol are effective in the treatment of chronic portal-systemic encephalopathy.
Article
To objectively determine the incidence of subclinical hepatic encephalopathy (SHE) and the relative sensitivity of different evoked potentials for its detection, 22 nonalcoholic cirrhotics without clinically detectable neurological abnormality and an equal number of matched healthy controls were studied. Of the three evoked potentials, visual evoked potential (VEP) studied by the pattern shift reversal method was not found to be abnormal in any patient. Short latency somatosensory evoked potential (SSEP) was abnormal in one (4.5%) and brain stem auditory evoked potential (BAEP) in nine (41%) patients. There was little advantage of performing both BAEP and SSEP in a patient, since the two together were abnormal in 10 (45.5%) patients, with SSEP adding only one more patient. Interpeak latencies I-III, III-V, and I-V in BAEP test were found to be the most sensitive parameters for the detection of SHE. Our results argue in favor of BAEP as the single investigation of choice for the objective assessment of SHE in patients with cirrhosis of the liver.
Article
Topographical analysis of cerebral electrical activity was performed in 44 patients with hepatic encephalopathy. These patients were classified in 5 groups according to clinical criteria. Eight healthy subjects were used as a control group. All were studied in an awake, eyes closed, condition and some [Control Group (CG), Group 0 (G0), Group 1 (G1) and Group 2 (G2)] also in an awake, eyes open, condition. The awake, eyes closed, maps showed marked differences in the power spectral density (PSD) of the different bands, when comparing normal subjects with patients with several degrees of hepatic encephalopathy. These differences were related to the degree of clinical involvement, mainly in the alpha and delta PSD bands. The combination of a decreased alpha PSD, increased delta PSD, and decreased mean dominant frequency (MDF) allowed a clear discrimination between the different clinical groups. The differences observed between awake, eyes closed, and awake, eyes open, conditions were especially helpful to discriminate between CG subjects and G0, G1 and G2 patients.
Article
To evaluate the influence of necrotic liver tissue on the cerebral metabolism and cerebral function in acute liver failure, comparison was made between hepatectomy and total liver devascularization in pigs. In both groups the cerebral blood flow and glucose uptake were significantly decreased. The cerebral oxygen uptake was not reduced. The EEG frequency gradually fell from 12-14 Hz to 1-2 Hz, with intermittent and finally persistent flattening of cortical activity. The visual evoked potentials were unchanged throughout the observation period. The vascular autoregulation and the CO2-reactivity of cerebral circulation disappeared, indicating complete vasoparalysis. As no difference was found between the two groups, it is concluded that the encephalopathy was not due to intoxication from necrotic liver tissue in the abdominal cavity, but to deprivation of liver function.
Median nerve somatic evoked potentials (SEPs) were serially recorded in 12 Reye syndrome patients from shortly after admission to discharge. Recovery was clinically satisfactory in nine, unsatisfactory in two, and one died. All SEP components were absent or markedly depressed in initial recordings. Early progressive recovery of primary cortical components was associated with patient survival; lack of it was associated with death. Progressive recovery of SEP components later than 100 msec was associated with satisfactory clinical recovery; failure of recovery of these components was associated with residual neuropsychological deficit. Evaluation of late component recovery required comparison with age-dependent SEP configurations in normal children which differ from adults. We conclude that serial SEP recording is of significant value and superior to the EEG in early prognosis for survival, prognosis for clinically satisfactory or unsatisfactory recovery, and general evaluation of neurologic status in Reye syndrome.
Article
We have used short latency somatosensory evoked potential (SEP) in 108 patients with liver cirrhosis by viral hepatitis to evaluate hepatic encephalopathy. Short-latency SEPs were recorded by the MEM-4104 apparatus (Nihon Kohden Inc., Tokyo) in response to median nerve stimulation. For a precise analysis of the early components, we averaged 1000 responses during a 30-msec period. Early SEP components were prolonged in patients with decompensated, but not in those with compensated, cirrhosis. We also examined the relationship between consciousness level and interpeak latency (IPL) N13-N20 of SEP and between consciousness level and electroencephalograph in 51 patients among 108 patients with liver cirrhosis. The IPL N13-N20 was prolonged in the decompensated stage with normal consciousness, but EEG findings had not deteriorated in this stage. EEG grade became worse in the stage of abnormal consciousness. The prolongation of the IPL N13-N20 was attributed to the central conduction impairment. We postulate that subcortical impairment may occur in patients with subclinical hepatic encephalopathy. when the cortex is little affected.
Article
Sensory evoked potentials are markedly changed in patients with fulminant liver failure. It is unknown, however, whether serial recordings of sensory evoked potentials provide useful prognostic informations for patient management in fulminant liver failure. Ninety recordings of bilateral median nerve-stimulated short- and long-latency sensory evoked potentials were performed in 25 patients with fulminant liver failure (9 patients spontaneously recovered and survived, 8 patients were referred to emergency liver transplantation and 8 patients died). In all nine survivors the cortical long-latency sensory evoked potential N70 peak was constantly detectable between 74 and 162 ms. In all eight patients who subsequently underwent liver transplantation and in seven of eight patients who died, loss of the N70 peak developed during the course of fulminant liver failure. In 4 of 15 patients who were selected for liver transplantation according to the King's College criteria, the N70 peak was constantly detectable. All four transplantation candidates spontaneously recovered and survived without transplantation. In contrast, eight patients never did fulfill the criteria for liver transplantation. Five of them with constantly detectable N70 peak recovered spontaneously. However, in the remaining three patients loss of the N70 peak developed, and they ultimately died. The probability of correct outcome prediction by sensory evoked potentials is superior to that based on clinical criteria alone (0.96 vs. 0.72). Therefore serial recording of sensory evoked potentials may help identify (a) a subgroup among liver transplantation candidates who may spontaneously recover without transplantation and (b) a subgroup of patients with severe brain dysfunction who should undergo early liver transplantation even though they do not fulfill King's College criteria.
Article
The scalp-recorded somatosensory evoked potentials (SSEPs) of 14 patients who died of hepatic encephalopathy (HE) caused by severe acute hepatitis and 22 normal volunteers were studied. The present data showed that progressive deterioration of HE resulted in sequential prolongation and eventual disappearance of SSEP components beginning from the late P90 component towards the early P25 and N20 components. Four patients with systemic hypotension, supposedly due to brain edema and increased intracranial pressure, showed disappearance of the N20 and P25 components and died within 24 hours. The N20 and P25 components were preserved in the other 10 patients without systemic hypotension. The disappearance of the N20 and P25 components as well as later components suggests an almost total loss of cortical function. The present study suggests that the disappearance of the N20 and P25 components during the course of HE is an ominous sign in severe acute hepatitis.
Article
We monitored the effect of 7 intermittent machine hemofiltration treatments in 4 patients with fulminant hepatic failure who had progressed to grade IV coma and developed acute oliguric renal failure. Prior to treatment the processed EEG showed excess slow wave activity, and the latency of the later visual evoked potentials (N2 and P2) was delayed. Following treatment there was a further increase in both EEG slow wave activity and latency of the N1, N2, and P2 potentials. Intracranial pressure increased from a median of 8 mm Hg (2-12, range) to 14 (8-28) following treatment, p < 0.05. There was a correlation between intracranial pressure and all of the later visual evoked potentials, for N3 r = 0.71, for P1 r = 0.39, and P2 r = 0.74, all p < 0.05. Although there appeared to be a good correlation between intracranial pressure and the noninvasive electrophysiological recordings, there were major changes in intracranial pressure, cerebral perfusion pressure, and cerebrospinal fluid pH during the first hour of treatment, during which time there were no discernable changes in EEG or evoked potentials. In this study, non-invasive neurophysiological methods were not found to be reliable as invasive methods in assessing acute, minute-by-minute changes in cerebral metabolism but these methods may have a role in the longer term in assessing patient prognosis.
Article
As with other methods long used in intensive care units (ICU) and operating rooms (OR), the goal of neuroscience ICU continuous EEG (NICU-CEEG) and evoked potential (NICU-EP) monitoring is to extend our powers of observation to detect abnormalities at a reversible stage. EEG is an appropriate monitoring tool because it is linked to cerebral metabolism, is sensitive to ischemia and hypoxemia, correlates with cerebral topography, detects neuronal dysfunction at a reversible stage, and is the best method for detecting seizure activity. When applied systematically, it can impact medical decision-making in 81% of monitored patients. It is useful in monitoring precarious cerebral perfusion at the bedside, and it has revealed that nonconvulsive seizures, undetectable otherwise, occur in 34% of NICU patients. In convulsive status epilepticus, NICU-CEEG can help avoid undertreatment and overtreatment. In comatose patients, it can provide useful prognostic information as well as detect potentially treatable causes. Traditional impediments to its application are yielding to technological advances and educational efforts. Real-time digitized EEG in particular has been a major advance. Within limits, somatosensory evoked potential monitoring (ICU-SEP) is useful in the prognosis of coma, but it is less helpful in monitoring focal cerebral ischemia. Brainstem auditory evoked potential monitoring has a relatively restricted role in the NICU but is helpful in distinguishing structural from nonstructural causes of coma and can supplement ICU-SEP in predicting outcome.
Article
Three-modality evoked potentials (TMEPs) were recorded in 184 comatose patients (52 anoxic, 132 traumatic). Both types of comas were associated with different TMEP patterns. Anoxic comas were associated with prognostically relevant abnormalities of cortical (visual and somatosensory) evoked potentials (EPs), while brainstem (auditory and somatosensory) EPs were not specifically altered. The prognostic value of TMEPs in anoxic comas depended on the time elapsed from the acute episode: mildly altered EPs were associated with a better prognosis in the first 10 days; strongly altered TMEPs were associated with a poorer prognosis from the first day; no definite conclusion could be drawn from mildly altered EPs after the 10th day, or from strongly altered TMEPs in the first 24 h. By contrast, both the cortical and the brain-stem activities were altered in head trauma. The abnormalities were clustered into four patterns: hemispheric damage without brain-stem involvement (pattern 1), mesencephalic lesion (pattern 2), transtentorial herniation (pattern 3), and brain death (pattern 4). Patterns 3 and 4 were uniformly associated with death. The prognostic value of pattern 1 was similar to that observed in anoxic comas. The outcome of patients presenting pattern 2 depended on the extent of hemispheric damage associated with the mesencephalic lesion; we thus suggest to systematically perform magnetic resonance imaging (MRI) in patients presenting TMEP pattern 2. We finally demonstrated that a few patients presenting absent cortical activities in the very acute stage of coma can eventually recover a good neurological function.
Article
Neuropsychological tests used for the assessment of subclinical hepatic encephalopathy (SHE) may overdiagnose SHE because scores are usually not corrected for age. The aim of this study was to estimate the prevalence of SHE using two easy administrable psychometric tests (Number Connection Test part A [NCT-A], Symbol Digit Test [SDT]) with age-related normal values. In addition, spectral electroencephalogram (EEG) was used, which is the in-house electrophysiological method for quantifying encephalopathy. One hundred and thirty-seven consecutive patients (mean age 49 years, range 17-77) with cirrhosis without any clinical signs of encephalopathy, were screened for SHE. In addition, the Child-Pugh score and the arterial blood ammonia were determined. Patients with concurrent use of alcohol, benzodiazepines or anti-epileptics were excluded. Fifty percent of the patients had an abnormal NCT according to the standard recommended procedure, in contrast only 7% of the patients had an abnormal NCT when scores corrected for age were used. Combining the results of the spectral EEG and the psychometric tests corrected for age yielded a higher prevalence of SHE (23%) than when each test method was used alone (17% vs. 10% abnormal, respectively). Severity of liver disease correlated with the presence of SHE, because the prevalence of abnormal tests increased from 14% in Child-Pugh grade A to 45% in Child-Pugh grade B or C. Age above 40 years and an elevated blood ammonia level were significant determinants related to an abnormal EEG. We conclude that the NCT uncorrected for age markedly overdiagnoses SHE and, therefore, should not be used as a test for the screening of SHE. Using a combination of spectral EEG and two psychometric tests with age-corrected normal values a low prevalence of SHE in patients with Child A liver cirrhosis is found. Older patients with an elevated arterial ammonia are more prone to develop SHE than younger patients with an equal arterial ammonia concentration.
Article
Unlabelled: The prevalence of subclinical hepatic encephalopathy (SHE) varies according to the diagnostic tool used in its detection. Since a standardised approach to the diagnosis of SHE is not yet available, we compared psychometric tests and EEG spectral analysis. On the same day 32 cirrhotic patients without overt hepatic encephalopathy and 18 controls were assessed by psychometric tests, both standard and computerized (CPT), and by EEG spectral analysis (EEG-SA). The CPT, measuring reaction time (Rt) and errors (er), were Font, Choice1, Choice2 and Scan test. The standard psychometric tests were the number connection test (NCT), the Reitan-B test, the Line Tracing Test [for time: LTT(t) and for errors: LTT(er)], and the Symbol Digit test (SD). Both psychometric tests [Reitan-B test, LTT(er) and CPT but Font (Rt) and Choice2 (er)] and EEG-SA parameters [mean dominant frequency (MDF) and theta power (theta %)] significantly correlated (p < 0.05) with albumin plasma levels. LTT(er), Scan, Font, Choice1 and Choice2 were significantly related to theta % and MDF. There was no control with positive EEG-SA, though one control was positive with LTT(t) and with the number of errors made during Font and Scan tests. The percentage of cirrhotics with positive EEG-SA was 34% (CI95% = 19-53), while 9-66% were positive with psychometric tests, depending on the test considered. In spite of the correlation between neuropsychological and neurophysiological parameters, the diagnostic agreement between EEG-SA and each psychometric test was not high. In conclusion: 1) neurophysiological and neuropsychological impairment in cirrhotics without overt hepatic encephalopathy were found linked to each other and to hepatic dysfunction; 2) psychometric tests were not sufficiently good predictors of EEG alterations; therefore, neuropsychological tools can not substitute neurophysiological ones to detect CNS dysfunction in liver disease.
Transcranial magnetic stimulation of the cerebral cortex was used to study motor system function in 31 cirrhotics (29 post-necrotic and 2 cryptogenic) with and without hepatic encephalopathy (HE). The results were compared with those of 14 healthy subjects matched for age. A significant increase of central motor conduction time, a significant raising of the motor evoked potential (MEP) threshold at rest and a significant reduction of the MEP/muscle action potential (MAP) amplitude ratio were found only in patients with chronic stable (12 patients) and recurrent (9 patients) HE. Vice versa, a significant shortening of the central silent period was observed in all 31 cirrhotic patients. The peripheral silent period was normal in all instances. These results indicate that the damage to the cortico-spinal pathways is related to the progression of cirrhosis to HE, and that cirrhotic patients present a dysfunction of the inhibitory motor mechanisms before HE is clinically manifest.
Article
Evoked responses have not been studied in patients with acute severe hepatitis (ASH) with or without hepatic encephalopathy. This prospective study was undertaken to find out diagnostic as well as prognostic value of visual evoked responses (VER), and brain stem auditory evoked responses (BAER) in patients with ASH with or without encephalopathy. Visual evoked responses and BAER were studied in 20 patients (14 males and six females) with ASH. The patients were diagnosed as having severe hepatitis if acute hepatitis was associated with raised serum bilirubin and serum transaminases, and if they had a prothrombin time index of < 50%. After a detailed neuropsychiatric examination of each patient, the study sample was divided into two groups of 10 patients: ASH without encephalopathy (ASH-WOE), and ASH with encephalopathy (fulminant hepatic failure, FHF). The median P100 latencies of FHF patients were significantly increased compared with controls and patients in the ASH-WOE group. Abnormal P100 latencies, exceeding 95th percentile values of the controls, were present in one patient in the ASH-WOE group and six patients in the FHF group. The median interpeak latencies I-III, III-V and I-V were significantly prolonged in the FHF group. Interpeak latencies III-V were also increased significantly in patients in the ASH-WOE group. While abnormal BAER were seen frequently in both groups, VER abnormalities were largely confined to patients in the FHF group. In the FHF group, six out of 10 patients survived and exhibited clinical improvement in the status of hepatic encephalopathy. Evoked responses were repeated after 2-3 weeks of recovery in these patients and VER abnormalities showed a tendency to normalize, thereby suggesting a prognostic implication. The incidence of abnormal VER in hepatic encephalopathy complicating ASH far exceeded that of abnormal BAER. Markedly prolonged P100 latencies in FHF patients indicate poor prognosis.
Article
The rationale for use of benzodiazepine receptor antagonists is based on the so-called benzodiazepine pathogenetic hypothesis of hepatic encephalopathy (HE). To assess the efficacy of flumazenil, a specific benzodiazepine receptor antagonist, in a large and selected population of cirrhotic patients with severe HE, we conducted a double-blind, placebo-controlled, cross-over trial on 527 cirrhotic patients with HE grade III and IVa admitted to Intensive Care Units over a 5-year period; among them, 265 (132 of grade III and 133 of grade IVa) received flumazenil, whereas 262 (130 of grade III and 132 of grade IVa) received placebo. Treatment was begun within 15 minutes of randomization; the response to treatment was assessed by neurological score and by continuous electroencephalographic (EEG) recordings. Improvement of the neurological score was documented in 17.5% of grade III patients treated with flumazenil and in 14.7% of grade IVa patients, compared, respectively, with 3.8% and 2.7% of the patients of both groups treated with placebo. Improvements in EEG tracings were observed in 27.8% of grade III patients and in 21.5% of grade IVa patients, compared, respectively, with 5% and 3.3% of the patients of both groups treated with placebo. Benzodiazepines were detected in the serum of 10 patients (4 in grade III group and 6 in grade IVa group). Flumazenil is beneficial only in a selected subset of cirrhotic patients with severe HE; the applicability of this treatment to unselected patients with severe HE still remains to be determined.
Article
Studies to assess the prognostic value of early neurological and neurophysiological findings in patients with anoxic-ischaemic coma have not led to precise, generally accepted, prognostic rules. We did a systematic review of the relevant literature to assess whether such rules could be derived from the combined results of these studies. From Medline and Embase databases we selected studies concerning patients older than 10 years with anoxic-ischaemic coma in which findings from early neurological examination, electroencephalogram (EEG), or somatosensory evoked potentials (SSEP) were related to poor outcome--defined as death or survival in a vegetative state. We selected variables with a specificity of 100% for poor outcome in all studies, and expressed the overall prognostic accuracy of these variables as pooled positive-likelihood ratios and as 95% CIs of the pooled false-positive test rates. In 33 studies, 14 prognostic variables were studied, three of which had a specificity of 100%: absence of pupillary light reflexes on day 3 (pooled positive-likelihood ratio 10.5 [95% CI 2.1-52.4]; 95% CI pooled false-positive test rate 0-11.9%); absent motor response to pain on day 3 (16.8 [3.4-84.1]; 0-6.7%); and bilateral absence of early cortical SSEP within the first week (12.0 [5.3-27.6]; 0-2.0%). EEG recordings with an isoelectric or burst-suppression pattern had a specificity of 100% in five of six relevant studies (pooled positive-likelihood ratio 9.0 [2.5-33.1]; 95%CI pooled false-positive test rate 0.2-5.9%). These characteristics were present in 19%, 31%, 33%, and 33% of pooled patient populations, respectively. For the 11 SSEP studies, results did not significantly differ between studies in which the treating physicians were or were not masked from the test result, prospective and retrospective studies, studies with short and long follow-up periods, and studies with high or low overall poor outcome. SSEP has the smallest CI of its pooled positive-likelihood ratio and its pooled false-positive test rate. Because evoked potentials are also the least susceptible to metabolic changes and drugs, recording of SSEP is the most useful method to predict poor outcome.
Article
This article reviews established, emergent, and potential applications of continuous EEG (CEEG) monitoring in the Neuroscience Intensive Care Unit (NICU) and Emergency Department. In each application, its goal as a neurophysiologic monitor is to extend our powers of observation to detect abnormalities at a reversible stage and to guide timely and physiologically sound interventions. Since this subject was reviewed 5 years ago, the use of CEEG monitoring has become more widespread. In a modern NICU, it is no longer novel to have CEEG data contributing to management decisions. A well-trained CEEG monitoring team is important for its optimal implementation. In the diagnosis and management of convulsive and nonconvulsive status epilepticus, its value appears established. It is finding benefit in the early diagnosis and management of precarious cerebral ischemia, including severe acute cerebral infarctions and post-SAH vasospasms. In comatose patients, it can provide diagnostic and prognostic information which is otherwise unobtainable. More recently, it has been found advantageous for targeting management of acute severe head trauma patients. Networking technology has facilitated the implementation and oversight of CEEG monitoring and promises to expand its availability, credibility, and effectiveness. The maturing of CEEG use is reflected in preliminary efforts to assess its cost benefit, cost effectiveness, and impact on patient outcomes.