Review

New assessment of hepatic encephalopathy

Juan Crdoba
Servei de Medicina Interna-Hepatologia, Hospital Vall dHebron, Universitat Autnoma de Barcelona and Centro de Investigacin Biomdica en Red de Enfermedades Hepticas y Digestivas (CIBEREHD), Paseo Vall dHebron 119, Barcelona 08035, Spain

Hepatic encephalopathy (HE) is a common complication of cirrhosis that requires careful appraisal of the clinical manifestations, evaluation of the underlying neurological disorders, and assessment of liver function and the portal-systemic circulation. This article reviews recent developments in the assessment of HE and discusses the controversy regarding the use of a categorical or a continuous approach in measuring the severity of this condition. New scales facilitate effective monitoring and assessment of episodic HE. Neuropsychological test batteries and neurophysiological tests are of value for evaluating cognitive function in outpatients and can establish the diagnosis of minimal HE, and the severity of low-grade HE. These tools allow better evaluation of the origin of cognitive complaints and help in estimating the risk of accidents. It is now possible to complete the evaluation with measurement of the effects of cognitive impairment on daily living. In difcult cases, imaging of the brain and portal-systemic circulation with magnetic resonance imaging is especially helpful. Based on these studies, neurological signs and symptoms can be attributed to HE in patients with mild liver disease and in those with complex neurological manifestations. The new methods presented are also valuable for investigating the neurological manifestations occurring after liver transplantation. 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

hepatocarcinoma, hepatorenal syndrome), the management of HE patients is not uniform and requires precise assessment of the neurological and hepatic function [2]. The last decade has witnessed the development of several new tools that enable: (a) HE grading, (b) assessment of cognitive performance, (c) diagnosis of minimal HE, (d) evaluation of the consequences in daily living, (e) imaging of the brain, and (f) evaluation of the portalsystemic circulation. This article reviews the characteristics of these methods and discusses their use in several clinical scenarios: (a) during an episode of HE, (b) in asymptomatic outpatients, (c) in determining the origin of cognitive complaints, (d) in attributing neurological manifestations to HE, and (e) in post-transplantation follow-up.

New tools Clinical scales for grading episodic HE The neurological manifestations of episodic HE are typically uctuating and have multiple expressions, which have been described in detail elsewhere [3]. In clinical practice, these manifestations should be quantied and summarized into a simple score to facilitate monitoring of the clinical course and the effect of therapeutic interventions. Clinical scales that evaluate the presence of a series of neurological manifestations are effective tools for this purpose. Neurophysiological methods can provide a more objective assessment and are useful for investigating the effect of new treatments [4,5]. Standardization of neurological scales for HE is still in the initial phases [6]. The West Haven scale is an arbitrary method that establishes four stages of HE based on alterations in the state of consciousness, intellectual function, and behavior, and on neuromuscular signs [7]. The scale includes several manifestations for each stage, but lacks specic denitions (supplementary Table 1). In clinical practice, doctors do not check for the presence of all the manifestations listed; instead, they use the scale in an intuitive way (0 = absence of HE, 1 = mild manifestations, 2 = moderate manifestations, 3 = severe manifestations, 4 = coma). This makes HE grading subjective, a fact that does not invalidate the scale in individual cases, but causes discrepancies between different assessors. This limitation, which is especially relevant in clinical trials, has been overcome in the various adaptations of the West Haven scale [8,9]. The Hepatic Encephalopathy Scaling Algorithm (HESA) implements objective ways of measuring the parameters of the West

Introduction Hepatic encephalopathy (HE) is a common complication of cirrhosis, characterized by a myriad of neurological manifestations, diverse underlying liver disorders, and a variety of precipitating factors [1]. The importance of these elements, which determine the approach to the patient, is recognized in the classication (Table 1). As to the other complications of cirrhosis (e.g. jaundice,

Keywords: Hepatic encephalopathy; Diagnostic methods; Neuropsychology; Magnetic resonance; Cirrhosis. Received 25 July 2010; received in revised form 22 November 2010; accepted 23 November 2010 Tel.: +34 649877726; fax: +34 932746068. E-mail address: jcordoba@vhebron.net. Abbreviations: HE, hepatic encephalopathy; HESA, Hepatic Encephalopathy Scaling Algorithm; CHESS, Clinical Hepatic Encephalopathy Staging Scale; PHES, Psychometric Hepatic Encephalopathy Score; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; MR, magnetic resonance; FLAIR, uidattenuation inversion recovery; CT, computed tomography.

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Table 1. Classication of hepatic encephalopathy associated with cirrhosis.

Types Episodic

Subtypes Precipitated Spontaneous

Features Acute change in mental state induced by: gastrointestinal bleeding, constipation, excessive protein , intake, infection, renal failure, dehydratation, electrolyte disturbance. . Without recognized precipitating factors. Usually associated with large portosystemic shunts (spontaneous, surgical, TIPS) Cognitive disturbances that are not obvious in the standard neurological exam and are detected by neuropsychological or neurophysiological tests

Minimal Persistent Mild Severe

Chronic cognitive or motor manifestations that impact negatively on social and occupational activities but do not cause dependency Chronic manifestations that cause dependency (dementia, paraplegia, parkinsonism....)

The classication is based on the consensus of Vienna [1]. Patients with HE in the context of acute liver failure, portosystemic shunting in the absence of intrinsic liver disease and acute-on-chronic liver failure are classied separately.

Haven scale [10]. The HESA utilizes clinical indicators combined with validated neuropsychological tools and well-dened criteria for each stage (supplementary Table 2). The use of the HESA is still limited and its metric characteristics have not been fully analyzed [11]. One good favorable characteristic of the HESA is that it identies low grades of HE (grade I and II) more precisely, but it has the drawback of requiring training for proper use. Another new method is the Clinical Hepatic Encephalopathy Staging Scale (CHESS) [12]. In comparison to other clinical scales, the CHESS was developed without a previous arbitrary denition of the severity of HE. The authors assessed the presence or absence of 48 items in a group of 36 patients with episodic HE. The items were selected by a group of experts and were nally reduced to 9 after applying principal component analysis. The nal CHESS is a linear scale that scores HE from 0 (unimpaired) to 9 (deep coma) (supplementary Table 3). The CHESS shows good metric characteristics in terms of internal consistency, reproducibility, criterion-related validity, and external responsiveness, but it needs to be validated in other patient samples and other centers. The HESA and the CHESS, complemented with the Glasgow Coma Score (1), are adequate for clinical trials. The CHESS is simpler to use, but since direct comparisons with the HESA have not been performed, it is unknown whether the sensitivity of the two instruments is similar. For clinical purposes, it may not be necessary to establish many grades. House ofcers usually employ two levels of severity of the West Haven instrument, referred to as West Haven III, and West-Haven IIIIV. These levels of severity reect as to what extent the patient needs support (e.g. prevention of bronchial aspiration, need for articial nutrition, physical restraint) and clinical resources (e.g. admission to intensive care, specialized nursing, intensive monitoring). Assessment of cognitive performance The diagnosis of HE is based on the presence of neurological manifestations that are obvious on clinical examination [13]. There is a good agreement between observers in grading patients who exhibit severe manifestations or are completely alert, but categorization often varies between raters in patients who exhibit mild disturbances [11]. The term overt is used to emphasize the presence of clear neurological manifestations and the term covert

refers to disturbances that can only be recognized with specialized tests. The traditional view is that HE progress from unimpaired cognition (normal psychometric tests and normal clinical examination), to minimal HE (abnormal psychometric tests and normal clinical examination), to grade III HE (abnormal psychometric tests and abnormal clinical examination), and to grade IIIIV HE (psychometric tests cannot be applied due to decreased consciousness). However, the current trend is to interpret the neurocognitive impairment as a continuum and promote the use of cognitive ratings instead of categorical divisions [14]. As represented in Fig. 1, patients may exhibit cognitive impairment in the context of an acute confusional syndrome (episodic HE). Those with chronic cognitive impairment can be classied by severity as having low-grade HE [15], which may be covert or overt, or dementia (if the decit is severe and lasts long enough). The terms used for those with dementia are severe persistent HE or acquired hepatocerebral degeneration (when associated with motor disturbances: parkinsonism, chorea, myelopathy. . .). In patients with apparently unimpaired mental status or chronic low-grade HE, assessment of cognition can benet from the application of neuropsychological tests that quantify brain dysfunction and evaluate various cognitive domains [16]. These instruments are preferred over neurophysiological tests and other biological markers, as they directly measure cognitive functions (e.g. memory, attention, or visuospatial skills) that are relevant to the activities of daily living. Psychometric tests are not adequate for patients with a decreased level of consciousness; hence, confusion should be excluded before beginning neuropsychological testing. This is easily done with the four questions provided in the Confusion Assessment Method (CAM) [17] (supplementary Table 4). Extended neuropsychological assessment is the best way to demonstrate cognitive decits. Patients complete a series of tests, the results of which are compared to normative standards and interpreted by a neuropsychologist. Ideally, scores are adjusted for age, gender, and education level. Usually, the examiner selects a basic battery of psychometric tests attending to cultural and social parameters, available normative data, and prior experience. Additional tests are brought in, to further explore the domains that appear impaired in the basic assessment. The nal diagnosis (presence or absence of cognitive impairment) depends on inter-

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Categorical approach

Continuous approach UNIMPAIRED

NORMAL MINIMAL GRADE I Severity GRADE II GRADE III Coma GRADE IV UNSTABLE Acute confusional syndrome EPISODIC HE SEVERITY STABLE Covert CHRONIC LOW-GRADE HE Overt PERSISTENT SEVERE HE/ ACQUIRED HEPATOCEREBRAL DEGENERATION

Fig. 1. Cognitive function assessment in HE can be performed with a categorical or a continuous approach. In the categorical approach, the criteria that dene the categories are arbitrary and vary between raters. In the continuous approach, patients may be unimpaired (lack of cognitive impairment) or impaired (unstable or stable), and may move from one situation to another or remain stable for long periods of time. Those that are unstable exhibit an acute confusional syndrome (that can progress to coma). Those that are impaired, but stable, show chronic low-grade HE that may be covert (only revealed by psychometric tests) or overt (obvious on clinical exam). Patients with prolonged and severe cognitive decits (dementia) are diagnosed as having persistent severe HE or acquired hepatocerebral degeneration (when associated with motor manifestations). There is some overlapping between the grades of the categorical approach and the situations dened in the continuous approach, but there is no direct correspondence.

pretation of the test results and observation of the patients behavior. The pattern of neuropsychological impairment suggests the type of disorder, but the neuropsychological prole alone is not diagnostic of a specic disease. Short neuropsychological test batteries, developed to facilitate the diagnosis of the cognitive status in several neurological diseases, are an alternative to extended neuropsychological assessment. These batteries include a limited number of tests that can be given by trained technicians, and typically take less than 30 min to complete. The tests examine those cognitive domains that are expected to be abnormal in a certain disease. It is common practice to consider abnormal scores as those >1.52 SD below the reference population mean. A series of short neuropsychological batteries [18,19] are available to assess patients with cirrhosis (Table 2); some of them have computerized versions [20]. Short batteries are more heavily weighted to detect decits that characterize low-grade HE: impairment in attention, executive function, psychomotor abilities, and speed of information processing. They are typically performed in patients in a chronic non-uctuating situation, in whom confusion has been excluded. These batteries can quantify the cognitive impairment present in minimal HE and in mild persistent HE, but they do not differentiate between these situations, because it depends on the threshold that is chosen to distinguish covert from overt HE. Recommendations and therapeutic measures can be established based on the results [21]. When repeated testing is performed (e.g. to monitor the effect of therapy) it is important to control for learning effects. Parallel versions of the same test could lessen this effect, but few tests have well-standardized parallel versions. The choice of which 1032

battery to use should be based on the availability of local translations and normative data [16]. Screening tests for minimal HE Minimal HE is a highly prevalent asymptomatic disturbance, especially in patients with advanced disease (Child-Pugh B/C) [22]. The fact that minimal HE can have important consequences on daily living even though patients are asymptomatic [23] has led to the need for screening tests. These tests should be easy to use, and quantiable in a few minutes. Several simple computerized tests have been developed for this purpose, and they are reliable in repeated testing (Table 2). Most of them essentially assess one cognitive domain: attention decit and slow information processing, which are the most prominent disturbances in minimal HE [24]. Various authors have proposed that an abnormal test result is sufcient to establish the diagnosis of minimal HE [2527]. However, the tests are not specic and can be easily affected by several factors, such as patient anxiety or fatigue, and other circumstantial elements that act as distracters. Few studies have compared this group of tests to short neuropsychological batteries [22] or extended neuropsychological assessment. Furthermore, the use of these tests in populations different from the one included in the original description has yielded conicting results, with a high number of abnormal results in control groups [28]. For this reason, it is recommendable to conrm the cognitive impairment with additional neuropsychological assessments before making clinical decisions, such as initiating treatment for minimal HE.

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Table 2. Neuropsychological tools for the diagnosis of cognitive decits in patients with cirrhosis.

Methods Extended neuropsychological assessment RBANS [18]

Characteristics in-house selection of tests that examine multiple domains Short battery (paper-pencil tests)

Validation Difficult Diagnosis based on expert Large normative data Available in multiple languages Most studies in Alzheimers diseases Few data in cirrhosis Parallel versions available for repeated testing Several studies in cirrhosis Normative data in several countries Parallel versions available for repeated testing Large normative data in United Kingdom Few data in cirrhosis Parallel versions available for repeated testing Not affected by education or age Measures general arousal Identifies patients with abnormal PHES Highly demanding test Studies in USA support its use in cirrhosis Needs to be standardized to each population Recognition task based on the Sternberg paradigm Studies in Italy support its use in cirrhosis

PHES [19]

Short battery (paper-pencil tests)

Cognitive Drug Research [20]

Computerized neuropsychological battery

Critical Flicker Frequency [25]

Psychophysical measurement

Inhibitory Control Test [26]

Computerized neuropsychological test Computerized neuropsychological test

Scan test [27]

RBANS: Repeatable Battery for the Assessment of Neuropsychological Status. PHES: Psychometric Hepatic Encephalopathy Score.

Functional scales for assessing the impact of chronic low-grade HE One important aspect of the neuropsychological assessment is to determine as to what extent the cognitive decits affect daily life [29]. This can be done in a systematic manner with the aid of questionnaires. The SF-36 and the Chronic Liver Disease Questionnaire have been extensively used in patients with cirrhosis. These easily administered questionnaires can detect a decrease in quality of life associated with minimal HE [30]. They are, however, probably less sensitive than the Sickness Impact Prole, a long questionnaire (136 items) that covers numerous aspects of daily living and has been shown to detect the benets of therapeutic interventions [31]. Patient interview alone does not sufce to determine the consequences of cognitive decits on daily living [32]. The patients relatives perceive cognitive decits better than they themselves do, and for this reason relatives of patients with dementia are interviewed with tools such as the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Another of these, the Clinical Global Assessment of HE (CGA-HE), is an attractive approach developed by Dr. C. Randolph that is currently under validation. The CGA-HE obtains information on cognitive, motor, and functional status by interviewing the patient and a caregiver or family member, and provides a nal score. Magnetic resonance of the brain Magnetic resonance (MR) of the brain has become a standard technique for assessing patients with neurological manifestations. In patients with cirrhosis, MR is useful to exclude alternative diagno-

ses, such a Wernickes encephalopathy, viral encephalitis, and stroke. In addition, MR can detect a series of abnormalities [33] that are characteristically present in the brain of cirrhosis patients who develop HE: (a) Deposition of paramagnetic substances in the basal ganglia. These substances cause a high signal intensity on T1-weighted imaging, characteristically at the globus pallidus [34]. The hyperintensity probably corresponds to manganese deposition secondary to portosystemic shunting, and it may be present in the absence of cirrhosis or secondary to other causes of manganese deposition [35]. The intensity of the signaI is not related to the severity of HE [36], but the absence of T1 hyperintensity in a patient with cirrhosis and neurological manifestations suggests that the neurological symptoms are not caused by HE. (b) A decrease in the size of the brain. Brain atrophy has been characteristically associated with cirrhosis, particularly cases in which the etiology is related to alcohol abuse [37]. The decrease in brain parenchyma is more pronounced in specic areas, such as the frontal lobes and cerebellum. The mechanism by which cirrhosis induces brain atrophy is not known, but appears to be related to chronic portosystemic shunting and ammonia exposure [38]. The decrease in brain volume caused by alcohol recovers (at least partially) after abstinence. The coexistence of low-grade brain edema may make recognition of atrophy difcult, but it can become more evident after liver transplantation [39]. 1033

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Fig. 2. MR of the brain in a patient exhibiting grade II HE, and repeated 6 weeks later when the patient exhibited minimal HE. (A) (fast-FLAIR) shows hyperintense focal white matter lesions (leukoaraiosis) that decrease in volume after the resolution of HE. (B) (MR-spectroscopy) at follow-up shows decrease of the high glutaminecontaining (Glx) peak and increase of the low of myo-inositol (mIns) peak. The other peaks correspond to choline-containing compounds (Cho), n-acetyl-aspartate (NAA), and creatine (Cr).

(c) An increase in brain water. Brain edema has been demonstrated using sophisticated MR techniques in patients with chronic liver failure [40] and by laboratory methods in experimental models [41]. The location and severity of edema seems to differ according to the duration of liver failure and the degree of hyperammonemia. Chronic liver failure induces low-grade interstitial brain edema [42], whereas acute liver failure causes intracellular edema that can be severe and lead to brain herniation [43]. In conventional MR techniques, brain water changes are reected as an increase in signal intensity on fast-FLAIR imaging in periventricular regions, and as focal white matter lesions (Fig. 2-A) or lesions along the corticospinal tract [33]. Diffusion-weighted maps typically show an increase in the apparent diffusion coefcient in chronic liver failure and a decrease during episodic HE that is more apparent in certain areas [44]. (d) Changes in organic osmolytes and ammonia related-metabolites. MR-spectroscopy of the brain shows a typical pattern 1034

in HE patients: an increase in the glutamine peak and a decrease in the choline-containing and myo-inositol peaks (Fig. 2-B) [45]. This pattern is attributed to ammonia metabolism to glutamine in astrocytes, which induces astrocyte swelling, and to a compensatory osmotic response (decrease in organic osmolytes: myo-inositol and cholinecontaining compounds)[46]. The severity of HE has been associated with the intensity of this abnormality [47]. Nevertheless, cut-off values have not been established and the diagnostic accuracy of this pattern is uncertain.

Assessment of portosystemic shunting The importance of portosystemic shunting in inducing HE is well known from the experience with surgical shunts and transjugular intrahepatic portosystemic shunts (TIPS) [48]. The development of HE is rare in the absence of signicant liver disease, but not exceptional [49]. Portosystemic shunts can be visualized by

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Fig. 3. Dynamic helical CT scanning discloses a splenorenal shunt (arrow) during the arterial phase (left image) that becomes more evident in the venous phase (right image).

various imaging techniques, the most valuable being helical computed tomography (CT) (Fig. 3), MR, and endoscopic ultrasonography. Portal ow steal is a critical mechanism in the induction of HE in these patients [50]. The arterial concentration of substances with a high rst-pass metabolism, such as ammonia, is highly dependent on portal ow. This fact offers the possibility of exploring the functional consequences of the shunts. The oral glutamine challenge test consists in the measurement of plasma ammonia after ingestion of glutamine in a fasting state [51]. The test has not been standardized and normal values are based on the experience of independent investigators [49,52]. In our experience, oral glutamine challenge is very helpful for assessing complex clinical situations. We have observed at ammonia curves in some patients with cirrhosis and abnormal psychometric tests, and interpret this nding as a strong argument against attributing cognitive disturbances to HE. This interpretation is supported by the theoretical basis and the outcomes in cases where we had the opportunity to assess. Approach to patients Episodic HE Patients with cirrhosis and an acute change in mental state should be managed following a protocol that will exclude alternative neurological disorders, search for precipitating factors, and assess predisposing conditions (Fig. 4). HE episodes have been traditionally related to the occurrence of a precipitating factor, which can be dened as a clinical event that does not cause direct injury to the liver or portal-systemic circulation and is responsible for the acute change in mental status. Precipitating factors appear to act by increasing the generation of putative toxins or enhancing the effects of toxins on the central nervous system. They are temporally related to the development of HE, and their correction to re-establishment of consciousness. Several factors are commonly considered under this category (gastrointestinal bleeding, constipation, excessive protein intake, dehydration, electrolyte disturbances, renal failure, and infection), and are thought to explain the majority of HE episodes. However, a signicant number of episodes are not related to a precipitating factor [53].

Patients that have experienced an episode of HE should undergo liver function testing and imaging of the liver and portal-systemic circulation to investigate the presence of predisposing conditions. These may be dened as disturbances in liver function and portal-systemic circulation that facilitate the development of episodic HE. These conditions are present for a longer time than the precipitating factor, and they may be difcult to relate to the acute episode. Liver function disturbances can develop over a short period of time (weeks) in relation to an insult (e.g. alcohol) that usually causes a severe, but potentially reversible, inammatory injury. This situation has been proposed to be termed acute-on-chronic liver failure [54] and should be managed separately from episodic HE. Multiple factors that may interfere directly with mental status are involved (e.g. sepis, circulatory dysfunction, respiratory failure, etc. . .). These factors require specic therapeutic approaches in addition to measures for HE. On other occasions (e.g. advanced hepatocarcinoma), liver function disturbances develop slowly to a terminal stage that is suspected by progressive deterioration of the performance status, which precedes the appearance of HE. Portal-systemic circulation disturbances can either be caused by the presence of a TIPS or a surgically induced portosystemic shunt, as well as by the existence of large, spontaneous portosystemic shunts [55]. Recognition of spontaneous shunts is important, because occlusion is a treatment option in patients with recurrent HE and good hepatocellular function (low bilirubin) [56]. One interesting recent observation is the identication of specic polymorphisms in the glutaminase gene that may increase intestinal glutaminase activity and predispose affected individuals to the development of episodic HE [57]. If these ndings are conrmed, genetic polymorphism should be included in the group of predisposing conditions. Apart from identifying high-risk patients, polymorphism assessment may initiate an era of personalized medicine in the eld of HE. Asymptomatic outpatient with cirrhosis Neuropsychological impairment, which is common among outpatients with cirrhosis, is frequently asymptomatic and in many cases not perceived by the physician (minimal or covert HE). Assessment of cognitive function requires the use of psychometric tests under neuropsychological supervision. In many cen1035

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Exclusion of alternative neurological disorders
1. 2. 3. 4. 5. 6. Medical history + physical exam: presence of headache, focal neurological signs, meningeal signs Basic analysis: glycemia, PCO2 Toxics in blood or urine: benzodiacepines (consider flumazenil if suspicous), alcohol Assess B1 deficit in blood (or give thiamine if suspicion) Neuroimaging (CT, MR) if any abnormality in 1 or coma (unless rapid improvement). EEG if suspicion of seizures or nonconvulsive status.

Cirrhosis + acute change in mental state

Search of precipitating factors

1. 2. 3. 4. 5. Medical history + physical exam: explore signs of gastrointestinal bleeding, constipation, dehydration, infection (fever, localized signs) Basic analysis: Hemoglobin, leukocytes, creatinine, Na, K, pH, Leukocytes in urine and ascites (if present) X-rays (thorax and abdomen). Cultures of blood, urine, ascites or other body fluids (if abnormal)

Liver function and portal-systemic circulation

1. 2. 3. Medical history+physical exam: signs of complications of cirrhosis Blood test: bilirubin, albumin, prothrombin, AST ALT , Imaging of liver and portal-systemic circulation: CT MR ,

Acute-on-chronic liver failure

Factor that induces injury (alcohol, infection..), usually inflammatory-mediated Recent decompensation (2-4 weeks) Jaundice (bilirubin > 5 mg/dl) Circulatory dysfunction (hypotension, renal failure)

Episodic HE
Prior to HE: good performance status. Underlying: precipitating factor or large portosystemic shunts

Terminal
Prior to HE: low performance status Underlying: advanced hepatocarcinoma or severe cirrhosis

Fig. 4. Evaluation of a patient with cirrhosis and an acute change in mental status should be initiated by excluding toxic, metabolic, and structural encephalopathies. In parallel, the patient should be assessed following a protocol to investigate precipitating factors and undergo blood tests and imaging studies to evaluate liver function and portal-systemic circulation. According to the results, patients are classied as episodic HE, acute-on-chronic liver failure, or terminal liver disease, and are managed accordingly.

ters, this assessment is not easily available and is limited to patients with cognitive complaints. The main reason for limiting neuropsychological assessment to symptomatic patients is the uncertainty about the implications of establishing a diagnosis of minimal HE [58]. Although one study has shown that treatment improves the patients quality of life [31], the actual benet of treating mild cognitive impairment is still uncertain [21]. Several studies have shown that the decline in cognitive function that characterizes minimal HE worsens the ability to drive a car [59] and increases the risk of automobile accidents [60]. Impaired visuo-motor coordination and working memory is reected by insufcient navigation skills [61], a key element for proper driving. Attention disturbance and slow mental processing reduces the ability to react to unexpected trafc conditions, such as an illegal incursion by another vehicle at an intersection. Establishing the diagnosis of minimal HE helps to identify patients at a higher risk of incurring accidents, but does not invalidate the patient to drive a car [62]. One study observed that the percentage of patients with minimal HE that experienced trafc accidents was small (816%, depending on the diagnostic test) [60]. Driving is a complex activity that depends on many factors, especially pre-morbid skills. Experienced drivers may compensate for the cognitive decline by taking additional precautions [63]. It is recommendable to investigate the presence of minimal HE in cirrhotic patients who drive, but general advice based on the presence or absence of this condition cannot be given. The 1036

evaluation cannot rely on the patients judgment because they overestimate their driving abilities [59,32]. A history of recent trafc violations or minor accidents and the observation of changes in driving performance by relatives are important clues. Unfortunately, computer-based tests cannot reliably predict tness to drive and a nal recommendation may require consultation with specialized experts [59]. In asymptomatic patients, medical advice about the risk of accidents may be more important than treatment for minimal HE. The risk extends to accidental falls [64] and injury when handling machinery [21]. It is recommendable (Fig. 5) to screen for cognitive defects that may increase risk, and take preventive actions. Patients should be asked about their habits when driving and using machinery. The interview should address recent accidents and falls, and include queries to relatives about whether they have observed a decline in performance. Some data support the value of screening tests [60] for this purpose, but they do not sufce [28] to recommend a specic test [14]. Each center should decide what test to apply according to the available resources and experience (Table 2). One easily performed test commonly used in geriatrics to estimate the risk of falls, the timed up and go test, can be helpful [65]. According to the results of the interview and cognitive testing, general recommendations can be given (e.g. avoid doing other tasks while walking, avoid slippery ground). However, avoiding risk situations is not always possible or acceptable to the patient. This is often the case when patients

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Asymptomatic patient with cirrhosis

Possible risk of accidents 1. Drivers 2. Handling machinery 3. History of falls

Screening tests for the presence of minimal HE Positive results Consider preventive measures with the patient Driving issues
Fig. 5. Asymptomatic outpatients with cirrhosis at risk of experiencing an accident should undergo additional tests to investigate the presence of low-grade HE. Preventive measures should be recommended for those with abnormal results. Neuropsychological assessment should be more detailed and may require expert advice in patients who want to keep on driving.

Additional assessment to confirm risks of driving

are advised to quit driving; at this stage, additional evaluation by experts may be needed. Cognitive complaints in patients with cirrhosis Some cirrhosis patients request consultation for cognitive complaints or because relatives or coworkers have observed a decline in their performance of social activities. The impact of minimal HE on daily living depends on the cognitive demands [32]. Many patients, particularly those of advanced age, decrease their activities or receive the help of caregivers, and accept the decline as part of the general effects of the disease or the consequence of aging. Although the effect of minimal HE on working performance has not been studied directly, cirrhotic patients with minimal HE are more likely to not be working than those without this condition [66]. Unless cognitive impairment is severe, it is difcult to perceive in the clinical examination and requires psychometric testing. Common decits are usually mild and do not interfere in instrumental activities (shopping, answering the phone, taking public transportation) or basic daily life activities (dressing, personal hygiene, eating) [14]. However, decits in attention, executive function, and psychomotor skills may impair complex activities (planning a trip, handling nances, gardening, performing a job) and can elicit a consultation. One study in patients with minimal HE related their complaints to a decrease in psychomotor performance (I have difculty doing handwork. . .), impaired attention (I am confused. . .) and poor memory (I forget a lot. . .) [66]. The study also found that an important number of patients reporting cognitive complaints did not exhibit neuropsy-

chological or neurophysiological abnormalities. The complaints can have multiple origins and may reect psycho-affective or health problems unrelated to cognition [67]. Discrepancies between complaints and cognitive function are not infrequent in other clinical situations [68]. For this reason, additional assessment is needed before low-grade HE can be interpreted as the cause of cognitive complaints. In most cases, psychometric tests will sufce to establish the origin of cognitive complaints. However, the results may be difcult to interpret in some cases, because of a low education level on the part of patients, linguistic barriers, and sensorial defects (sight, hearing) or other handicaps. Furthermore, since neuropsychological scores are calculated in relation to normative data, they may not detect a decline in patients who had above-average pre-morbid performance. In these cases, the best option is to perform neurophysiological tests, such as electroencephalography or evoked potentials [69]. Normal results are helpful to reassure that cognitive complaints are not secondary to minimal HE. Attributing neurological manifestations to HE in complex cases The diagnosis of HE is based on the presence of neurological manifestations that can be attributed to liver failure or portosystemic shunting. In practice, this is done without major difculties by identifying the characteristic manifestations, excluding other neurological disorders, and judging whether the liver disease is severe enough to explain HE. However, in some cases the diagnosis is difcult, as occurs in patients with normal or only slightly abnormal liver tests [70], and those that exhibit unusual 1037

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neurological manifestations or neurological co-morbidities. This latter situation is critical when contemplating liver transplantation, a treatment that resolves neurological manifestations secondary to HE [71], but is ineffective for other neurological disorders, such as vascular cognitive impairment and early Alzheimers disease. The most common error that occurs when evaluating patients with prominent neurological manifestations and almost normal liver tests is to miss cirrhosis associated with large portosystemic shunts. A valuable diagnostic test in these cases is CT scanning of the liver. Once the condition is properly diagnosed, patients should receive adequate treatment for HE [72], which includes avoidance of diuretics, and possibly, occlusion of the shunts. The best option in patients with cirrhosis and complex neurological manifestations (e.g. behavioral and personality changes, paraparesis, chorea, ataxia) in whom alternative diagnoses have been excluded (e.g. hypothyroidism, vitamin B1 deciency, hypoglycemia) and psychiatric and neurological consultation has been obtained, is to perform MR imaging and spectroscopy. The evaluation may be completed by searching for portosystemic shunts with abdominal CT scanning and performing an oral glutamine challenge test. As was indicated above, a lack of the typical features associated with HE is a strong argument against the diagnosis. MR can identify white matter lesions secondary to small-vessel cerebral disease. These ndings prompt the diagnosis of vascular cognitive impairment [73], which has a pattern of cognitive deterioration similar to low-grade HE. The lesions show a marked reduction in size with reversal of HE [74]. Thus, their presence, even when extensive, does not imply that the cognitive impairment will not improve with transplantation. Similarly, mild to moderate brain atrophy is found in most patients with persistent HE [75] and does not necessarily indicate progressive dementia. In patients with these ndings on MR imaging, our practice is to attribute the neurological manifestations to HE if they have a uctuating course and if magnetic resonance spectroscopy of the brain shows high levels of glutamine and normal or only slightly decreased levels of n-acetyl-aspartate (a neuronal marker). Neurological manifestations after liver transplantation Neurological complications are common after liver transplantation, mainly in the early postoperative period [76]. A frequent manifestation is acute confusional syndrome (delirium). Neuroimaging and microbiological investigation are helpful to exclude vascular disorders and central nervous system infections, but it is more difcult to ascertain the origin of the syndrome when these tests are normal, and the patient has several metabolic disturbances or is taking certain drugs. Metabolic encephalopathy is usually considered multifactorial, and treatment is directed toward correcting the derangements and the judicious use of potentially neurotoxic drugs. This condition is more common in patients with cirrhosis of alcoholic etiology, prior HE, or a severe preoperative situation [77]; the presence of these factors may help to support the diagnosis of a metabolic origin. An unresolved issue is to what extent an acute confusional syndrome in the postoperative period may be caused by HE. The metabolic disturbances identied by brain MR spectroscopy take several months to normalize [78]. Similarly, portosystemic shunts may persist despite a normally functioning graft and can be responsible for acute changes in the mental state [79]. Liver transplantation improves HE, even in patients with severe manifestations [73,80]. Nevertheless, studies that have assessed neuropsychological function following liver transplantation have challenged the notion of complete reversibility [81]. Some sequelae may persist, but most of the patients exhibit normal cognitive function [82]. In a prospective assessment of patients up to nine years after liver transplantation, long-term cognitive function was associated with vascular risk factors and signs of small-vessel cerebral disease on MR imaging [39]. Thus, it is important to prevent premature aging of the brain by identifying and treating vascular risk factors, such as diabetes mellitus and arterial hypertension, and prescribing the smallest possible dose of immunosuppressive drugs.

Financial support CIBEREHD is supported by Instituto de Salud Carlos III, Madrid, Spain. The data used to generate the gures in the article were obtained with the support of a grant from the Spanish Ministry of Health (FIS 07/06419).

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Conict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conict of interest with respect to this manuscript. Acknowledgments I am indebted to Dr. Alex Rovira and Dr. Juli Alonso, neuroradiologists, Dr. Carlos Jacas, neuropsychologist, and Dr. Rita GarcaMartinez, hepatologist, for their critical review of the manuscript and helpful discussions on the diagnosis of HE during several years of collaborative work.
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Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jhep.2010.11.015. References
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