Spectrum of neurocognitive impairment in cirrhosis

Cirrhosis and chronic liver disease adversely affect neurocognitive functioning.1 These deficits range from neurological complications such as hepatic myelopathy to cognitive and mental status changes such as hepatic encephalopathy (HE).2 These neurocognitive difficulties can also severely restrict the patient's functioning and result in morbidity and mortality.3-6 The most prominent neurocognitive complication of cirrhosis is HE, which reflects a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease.7 The current system for studying HE is based on a subjective clinical classification largely based on mental status changes, the West Haven scale.2, 7-9 In addition to the mental status changes detected by clinical scales such as the West Haven scale, there are significant neurocognitive disturbances in those with normal mental status, which is characterized by impaired neuropsychological and perceptual motor dysfunction.10 The current system of HE classification does not take into account the continuum of this neurocognitive dysfunction in HE, which forms a spectrum of neurocognitive impairment in cirrhosis (SONIC).7, 11, 12 This spectrum spans a patient's performance from normal to overt HE to coma. The continuous nature of these impairments is supported by the presence of psychometric and neurophysiological impairments in patients even before they reach overt HE,13 poorer performance on tests in patients with treated overt HE than those without overt HE,1, 14 and persistence of psychometric deficits even after adequate resolution of an episode of overt HE.15 In addition, the worse clinical outcomes in patients with poor psychometric performance as a continuous measure have also been described.16 This review focuses on the available techniques and systems for characterizing HE and discusses the need for an approach for gauging severity of early HE as a continuum based on relevant clinical outcomes. The overall neurological complications of cirrhosis can be HE-related or independent of HE, and it is important to review these separately. Patients with cirrhosis can benefit from a detailed neurological examination; traditional teaching is that patients with difficulties in consciousness who also exhibit focal neurological deficits do not have HE. However, there is a high prevalence of focal deficits in patients with cirrhosis that is unrelated to HE, which may be due to (1) prior alcohol use resulting in cirrhosis and focal deficits, such as neuropathy and cerebellar signs17; (2) direct effects of cirrhosis on the nervous system, such as hepatic myelopathy and extra-pyramidal signs18, 19; (3) deficits unrelated to liver disease, such as residual deficits of prior strokes; and (4) diseases that affect the brain and liver concurrently, such as Wilson's disease.20 Therefore, the mere presence of focal deficits does not specifically exclude HE. Existing focal neurological deficits are also dependent on the depth of examination. A study by Krieger et al.21 revealed that 50% of patients with HE had “focal neurological signs”; these signs were mostly observed in those with a history of prior overt HE. However, most patients that have been included in recent studies do not have any specific focal neurological signs. Hepatic myelopathy is diagnosed as a spastic paraparesis and hyperreflexia without sensory loss; it does not improve with HE therapies but can reverse after liver transplantation.22, 23 Less than 1% of cirrhotic patients also present with acquired hepatolenticular degeneration with extrapyramidal and cerebellar symptoms. Unlike hepatic myelopathy, this responds to HE therapy.18 Although the above syndromes are important in our overall understanding of the neurological complications of cirrhosis, HE remains the most prevalent of these complications. BDT, Block Design test; CFF, critical flicker frequency; DST, digit symbol test; EEG, electroencephalogram; HE, hepatic encephalopathy; HESA, hepatic encephalopathy scoring algorithm; ICT, inhibitory control test; MHE, minimal hepatic encephalopathy; NCT-A/B, number connection tests A/B; PHES, Psychometric Hepatic Encephalopathy Score; RBANS, repeatable battery for assessment of neuropsychological status. HE is clinically divided into normal or overt HE. However when psychometric or neurophysiological tests are also used, it can be divided into normal, minimal HE (MHE), and overt HE.7, 24 This is because minimal HE cannot be diagnosed using just the clinical examination without these specialized tests. The well-known West Haven criteria have been used in several studies, but these criteria suffer from a lack of consistency in their application (Table 1).9, 24 There is a lack of reproducibility apart from the extremes of consciousness.24 Recent studies have shown that there is good agreement among observers in grading patients who are in a coma and those who are completely alert.7, 25 The Glasgow Coma Scale is used to further classify patients with HE who are in a coma.24, 26 The clinical hepatic encephalopathy staging scale (CHESS) is promising for mental status assessment but is currently undergoing validation trials.27 Although the clinical scales are easy to apply, there remains a large gray zone in the quantification of changes between the two extremes of normal and coma (Fig. 1).8, 25 Agreement of clinical scales in HE. There is insufficient agreement between observers in the clinical scales of HE except in the extremes. The large population of HE that exists between coma and appearing clinically normal is prone to misclassification using pure clinical scales, which leads to subjectivity. Stage 0 encompasses patients with normal cognitive function and minimal HE, the only definition being that patients have no current clinical signs and symptoms of overt HE.24 This differentiation between stage 0 and stage 1 of the West Haven criteria, which is critical for inclusion or exclusion into research trials or therapy, is clouded in uncertainty due to the nonspecificity of signs and symptoms of stage 1 HE (Fig. 2).9 The problem is this: What profile constitutes symptoms of HE in patients who are otherwise ambulatory? This is a difficult question when using pure clinical scales, as evidenced anecdotally by clinicians and through systematic studies. Characterization of HE stages using clinical and psychometric/neurophysiological tests. Using clinical and specialized testing, patients evaluated for HE are classified as normal, minimal HE, or overt HE. Depending on the specialized tests used and the availability of population norms, the diagnosis of MHE versus normal can vary between populations. In addition, the important distinction between stage I overt HE using West Haven criteria and minimal HE is often blurred due to the inability of the clinical scales to accurately define this stage. This furthers the subjectivity of this categorical approach in the initial stages of HE. The assessment of stage II, when patients begin to exhibit disorientation, is fairly reliable between raters. In addition to the difficulties faced in dividing patients into normal (stage 0) and stage 1, there is even more controversy surrounding the division of stage 0 into normal and MHE. MHE is defined as cognitive dysfunction without clinical signs of overt HE.13, 28 The diagnosis of MHE is only possible through specialized psychometric and neurophysiological measures.29 These methods are sensitive and reproducible to a large extent, but the applications across several populations are limited because of lack of norms and lack of appropriate language forms.29 Cognitive dysfunction in patients with MHE is characterized by attention deficit, working memory problems, and defects in executive functions such as response inhibition.1, 30 There is no evidence of long-term memory or language function decline in patients with MHE. Therefore, testing strategies for MHE are traditionally focused on these neurocognitive domains. Details of individual psychometric and neurophysiological tests are listed in Table 2, and the specific domains are shown in Fig. 3. Although these tests are sensitive, their specificity is in question, because patients with other metabolic and traumatic insults to the brain can have similar deficits. Therefore, the test performances have to be interpreted in the context of the patient's overall medical history, examination findings, and socio-economic status. Psychometric testing in order of complexity and functions tested. From the bottom up, there is an increasing complexity of functions tested by the various methods. Clinical scales primarily establish orientation, whereas psychometric tests start from the basic reaction times and proceed to complex executive functions. The tests must be used judiciously given the background of the particular patient and domains that need to be tested. The tests also may worsen in the reverse order with worsening HE. The traditional batteries used are paper-pencil batteries, which have the benefit of being portable, easily translatable, and with alternate forms to prevent learning effects. The recommended battery is the portosystemic encephalopathy syndrome test or Psychometric Hepatic Encephalopathy Score (PHES).1, 7, 10, 30 This battery consists of five tests: the number connection tests A and B (NCT-A/B), digit symbol test (DST), serial dotting test, and line tracing test. The NCT-A (or trails test A) tests for psychomotor function, whereas the NCT-B analyzes divided attention and executive function. The DST is a test of attention and processing speed. Serial dotting and line tracing are also tests of processing speed. All these tests are compared against age- and education-matched controls, and from these five tests, six scores are generated (the line tracing test has a score for time and errors), which are added to give a composite. The total score is a summation of the number of standard deviations (>−1 to 2 standard deviations impaired beyond comparable controls.7 In therapeutic HE trials, the decision for HE reversal versus persistence can therefore often boil down to a few seconds or limited change in raw scores on the individual tests, which can result in important changes in patient classification. The current system could also be improved by focusing on hard outcomes such as development of overt HE and traffic studies have shown that MHE patients are more to overt HE and be in traffic however, this is by no a because the of MHE patients do not overt HE and are not in traffic A better method be to on the outcomes and which criteria those outcomes with It is also that the uncertainty between the various methods to patients into normal, minimal HE, and overt HE be by neurocognitive performance in cirrhosis as a as this The proposed spectrum of neurocognitive impairment in cirrhosis validation in a This study of several measures psychometric and neurophysiological domains of the available tests is as a the development of clinically relevant outcomes. In there are several tests and grading methods for HE. The current system of grading patients into of normal, minimal HE, and overt HE methods can subjectivity. this neurocognitive dysfunction as a continuum (i.e., the spectrum of neurocognitive impairment in with outcomes could improve the understanding of this disease and its application in