Approximately 2500 years ago Hippocrates (460–370 BC) stated that ‘those who are mad on account of phlegm are quiet, but those on account of bile are vociferous, vicious, and do not keep quiet’ . As far as is known this was the first time that an association between liver disease and cerebral dysfunction was suggested in the literature. In the more recent past, Sherlock et al.  gave a detailed description of the clinical features of hepatic encephalopathy (HE) associated with liver cirrhosis and portosystemic shunting. There is not too much to add to their statements. New findings, however, have been presented with regard to the neurological complications of acute liver failure, the pathophysiology of HE in cirrhotic patients, and the natural course of hepatic myelopathy (HM). This review presents the current knowledge on the neuropsychiatric features of acute liver failure and liver cirrhosis, and the characteristic neurological findings in HM. In addition, the first hints of an involvement of the central nervous system in hepatitis C virus (HCV) infection are reported.
Acute liver failure
The clinical presentation of metabolic encephalopathies depends on the extent of the metabolic alteration and the rate at which organ dysfunction takes place. Therefore, the clinical features of HE in patients with acute liver failure differs from that of HE in patients with cirrhosis. Whereas HE in cirrhotic patients progresses from sleep disturbances and slight attention deficits to disorientation, disturbed consciousness and perhaps coma over time periods ranging from several days up to months, patients with acute liver failure may present with altered behaviour even before the first clinical signs of altered liver function are present. In contrast to cirrhotic patients with HE, patients with acute liver failure are often irritable and restless. This stage of acute HE may develop within hours to a profound decrease in consciousness. As hypoglycemia and brain oedema are frequent complications of fulminant hepatic failure, alterations of consciousness in patients with acute liver failure may be caused either by HE or one of these complications. In addition, seizures may occur as a consequence of hyperammonemia, the development of brain oedema, relative ischaemia or hypoglycemia. They may even occur in patients treated by neuroleptanalgesia, in which case they are totally undetectable by clinical examination.
The detection of epileptic fits or an epileptic status, however, is very important as epileptic activity may increase brain oedema and thus may be part of a vicious circle. Ellis and coworkers  recently published the results of a controlled clinical trial on the frequency of subclinical seizure activity and the effect of prophylactic phenytoin infusion in acute liver failure. Forty-two patients were enrolled in the trial: 20 patients were given phenytoin, and 22 were not treated with phenytoin. Subclinical seizure activity was recorded in 15% of the treated patients and in 32% of the non-treated group; pupillary abnormalities were observed in 25 and 50%, respectively, intracranial pressure elevation in 15% of the treated and 32% of the non-treated patients. Autopsy was performed in nine patients of the phenytoin group and in 10 of the no phenytoin group. Brain oedema was found in 22% of the phenytoin group and in 70% of the non-treated group. Survival was 83% in the treated and 75% in the control group with regard to the transplanted patients, and 100% in the treated compared with 33% in the control group in those patients who did not fulfill the criteria for orthotopic liver transplantation. These findings underscore the clinical meaning of seizure activity in acute liver failure, and should be answered by obligatory electroencephalograph monitoring in patients with acute liver failure aimed at the detection of seizures and immediate therapy.
Hepatic encephalopathy in cirrhotic patients
HE is one of the most frequent complications of liver cirrhosis. It is assumed that approximately 60–80% of cirrhotic patients suffer from HE of various extent in the course of the disease . Although cirrhotic patients do not die as a result of HE, HE is a severe prognostic sign. According to the results of a recent study , the survival probability after the first episode of overt encephalopathy in patients with chronic liver disease is 42% at one year of follow-up and 23% at 3 years.
The clinical features of HE in cirrhosis are manifold. In most patients, HE occurs episodically and resolves after adequate treatment, either to a normal neurological status or to minor grades of encephalopathy such as minimal or grade I HE. Some patients, however, develop chronic persistent HE, which may persist even after ammonia-lowering therapy. Persistent HE is a rare manifestation of the syndrome and has been observed predominantly in patients with extensive portocaval collateral circulation or after shunt operation and the transjugular portosystemic stent shunt procedure. Patients may present with progressing extrapyramidal symptoms or progressing paraparesis [6,7].
There is agreement to grade HE predominantly with respect to the severity of the disturbance of consciousness (Fig. 1) .
The earliest signs of HE are often sleep disturbances and subtle behavioural changes, which are not obvious to the examiner, but are reported by the patients’ relatives and friends. As verbal abilities are usually preserved in this stage of HE, the so-called ‘minimal HE’, cerebral dysfunction is not detectable by routine clinical examination, but only by neuropsychological or neurophysiological measures . Patients with minimal HE do worse than healthy controls, especially in tests of psychomotor speed, visual perception and attention [9–13]. Some of them also show a pathological slowing of the electroencephalograph and prolonged latencies of exogenous potentials such as checkerboard evoked visual potentials or endogenous evoked potentials, especially the P300 wave [8,14]. The prevalence of this ‘minimal’ form of HE is estimated to be approximately 30–70% in cirrhotic patients without overt clinical signs of HE . In the past ‘minimal HE’ has been referred to as ‘latent’ or ‘subclinical’ HE. Recently, however, the use of these terms has been discouraged as minimal HE is undoubtedly of clinical significance for the patient [15,16]. It has been shown to interfere with the patient's ability to drive a car, with their earning capability and their quality of life . In addition, minimal HE is of prognostic significance as after a follow-up period of 3 years approximately 50% of cirrhotic patients with minimal HE present with clinically overt HE, compared with only 8% of those without minimal HE .
With further progression of HE, cognitive dysfunction becomes obvious, motor function is impaired and consciousness decreases. Patients present with mild confusion in grade I, drowsiness, lethargy and disorientation in grade II, somnolence or stupor in grade III, and coma with or without response to painful stimuli in grade IV (a and b) (Fig. 1).
The combination of neuropsychiatric symptoms characteristic of patients with HE is most obvious in patients with grade II HE. In one of her excellent descriptions of the clinical features of HE, Dame Sheila Sherlock stated: ‘During their nocturnal wanderings they would urinate into various containers such as drawers, baths, or shoes. One patient, although seeing clearly, would shave with his toothbrush and clean his teeth with hair cream. Confronted with his breakfast he had to stop and to think “That is the marmelade and that is the sugar basin” . These symptoms are usually referred to as confusion by the clinician. As we know from the work of Sherlock et al. , patients in this stage of the disease may show macropsia, distortions, synaesthesia and also visual agnosia, as described above. These symptoms are accompanied by dyspraxia and dysphasia. In addition to the behavioural changes, grade II HE is characterized by definite motor symptoms such as asterixis, ataxia, dysarthria, rigor, tremor, hypomimia and hypokinesia. However, although the classical grading systems of HE list these motor symptoms with grade II HE, in practice they are detectable by subtle neurological assessment even in patients who appear to be clinically unaffected . Asterixis, for example, may be observed even in patients without cognitive dysfunction, and speech disturbances are one of the first symptoms of HE. In the beginning, speech is slow and monotonous. Then it becomes slurred and dysarthric. Stuporous HE patients show perseveration. Concomitant with speech disturbances, writing disabilities can occur and be used for the documentation of the patients’ grade of impairment. The omission of single letters, reversal of order and mis-spellings are common in the early phases. With deterioration writing becomes tremulous, letters are superimposed, and lines of writing converge. Finally, the patients become unable even to sign their names. Hyperreflexia and ankle clonus is a characteristic finding in grade III HE, but can also be observed earlier in the course of the disease.
Besides the disturbances of motor function and consciousness the presence of personality changes and mood disorders in HE must be emphasized. Most of the patients show varying degrees of remittent personality change. In some patients behaviour is uninhibited during acute exacerbations of HE, in others previous personality trends are intensified. Mood fluctuates. In some patients depression and euphoria follow each other abruptly. In others, only depression or euphoria are observed to interchange with a stable mood.
Paranoid symptoms are common during stupor as a result of the perceptual difficulties and misinterpretations. In addition, hallucinations may be observed . Rare symptoms of HE in cirrhotic patients are headaches, blurred or double vision and epileptic seizures. Considering the differential diagnosis of HE episodes, it must be mentioned that HE may even present with focal neurological signs such as hemiparesis .
The behavioural changes seen in patients with HE are caused by an impairment of cognitive function resulting from bilateral forebrain and parieto-occipital dysfunction. In the beginning, in minimal HE and grade I HE, attention deficits predominate in the clinical presentation of the patients. According to Posner and coworkers  attention processing can be subdivided into three categories, orienting, vigilance and executive attention. These three functional subsystems are bound to the cingulate gyrus, orbitofrontal and dorsolateral frontal cortex, the parietal cortex, the superior temporal gyrus and the thalamus.
One tool to assess brain function in humans is 18F-fluoro-desoxy-glucose positron emission tomography (FDG–PET). Several years ago we performed a FDG–PET study of cerebral glucose utilization at rest in 20 cirrhotic patients with and without HE compared with healthy controls with Lockwood and colleagues . The authors were able to show that patients with HE grade I or II differed significantly from controls with regard to their glucose utilization at rest in several circumscribed brain areas. The ratio of regional glucose utilization compared with the whole brain glucose utilization rate was decreased in the cingulate gyrus, the frontolateral and the parieto-occipital cortex, whereas it was increased in the basal ganglia and hippocampus. Even patients with minimal HE differed significantly from controls with regard to their glucose utilization rates within the cingulate and the frontal and to a lesser extent also the parieto-occipital cortex. The glucose utilization rate correlated significantly with the extent of their cognitive dysfunction as represented by the PSE syndrome test results [17,22]. We found significant correlations between the FDG–PET data with the sum score of the PSE syndrome test, the so-called psychometric HE score, as with the results of the single tests of the battery.
In a more recent study (unpublished data) we were able to show a significant correlation between the results of several attention and memory tests and the glucose utilization of several cortical regions, which are considered to be related to attention processing such as the cingulate gyrus, the orbitofrontal and dorsolateral frontal cortex, the parietal cortex or the superior temporal gyrus. The glucose utilization within the temporomedial region, however, remained unchanged. This is in accordance with the results of another recent study , in which we were able to show that patients with early grades of HE suffer from attention deficits, but not memory deficits, and that the pathological results in memory tests in these patients are probably the result of encoding deficits caused by attention disturbances instead of retrieval deficits.
As mentioned above, motor symptoms are the most characteristic clinical signs of HE besides attentional deficits and the deterioration of visual perception. Patients with HE present predominantly with extrapyramidal and cerebellar symptoms. Sometimes patients with HE even mimic neurodegenerative disorders such as Parkinson's disease or multiple system atrophy in their clinical presentation . If HE progresses to grades III and IV, pyramidal signs are also to be observed.
With regard to the clinical presentation, bradykinesia in HE resembles that in patients with Parkinson's disease. However, when applying a three-dimensional computer-assisted movement analysis, we were able to show significant differences between dysdiadochokinetic movements in patients with Parkinson's disease and cirrhotic patients with early grades of HE . Whereas the movement trajectories in Parkinson's disease patients were generally slowed and were superimposed by the presence of tremor, cirrhotic patients with early HE showed no alteration of movement velocity but an increase in the time period needed to start any subsequent movement cycle in a dysdiadochokinetic movement. In other words, bradykinesia in patients with HE seems to be caused mainly by alterations of movement initiation. The process of movement initiation is not understood in detail. Anterior and posterior cingulate regions, the supplementary motor area, the frontomesial motor area, the dorsolateral premotor cortex and its parietal connections, the basal ganglia and the cerebellum, however, have been shown to be involved in this complex process.
Read et al.  described paraplegia as one of five different syndromes of chronic persistent HE. Paraplegia in patients with chronic liver disease is currently referred to as HM . The typical feature of HM is progressive spasticity and weakness in the lower extremities, which will render the patient bound to a wheelchair within months. Upper extremities are affected minimally, if at all. Brisk tendon reflexes and increased tone of the lower extremities are the predominant findings. Plantar reflexes may be flexor. Disturbances of sensation or bladder function are uncommon. For unknown reasons, most patients described are men. Imaging of the spinal cord reveals normal results, as does examination of the cerebrospinal fluid. The main pathological finding in HM is demyelination of the corticospinal tracts predominantly in the lower part of the cervical and the thoracic spinal cord. HM may be the presenting feature of liver failure. In most cases, however, HM will develop after several episodes of HE. With recurrent episodes of HE the pyramidal tract lesion seems to increase.
Classic therapy of HE has no effect in HM. Therefore, transplantation should be considered as soon as the diagnosis is made because the patient has a chance of improvement with successful liver transplantation .
Hepatitis C virus infection-associated encephalopathy
Chronic liver disease has been associated with chronic fatigue. Patients’ complaints about disabling fatigue, however, are usually not taken seriously if there is only mild liver dysfunction. Several groups recently reported that approximately two-thirds of patients with chronic hepatitis C infection suffer from mild to severe chronic fatigue even in the absence of considerable liver disease [27,28]. In addition to fatigue, musculoskeletal pain, right upper abdominal discomfort, depression, mental clouding and the perception of an inability to function effectively are frequent complaints of HCV-infected patients with normal liver function. These so-called extrahepatic manifestations of chronic HCV infection have been shown to interfere severely with the health-related quality of life . Somewhat astonishing was the observation that the extent of the extrahepatic manifestations does not depend on the degree of hepatitis. Even after successful treatment of the HCV infection, disabling fatigue was present in approximately 30% of the responders . Three studies have shown cognitive dysfunction in HCV-infected patients with only mild liver disease [31–33]. The corresponding finding of the studies was a selective impairment of attention and concentration in HCV-infected patients. According to the data of Forton et al. , the cognitive decline in patients was accompanied by a significant increase in the choline/creatine ratio within a basal ganglia voxel studied by magnetic resonance spectroscopy.
Comparing psychometric data of HCV-infected patients with and without fatigue with those of cirrhotic patients with early grades of HE and those of healthy controls, we were able to show that in contrast to cirrhotic patients, HCV-infected patients show no deficits with regard to motor speed and accuracy. HCV-infected patients show clear attention deficits. These, however, are less pronounced than in cirrhotic patients with HE. There thus seems to be a difference between HE and HCV infection-associated encephalopathy, namely the presence of motor dysfunction in HE but not HCV encephalopathy, whereas in both conditions we have to deal with significant attentional deficits (unpublished data).
The authors wish to express their gratitude to Elinor Switzer for the English proof-reading.
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