Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:279–293 279 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

NEUROLOGY AND MEDICINE

Neurology and the liver

E A Jones, K Weissenborn

Neurological syndromes commonly occur in pathy associated with increased portal- patients with liver disease. A neurological syn- systemic shunting in the absence of drome associated with a liver disease may be a unequivocal evidence of hepatocellular complication of the disease, it may be induced insuYciency—for example, shunting second- by a factor that also contributes to the ary to a congenital portal-systemic shunt, disease—for example, alcohol—or it may have extrahepatic portal hypertension or portal no relation to the presence of the liver disease. hypertension due to hepatic fibrosis (for exam- Neurological deficits associated with liver ple, schistosomiasis). disease may aVect the CNS, the peripheral Subclinical hepatic encephalopathy is the nervous system, or both. This review focuses term applied to a patient with chronic liver dis- on syndromes characterised by altered CNS ease (for example, cirrhosis) when routine function associated with structural liver dis- neurological examination is normal, but appli- eases. Space does not permit consideration of cation of psychometric or electrophysiological peripheral neuropathies associated with liver tests discloses abnormal brain function that disease (for example, xanthomatous peripheral can be reversed by eVective treatment for neuropathy), diseases of childhood that aVect hepatic encephalopathy.8 the liver and CNS (for example, Reye’s Fulminant hepatic failure and subfulminant syndrome), or neurological consequences of (or late onset) hepatic failure are terms used copyright. hepatic lesions characterised by specific en- when the syndrome of acute liver failure is zyme deficiencies (for example, congenital complicated by hepatic encephalopathy within hyperammonaemias, the porphyrias, kern- one to several weeks of the first evidence of liver icterus, galactosaemia, and Zellweger’s syn- disease or the development of jaundice.910 drome (cerebrohepatorenal syndrome)). Hepatic encephalopathy occurring in a That there is a relationship between the patient with cirrhosis may be either acute or functional status of the liver and that of the chronic. The acute form in such a patient is brain has been known for centuries.1 The most usually associated with a clearly identifiable widely recognised aspect of this relation is that precipitating factor and usually resolves when hepatocellular failure may be complicated by the precipitating factor is removed or cor- the behavioural syndrome of hepatic encepha- rected. Failure to find a precipitating factor

lopathy, in which neurotransmission in the may imply that a decrease in overall hepatocel- http://jnnp.bmj.com/ brain is altered.23 Recently, it has been lular function has taken place. The term suggested that two other behavioural complica- chronic hepatic encephalopathy (or chronic tions of liver disease, scratching due to pruritus portal-systemic encephalopathy) is often ap- in cholestatic patients45 and profound fatigue plied to a patient with cirrhosis and substantial in patients with chronic cholestasis,67may also Department of portal-systemic shunting, who has hepatic Gastrointestinal and be associated with altered neurotransmission in encephalopathy that is persistent or episodic, Liver Diseases, the brain. with or without complete resolution of en-

Academic Medical cephalopathy between episodes. on September 24, 2021 by guest. Protected Center, 1105 AZ Hepatic encephalopathy It has been conventional to classify hepatic Amsterdam, The DEFINITIONS AND CLASSIFICATION encephalopathy as a reversible metabolic en- Netherlands E A Jones The term hepatic encephalopathy refers to the cephalopathy. This definition excludes rare syndrome of neuropsychiatric disturbances neurodegenerative disorders associated with Neurologische Klinik, that may arise as a complication of acute, suba- chronic liver disease and extensive portal Medizinische cute, or chronic hepatocellular failure. The systemic shunting (see Degenerative disorders Hochschule Hannover, syndrome is associated with increased portal- section). However, this widely accepted 30623 Hannover, systemic shunting of gut derived constituents classification of hepatic encephalopathy may Germany 11 12 K Weissenborn of portal venous blood, due to their impaired need reappraisal. It is probably useful to extraction by the failing liver and, in most classify cerebral oedema and raised intracranial Correspondence to: instances, their passage through intrahepatic pressure (ICP) occurring in patients with Dr E A Jones, Academisch and/or extrahepatic portal-systemic venous fulminant hepatic failure separately from he- Medisch Centrum, Department of collateral channels. patic encephalopathy. However, these compli- Gastrointestinal and Liver The term portal-systemic encephalopathy is cations of fulminant hepatic failure contribute Diseases, Room C2–330, often used interchangeably with hepatic en- to encephalopathy, occur together with hepatic Meibergdreef 9, 1105 AZ Amsterdam Zuidoost, The cephalopathy, but portal-systemic encephalo- encephalopathy, and may share pathogenic fac- Netherlands. pathy can be defined to include encephalo- tors with hepatic encephalopathy (for example, 280 Jones, Weissenborn J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

Table 1 The clinical stages of hepatic encephalopathy pathognomonic, of liver failure; it may occur in hypoxia, hypercapnia, uraemia, heart failure, or Stage Mental state sedative overdosage. I Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, untidiness, slurred speech, irritability, DIFFERENTIAL DIAGNOSIS reversal of sleep rhythm II Drowsiness, lethargy, gross deficits in ability to perform mental tasks, The diVerential diagnosis of hepatic encepha- obvious personality changes, inappropriate behaviour, intermittent lopathy includes alcohol intoxication and with- disorientation (usually for time), lack of sphincter control drawal syndromes, Wernicke’s encephalopathy, III Somnolent but rousable, unable to perform mental tasks, persistent disorientation with respect to time and/or place, amnesia, occasional fits KorsakoV’s syndrome, intoxication with of rage, speech present but incoherent, pronounced confusion sedative/hypnotic drugs, other metabolic en- IV Coma, with (IVA) or without (IVB) response to painful stimuli cephalopathies (for example, hypernatraemia From Adams and Foley13 with modifications. or hyponatraemia, uraemia, hyperglycaemia or hypoglycaemia, hypercapnia), Wilson’s disease, raised ammonia concentrations) (see Fulmi- consequences of head trauma (for example, nant hepatic failure section). subdural haematoma) and organic intracranial lesions. Delirium tremens (DTs) may occur in CLINICAL FEATURES a patient with underlying alcoholic liver The term encephalopathy covers a wide range disease. It is important, therefore, to distin- of neuropsychiatric disturbances ranging from guish this syndrome from hepatic encephalopa- minimal changes in personality or altered sleep thy. In contrast to asterixis associated with pattern to deep coma13 (table 1). The earliest hepatic encephalopathy, patients with DTs clinical signs of hepatic encephalopathy (stage have a rapid postural and action tremor. 1) are often subtle psychiatric and behavioural Furthermore, the manifestations of DTs, changes that may be more apparent to the including delirium, suggest cortical excitation patient’s family and close friends than to the rather than the presumed cortical inhibition neurologist.14 15 These changes are primarily that seems to characterise hepatic encepha- due to mild impairment of intellectual function lopathy. Benzodiazepines are commonly given that reflect predominantly bilateral forebrain, in the management of DTs. Patients with parietal, and temporal dysfunction. In early chronic liver disease have increased sensitivity stages of hepatic encephalopathy the presence to the neuroinhibitory eVects of these drugs.20 of pronounced intellectual impairment may be Other CNS complications of alcoholism, such masked by relatively well preserved verbal as Wernicke’s encephalopathy and KorsakoV’s ability.16 17 Whether patients with subclinical psychosis, are also not dependent on the devel- copyright. hepatic encephalopathy should be considered opment of alcoholic liver disease. unfit to drive a car is uncertain.17 18 As encephalopathy progresses, intellectual abili- DIAGNOSIS ties deteriorate overtly (with deterioration of When patients, with and without known liver performance at school or work), motor func- disease, present with neuropsychiatric symp- tion becomes impaired, and consciousness toms or neurological signs, it is necessary to ask decreases. With further progression coma one of the following questions: (1) Does this ensues. Neurological signs vary with progres- patient have hepatic encephalopathy? or (2) sion of hepatic encephalopathy. Hypertonia, Could this patient have hepatic encephalopa- hyperreflexia, and positive Babinski signs may thy? There are two components to making a be elicited and tend to precede the occurrence diagnosis of hepatic encephalopathy: one is to

of hypotonia and diminished deep tendon determine that subclinical or overt encepha- http://jnnp.bmj.com/ reflexes in late stages of hepatic encephalopa- lopathy is present (table 1 and sections on psy- thy. In contrast to most other metabolic chometric tests and electrophysiology), and the encephalopathies, features of hepatic encepha- other is to obtain information consistent with lopathy may include manifestations of extrapy- hepatocellular insuYciency and increased ramidal dysfunction, such as hypomimia, mus- portal-systemic shunting. cular rigidity, bradykinesia, hypokinesia, Initially it is mandatory to take a meticulous monotony of speech, a Parkinsonian-like clinical history (usually from the patient’s rela-

tremor, and dyskinesia. tives and friends) and to conduct a detailed on September 24, 2021 by guest. Protected Asterixis or “liver flap” is often present in the physical examination. Information elicited early stages of hepatic encephalopathy. Aster- should include a history of past or present liver ixis consists of infrequent involuntary flexion- disease, any family history of liver disease, and extension movements of the hand (one flap potential exposure to a hepatotoxic drug or every one to two seconds), which may result in other hepatotoxin or to a hepatitis virus. There part from an impairment of the normal inflow are no specific clinical features or patterns of of joint position sense to the brain stem reticu- laboratory test results that are diagnostic of lar formation.19 Asterixis should be classified as hepatic encephalopathy. Accordingly, the diag- a negative myoclonus rather than a tremor. It is nosis of hepatic encephalopathy requires clini- usually best demonstrated with the patient’s cal judgment and involves establishing the arms outstretched, the wrists hyperextended, presence of hepatocellular insuYciency and and the fingers separated (as if trying to stop excluding other causes of encephalopathy. The traYc). Also, if the patient uses a hand to grip main clinical (non-encephalopathic) manifes- two of the neurologist’s outstretched fingers, tations of liver failure, which may be associated asterixis is indicated by rhythmic squeezing of with hepatic encephalopathy, are hepatocellu- the neurologist’s fingers (milk maid’s grip). lar jaundice, fluid retention (ascites, ankle This useful sign is characteristic, but not oedema), and an increased bleeding tendency Neurology and the liver 281 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

(bruises). Signs of increased portal-systemic ICP is increased in fulminant hepatic failure, shunting include ascites, dilated veins in the the possibility of precipitating cerebral hernia- abdominal wall, in which blood flow is away tion. from the umbilicus, and a venous hum, with or without a thrill, in the region of the umbilicus Brain imaging or xiphoid process. Furthermore, classic, but Computed tomography is not useful for the non-specific, stigmata of liver disease (for diagnosis of hepatic encephalopathy. It should example, spider angiomata, palmar erythema) be done, however, in each case in which the may be found. Hypoalbuminaemia and a diVerential diagnosis includes intracranial prolonged prothrombin time are useful labora- bleeding, especially the presence of a subdural tory findings, which suggest impaired synthetic haematoma. function of the liver and hence hepatocellular Magnetic resonance imaging cannot be used insuYciency. for the diagnosis of hepatic encephalopathy. Occasionally, when making a confident diag- However, characteristic MRI abnormalities are nosis of hepatic encephalopathy is diYcult, the found in patients with cirrhosis. The main clinical and electrophysiological responses to a abnormal finding is symmetric pallidal hyper- treatment for hepatic encephalopathy (for intensities in T1 weighted images, which may example, dietary protein restriction, evacuation be accompanied by similar changes in the of the bowel, or an intravenous injection of region of the nigral substance and the dentate flumazenil—see Treatment section) may help cerebellar nucleus.23–25 These MRI abnormali- to resolve the issue. Making a diagnosis of ties do not correlate closely with the stage of hepatic coma (stage IV hepatic encephalo- hepatic encephalopathy, but in individual cases pathy) can be particularly challenging, as the seem to correlate with the degree of impair- diVerential diagnosis of coma is so large and a ment of hepatocellular function. T1 weighted relevant history may be unavailable. In this pallidal hyperintensities have been shown to clinical situation the finding of a raised plasma disappear within one year in a cirrhotic patient ammonia concentration can be useful in undergoing liver transplantation.26 27 The cause suggesting that liver disease may be the of the MRI abnormalities in the CNS of primary cause of the coma (see Laboratory cirrhotic patients is unknown. Possibilities that section). The correct diagnostic approach to are being considered include an increased the comatose patient has been well described in deposition of manganese in the basal ganglia the authoritative monograph of Plum and and regional changes in the relaxation time Posner.21 caused by an increase in the number of copyright. biological membranes (mitochondria, endo-

ASSESSMENT plasmic reticulum) as a consequence of astro- 21 Clinical cytic proliferation. Classification of the severity of the encepha- Like MRI findings, studies in cirrhotic lopathy in terms of four principal clinical stages patients involving the application of magnetic is routine (table 1).13 Asterixis may be elicited, resonance spectroscopy and 18-fluoro-deoxy- particularly in the early stages (I and II) of glucose positron emission tomography have hepatic encephalopathy. As asterixis represents also disclosed abnormal findings in the basal a defect of neuromuscular function rather than ganglia. The relationship of these abnormali- a feature of disordered consciousness, asterixis ties to hepatic encephalopathy is uncertain. should probably be assessed independently of Details of these studies are beyond the scope of this article and the interested reader is referred http://jnnp.bmj.com/ the mental state and clinical stage of hepatic 28–32 encephalopathy. to relevant literature. Psychometric tests Laboratory Psychometric tests can be applied to detect and When encephalopathy is attributable to hepatic quantitate subtle abnormalities of mental encephalopathy alone, abnormal results of function in patients with liver diseases, who serum biochemical tests reflect the underlying have subclinical hepatic encephalopathy or

liver disease. Routine laboratory test results aid early prestupor stages of hepatic encephalo- on September 24, 2021 by guest. Protected in the diVerential diagnosis of encephalopa- pathy (that is, many ambulatory patients with thies (for example, uraemia, hypoglycaemia, cirrhosis).15 Simple psychometric tests include hypercapnia) and in the detection of factors orientation to time, person, and place, recall of that may precipitate hepatic encephalopathy current events, subtraction of serial sevens, (for example, hypokalaemic metabolic alkalo- handwriting, and figure drawing. The inability sis). Plasma ammonia concentrations are not to draw a five pointed star (constructional or consistently raised in patients with hepatic ideational dyspraxia) has received special encephalopathy; they correlate poorly with the attention.33 Of the many quantitative psycho- stage of hepatic encephalopathy and they do metric tests available, one that is easy to apply not provide a reliable index of the eYcacy of 2 and has been extensively used in the assess- treatments for hepatic encephalopathy. ment of early hepatic encephalopathy is a modification of the Reitan trail making test, Lumbar puncture known as the number connection test.34 Lumbar puncture is not done unless indicated Repeated application of this test can be useful, by atypical clinical or laboratory findings. but care must be taken to exclude an eVect of Lumbar puncture carries increased risk be- learning and age on test scores.35 36 In addition, cause of the presence of coagulopathy and, if tests of reaction times to auditory or visual 282 Jones, Weissenborn J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

Table 2 Grading of electroencephalographic changes in hepatic encephalopathy patients with subclinical hepatic encephalopathy.40 41 Grade Features

A Generalised suppression of alpha rhythm PRECIPITATING FACTORS B Unstable alpha rhythm with paroxysmal waves at 5 to 7 per second; Any factor which increases portal-systemic occasional underlying fast activity C Runs of medium voltage 5 to 6 per second waves bilaterally over frontal and shunting (for example, surgically created temporal lobes; alpha rhythm seen occasionally portal-systemic shunt or transjugular intra- D Constant 5 to 6 per second waves in all areas hepatic portal-systemic shunt (TIPSS)) or fur- E Bilaterally synchronous, 2 to 3 per second waves, predominating over frontal lobes and spreading backward to occipital lobes; occasional short-lived ther impairs hepatocellular function (for exam- appearance of faster rhythms (5 to 6 per second) ple, surgery under general anaesthesia) will tend to precipitate or exacerbate hepatic From Parsons-Smith 22 et al. encephalopathy. Table 3 shows some of the Table 3 Factors that may precipitate hepatic encephalopathy many recognised precipitating factors. These tend to be more readily apparent in patients Oral protein load  Upper gastrointestinal bleed  Act through gut factors with chronic, rather than acute, liver failure. Constipation  With the notable exception of sedative- Diarrhoea and vomiting  hypnotic drugs that act on the ã-aminobutyric Dehydration; electrolyte and acid/base imbalance Diuretic therapy   (for example, hypokalaemic alkalosis) acid A (GABAA)/benzodiazepine receptor Abdominal paracentesis complex (for example, benzodiazepines and Hypoxia  barbiturates), the relationship of common pre- Hypotension  Adverse eVects on both liver and brain cipitating factors to pathogenesis is poorly Anaemia  Hypoglycaemia understood. Sedative/hypnotic drugs* Azotaemia† PROGNOSIS Infection‡ In a patient with chronic hepatocellular disease Induction of medical or an episode of hepatic encephalopathy usually surgical portal-systemic shunt resolves if overall hepatocellular function re- General surgery mains relatively well maintained and a precipi- tating factor can be identified and corrected. *Includes drugs acting on the GABAA/benzodiazepine receptor complex. †Blood urea is a source of intestinal ammonia. Alternatively, if an obvious precipitating factor ‡May cause dehydration and augmented release of nitrogenous substances. cannot be identified, a poor prognosis is likely.

8 About 50% of patients with cirrhosis die within stimuli may also be useful. Detailed psycho- one year of their first episode of hepatic copyright. metric testing, involving the application of a encephalopathy and about 80% within five battery of psychometric tests, is more sensitive years, not as a direct consequence of hepatic in the detection of subtle deficits of mental encephalopathy, but as a consequence of function than either conventional clinical chronic hepatocellular failure.42 assessment of the mental state or the EEG.837 Results of quantitative psychometric tests NEUROPATHOLOGY should be assessed in relation to age related Structural changes in neurons, as assessed by data on normal subjects and an assessment of light microscopy, are not found in the brains of cognitive dysfunction should be based on a test patients who had hepatic encephalopathy when set that allows the assessment of several diVer- they died.13 However, in patients who die with ent cerebral functions.38 cirrhosis and portal-systemic shunts, an in-

crease in the number and size of astrocytes, http://jnnp.bmj.com/ particularly Alzheimer type 2 astrocytes is Electrophysiology commonly found.13 Such changes may be Electrophysiological evaluation of hepatic en- 15 induced by raised concentrations of cephalopathy is not routine. The EEG may be ammonia,43 but they are not a feature of the abnormal in subclinical hepatic encephalopa- brain in fulminant hepatic failure. thy and early stages of hepatic encephalopathy.

It is usually abnormal in late stages of hepatic PATHOGENESIS

encephalopathy. The EEG abnormalities that A normally functioning liver is necessary to on September 24, 2021 by guest. Protected occur in hepatic encephalopathy are non- maintain normal brain function. Theoretically, specific, being found in other metabolic hepatic encephalopathy might occur as a encephalopathies. The main EEG abnormali- consequence of (1) reduced synthesis by the ties in hepatic encephalopathy are a progressive failing liver of a substance(s) necessary for nor- bilaterally synchronous decrease in wave fre- mal brain function; (2) synthesis by the failing quency and an increase in wave amplitude. liver of an encephalopathogenic substance(s); Preterminally there is a loss of wave amplitude and (3) reduced extraction and metabolism by (table 2).22 In common with other metabolic the failing liver of encephalopathogenic sub- encephalopathies, paroxysmal triphasic waves stances or precursors of such substances. may occur, even in the early stages of hepatic Available data that have potential relevance to encephalopathy, and are characteristically asso- the pathogenesis of hepatic encephalopathy ciated with a frontal to occipital phase shift.39 A apply predominantly to the last of these three good correlation between the clinical stage of possibilities. hepatic encephalopathy and the degree of Traditionally gut factors have been consid- abnormality of the EEG is not invariable.33 ered to play important roles in pathogenesis, Abnormalities of event related potentials (for because hepatic encephalopathy may be pre- example, the P300 wave) may be detected in cipitated by an oral protein load, a gastrointes- Neurology and the liver 283 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

Table 4 Treatment of hepatic encephalopathy increased concentrations of natural benzodi- azepines in the brain in liver failure may be Treatment Comment heterogeneous2 and specific factors, such as I. Correction or removal of precipitating factors Mandatory increased synaptic concentrations of GABA and the modestly increased concentrations of II. Minimise absorption of nitrogenous substances  Dietary protein restriction  ammonia that occur in liver failure (see below), Evacuation of bowel  Routine may potentiate the neuroinhibitory actions of Lactulose (or a related sugar) and/or oral broad  natural benzodiazepines in liver failure.248 spectrum antibiotic (for example, neomycin)  Increased sensitivity of the brain of patients III. Reduction of portal-systemic shunting Rarely practical with cirrhosis to an exogenously administered benzodiazepine has been demonstrated.20 In IV. Direct reversal of neuropathophysiology Experimental Flumazenil assessing the potential role of natural benzodi- azepines in an encephalopathic patient with liver disease, it may not be easy to ascertain tinal haemorrhage, or constipation (table 3) whether the patient had taken pharmaceutical and may be ameliorated by evacuation of the benzodiazepines recently, as several of the bowel and dietary protein restriction (table natural benzodiazepines present in increased 4).33 The relationship of portal-systemic en- concentrations not only in the brain,248but also cephalopathy in the absence of hepatocellular in plasma49 in liver failure, seem to be identical failure to hepatic encephalopathy is uncertain. to pharmaceutical benzodiazepines. For example, in contrast to patients with Ammonia was originally implicated in the chronic hepatic insuYciency, encephalopathy pathogenesis of hepatic encephalopathy be- that develops in dogs with an Eck fistula (a cause it was recognised to be neurotoxic, portacaval shunt) fed a standard diet can be plasma concentrations tend to be raised in prevented by giving a palatable nutritious diet patients with liver failure, and plasma ammonia that prevents weight loss and malnutrition, but 246 44 readily enters the brain. However, plasma not hepatic atrophy. It has been proposed that ammonia concentrations higher than those in liver failure some gut derived neuroactive usually found in liver failure (>1 mM) are substances (for example, ammonia, GABA), associated with eVects that do not mimic that are present in increased concentrations in hepatic encephalopathy; in particular, they peripheral blood plasma, cross the blood-brain 245 suppress inhibitory postsynaptic potential for- barrier and modulate brain function. The mation and hence promote phenomena attrib- blood-brain barrier is normally highly perme- utable to neuronal excitation, such as a copyright. able to non-polar substances, such as non-ionic preconvulsive state and seizures.2465051 Inter- ammonia and benzodiazepine receptor ligands, estingly, administration of ammonium salts to but has a low permeability to polar com- cirrhotic patients does not readily induce EEG pounds. However, in liver failure the perme- changes similar to those found in hepatic ability of this barrier to polar compounds, some encephalopathy.52 of which are neuroinhibitory (for example, The question arises whether the modestly 46 GABA), may increase. raised plasma ammonia concentrations typi- It is widely thought that the pathogenesis of cally found in patients with precomatose hepatic encephalopathy is multifactorial. Cur- hepatic encephalopathy (stages I-III) (100-400 rently, the two factors considered to be most µM)46 can be associated with an ammonia important in pathogenesis are raised brain induced enhancement of neuronal inhibition.

concentrations of ammonia and increased This could occur if ammonia at these concen- http://jnnp.bmj.com/ GABA mediated neurotransmission. The hy- trations promotes astrocytic synthesis of neu- potheses implicating these two phenomena rosteroids that activate the GABAA receptor have appeared to be unrelated, but recent complex43 46 or acts directly on this complex to evidence suggests that they may be interrelated enhance neuronal inhibition.46 Recently, am- and mutually compatible.46 monia, in concentrations that commonly occur Increased GABA mediated neurotransmis- in plasma in liver failure (but not higher sion is associated with impairments of motor concentrations), has been shown to facilitate 247 − function and decreased consciousness, two GABA-gated Cl currents in cultured cortical on September 24, 2021 by guest. Protected of the cardinal manifestations of hepatic neurons46 and to increase selectively the binding encephalopathy. There are four lines of evi- of agonist ligands, including the benzodiazepine

dence, largely from studies in animal models, receptor agonist, flunitrazepam, to the GABAA/ which support the hypothesis that increased benzodiazepine receptor complex.46 Thus in GABA mediated neurotransmission contrib- liver failure ammonia may potentiate GABAer- utes to the manifestations of hepatic gic neurotransmission as a consequence of encephalopathy.47 Potential mechanisms for direct synergistic interactions with agonist

increased GABAergic tone in hepatic encepha- ligands of the GABAA/benzodiazepine receptor lopathy include increased availability of GABA complex. Furthermore, ammonia appears to in synaptic clefts, due to loss of presynaptic increase the binding of agonist ligands, such as feedback inhibition of GABA release associ- diazepam binding inhibitor, to astrocytic pe- 43 ated with a decrease in GABAB receptors ripheral benzodiazepine receptors, the density and/or increased blood to brain transfer of of which is increased in patients who die with GABA,46 increased astrocytic synthesis, and cirrhosis and hepatic encephalopathy.53 These release of neurosteroids43 and increased brain findings raise the possibility that in liver failure concentrations of natural benzodiazepine re- there may be an increase in peripheral benzodi- ceptor agonist ligands.248 The distribution of azepine receptor mediated astrocytic synthesis 284 Jones, Weissenborn J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

and release of neurosteroids, such as 3-á- pounds other than ammonia and, conse- hydroxysteroids. Such compounds, by interact- quently, they do not have specificity for the ing with specific steroid binding sites on the ammonia hypothesis. Potential treatments that

GABAA receptor complex, induce positive induce relatively selective decreases in plasma 54 modulation of the GABAA receptor and hence ammonia concentrations include arginine, or- may contribute to increased inhibitory neuro- nithine, and sodium benzoate.58–60 The ration- transmission in hepatic encephalopathy.24346 ales for levodopa, bromocriptine, and infusions It has been postulated that additional distur- of branched chain amino acids are based on the bances of neuron-astrocyte interactions, some false neurotransmitter hypothesis; the eYcacy of which may be induced by ammonia, may also of none of these three treatments has been contribute to hepatic encephalopathy.34355 In convincingly shown.2 The rationale for the addition, possible roles for neurotransmitter benzodiazepine receptor antagonist flumazenil systems, other than the GABA system, in is based on the GABAergic neurotransmission hepatic encephalopathy have been postulated— hypothesis.61 for example, the glutamate, dopamine, sero- The association of increased brain concen- tonin, and opioid systems.3 The demonstration trations of natural benzodiazepine receptor of impaired astrocytic uptake of glutamate and agonists with hepatic encephalopathy248 pro- down regulation of glutamate binding sites in vides a strong justification for giving a benzodi- animal models of hepatic encephalopathy,3 may azepine receptor antagonist in the management imply a decrease in excitatory glutamatergic of hepatic encephalopathy. The imidazobenzo- neurotransmission. Furthermore, some of the diazepine, flumazenil, is a selective, high aYn- symptomatology of hepatic encephalopathy can ity, competitive antagonist of central benzodi-

be explained by disturbances in functional azepine receptors on the GABAA/ loops of basal ganglia, which could arise as a benzodiazepine receptor complex. It rapidly consequence of an imbalance between glut- gains access to these receptors after its amatergic and GABAergic neurotransmission. intravenous administration.262 It competes Evidence supporting hypotheses of pathogen- with high specificity with benzodiazepine esis that implicate primary roles for impaired receptor agonist ligands (for example, di- brain energy metabolism, the synergistic action azepam) for binding to these receptors and of neurotoxins such as mercaptans and short rapidly reverses neurological eVects attribut- chain fatty acids with ammonia, and false neu- able to benzodiazepine agonist induced en- rotransmitters (including an imbalance of hancement of GABAergic neurotransmission.62 adrenergic, serotoninergic, and dopaminergic Current evidence suggests that GABAergic copyright. neurotransmission) is currently considered to tone may be increased in hepatic encephalopa- be less strong than evidence supporting the thy, not only by benzodiazepine agonists, but ammonia and GABAergic neurotransmission also by mechanisms that are independent of hypotheses.2 Decreased cerebral oxygen con- these ligands (see Pathogenesis section). Thus sumption and glucose metabolism may be con- the reduction in GABAergic tone in hepatic sequences of hepatic encephalopathy rather encephalopathy induced by antagonising the than primary pathogenic factors.2 Roles for eVects of natural benzodiazepine receptor ago- zinc56 and manganese3 in hepatic encephalo- nists may be insuYcient to normalise GABAer- pathy have also been suggested. gic tone and, consequently, may be associated, at the most, with only a partial amelioration of TREATMENT hepatic encephalopathy. It should be noted that

The following general principles are relevant to antagonists of the central benzodiazepine http://jnnp.bmj.com/ the management of hepatic encephalopathy receptor with weak partial agonist actions, such (table 4): (1) removal or correction of any pre- as flumazenil have an acceptable safety profile, cipitating factors (table 3); (2) reduction of because an overdose is likely to be associated absorption of nitrogenous substances from the with only mild diazepam-like eVects. intestinal tract (for example, evacuation of the Anecdotal reports of uncontrolled observa- bowel by purgation, enemas, and elimination of tions have suggested that a benzodiazepine dietary protein);57 (3) reduction of increased antagonist may be useful in the management of

portal-systemic shunting; and (4) reversal of hepatic encephalopathy. When flumazenil has on September 24, 2021 by guest. Protected contributing neuropathophysiological events been given parenterally, usually as intravenous by administration of drugs that act directly on bolus injections, clinical and electrophysiologi- the brain. Approach (1) is mandatory; (2) is cal ameliorations of hepatic encephalopathy routine; (3) is rarely practical; and (4) is still have been documented in patients with clini- experimental. The section on pathogenesis cally and electrophysiologically stable hepatic above provides rationales for treatments for encephalopathy due to fulminant hepatic hepatic encephalopathy that decrease GABA failure or cirrhosis (fig 1).2 61–64 Characteristics mediated inhibitory neurotransmission and/or of the responses to intravenous injections of lower ammonia concentrations. this drug are as follows:65 (1) they are often Certain treatments for hepatic encephalopa- reproducible in an individual patient; (2) they thy have relevance to specific hypotheses of are inconsistent, occurring in only about 60% pathogenesis. For example, evacuation of the of patients; (3) they occur rapidly, within four bowel or oral administration of lactulose or minutes of drug administration; (4) substantial broad spectrum antibiotics (for example, neo- ameliorations occur after low doses—for exam- mycin) tend to reduce intestinal absorption of ple, 0.3-0.5 mg—suggesting that only small ammonia.57 However, these therapeutic inter- amounts of the drug are necessary to occupy a ventions aVect the metabolism of many com- large proportion of central benzodiazepine Neurology and the liver 285 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

Electrophysiological amelioration of hepatic encephalopathy in a 58 year old woman with cirrhosis after intravenous flumazenil. L Before treatment, when the patient was in stage IV hepatic encephalopathy, the EEG showed continuous 1 to 2 Hz triphasic activity. R Forty seconds after the administration of 0.3 mg flumazenil, the severity of hepatic encephalopathy had improved to stage II, and the EEG showed 4 to 5 Hz theta background activity. From Bansky G, Meier PJ, Ziegler WH, Walser H, Schmid M, Huber M. Lancet 1985;i:1324-5. © by the Lancet Ltd, 1985. receptors; (5) ameliorations are always of short tion to the manifestations of hepatic duration, consistent with the rapid rate of encephalopathy in a majority of patients with metabolism of the drug;62 and (6) ameliora- liver failure. The data on the eVects of tions are usually partial (for example, one or flumazenil on hepatic encephalopathy in hu- two clinical stages). In addition, an intravenous mans may, however, underestimate the magni- copyright. infusion of flumazenil (0.2 mg) has been shown tude of this phenomenon for the following rea- to improve the cognitive component of a reac- sons: (1) other complicating metabolic tion time task in patients with subclinical disturbances in liver failure may mask the con- hepatic encephalopathy.66 Controlled trials tribution of natural benzodiazepine agonist lig- have confirmed that the mean severity of ands; (2) the design of the published controlled hepatic encephalopathy in cirrhotic patients trials of flumazenil in patients with hepatic after treatment with parenteral flumazenil was encephalopathy67 may not have been optimal; significantly less than that after treatment with (3) flumazenil does not have the properties of placebo.67 In a single case study oral flumazenil an ideal benzodiazepine antagonist for admin- (25 mg twice daily) successfully reversed the istration to patients with hepatic encephalopathy;47 65 and (4) factors other than manifestations of chronic intractable hepatic http://jnnp.bmj.com/ encephalopathy and normalised oral protein natural benzodiazepines may contribute to tolerance.68 increased GABAergic tone in hepatic encepha- Because of the specificity of the action of lopathy (see Pathogenesis section). None of the flumazenil on the central benzodiazepine traditional treatments for hepatic encephalopa- receptor and its weak partial agonist properties thy, such as lactulose and neomycin, induce at this receptor, the most logical explanation such substantial ameliorations of hepatic en- for a flumazenil induced amelioration of cephalopathy so often and so rapidly after their administration as those that have been docu- hepatic encephalopathy is that the drug re- on September 24, 2021 by guest. Protected duces increased GABAergic tone by displacing mented after intravenous flumazenil. Demon- natural benzodiazepine agonist ligands from stration of the eYcacy of other more appropri- 69 central benzodiazepine receptors. This phe- ate benzodiazepine receptor ligands and/or nomenon would lead to a dysinhibition of neu- specific antagonists of other neurotransmitter rons and hence an increase in their spontane- systems in reversing manifestations of hepatic ous activity. Furthermore, the transient anxiety encephalopathy may open up new pharmaco- that consistently occurred shortly after the oral logical horizons in the management of this administration of flumazenil to a patient with syndrome. chronic portal-systemic encephalopathy68 can also be explained by this mechanism. The eY- Fulminant hepatic failure cacy of flumazenil in reversing manifestations Convincing evidence that hepatic encepha- of hepatic encephalopathy may be related lopathy in fulminant hepatic failure and hepatic primarily to brain concentrations of natural encephalopathy complicating cirrhosis involve benzodiazepine agonists. diVerent mechanisms is not available. How- The available data suggest that augmenta- ever, fulminant hepatic failure is a syndrome of tion of GABAergic tone by natural benzodi- multiorgan failure, the neurological manifesta- azepine agonists makes a substantial contribu- tions of which are not limited to hepatic 286 Jones, Weissenborn J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

encephalopathy. In particular, raised ICP due scopic study.74 In the late stages of encepha- to cerebral oedema, and hypoglycaemia may lopathy loss of autoregulation of the cerebral also contribute to neurological deficits, includ- circulation75 may contribute to neurological ing encephalopathy. Thus in general, deficits. The development of cerebral oedema neurological abnormalities associated with ful- and raised ICP occurs together with hepatic minant hepatic failure tend to be more encephalopathy in fulminant hepatic failure. complex than those associated with hepatic Clinical signs often preceding or occurring encephalopathy complicating chronic liver fail- with increases in ICP in fulminant hepatic fail- ure. Accordingly, the neurological status of ure include psychomotor agitation, hyperten- patients with fulminant hepatic failure usually sion, hyperventilation, vomiting, and increased requires more extensive evaluation than that of muscle tone.76 However, clinical signs are patients with cirrhosis and some of the unreliable in the evaluation of raised ICP in treatments indicated for neurological deficits patients with fulminant hepatic failure, particu- associated with fulminant hepatic failure are larly if the patient is receiving artificial ventila- not indicated for neurological consequences of tion. chronic liver disease. At least three potential roles of ammonia in PROGNOSIS the pathophysiology of fulminant hepatic In general, when hepatic encephalopathy is failure have been proposed: (1) it is postulated associated with fulminant hepatic failure the to contribute to hepatic encephalopathy (see mortality is high, particularly if encephalopathy section on pathogenesis of hepatic encepha- is severe and prolonged, if encephalopathy lopathy); (2) it may contribute to the pathogen- develops rapidly after the onset of jaundice,10 esis of cerebral oedema and raised ICP by pro- and if encephalopathy rapidly progresses to moting increased conversion of glutamate to stage IV. In fulminant hepatic failure no the organic osmolyte glutamine in astrocytes, relationship has been found between the pres- thereby inducing impaired cellular ence or absence of motor responses to pain, the osmoregulation;70 71 and (3) ammonia concen- pupillary light reflex, and the oculocephalic trations higher than those usually associated reflex and subsequent recovery of with hepatic encephalopathy in cirrhotic pa- consciousness.77 However, loss of the oculoves- tients may occur and may be responsible for tibular reflex in fulminant hepatic failure is neuroexcitatory phenomena, such as psycho- usually associated with a fatal outcome.77 motor agitation, multifocal random muscle Resolution of intracranial hypertension, as twitching, mania, delirium, and/or seizures, indicated by an epidural pressure transducer copyright. that sometimes occur during the course of ful- (see Management section), may be a reliable minant hepatic failure, particularly in prognostic indicator of recovery without liver children.46 transplantation.78 79

CEREBRAL OEDEMA AND RAISED INTRACRANIAL MANAGEMENT PRESSURE Frequent and precise monitoring of Cerebral oedema and raised ICP seem to occur neurological status, using an appropriate coma rarely in patients with chronic liver failure.71 profile, is desirable.80 It is essential to estimate They are much better recognised as serious blood sugar at frequent intervals so that complications of fulminant hepatic failure, hypoglycaemia can be detected early and its occurring in 75%-80% of cases that progress to neurological consequences corrected promptly 71 stage IV encephalopathy. Cerebral oedema by administration of hypertonic dextrose into a http://jnnp.bmj.com/ and raised ICP are probably manifestations of central vein. the same pathological process. Cerebral Continuous bipolar EEG monitoring may oedema leads to raised ICP once the compli- facilitate the early detection and treatment of ance of the brain cavity has been exceeded.70 It complications, such as hypoglycaemia or in- seems that rapid rather than slow loss of hepa- tracranial hypertension, in patients not receiv- tocellular function favours the development of ing ventilatory support. The development of cerebral oedema and raised ICP, possibly these complications is usually heralded by a

because an appreciable time interval is re- sudden increase in the degree of abnormality of on September 24, 2021 by guest. Protected quired for osmolar compensation to take place the EEG.81 The EEG may disclose the presence in response to changes in metabolites in the of complex partial seizures. brain when the liver fails.71 An acute or chronic Cerebral oedema is not reliably detected by increase in ICP in fulminant hepatic failure CT.82 As sudden and repeated increases of ICP, may lead to brain ischaemia due to compres- that require immediate treatment, are to be sion of cerebral vasculature72 and/or brain stem expected, CT cannot be recommended. herniation. Indeed, herniation of the cerebel- Ideally, ICP should be monitored by direct lum or uncinate process secondary to raised measurement in the late stages of encephalopa- ICP is a common cause of death in patients thy, and this is considered mandatory by some with fulminant hepatic failure.73 The pathogen- authorities when liver transplantation is under esis of cerebral oedema in fulminant hepatic serious consideration.78 79 83 84 The creation of a failure is currently uncertain; potential mecha- burr hole and placement of a stable, drift free, nisms include a breakdown of the blood-brain pressure transducer intracranially enables di- barrier (vasogenic oedema) and impaired rect, accurate, and continuous measurements cellular osmoregulation (cellular or cytotoxic of ICP. When a decision to embark on such oedema),70 71 with the latter mechanism being measurements is made, it is first necessary to favoured by evidence from an electron micro- correct, at least partially, the associated coagu- Neurology and the liver 287 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

lopathy by giving fresh frozen plasma, or plate- epilepsy, dementia, and/or paraplegia. The lets, or both so that the prothrombin time is neurological deficits in these syndromes re- prolonged less than three seconds (Quick score spond only partially to treatment for hepatic at least 50%) and the platelet count at least encephalopathy. The precise relationship of 50 000/cu mm when the burr hole is made.76 these syndromes to chronic hepatic insuY- Epidural transducers are safer but less precise ciency or chronic hepatic encephalopathy is than subdural or parenchymal monitors.85 uncertain.94–97 Direct measurements of ICP enable the indications for treatment of raised ICP to be clearly defined and facilitate monitoring the Wilson’s disease eVects of treatments on ICP. Wilson’s disease is a genetic disorder of copper The patient is nursed supine with the head metabolism. The responsible gene has been ° ° identified and cloned and is located on and upper body raised 20 -30 above the 98 horizontal.76 86 Factors that increase ICP are chromosome 13. Most of the clinical manifes- avoided.76 If psychomotor agitation becomes a tations of Wilson’s disease appear to be the problem, great caution must be exercised with direct result of excessive accumulation of cop- the use of sedatives (for example, a small dose per in various organ systems, particularly the of a short acting benzodiazepine or a small dose liver and brain. of morphine) or paralysing agents and appro- priate antidotes should be available (for exam- CLINICAL FEATURES ple, flumazenil, naloxone).76 Sedation or pa- Presentation is unusual before the age of 5 99 ralysis confound the use of changes in years or after the age of 30 years. Typically, neurological status to monitor progression or patients present with hepatic and/or 100 recovery.21 Cerebral perfusion pressure (mean neurological dysfunction. arterial pressure minus intracranial pressure) should be maintained above 50 mm Hg to Hepatic avoid hypoperfusion of the brain.76 The ICP Hepatic dysfunction tends to become manifest should be maintained below 20 mm Hg.76 The at a younger age than neurological dysfunction. eYcacy of mannitol (0.5-1.0 g/kg intravenously The best recognised hepatic lesions due to over five minutes in the absence of renal Wilson’s disease are a fulminant hepatic failure) but not dexamethasone in lowering failure-like syndrome, chronic active hepatitis, raised ICP in patients with fulminant hepatic and cirrhosis.100 failure has been shown in a controlled trial.87 copyright. The value of controlled hyperventilation88 or Neurological barbiturates76 89 in the management of raised Neurological Wilson’s disease usually presents ICP has not been established. in the second or third decade of life and may As an indirect index of ICP, cerebral perfusion occur without overt clinical signs of liver may be assessed non-invasively by continuous disease.101 Initial symptoms may be subtle, such transcranial Doppler monitoring.90 91 as abnormal behaviour and deteriorating per- It is sometimes uncertain whether the formance at school. Subsequently more overt severely abnormal complex neurological status neurological deficits occur; in particular, inco- exibited by a patient with fulminant hepatic ordination (especially involving fine move- failure would be completely reversed either by ments), clumsiness, slowness of voluntary limb a spontaneous improvement in hepatocellular movements and speech, tremor, dysarthria, 92 93 function or by liver transplantation. excessive salivation, ataxia, dysphagia, and http://jnnp.bmj.com/ Whether certain clinical findings—for exam- mask-like facies.101–104 Movement disorders ple, fixed dilated pupils, a low cerebral tend to dominate the neurological features perfusion pressure (for example, <50 mm Hg), (table 5). In patients who have been inad- or a flat EEG recording for a specified period of equately treated, late neurological manifesta- time—imply neurological injury that is not tions include dystonia, spasticity, grand mal reversible by liver transplantation has not been seizures, rigidity, and flexion contractures. clearly defined (R Williams, personal commu- Neurological deterioration is progressive with-

nication) and the interpretation of such find- out treatment. However, chelation therapy on September 24, 2021 by guest. Protected ings may be confounded if barbiturates are 76 used in the management of raised ICP. How- Table 5 Neurological symptoms and signs in Wilson’s ever, in this context it has been suggested that disease liver transplantation is contraindicated if medi- cal therapy has failed to control intracranial Symptoms and signs Patients (%) hypertension.79 Dysdiadochokinesia 51 Dysarthria 49 Bradykinesia 38 Degenerative disorders Posture tremor 31 Rare CNS degenerative disorders that may Wing beating 31 occur in patients with longstanding cirrhosis Action tremor 31 Writing tremor 29 and increased portal-systemic shunting include Resting tremor 20 hepatocerebral degeneration and transverse Hyomimia 20 Gait disturbance 18 myelitis. The former disorder is associated with Hypersalivation 18 irreversible neuronal injury or degeneration Chorea 13 and the latter with demyelination. Patients may Head tremor 13 have chronic cerebellar and basal ganglia signs Dystonia 11 with parkinsonism, focal cerebral symptoms, Data based on a study of 45 patients (from Oder et al 101). 288 Jones, Weissenborn J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

often reverses the neurological sequelae of the other ocular manifestation of the disease, are disease, particularly if treatment is instituted at less common than Kayser-Fleischer rings.119 an early stage.105 106 Recently, by the application of exploratory Haematological factor analysis to correlate neuropsychiatric Intravascular haemolysis, which may be acute, symptoms with structural lesions found on often occurs.100 MRI, three distinct subsets of patients with 107 Wilson’s disease have been recognised: NEUROPATHOLOGY Pseudoparkinsonian—These patients, with Histological studies of the brain at necropsy dilatation of the third ventricle, have signs of have disclosed degeneration and cavitation bradykinesia, rigidity, cognitive impairment, involving the putamen, globus pallidus, cau- and an organic mood syndrome. date nucleus, thalamus, and, less often, the Pseudosclerosis—These patients, with focal frontal cortex.120 The most severely aVected thalamic lesions, exhibit ataxia, tremor, and regions of the brain are the basal ganglia, reduced functional capacity. particularly the putamen.109 121 Abnormalities Dyskinesia—These patients, with focal ab- of the white matter and cerebral cortex occur in normalities in the putamen and globus pal- about 10% of cases.110 Total cerebral copper lidus, exhibit dyskinesia, dysarthria, and an content seems to correlate with the severity of organic personality syndrome. both the histological abnormalities and The incidence of seizures in patients with neurological symptoms,106 120 but copper con- Wilson’s disease (about 6%) is about 10-fold centrations in aVected and unaVected regions greater than that in the general population.108 of the brain are similar.110 The seizures usually have a focal cortical origin, with or without secondary CEREBRAL IMAGING generalisation.109 Cerebral CT abnormalities seem to correlate with neurological deficits and histological find- Psychiatric ings in the CNS.122 123 The cranial lesions are In about a third of cases psychiatric or typically bilateral and have been divided into behavioural symptoms are the presenting or two categories:124 (1) well defined slit-like low predominant manifestation of the disease.102 110 attenuation foci involving the basal ganglia, At the time of presentation at least one half of particularly the putamen, and (2) larger patients have some evidence of psychiatric or regions of low attenuation in the basal ganglia, behavioural disturbance.111 112 Psychiatric thalamus, or dentate nucleus. Widening of the copyright. manifestations of Wilson’s disease are protean, frontal horns of the lateral ventricles and but are predominantly personality changes. diVuse cerebral and cerebellar atrophy have Four basic categories of disturbance have been also been reported.122 123 Brain CT is likely to described: behavioural/personality, aVective, be abnormal in 50% of asymptomatic patients schizophrenia-like, and cognitive.113 114 The and 75% of patients with hepatic incidence of schizophrenia-like symptoms may dysfunction.123 MRI of the brain seems to be not be increased in Wilson’s disease and more sensitive than CT in detecting early depression and cognitive impairment may lesions125 and has shown an apparently distinct largely reflect the degree of hepatocellular “face of the giant panda” sign.126 In contrast to insuYciency. Patients often exhibit personality CT findings, MRI abnormalities and changes with lability of mood, emotionalism, neurological deficits correlate poorly.127 Cranial

and sometimes impulsive and antisocial CT and MRI findings (other than brain http://jnnp.bmj.com/ behaviour.109 Psychiatric symptoms often cor- atrophy) are usually reversed by chelation relate with the severity of the neurological therapy.128 129 Involvement of the CNS in disturbances.111 114 Both the eVects of cerebral Wilson’s disease has also been evaluated using copper deposition and the reaction to progres- PET129 130 and SPECT.129 The abnormalities sive neurological deficits may contribute to the found using these techniques improve with psychobehavioural disturbances. The inci- chelation therapy.129 dence of psychoneuroses, depression, and 111 schizophrenia-like psychosis is low and the DIAGNOSIS on September 24, 2021 by guest. Protected incidence of delusional disorders and aVective The diagnosis of Wilson’s disease should be disorders may not be increased.109 Psychomet- based on confirmatory clinical and biochemi- ric analyses have disclosed minimal impair- cal data.131 In a patient with neurological ment of cognitive function in Wilson’s symptoms or signs a diagnosis of Wilson’s dis- disease.109 115–117 ease can be made if Kayser-Fleischer rings are present and the caeruloplasmin concentration Ophthalmological is <20 mg/dl. Eighty to ninety per cent of The Kayser-Fleischer ring is a golden brown or patients with the disease have low serum caeru- greenish discolouration in the limbic region of loplasmin concentrations (<20 mg/dl).102 110 the cornea due to copper deposition in Urinary copper excretion is >100 µg/24 hours Descemet’s membrane. The rings are almost (normal <40) in most patients with sympto- invariably present in untreated patients with matic disease.124 Measurement of the hepatic neurological manifestations of the disease.110 118 copper concentration is necessary to establish a Kayser-Fleischer rings may not be visible to the diagnosis of Wilson’s disease in the absence of naked eye; their presence should be sought or Kayser-Fleischer rings, a low serum caerulo- confirmed by an ophthalmologist using a slit plasmin, or neurological abnormalities. The lamp or gonioscopy. Sunflower cataracts, an- demonstration of a lack of incorporation of Neurology and the liver 289 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

radiocopper (64Cu) into caeruloplasmin can be reversal or substantial alleviation of hepatic, used to confirm the diagnosis in rare diYcult neurological, and psychiatric manifestations of cases.132 Kayser-Fleischer rings may be found in the disease.100 Supplementation with 25 mg certain other chronic liver diseases, notably oral pyridoxine daily is given routinely to chronic cholestatic disorders, such as primary counteract the antipyridoxine eVect of biliary cirrhosis, that are not associated with D-penicillamine.99 In about 20% of patients focal CNS functional deficits and are usually with neurological symptoms, worsening of readily distinguished from Wilson’s disease. neurological dysfunction may occur during the first four weeks of treatment,106 136 and rarely PATHOGENESIS neurological dysfunction may first become The fundamental cause of the copper overload apparent shortly after initiating chelation in Wilson’s disease is thought to be impaired therapy.137 When neurological symptoms ap- biliary secretion of copper due to a hepatocel- pear to be precipitated or exacerbated by lular lysosomal defect.133 Confirmation that the D-penicillamine treatment, the dose can be primary defect resides within the liver is decreased to 250 mg daily and subsequently provided by the prompt reversal of the increased by 250 mg/day every four to seven abnormalities of copper metabolism after days until urinary copper excretion is >2 orthotopic liver transplantation.134 mg/day. An alternative approach is to initiate D-penicillamine treatment at a low dose in NATURAL HISTORY asymptomatic patients and patients with mild The natural history of Wilson’s disease can be symptomatology110 136 137 and gradually increase divided into four stages.124 the dose to within the therapeutic range. Even if early clinical deterioration occurs, continued Stage I chelation therapy is mandatory.106 Although During this initial phase copper accumulates at various side eVects100 110 sometimes limit its use, cytosolic hepatocellular binding sites and D-penicillamine remains the treatment of first patients are usually asymptomatic. choice for this disorder. Chelation therapy should not be interrupted. Cessation of therapy Stage II may precipitate rapid and irreversible hepatic When cytosolic binding sites become saturated or neurological deterioration.138 139 Trientine further accumulation of copper occurs in (triethylene tetramine dihydrochloride) is an hepatocellular lysosomes and there may be alternative chelating agent that can be given to release of copper into the systemic circulation. patients who experience severe toxic reactions copyright. These phenomena may lead to hepatocellular to D-penicillamine.139 Oral zinc may be given to necrosis and intravascular haemolysis, respec- the rare patient who cannot tolerate either tively. Thus stage II disease may be associated D-penicillamine or trientine.99 121 Oral zinc is with hepatic and haematological abnormalities. the preferred treatment for Wilson’s disease in some countries—for example, The Nether- Stage III lands. During this stage there is not only continuing When psychiatric disturbances are trouble- accumulation of copper in the liver, but also some psychotherapy together with tranquillis- chronic accumulation of copper in the brain ers or antidepressant drugs may be indicated in and other extrahepatic tissues. The clinical addition to copper chelation therapy. Pheno- presentation of the disease depends on the rate thiazines may exacerbate both neurological and

of copper accumulation in diVerent organ sys- psychiatric manifestations of the disease. Most http://jnnp.bmj.com/ tems. It is typically during stage III disease that of the psychiatric manifestations, but particu- neurological abnormalities occur. However, if larly behavioural and cognitive deficits, usually an inactive cirrhosis develops and cerebral respond to copper chelation therapy.113 115 Psy- accumulation of copper is slow, patients may chometric testing in treated patients may be remain asymptomatic for years.135 normal.115 However, when patients with com- bined neurological and psychiatric abnormali- Stage IV ties are diagnosed late in the clinical course of

This is the stage in which normal copper the disease, some psychiatric dysfunction may on September 24, 2021 by guest. Protected balance has been achieved as a result of chela- remain after treatment.109 113 tion therapy. Some patients continue to have Pregnancy is not contraindicated. Chelation residual neurological or hepatic dysfunction as therapy must be continued during pregnancy a result of irreversible organ damage, whereas and pregnancy is not an indication to change other patients, who previously had sympto- the chelating agent being given.140 matic disease, are asymptomatic. General surgery should, if possible, be avoided as it may precipitate neurological dete- TREATMENT rioration. However, liver transplantation must Once the diagnosis of presymptomatic or be seriously considered for patients who symptomatic Wilson’s disease is established, develop manifestations of acute or chronic lifelong chelation therapy should be com- hepatocellular failure141 142 and for patients in menced forthwith. It is routine to advise whom conventional treatment has not achieved patients undergoing copper chelation therapy adequate copper chelation.143 In general, liver to avoid foods with a high copper content. Oral transplantation is not recommended for pa- therapy with the copper chelating drug, tients with neurological deterioration D-penicillamine (250-500 mg four times a day alone.141 142 Liver transplantation is associated before meals), usually results in complete with reversal of abnormalities of copper 290 Jones, Weissenborn J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from

metabolism,134 although the reversal may not asterixis. The diagnosis requires evidence of be complete.143 It is also associated with hepatocellular insuYciency and exclusion of substantial improvement in most symptoms other causes of encephalopathy. Hepatic en- and signs of the disease, including neurological cephalopathy occurs most often in cirrhotic abnormalities.141 142 patients with a precipitating factor. A cirrhotic patient with a normal neurological examin- SCREENING FOR WILSON’S DISEASE ation but abnormal results of psychometric or It is imperative that all first degree relatives of a neuroelectrophysiological tests may have sub- patient with Wilson’s disease, who are older clinical hepatic encephalopathy. The syndrome than 3 years, and especially siblings of the has been classified as a reversible metabolic patient, be screened for the presence of the encephalopathy with a multifactorial patho- disease.144 A simple screening evaluation for genesis. Major hypotheses of pathogenesis Wilson’s disease consists of a slit lamp examin- implicate raised brain concentrations of ammo- ation of the eyes, and measurements of serum nia and increased GABA mediated neurotrans- caeruloplasmin and aminotransferases (ALT, mission. Modestly raised concentrations of AST). It is prudent to screen for Wilson’s dis- ammonia, increased brain concentrations of ease all patients with psychiatric disease, who natural benzodiazepines, and increased avail- have evidence of hepatic or neurological ability of GABA at GABAA receptors appear to disease, who have a family history of Wilson’s be factors which enhance GABAergic tone in disease, or who are refractory to therapy for liver failure, and hence contribute to impair- their psychiatric disease. ments of motor function and decreased con- sciousness. Routine treatments correct precipi- The pruritus of cholestasis tating factors and reduce intestinal absorption Pruritus is a common complication of intrahe- of nitrogenous compounds. Treatment with patic or extrahepatic cholestatic disorders. The flumazenil is experimental. Fulminant hepatic aetiology of this complication of cholestasis has failure is the syndrome of acute liver failure and not been established and conventional treat- hepatic encephalopathy, in which additional ments tend to be empirical. Unrelieved pruri- factors may contribute to encephalopathy, tus of cholestasis may lead to severe sleep de- notably cerebral oedema and raised intracra- privation and even suicidal ideation. A recent nial pressure, and hypoglycaemia. Rare degen- hypothesis of the pathogenesis of the pruritus erative neurological disorders in patients with of cholestasis suggests that the neural events longstanding cirrhosis include hepatocerebral that initiate this form of pruritus may originate degeneration and transverse myelitis. copyright. centrally in the CNS, rather than peripherally Neurological manifestations of Wilson’s dis- 4 in the skin. Three lines of evidence provide ease are attributable to accumulation of copper support for this hypothesis: (1) opioid agonists in the brain as a consequence of a congenital (for example, morphine) induce pruritus by a impairment in the hepatocellular secretion of 4 central mechanism; (2) central opioidergic copper into bile. Movement disorders pre- 4 tone is increased in cholestasis; and (3) opiate dominate and psychiatric disturbances are antagonists ameliorate the pruritus of common. In untreated patients with 5 cholestasis. That central opioidergic tone is neurological deficits, Kayser Fleischer rings increased in patients with chronic cholestatic and serum caeruloplasmin <20 mg/dl are diag- liver disease is illustrated by the striking opioid nostic. The diagnosis is an indication for withdrawal-like syndrome that can be abruptly lifelong chelation therapy. induced in such patients by the oral adminis- In patients with cholestatic liver diseases http://jnnp.bmj.com/ 145 tration of a potent opiate antagonist. increased central opioidergic neurotransmis- sion may contribute to pruritus. Fatigue Patients with chronic liver disease, particularly chronic cholestatic liver diseases such as 1 Frerichs FT. A clinical treatise on diseases of the liver. Vol 1. Translated by Murchison C. London: The New Sydenham primary biliary cirrhosis, often complain of Society, 1860:193–246. incapacitating fatigue that seems to be out of 2 Basile AS, Jones EA, Skolnick P. The pathogenesis and treatment of hepatic encephalopathy: evidence for the proportion to their general medical condition. involvement of benzodiazepine receptor ligands. Pharmacol on September 24, 2021 by guest. Protected Whether excessive fatigue has specificity for the Rev 1991;43:27–71. 3 Butterworth RF. The neurobiology of hepatic encephalopa- syndrome of chronic cholestasis is uncertain. thy. Semin Liver Dis 1996;16:235–44. However, there is some evidence which sug- 4 Bergasa NV, Jones EA. The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids. Gastro- gests that altered central neurotransmission, enterology 1995;108:1582–8. possibly involving the serotonin system, may 5 Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, et al.EVects of naloxone infusions in contribute to fatigue in patients with chronic patients with the pruritus of cholestasis: a double-blind liver disease.67 randomized controlled trial. Ann Intern Med 1995;123: 161–7. 6 Jones EA. Fatigue associated with chronic liver disease: a Summary riddle wrapped in a mystery inside an enigma. Hepatology 1995;22:1606–8. Hepatic encephalopathy is a syndrome of neu- 7 Jones EA, Yurdaydin C. Is fatigue associated with cholesta- ropsychiatric disturbances that complicates sis mediated by altered central neurotransmission? Hepatol- ogy 1997;25:492–4. hepatocellular failure; it is associated with 8 Rikkers L, Jenko P, Rudman D, Freides D. Subclinical increased portal-systemic shunting. The spec- hepatic encephalopathy: detection, prevalence and relation- ship to nitrogen metabolism. Gastroenterology 1978;75:462– trum of hepatic encephalopathy varies from 9. mild intellectual impairment to deep coma, 9 Bernuau J, Benhamou JP. Classifying acute liver failure. Lancet 1993;342:252–3. and includes manifestations of motor dysfunc- 10 O’Grady JG, Schalm SW, Williams R. 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NEUROLOGICAL STAMP

Allesandro Volta (1745-87) Lulgi Galvani (1738-98) thought that muscles contained copyright. animal electricity secreted by the brain and distributed by the nerves. Volta, a friend of Galvani, had diYculty with this concept of animal electricity. Volta showed that production of electric current did not need the presence of animal tissue, as Galvani and others had supposed. He also showed that muscles would contract with electrical stimu- lation but Galvani had also shown that the muscles of a frog twitched when touched by a spark from an electric machine or condenser such as a Leyden jar. Volta produced the famous voltaic pile consisting of alternating columns of zinc and silver discs separated by porous cardboard soaked in brine. This was essentially the first electrical battery and http://jnnp.bmj.com/ it revolutionised the study of electricity by producing a steady available source of current. This led almost immediately to William Nicholson’s decomposition of water by electrolysis, and later the discovery by Humphrey Davy of potassium and other metals by the same process. Volta was philatelically honoured in 1927 (Stanley Gibbons 209, Scott 189). It is in his honour that the unit of electrical potential or potential diVerence is called the volt. on September 24, 2021 by guest. Protected L F HAAS