Toxic and Metabolic Encephalopathies

Toxic and metabolic encephalopathies are a group of neurological disorders characterized by an altered mental status—that is, a delirium , defined as a disturbance of consciousness characterized by a reduced ability to focus, sustain, or shift attention that cannot be accounted for by preexisting or evolving dementia and that is caused by the direct physiological consequences of a general medical condition (see Chapter 4 ). Fluctuation of the signs and symptoms of the delirium over relatively short time periods is typical. Although the brain is isolated from the rest of the body by the blood-brain barrier, the nervous system is often affected severely by organ failure that may lead to the build-up of toxic substances normally removed from the body. This is encountered in patients with hepatic and renal failure. Damage to homeostatic mechanisms affecting the internal milieu of the brain, such as the abnormalities of electrolyte and water metabolism also affects brain function. In some cases, a deficiency of a critical substrate such as glucose is the precipitating factor. Frequently, the history and physical examination provide information that defines the affected organ system. In other cases, the cause is evident only after laboratory data are examined.

Clinical Manifestations

Encephalopathy that develops insidiously may be difficult to detect. The slowness with which abnormalities evolve and replace normal cerebral functions makes it difficult for patients and families to recognize deficits. When examining patients with diseases of organs that are commonly associated with encephalopathy, neurologists should include encephalopathy in the differential diagnosis.

Mental status abnormalities are always present and may range from subtle abnormalities, detected by neuropsychological testing, to deep coma. The level and content of consciousness reflect involvement of the reticular activating system and the cerebral cortex. Deficits in selective attention and the ability to process information underlie many metabolic encephalopathies and affect performance on many tasks. These deficits are manifested as disorders of orientation, cognition, memory, affect, perception, judgment, and the ability to concentrate on a specific task. Evidence from studies of patients with cirrhosis suggests that metabolic encephalopathies are the result of a multifocal subcortical and cortical disorder rather than uniform involvement of all brain regions. Abnormalities of psychomotor function may also be present. Among patients with coma of unknown cause, nearly two-thirds ultimately are found to have a metabolic cause. A complete discussion of coma is found in Chapter 5 .

The neuro-ophthalmological examination is extremely important in differentiating patients with metabolic disorders from those with structural lesions. The pupillary light reflex and vestibular responses are almost always present, even in patients in deep coma. However, it is common for these reflexes to be blunted. Exceptions include severe hypoxia, ingestion of large amounts of atropine or scopolamine, and deep barbiturate coma, which is usually associated with circulatory collapse and an isoelectric electroencephalogram (EEG). The pupils are usually slightly smaller than normal and may be somewhat irregular. The eyes may be aligned normally in patients with mild encephalopathy. With more severe encephalopathy, dysconjugate roving movements are common. Other cranial nerve abnormalities may be present but are less useful in formulating a differential diagnosis. Motor system abnormalities, particularly slight increases in tone, are common. Other signs and symptoms of metabolic disorders may include spasticity with extensor plantar signs and extrapyramidal as well as cerebellar signs (in patients with liver disease), multifocal myoclonus (in patients with uremia), cramps (in patients with electrolyte disorders), Trousseau sign (in patients with hypocalcemia), tremors, and weakness.

Asterixis, a sudden loss of postural tone, is common. To elicit this sign, the patient should extend the arms and elbows while dorsiflexing the wrists and spreading the fingers. Small lateral movements of the fingers may be the earliest manifestation. More characteristically, there is a sudden flexion of the wrist with rapid resumption of the extended position, the so-called flapping tremor. Asterixis also may be evident during forced extrusion of the tongue, forced eye closure, or at the knee in prone patients asked to sustain flexion of the knee. Electrophysiological studies have shown that the onset of the lapse of posture is associated with complete electrical silence in the tested muscle. This sign, once thought to be pathognomonic of hepatic encephalopathy (HE), occurs in a variety of conditions including uremia, other metabolic encephalopathies, and drug intoxication. Asterixis may also be present in patients with structural brain lesions, especially thalamic lesions.

Generalized seizures occur in patients with water intoxication, hypoxia, uremia, and hypoglycemia, but only rarely as a manifestation of chronic liver failure. Seizures in patients with liver failure are generally due to alcohol or other drug withdrawal, or cerebral edema associated with acute liver failure (ALF). Focal seizures, including epilepsia partialis continua, may be seen in patients with hyperglycemia, and multifocal myoclonic seizures may occur in patients with uremia. Myoclonic status epilepticus may complicate hypoxic brain injury (see Chapter 83 ).

Toxic Encephalopathies

Hepatic Encephalopathy

Cirrhosis of the liver affects an estimated 5.5 million adults in the United States. In 2011, over 33,000 Americans died as the result of chronic liver disease ( ). Among the poor, the incidence of cirrhosis may be as much as 10 times higher than the national average and accounts for almost 20% of their excess mortality. As patients with chronic liver disease enter the terminal phases of their illness, HE becomes an increasingly important cause of morbidity and mortality. In this portion of the chapter, the term hepatic encephalopathy will be used to differentiate this condition from disorders associated with ALF, discussed in the next section. About 20,000 patients per year were hospitalized in the United States between 2005 and 2009 after developing HE ( ). It is important to stress that minimal HE—the mildest form of HE, which interferes with the patients’ daily living ability but usually does not result in seeking medical care—is far more common, affecting about half of all patients with cirrhosis. Minimal HE can be diagnosed using neuropsychological tests, EEG, or critical flicker frequency (CFF), for example, but is commonly overlooked.

A World Gastroenterological Association consensus statement seeks to minimize the substantial confusion in the literature and in clinical practice concerning the diagnosis of HE by using a multiaxial approach ( ). The initial categorization addresses the presence of hepatocellular disease and portacaval shunting. Patients with acute liver disease or fulminating hepatic failure, a disorder occurring in patients with previously normal livers who exhibit neurological signs within 8 weeks of developing liver disease, form the first group (type A HE). A second group consists of a small number of patients who are free of hepatocellular disease but have portacaval shunting of blood (type B HE). The largest number of patients have hepatocellular disease with shunts (type C HE). Further subdivisions address temporal aspects—whether HE is episodic, chronic progressive, or persistent. Causal considerations are then applied to separate patients with precipitated HE from those with recurrent and idiopathic encephalopathy, and to identify the severity of the syndrome. The features that differentiate patients with ALF from those with the much more common portal systemic encephalopathy are shown in Table 84.1 .

TABLE 84.1

Features Distinguishing Acute Liver Failure from Chronic Hepatic Encephalopathy or Portal Systemic Encephalopathy

Feature	Acute Liver Failure	Portal Systemic Encephalopathy
History
Onset	Usually acute	Varies; may be insidious or subacute
Mental state	Mania may evolve to deep coma	Blunted consciousness
Precipitating factor	Viral infection or hepatotoxin	Gastrointestinal hemorrhage, exogenous protein, drugs, uremia, infection
History of liver disease	No	Usually yes
Symptoms
Nausea, vomiting	Common	Unusual
Abdominal pain	Common	Unusual
Signs
Liver	Small, soft, tender	Usually large, firm, no pain
Nutritional state	Normal	Cachectic
Collateral circulation	Absent	May be present
Ascites	Absent	May be present
Laboratory Test
Transaminases	Very high	Normal or slightly high
Coagulopathy	Present	Often present

Rating the severity of HE is complex but essential for evaluating the results of the treatment of individual patients and for evaluating potential treatments in the research setting. The so-called West Haven criteria supplemented by an evaluation of asterixis was used in the large multicenter trial that led to the approval of rifaximin for the treatment of HE. Both scales are ordinal. The West Haven Scale is scored as the following: 0, no personality or behavioral abnormality detected; 1, trivial lack of awareness, euphoria, or anxiety, shortened attention span, or impairment of the ability to add or subtract; 2, lethargy, disorientation with respect to time, obvious personality change or inappropriate behavior; 3, somnolence or semistupor, responsiveness to verbal stimuli with confusion or gross disorientation; 4, coma. Asterixis is graded as follows: 0, no tremors; 1, few flapping tremors; 2, occasional flapping tremors; 3, frequent flapping tremors; 4, almost continuous flapping tremors.

Recently, a subdivision into “covert” and “overt” HE has been recommended ( ). Patients with grade 2–4 according to the West Haven Scale thereby are included in the “overt HE” group, while those with grade 1 according to the West Haven Scale and those with only psychometric or neurophysiological but no clinical signs of HE are included in the “covert HE” group. The decision to combine grade 1 HE and minimal HE to “covert HE” originates from the observation of a significant inter-rater variability in diagnosing grade 1 HE but is still controversial.

An episode of HE may be precipitated by one or more factors, some of which are iatrogenic. In one series, the use of sedatives accounted for almost 25% of all cases. A gastrointestinal (GI) hemorrhage was the next most common event (18%), followed by drug-induced azotemia and other causes of azotemia (15% each). Excessive dietary protein accounted for 10% of episodes; hypokalemia, constipation, infections, and other causes accounted for the remaining cases. As liver disease progresses, patients appear to become more susceptible to the effects of precipitants. This phenomenon has been referred to as toxin hypersensitivity . A transjugular intrahepatic portosystemic shunt (TIPSS), an endovascular procedure developed to treat intractable severe ascites, predisposes a patient to the development of encephalopathy, particularly among the elderly. TIPSS is more effective than large-volume paracentesis but does not prolong survival. TIPSS-related encephalopathy often responds to conventional treatment. Refractory cases may require endovascular treatment with coils to block a portion of the shunted blood.

Laboratory Evaluations

The diagnosis of HE is based on the signs and symptoms of cerebral dysfunction in a setting of hepatic failure. Usually, standard laboratory test results, including serum bilirubin and hepatic enzymes, are abnormal. Products of normal hepatic function, including serum albumin and clotting factors, often are low, leading to elevation of the international normalized ratio (INR). Measurements of the arterial ammonia level may be helpful in diagnosing HE, but an ammonia level within the normal range does not exclude HE.

Several consensus conferences sponsored by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism have made recommendations concerning the use of electrophysiological and neuropsychological tests to evaluate patients with HE ( ; ). The favored electrophysiological tests are those that are responsive to cortical function and include event-related potentials (ERPs) such as P300 tests and the EEG. Bursts of moderate- to high-amplitude (100–300 μV), low-frequency (1.5–2.5 Hz) waves with predominance in the frontal derivations are the most characteristic EEG abnormality in patients with severe HE. But even patients without clinical signs of HE may show a reduction of the mean dominant frequency. Recently EEG was used to investigate functional cortical connectivity in patients with liver cirrhosis and an alteration was shown as well in patients with normal cognitive function compared to controls ( ). Abnormal ERPs may also be found in patients with minimal encephalopathy. Auditory P300 potential recordings, in which the subject is asked to discriminate between a rare and a common tone, showed prolonged latencies in patients with overt encephalopathy (including HE grade 1) and in some of the patients without clinical evidence of HE, indicating minimal encephalopathy. The need of more sophisticated equipment for the P300 assessment than for the EEG assessment has precluded broad use of this method for clinical purposes.

Neuropsychological tests are useful for diagnosing minimal HE and for follow-up of patients with low-grade HE (grades mHE–grade II HE). Domains to be evaluated include attention, visuoconstructional ability, and motor speed and accuracy.

Up to 60% of all patients with cirrhosis with no overt evidence of encephalopathy exhibit significant abnormalities when given a battery of neuropsychological tests. Tests of attention, concentration, visuospatial perception, and motor speed and accuracy are the most likely to be abnormal ( ). The Portosystematic Encephalopathy (PSE) Syndrome Test—a test battery consisting of the Number Connection Tests A and B, serial dotting, line tracing, and the Digit Symbol Test—has been recommended for evaluating patients who may have HE ( ; ). This battery is sensitive and relatively specific for the disorder, compared with other metabolic encephalopathies.

Besides EEG and neuropsychological tests, occasionally the analysis of the CFF is used for diagnosing HE and follow-up ( ).

Subclinical cognitive impairment of patients with cirrhosis, particularly attention deficits and impairment in the visuospatial sphere, may be severe enough to interfere with the safe operation of an automobile or other dangerous equipment. A study comparing patients with minimal encephalopathy with nonencephalopathic patients with cirrhosis and a third group with GI disease found that those with minimal encephalopathy performed the worst during an on-the-road driving test. Specific problems centered on handling, adaptation to road conditions, and accident avoidance. Language functions are usually normal. These data, combined with other studies showing that the quality of life is affected by these abnormalities, suggest that neuropsychological tests should be used more extensively for routine evaluation of all patients with cirrhosis, particularly those without overt evidence of HE.

Although the diagnosis of HE is typically made on the basis of clinical criteria, neuroimaging techniques are commonly employed to exclude structural lesions. Magnetic resonance imaging (MRI) and spectroscopic (MRS) studies have revealed new insights into the pathophysiology of HE ( ). On T1-weighted images, it is common to find abnormally high signals arising in the pallidum. These are seen as whiter-than-normal areas in this portion of the brain, as shown in Fig. 84.1 . In addition to these more obvious abnormalities, a systematic analysis of MR images shows that the T1 signal abnormality is widespread and found in the limbic and extrapyramidal systems, and generally throughout the white matter. A generalized shortening of the T2 signal also occurs. These abnormalities have been linked to an increase in the cerebral manganese content. The abnormalities become more prominent with time and regress after successful liver transplantation. The unexpected finding of high T1 signals in the pallidum should suggest the possibility of liver cirrhosis.

Fig. 84.1, T1-weighted magnetic resonance images from a patient with cirrhosis of the liver. Note high signal in basal ganglia, cerebral peduncles, and substantia nigra.

Proton MRS techniques also have been applied to the study of patients with cirrhosis and are available in many centers. In the absence of absolute measures that are referable to concentrations, the signal of specific compounds has often been referenced to creatine and expressed as a compound-to-creatine ratio in the past. Irrespective of the use of a quantitative or semi-quantitative approach, there is general agreement among studies that an increase in the intensity of the signal occurs at approximately 2.5 ppm; this is attributed to glutamine plus glutamate (Glx). With high-field-strength magnets, this peak can be resolved into its components; the increase is attributed to glutamine, as expected on the basis of animal investigations. Glx increase is accompanied by a decrease in my-oinositol and choline signals, whereas N -acetylaspartate resonances (a neuronal marker) are consistently normal. Correlations between the glutamine concentration, generally considered to be a reflection of exposure of the brain to ammonia, and the severity of the encephalopathy, have led some to propose that MR spectroscopy may be useful in the diagnosis of HE. However, the data currently available are controversial.

Neuroimaging is useful in the diagnosis of coexisting structural lesions of the brain, such as subdural hematomas or other evidence of cerebral trauma, or complications of alcohol abuse or thiamine deficiency, or both, such as midline cerebellar atrophy, third ventricle dilatation, mamillary body atrophy, or high-signal-strength lesions in the periventricular area on T2 fluid-attenuated inversion recovery (FLAIR) images.

It must be emphasized that none of the methods described in this section delivers findings that are specific for HE. Thus, a diagnosis of HE can be made only after exclusion of other possible causes of cerebral dysfunction.

Pathophysiology

The pathophysiological basis for the development of HE is still not completely known. However, treatment strategies for the disorder are all founded on theoretical pathophysiological mechanisms. A number of hypotheses have been advanced to explain the development of the disorder. Suspected factors include hyperammonemia, altered amino acids and neurotransmitters—especially those related to the γ-aminobutyric acid (GABA)–benzodiazepine complex—mercaptans, short-chain fatty acids, and manganese deposition in the brain. An interaction between hyperammonemia and a systemic pro-inflammatory status is now considered a major cause of HE ( ).

Cerebral Blood Flow and Glucose Metabolism

Whole-brain measurements of cerebral blood flow (CBF) and metabolism are normal in patients with grade 0–1 HE. Reductions occur in more severely affected patients. Sophisticated statistical techniques designed to analyze images have made it possible to identify specific brain regions in which glucose metabolism is abnormal in patients with low-grade encephalopathy and abnormal neuropsychological test scores ( ). These positron emission tomography (PET) data show clearly that minimal forms of HE are caused by the selective impairment of specific neural systems rather than by global cerebral dysfunction. Reductions occur in the cingulate gyrus, an important element in the attentional system of the brain, and in frontal and parietal association cortices. These PET data are in accord with cortical localizations based on the results of neuropsychological tests. Fig. 84.2 shows the results of correlation analyses between scores on selected neuropsychological tests and sites of reduced cerebral glucose metabolism.

Fig. 84.2, Correlations between performance in the various subtests of the PSE Syndrome Test, as measured by age-corrected z scores, and cerebral glucose metabolism, as measured by fluorodeoxyglucose-positron emission tomography metabolism. Only those subjects able to complete the test are included in the analyses. The statistical parametric mapping Z image projections show significant correlations with bilateral parietal associative cortex, with increasing correlations with frontal regions.

Role of Ammonia

HE is linked to hyperammonemia. Patients with encephalopathy have elevated blood ammonia levels that correlate to a degree with the severity of the encephalopathy. Metabolic products formed from ammonia—most notably glutamine and its transamination product, α-ketoglutaramic acid—also are present in excess in cerebrospinal fluid (CSF) in patients with liver disease. Treatment strategies that lower blood ammonia levels are the cornerstone of therapy.

Tracer studies performed with [ ¹³ N]-ammonia have helped clarify the role of this toxin in the pathophysiology of HE. Ammonia and other toxins are formed in the GI tract and carried to the liver by the hepatic portal vein, where detoxification reactions take place. Portal systemic shunts cause ammonia to bypass the liver and enter the system circulation, where it is transported to the various organs as determined by their blood flow. The liver is the most important organ for the detoxification of ammonia. However, in patients with portacaval shunting of blood, because of the formation of varices, TIPS, or other surgically created shunts, skeletal muscle becomes more important as the fraction of blood bypassing the liver increases. Under the most extreme conditions, muscle becomes the most important organ for ammonia detoxification. It is partly for this reason that nutritional therapy for patients should be designed to prevent development of a catabolic state and muscle wasting.

Ammonia is always extracted by the brain as arterial blood passes through the cerebral capillaries. When ammonia enters the brain, metabolic trapping reactions convert free ammonia into metabolites ( Fig. 84.3 ). The adenosine triphosphate (ATP)–catalyzed glutamine synthetase reaction is the most important of these reactions. The blood-brain barrier is approximately 200 times more permeable to uncharged ammonia gas (NH ₃ ) than it is to the ammonium ion (NH ₄ ⁺ ); however, because the ionic form is much more abundant than the gas at physiological pH values, substantial amounts of both species appear to cross the blood-brain barrier. Because of this permeability difference and because ammonia is a weak base, relatively small changes in the pH of blood relative to the brain have a significant effect on brain ammonia extraction. As blood becomes more alkalotic, more ammonia is present as the gas and cerebral ammonia extraction increases; however, the role this has in the production of HE is not known. The permeability surface-area (PS) product of the blood-brain barrier may be affected by prolonged liver disease. However, the experimental data about this change are in conflict: one study reported an increase in the PS product, others reported no change ( ; ; ; ; ).

Other Pathophysiological Mechanisms

Astrocyte swelling and the role of concomitant disorders

Although there is a strong correlation between the plasma ammonia level and the grade of HE, there is also substantial overlap in ammonia levels by grade of HE, indicating that other factors besides hyperammonemia must play a role in the development of HE. An increase in ammonia detoxification in the brain is associated with an increase of glutamine concentrations within astrocytes and cell swelling. Initially, glutamine is counterbalanced by the release of cellular osmolytes such as myo-inositol to avert cell swelling. If the cells are depleted of myo-inositol, cell swelling can be induced with small amounts of ammonia. Astrocyte swelling may be induced also by inflammatory cytokines, hyponatremia, or benzodiazepines. This is of special interest since HE episodes are frequently precipitated by infection, electrolyte dysbalance, or the application of sedative drugs. Overall, the vulnerability of the brain against these precipitating factors increases with decreasing concentration of intracellular myo-inositol.

Astrocyte swelling is considered a key factor in the pathogenesis of HE ( ). It has been shown to trigger multiple alterations of astrocyte function and gene expression. Astrocyte swelling induces the formation of reactive oxygen species and nitrogen oxide. Ammonia has been shown to induce the mitochondrial permeability transition (mPT) probably mediated by oxidative stress. Induction of the mPT leads to a collapse of the mitochondrial inner membrane potential, swelling of the mitochondrial matrix, defective oxidative phosphorylation, cessation of ATP synthesis, and finally the generation of reactive oxygen species. Thus, induction of the mPT is part of the vicious circle of oxidative/nitrosative stress and astrocytic dysfunction ( ). Oxidative stress is closely related to astrocytic senescence; it has recently been suggested that this plays an important role in the pathophysiology of HE ( ).

Abnormalities of neurotransmission

Since the early 1970s, a variety of hypotheses have suggested that HE is caused by disordered neurotransmission. Although early hypotheses related to putative false neurotransmitters were disproved, there is still effort in this direction.

As a result of the false neurotransmitter hypothesis, it was shown that the ratio of plasma amino acids (valine + leucine + isoleucine) to (phenylalanine + tyrosine) was abnormal in encephalopathic patients, leading to the development of branched chain amino acid (BCAA) solutions designed to normalize this ratio, which are now commercially available. A meta-analysis of studies analyzing the effects of oral or intravenous application of BCAA came to the conclusion that BCAAs have a beneficial effect upon HE, but not upon mortality in patients with liver cirrhosis ( ). Substantial effort has been focused on potential abnormalities of the GABA–benzodiazepine complex. Initial attention was directed at GABA itself. However, early reports that GABA concentrations were elevated in patients with encephalopathy have been disproved. Still, a number of anecdotal reports have described dramatic improvements in patients after they were given flumazenil—a benzodiazepine antagonist; very low concentrations of benzodiazepines and their metabolites may be found in blood and CSF of patients with encephalopathy. In controlled studies, patients given flumazenil are more likely to improve than those given placebo. It is unclear whether benzodiazepine displacement is the mechanism because these patients do not usually have clinically significant blood levels of benzodiazepines.

More recent theories have linked the presence of increased expression of peripheral types of benzodiazepine receptors (currently called translocator protein [TSPO]) to HE. These receptors are found on mitochondrial membranes and are implicated in intermediary metabolism and neurosteroid synthesis. Hyperammonemia causes an increase in TSPO and thereby stimulates the production of neurosteroids such as allopregnanolone, which activates GABA and benzodiazepine receptor sites of the GABA-A receptor, resulting in an increase in GABA-ergic tone in the brain.

In addition, there are significant alterations in cerebral serotonin and dopamine metabolism and a reduction in postsynaptic glutamate receptors of the N -methyl- d -aspartate type. Thus, there is a substantial interest in the potential role of neurotransmitters in the pathogenesis of HE. As of yet, there is no unifying hypothesis and no rational therapeutic approach based on altering neurotransmission.

Manganese

Blood manganese levels are increased in patients with liver cirrhosis due to an impairment of biliary manganese excretion. Manganese deposition within the brain increases, with predominance in the basal ganglia. These manganese deposits are considered to cause the brain MRI signal alterations in patients with liver cirrhosis. Manganese potentiates the toxic effects of ammonia. Moreover, manganese deposition per se results in neuronal loss, Alzheimer type II astrocytosis, alteration of dopaminergic neurotransmission, and expression of the “peripheral-type” benzodiazepine receptor (TSPO) mentioned earlier ( ).

Neuropathology

The Alzheimer type II astrocyte is the neuropathological hallmark of hepatic coma. An account of the original descriptions of this change was provided in translation by Adams and Foley in 1953. In this report, they presented their own findings concerning this astrocyte change in the cerebral cortex and the lenticular, lateral thalamic, dentate, and red nuclei, offering the tentative proposal that the severity of these changes might be correlated with the length of coma. The cause of the astrocyte change was established by studies that reproduced the clinical and pathological characteristics of HE in primates by continuous infusions of ammonia. In studies of rats with portacaval shunts, astrocyte changes become evident after the fifth week. Before coma develops, astrocytic protoplasm increases and endoplasmic reticulum and mitochondria proliferate, suggesting that these are metabolically activated cells. After the production of coma, the more typical signs of the Alzheimer type II change became evident as mitochondrial and nuclear degeneration appeared. suggested that HE is an astrocytic disease, although oligodendroglial cells are affected as well. More recent evidence from his laboratory has shown that ammonia affects a wide variety of astrocytic functions and aquaporin-4.

The neuropathological–neurochemical link between astrocytes and the production of hyperammonemic coma is strengthened by immunohistochemical studies that localized glutamine synthetase to astrocytes and their end-feet. Similar findings for glutamate dehydrogenase have been described.

Long-standing or recurrent HE may lead to the degenerative changes in the brain characteristic of non-Wilson hepatocerebral degeneration. Brains of these patients have polymicrocavitary degenerative changes in layers five and six of the cortex, underlying white matter, basal ganglia, and cerebellum. Intranuclear inclusions that test positive by periodic acid–Schiff are also seen, as are abnormalities in tracts of the spinal cord. More recent histopathological studies showed lymphocyte infiltration in the meninges, microglia activation in the molecular layer, and loss of Purkinje and granular neurons of the cerebellum, already in patients with steatohepatitis grade 1, and increasing glial activation and neuronal loss with progression of the liver disease to cirrhosis ( ).

Treatment

Ideally, the management of cirrhosis should involve a cooperative effort between hepatologists, surgeons, neurologists, and psychologists, with additional input from nurses and dieticians. Practice guidelines published by the European and the American Association for the Study of the Liver (EASL/AASL) recommend a four-pronged approach to management of HE: (1) provision of supportive care, (2) identification and treatment of precipitating factors, (3) search for and treatment of concomitant causes of encephalopathy, and (4) commencement of empirical HE treatment ( ).

Initial diagnostic and therapeutic efforts should be directed at the identification and mitigation of precipitating factors, and at reducing the nitrogenous load arising from the GI tract. This is accomplished by a brief withdrawal of protein from the diet and the administration of cleansing enemas, followed by the use of lactulose. Antibiotics such as rifaximin, metronidazole, or neomycin may be used as an alternative or add-on to lactulose. Rifaximin has the advantage of showing no systemic side effects ( ). Oral BCAAs were shown to improve both overt and minimal HE, and thus are a possible add-on therapy if a patient does not respond to conventional therapy. After the acute phase of HE, patients should receive the maximum amount of protein that is tolerated. Prolonged periods of protein restriction should be avoided. Protein is required for the regeneration of hepatocytes and prevention of a catabolic state and muscle wasting.

In patients without overt encephalopathy, diagnostic efforts should be directed toward identifying patients with minimal encephalopathy and monitoring the effects of treatment. Patients with minimal encephalopathy have a diminished quality of life and benefit from therapy, typically lactulose. Follow-up testing is needed to monitor treatment.

Lactulose

Lactulose is a mainstay for the treatment of both acute and chronic forms of HE. It has been used for the treatment of overt HE for decades despite sparse data from randomized placebo-controlled trials. According to a recent Cochrane review, lactulose has a beneficial effect on minimal and overt HE and also may prevent recurrence of HE ( ). Lactulose is a synthetic disaccharide metabolized by colonic bacteria to produce acid, and causes an osmotic diarrhea. The effect of lactulose is attributable to its role as a substrate in bacterial metabolism, leading to an assimilation of ammonia by bacteria or reducing deamination of nitrogenous compounds. It is probably the single most important agent in the treatment of acute and chronic encephalopathy. The usual dose of lactulose is 20–30 g, 3 or 4 times a day, or an amount sufficient to produce 2 or 3 stools per day. Lactulose also can be given as an enema.

Amino acids

BCAAs improve skeletal muscular protein synthesis and thereby ammonia detoxification. A meta-analysis of 16 randomized controlled trials of BCAA versus placebo, diet, lactulose or neomycin showed a significant effect of BCAA upon minimal and overt HE ( ).

Antibiotics

Nonabsorbable antibiotics such as neomycin were among the initial treatments for HE but have been abandoned because of their nephrotoxicity and ototoxicity. In 2010, the US Food and Drug Administration (FDA) approved the use of oral rifaximin, 550 mg, twice daily “to reduce risk for recurrence of overt HE in patients with advanced liver disease.” This nonabsorbable antibiotic had a relatively long history of use for the treatment of traveler’s diarrhea. Its efficacy was shown in a multicenter randomized, placebo-controlled, double-blind clinical trial involving 299 patients who were in remission after sustaining at least two episodes of HE ( ). A breakthrough episode of HE occurred in 22.1% of the patients in the rifaximin group and in 45.9% of the patients in the placebo group, yielding a hazard ratio of 0.42 (95% confidence interval [CI] 0.28–0.64; P < .001). There was also a significant reduction in a secondary endpoint, the probability of rehospitalization. It is important to note that more than 90% of the patients in this trial were already receiving and continued to receive lactulose. Thus, rifaximin should be considered as a valuable add-on therapy.

Complications and Prognosis

Although studies done over 2 decades ago demonstrated that patients with hepatic coma were more likely to survive with minimal residua, this disorder still carries a substantial risk of death. Transplant-free survival at 1 year is less than 50% after an initial episode and less than 25% at 3 years. To aid in the selection of patients for transplantation, a simple rating system or MELD (Model for End-stage Liver Disease) score has been developed and validated to predict mortality. HE has no effect in the selection of patients for transplantation. The MELD score is based on bilirubin, serum creatinine, and the INR. The higher the MELD score, the worse the prognosis. Currently the use of the MELD score is controversial. While the mortality on the waiting list for liver transplantation decreased since introduction of the MELD score as a means for organ allocation, the mortality after transplantation continuously increased.

The incidence of HE is probably underestimated, mainly because neurologists are not usually the primary physicians of these patients, and early subtle signs of cerebral dysfunction may be missed. It is important to establish the diagnosis of HE promptly and proceed with vigorous treatment. HE was considered completely reversible in the past. There is, however, increasing evidence that the recovery may remain incomplete ( ; ). Prolonged or repeated episodes risk transforming this reversible condition into non-Wilson hepatocerebral degeneration, a severe disease with fixed or progressive neurological deficits including dementia, dysarthria, gait ataxia with intention tremor, choreoathetosis, and—most frequently—parkinsonism ( ). Other patients may develop evidence of spinal cord damage, usually manifested by a spastic paraplegia. This complication may be a part of the spectrum of hepatocerebral degeneration. Differentiating correctly between early myelopathy or hepatocerebral degeneration and the motor abnormalities that characterize reversible encephalopathy may not always be possible in a first visit but can be done with follow-up examinations.

Patients with HE may develop toxin hypersensitivity, wherein previously innocuous levels of toxins cause symptoms. This concept implies that there may be a steadily increasing risk for developing permanent neurological damage as toxin hypersensitivity evolves.

Acute Liver Failure

ALF is usually the result of massive necrosis of hepatocytes and is defined as a syndrome in which the signs of encephalopathy develop within up to 3 months after the onset of the symptoms of liver disease in a patient with a previously normal liver. Modern classifications differentiate between hyperacute (HE within 1 week), acute (HE within 4 weeks), and subacute courses (HE develops between 1 and 3 months after the onset of the liver disease). Hyperacute, acute, and subacute ALF differ in regard to etiology and prognosis ( ; ). HE in patients with ALF and HE in patients with cirrhosis share many symptoms. However, due to the different time course and extent of the metabolic alterations, there are some significant differences. In contrast to patients with cirrhosis, patients with ALF frequently develop irritability, agitation, seizures, and brain edema, whereas extrapyramidal and cerebellar symptoms, which are frequent in patients with cirrhosis, are lacking in ALF. In patients with ALF, blood ammonia levels may rise extremely, and have been shown to correlate with intracranial pressure (ICP), severity of clinical presentation, and death by brain herniation ( ; ). Recently, it was shown that persistent hyperammonemia above 122 μmol/L for 3 days is accompanied with increased risk of developing brain edema, seizures, and death. Brain edema is present in 25%–35% of patients with grade 3 HE and in 65%–75% of those with grade 4 HE in ALF. According to a retrospective analysis from King’s College, London, the percentage of patients with intracranial hypertension significantly decreased between 1973 and 2008 from 76% to 20% ( ). Nevertheless, brain edema is one of the leading causes of mortality in ALF, while both diagnosis and treatment are difficult. The diagnosis is impeded by the fact that the patients are intubated and mechanically ventilated, and thus a clinical neurological assessment is impossible. Repeated brain imaging is not feasible. In addition, there is no strong correlation between ICP and CCT results. Therefore, occasionally continuous monitoring of ICP is recommended, but is not without controversy, since these patients with altered hemostasis may develop intracranial hemorrhages. In a series of 324 patients with acute hepatic failure, 28% underwent ICP monitoring. In a subset of these, 10.3% had radiographic evidence of an intracranial hemorrhage, half of which were incidental findings ( ).

Basic treatment of patients with ALF aims to reduce plasma ammonia levels and systemic cytokine levels, and to hold plasma sodium levels within the normal range. Therefore, patients are treated prophylactically with antibiotics as well as early renal support. Of note, lactulose has not shown a significant effect in ALF, neither with regard to plasma ammonia levels nor with survival. Brain edema is treated with mannitol infusion given either every 6 hours (1 g mannitol/kg body weight) or in patients with ICP monitoring as a response to ICP increases above 20–25 mm Hg. A precondition is that serum osmolality is less than 320 mOsm/L and patients have not yet developed acute renal dysfunction. Based on clinical observations, moderate hypothermia (32°C–34°C) has been recommended to reduce ICP in patients with uncontrolled intracranial hypertension who are awaiting emergency liver transplantation. However, a randomized, controlled, multicenter study has not confirmed these observations ( ). Besides supportive care, the quick identification of those patients who will need liver transplantation is important. Risk factors considered for this decision are the grade of encephalopathy and coagulopathy, age, bilirubin and creatinine plasma levels, and pH. Substantial research efforts have been devoted to the development of artificial livers or cell-based perfusion systems designed to remove toxins from circulating blood. But none of the systems has shown significant effect on survival ( ; ; ). In contrast, a recent multicenter study showed a significant effect of therapeutic plasma exchange upon liver transplant–free survival ( ).

ALF has been described as “metabolic chaos” because of coexisting acid-base, renal, electrolyte, cardiac, and hematological abnormalities, usually culminating in GI bleeding, ascites, sepsis, and often death. Due to continuous improvement in intensive care management and emergency liver transplantation, mortality of ALF decreased from about 80% in the 1970s to currently about 30%–40%.

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