Toxic and Metabolic Encephalopathies: Chapter Outline

84 Toxic and Metabolic Encephalopathies
Karin Weissenborn, Alan H. Lockwood
CHAPTER OUTLINE consciousness reflect involvement of the reticular activating

system and the cerebral cortex. Deficits in the spheres of selec-
tive attention and the ability to process information underlie
CLINICAL MANIFESTATIONS many metabolic encephalopathies and affect performance
TOXIC ENCEPHALOPATHIES on many tasks. These deficits are manifested as disorders of
Hepatic Encephalopathy orientation, cognition, memory, affect, perception, judgment,
Acute Liver Failure and the ability to concentrate on a specific task. Evidence from
Uremic Encephalopathy studies of patients with cirrhosis suggests that metabolic
encephalopathies are the result of a multifocal subcortical and
Twitch Convulsive Syndrome
cortical disorder rather than uniform involvement of all brain
Restless Leg Syndrome regions. Abnormalities of psychomotor function may also be
Wernicke Encephalopathy present. Among patients with coma of unknown cause, nearly
Mild Cognitive Impairment/Dementia in Chronic two-thirds ultimately are found to have a metabolic cause. A
Renal Disease complete discussion of coma is found in Chapter 5.
CNS Symptoms Associated with Dialysis Therapy The neuro-ophthalmological examination is extremely
METABOLIC DISTURBANCES important in differentiating patients with metabolic disorders
from those with structural lesions. The pupillary light reflex
Disorders of Glucose Metabolism
and vestibular responses are almost always present, even in
Disorders of Water and Electrolyte Metabolism 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 circu-
Toxic and metabolic encephalopathies are a group of neuro- latory collapse and an isoelectric electroencephalogram (EEG).
logical disorders characterized by an altered mental status— The pupils are usually slightly smaller than normal and may
that is, a delirium, defined as a disturbance of consciousness be somewhat irregular. The eyes may be aligned normally in
characterized by a reduced ability to focus, sustain, or shift patients with mild encephalopathy. With more severe enceph-
attention that cannot be accounted for by pre-existing or alopathy, dysconjugate roving movements are common. Other
evolving dementia and that is caused by the direct physiologi- cranial nerve abnormalities may be present but are less useful
cal consequences of a general medical condition (see Chapter in formulating a differential diagnosis. Motor system abnor-
4). Fluctuation of the signs and symptoms of the delirium over malities, particularly slight increases in tone, are common.
relatively short time periods is typical. Although the brain is Other signs and symptoms of metabolic disorders may include
isolated from the rest of the body by the blood–brain barrier, spasticity with extensor plantar signs and extrapyramidal as
the nervous system is often affected severely by organ failure well as cerebellar signs (in patients with liver disease), multifo-
that may lead to the build-up of toxic substances normally cal myoclonus (in patients with uremia), cramps (in patients
removed from the body. This is encountered in patients with with electrolyte disorders), Trousseau sign (in patients with
hepatic and renal failure. Damage to homeostatic mechanisms hypocalcemia), tremors, and weakness.
affecting the internal milieu of the brain, such as the abnor- Asterixis, a sudden loss of postural tone, is common. To
malities of electrolyte and water metabolism associated with elicit this sign, the patient should extend the arms and elbows
renal failure or the syndrome of inappropriate antidiuretic while dorsiflexing the wrists and spreading the fingers. Small
hormone (SIADH) secretion, also affects brain function. In lateral movements of the fingers may be the earliest manifesta-
some cases, a deficiency of a critical substrate after the cata- tion. More characteristically, there is a sudden flexion of the
strophic failure of an organ, such as hypoglycemia caused by wrist with rapid resumption of the extended position, the
fulminant hepatic failure, is the precipitating factor. Fre- so-called flapping tremor. Asterixis also may be evident during
quently, the history and physical examination provide infor- forced extrusion of the tongue, forced eye closure, or at the
mation that defines the affected organ system. In other cases, knee in prone patients asked to sustain flexion of the knee.
the cause is evident only after laboratory data are examined. 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 pathogno-
CLINICAL MANIFESTATIONS monic of hepatic encephalopathy, occurs in a variety of condi-
Encephalopathy that develops insidiously may be difficult to tions including uremia, other metabolic encephalopathies,
detect. The slowness with which abnormalities evolve and and drug intoxication. Asterixis may be present in patients
replace normal cerebral functions makes it difficult for patients with structural brain lesions, especially thalamic lesions.
and families to recognize deficits. When examining patients Generalized seizures occur in patients with water intoxica-
with diseases of organs that are commonly associated with tion, hypoxia, uremia, and hypoglycemia, but only rarely as a
encephalopathy, neurologists should include encephalopathy manifestation of chronic liver failure. Seizures in patients
in the differential diagnosis. with liver failure are generally due to alcohol or other drug
Mental status abnormalities are always present and may withdrawal, or cerebral edema associated with acute liver
range from subtle abnormalities, detected by neuropsycho- failure. Focal seizures, including epilepsia partialis continua,
logical testing, to deep coma. The level and content of may be seen in patients with hyperglycemia, and multifocal
1209
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1210 PART III Neurological Diseases and Their Treatment
myoclonic seizures may occur in patients with uremia. Myo- TABLE 84.1 Features Distinguishing Acute Liver Failure from Chronic
clonic status epilepticus may complicate hypoxic brain injury Hepatic Encephalopathy or Portal Systemic Encephalopathy
(see Chapter 83).
Acute liver Portal systemic
Feature failure encephalopathy
TOXIC ENCEPHALOPATHIES HISTORY
Hepatic Encephalopathy Onset Usually acute Varies; may be insidious

or subacute
Cirrhosis of the liver affects an estimated 5.5 million adults in Mental state Mania may evolve Blunted consciousness
the United States. In 2011, over 33,000 Americans died as the to deep coma
result of chronic liver disease (Tsochatzis et al., 2014). Among
the poor, the incidence of cirrhosis may be as much as 10 times Precipitating factor Viral infection or Gastrointestinal
hepatotoxin hemorrhage,
higher than the national average and accounts for almost 20%
exogenous protein,
of their excess mortality. As patients with chronic liver disease drugs, uremia
enter the terminal phases of their illness, hepatic encephalopa-
thy becomes an increasingly important cause of morbidity and History of liver No Usually yes
mortality. In this portion of the chapter, the term hepatic disease
encephalopathy (HE) will be used to differentiate this condition SYMPTOMS
from disorders associated with acute liver failure, discussed in Nausea, vomiting Common Unusual
the next section. About 20,000 patients per year were hospital-
ized in the United States between 2005 and 2009 after devel- Abdominal pain Common Unusual
oping HE (Stepanova et al., 2012). It is important to stress that SIGNS
minimal HE—the mildest form of HE, which interferes with
Liver Small, soft, tender Usually large, firm, no
the patients’ daily living ability but usually does not result in pain
seeking medical care—is far more common, affecting about
half of all patients with cirrhosis. Minimal HE can be diag- Nutritional state Normal Cachectic
nosed using neuropsychological tests, EEG or critical flicker Collateral circulation Absent May be present
frequency (CFF), for example, but is commonly overlooked.
Ascites Absent May be present
A World Gastroenterological Association consensus state-
ment seeks to minimize the substantial confusion in the lit- LABORATORY TEST
erature and in clinical practice concerning the diagnosis of HE Transaminases Very high Normal or slightly high
by using a multiaxial approach (Ferenci et al., 2002). The
Coagulopathy Present Often present
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 neurologi-
2–4 according to the West Haven Scale thereby are include in
cal signs within 8 weeks of developing liver disease, form the
the “overt HE” group, while those with grade 1 according to
first group (Type A HE). A second group consists of a small
the West Haven Scale and those with only psychometric or
number of patients who are free of hepatocellular disease but
neurophysiological but no clinical signs of HE are included
have portacaval shunting of blood (Type B HE). The largest
in the “covert HE” group. The decision to combine grade 1
number of patients have hepatocellular disease with shunts
HE and minimal HE to “covert HE” originates from the obser-
(Type C HE). Further subdivisions address temporal aspects—
vation of a significant inter-rater variability in diagnosing
whether HE is episodic, persistent, or minimal. Causal
grade 1 HE.
considerations are then applied to separate patients with
An episode of HE may be precipitated by one or more
precipitated HE from those with recurrent and idiopathic
factors, some of which are iatrogenic. In one series, the use of
encephalopathy, and to identify the severity of the syndrome.
sedatives accounted for almost 25% of all cases. A gastrointes-
The features that differentiate patients with acute liver failure
tinal (GI) hemorrhage was the next most common event
(ALF) from those with the much more common portal sys-
(18%), followed by drug-induced azotemia and other causes
temic encephalopathy are shown in Table 84.1.
of azotemia (15% each). Excessive dietary protein accounted
Rating the severity of HE is complex but essential for evalu-
for 10% of episodes; hypokalemia, constipation, infections,
ating the results of the treatment of individual patients and
and other causes accounted for the remaining cases. As liver
for evaluating potential treatments in the research setting. The
disease progresses, patients appear to become more suscepti-
so-called West Haven criteria supplemented by an evaluation
ble to the effects of precipitants. This phenomenon has been
of asterixis was used in the large multicenter trial that led to
referred to as toxin hypersensitivity. A transjugular intrahepatic
the approval of rifaximin for the treatment of HE. Both scales
portosystemic shunt (TIPSS), an endovascular procedure
are ordinal. The West Haven Scale is scored as the following:
developed to treat intractable severe ascites, predisposes a
0, no personality or behavioral abnormality detected; 1, trivial
patient to the development of encephalopathy, particularly
lack of awareness, euphoria or anxiety, shortened attention
among the elderly. TIPSS is more effective than large-volume
span, or impairment of the ability to add or subtract; 2, leth-
paracentesis but does not prolong survival. TIPSS-related
argy, disorientation with respect to time, obvious personality
encephalopathy often responds to conventional treatment.
change or inappropriate behavior; 3, somnolence or semistu-
Refractory cases may require endovascular treatment with coils
por, responsiveness to verbal stimuli with confusion or gross
to block a portion of the shunted blood.
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
Laboratory Evaluations
flapping tremors. The diagnosis of HE is based on the signs and symptoms of
Recently, a subdivision into “covert” and “overt” HE has cerebral dysfunction in a setting of hepatic failure. Usually,
been recommended (Vilstrup et al., 2014). Patients with grade standard laboratory test results, including serum bilirubin and
Toxic and Metabolic Encephalopathies 1211
hepatic enzymes, are abnormal. Products of normal hepatic

function, including serum albumin and clotting factors, often 84
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. When obtaining blood
samples for an ammonia determination, care must be taken
to be certain that the sample is of arterial origin (venous
ammonia levels may be artificially high, especially after the
outpouring of ammonia by muscle made ischemic by apply-
ing a tourniquet). The sample should be placed on ice and
carried by hand to the laboratory for immediate analysis.
Delays can result in ammonia production in the specimen,
producing a spuriously elevated result.
Several consensus conferences sponsored by the Interna-
tional Society for Hepatic Encephalopathy and Nitrogen
Metabolism have made recommendations concerning the use
of electrophysiological and neuropsychological tests to evalu-
ate patients with HE (Guerit et al., 2009; Randolph et al.,
2009). The favoured 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 deriva-
tions are the most characteristic EEG abnormality in patients
with severe hepatic encephalopathy. There are three stages in
the EEG evolution: a theta stage with diffuse 4- to 7-Hz waves;
a triphasic phase with surface-positive maximum deflections;
and a delta stage characterized by random arrhythmic slowing
with little bilateral synchrony. Computerized analysis of the Fig. 84.1 T1-weighted magnetic resonance images from a patient
EEG, designed to identify abnormalities in the spectra, may with cirrhosis of the liver. Note high signal in basal ganglia, cerebral
identify patients with minimal encephalopathy. The EEG is peduncles, and substantia nigra.
abnormal in 15–30% of patients with cirrhosis who do not
have clinical evidence of HE. Abnormal ERPs may be found
in patients with minimal encephalopathy as well. Auditory to interfere with the safe operation of an automobile or
P300 potential recordings, in which the subject is asked to other dangerous equipment. A study comparing patients with
discriminate between a rare and common tone, showed pro- minimal encephalopathy with nonencephalopathic patients
longed latencies in patients with overt encephalopathy with cirrhosis and a third group with gastrointestinal disease
(including HE grade 1) and in some of the patients without found that those with minimal encephalopathy performed the
clinical evidence of HE indicating minimal encephalopathy. worst during an on-the-road driving test. Specific problems
The need of a more sophisticated equipment for the P300 centered on handling, adaptation to road conditions, and
assessment than for the EEG assessment has precluded broad accident avoidance. Language functions are usually normal.
use of this method for clinical purposes. These data, combined with other studies showing that the
Neuropsychological tests are useful for diagnosing minimal quality of life is affected by these abnormalities, suggest that
HE and for follow-up of patients with low grade HE (grades neuropsychological tests should be used more extensively for
mHE–grade II HE). Domains to be evaluated include routine evaluation of all patients with cirrhosis, particularly
attention, visuo-constructional ability, and motor speed and those without overt evidence of HE.
accuracy. Although the diagnosis of HE is typically made on the basis
Neuropsychological tests are an underused and valuable of clinical criteria, neuroimaging techniques are commonly
means of diagnosing encephalopathy and monitoring the employed to exclude structural lesions. Magnetic resonance
response to therapy (see Chapter 43). Up to 60% of all patients imaging (MRI) and spectroscopic (MRS) studies have revealed
with cirrhosis with no overt evidence of encephalopathy new insights into the pathophysiology of HE (Lockwood
exhibit significant abnormalities when given a battery of neu- et al., 1997). On T1-weighted images, it is common to find
ropsychological tests. Tests of attention, concentration, visuo abnormally high signals arising in the pallidum. These are
spatial perception, and motor speed and accuracy are the most seen as whiter-than-normal areas in this portion of the brain,
likely to be abnormal (Schomerus and Hamster, 1998). The as shown in Fig. 84.1. In addition to these more obvious
PSE-Syndrom-Test—a test battery consisting of the Number abnormalities, a systematic analysis of MR images shows that
Connection Tests A and B, serial dotting, line tracing, and the the T1 signal abnormality is widespread and found in the
digit-symbol-test—has been recommended for evaluating limbic and extrapyramidal systems, and generally throughout
patients who may have hepatic encephalopathy (Randolph the white matter. A generalized shortening of the T2 signal
et al., 2009; Weissenborn et al, 2001). This battery is sensitive also occurs. These abnormalities have been linked to an
and relatively specific for the disorder, compared with other increase in the cerebral manganese content. The abnormalities
metabolic encephalopathies. become more prominent with time and regress after successful
Besides EEG and neuropsychological tests, occasionally the liver transplantation. The unexpected finding of high T1
analysis of the critical flicker frequency (CFF) is used for diag- signals in the pallidum should suggest the possibility of liver
nosing HE and follow-up (Vilstrup et al., 2014). disease.
Subclinical cognitive impairment of patients with cirrhosis, Proton MR spectroscopic techniques also have been applied
particularly in the visuospatial sphere, may be severe enough to the study of patients with cirrhosis and are available in
many centers. In the absence of absolute measures that are Role of Ammonia
referable to concentrations, the signal of specific compounds
has often been referenced to creatine and expressed as a Hepatic encephalopathy is linked to hyperammonemia.
compound-to-creatine ratio in the past. Irrespective of the use Patients with encephalopathy have elevated blood ammonia
of a quantitative or semi-quantitative approach there is general levels that correlate to a degree with the severity of the
agreement among studies that an increase in the intensity of encephalopathy. Metabolic products formed from ammonia—
the signal occurs at approximately 2.5 ppm; this is attributed most notably glutamine and its transamination product,
to glutamine plus glutamate (Glx). With high-field-strength α-ketoglutaramic acid—also are present in excess in cerebro
magnets, this peak can be resolved into its components, and spinal fluid (CSF) in patients with liver disease. Treatment
the increase is attributed to glutamine, as expected on the strategies that lower blood ammonia levels are the cornerstone
basis of animal investigations. Glx increase is accompanied of therapy.
by a decrease in myoinositol and choline signals, whereas Tracer studies performed with 13N-ammonia have helped
N-acetylaspartate resonances (a neuronal marker) are consist- clarify the role of this toxin in the pathophysiology of HE.
ently normal. Correlations between the glutamine concentra- Ammonia and other toxins are formed in the GI tract and
tion, generally considered to be a reflection of exposure of the carried to the liver by the hepatic portal vein, where detoxifica-
brain to ammonia, and the severity of the encephalopathy, tion reactions take place. Portal systemic shunts cause
have led some to propose that MR spectroscopy may be useful ammonia to bypass the liver and enter the system circulation,
in the diagnosis of HE. However, the data currently available where it is transported to the various organs as determined by
are controversial. their blood flow. The liver is the most important organ for the
Neuroimaging is useful in the diagnosis of coexisting struc- detoxification of ammonia. However, in patients with porta-
tural lesions of the brain, such as subdural hematomas or caval shunting of blood, because of the formation of varices,
other evidence of cerebral trauma, or complications of alcohol TIPS, or other surgically created shunts, skeletal muscle
abuse or thiamine deficiency, or both, such as midline cerebel- becomes more important as the fraction of blood bypassing
lar atrophy, third ventricle dilatation, mamillary body atrophy, the liver increases. Under the most extreme conditions, muscle
or high-signal-strength lesions in the periventricular area on becomes the most important organ for ammonia detoxifica-
T2 FLAIR images. tion. It is partly for this reason that nutritional therapy for
It must be emphasized that none of the methods described patients should be designed to prevent development of a cata-
in this section delivers findings that are specific for HE. Thus, bolic state and muscle wasting.
a diagnosis of HE can be made only after exclusion of other Ammonia is always extracted by the brain as arterial blood
possible causes of cerebral dysfunction. passes through the cerebral capillaries. When ammonia enters
the brain, metabolic trapping reactions convert free ammonia
Pathophysiology into metabolites (Fig. 84.3). The adenosine triphosphate
(ATP)-catalyzed glutamine synthetase reaction is the most
The pathophysiological basis for the development of HE important of these reactions. The blood–brain barrier is
is still not completely known. However, treatment strategies approximately 200 times more permeable to uncharged
for the disorder are all founded on theoretical pathophysio- ammonia gas (NH3) than it is to the ammonium ion (NH4+);
logical mechanisms. A number of hypotheses have been however, because the ionic form is much more abundant than
advanced to explain the development of the disorder. Sus- the gas at physiological pH values, substantial amounts of both
pected factors include hyperammonemia, altered amino species appear to cross the blood–brain barrier. Because of this
acids and neurotransmitters—especially those related to permeability difference and because ammonia is a weak base,
the γ-aminobutyric acid (GABA)–benzodiazepine complex— relatively small changes in the pH of blood relative to the brain
mercaptans, short-chain fatty acids, and manganese deposi- have a significant effect on brain ammonia extraction. As
tion in the brain. Although none of the current hypotheses are blood becomes more alkalotic, more ammonia is present as
completely capable of explaining the development of HE, it is the gas and cerebral ammonia extraction increases; however,
likely that ammonia plays a central role. Because of the com- the role this has in the production of HE is not known. The
plexity of the metabolic derangements that attend liver disease, permeability surface-area (PS) product of the blood–brain
other factors may contribute synergistically to the develop- barrier may be affected by prolonged liver disease. However,
ment of this complex disorder. the experimental data about this change are in conflict: one
study reported an increase in the PS product, others reported
Cerebral Blood Flow and Glucose Metabolism no change (Ahl et al., 2004; Dam et al., 2013; Goldbecker
Whole-brain measurements of cerebral blood flow (CBF) and et al., 2010; Keiding et al., 2006; Lockwood et al., 1991).
metabolism are normal in patients with grade 0 to 1 HE.
Reductions occur in more severely affected patients. Sophisti-
cated statistical techniques designed to analyze images have
Other Pathophysiological Mechanisms
made it possible to identify specific brain regions in which Astrocyte Swelling and the Role of Concomitant Disor-
glucose metabolism is abnormal in patients with low-grade ders. Although there is a strong correlation between the
encephalopathy and abnormal neuropsychological test scores plasma ammonia level and the grade of HE there is also sub-
(Lockwood et al., 2002). These positron emission tomogra- stantial overlap in ammonia levels by grade of HE, indicating
phy (PET) data show clearly that minimal forms of HE are that other factors besides hyperammonemia must play a role
caused by the selective impairment of specific neural systems in the development of HE. An increase in ammonia detoxifi-
rather than global cerebral dysfunction. Reductions occur in cation in the brain is associated with an increase of glutamine
the cingulate gyrus, an important element in the attentional concentrations within astrocytes and cell swelling. Initially,
system of the brain, and in frontal and parietal association glutamine is counterbalanced by the release of cellular osmo-
cortices. These PET data are in accord with cortical localiza- lytes such as myo-inositol to avert cell swelling. If the cells
tions based on the results of neuropsychological tests. Figure are depleted from myo-inositol, cell swelling can be induced
84.2 shows the results of correlation analyses between scores with small amounts of ammonia. Astrocyte swelling may be
on selected neuropsychological tests and sites of reduced induced also by inflammatory cytokines, hyponatremia, or
cerebral glucose metabolism. benzodiazepines. This is of special interest since HE episodes
84
Negative
linedrawing Negative
time dotting
Negative
Negative
linedrawing
trailmaking B
error
Positive Negative
symbol-digit trailmaking A
Fig. 84.2 Correlations between performance in the various sub-tests of the PSE-Syndrom-Test, as measured by age-corrected z scores,
and cerebral glucose metabolism as measured by FDG-PET 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. (Used with permission from Lockwood, A.H., Weissenborn, K., Bokemeyer, M., et al., 2002. Correla-
tions between cerebral glucose metabolism and neuropsychological test performance in nonalcoholic cirrhotics. Metab Brain Dis 17, 29–40.)
are frequently precipitated by infection, electrolyte dysbal- to trigger multiple alterations of astrocyte function and gene
ance, or the application of sedative drugs. Overall, the vul- expression. Astrocyte swelling induces the formation of reac-
nerability of the brain against these precipitating factors tive oxygen and nitrogen oxide species. Ammonia has been
increases with decreasing concentration of intracellular shown to induce the mitochondrial permeability transition
myo-inositol. (mPT) probably mediated by oxidative stress. Induction of the
Astrocyte swelling is considered a key factor in the patho- mPT leads to a collapse of the mitochondrial inner membrane
genesis of HE (Häussinger and Sies, 2013). It has been shown potential, swelling of the mitochondrial matrix, defective
Brain
Liver Glutamine Skeletal

synthetase muscle
Glutamine
Glutamine
Urea Urea synthetase
cycle
Glutamine
NH3
NH3 Glutamine NH3
Urea (NH3)
NH3 Glutamine
(NH3)
Ammonia
glutamine
Portacaval urea
shunt NH3 (NH3)
Systemic Kidney
vascular
Hepatic
pool Urea
portal
vein
GI tract Nitrogen
excretion
Nitrogen Urease amino

> > NH3
source acid oxidase
Fig. 84.3 Human ammonia metabolism. The brain becomes more sensitive to ammonia as time progresses. The reasons for this are largely
unknown. In addition, ammonia may cause anorexia by stimulating hypothalamic centers, leading to reductions in muscle mass and an impaired
ability of muscle to detoxify ammonia. GI, Gastrointestinal. (Adapted from Lockwood, A.H., McDonald, J.M., Reiman, R.E., et al., 1979. The
dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia. J Clin Invest 63, 449–460.)
oxidative phosphorylation, cessation of ATP synthesis, and may be found in blood and CSF of patients with encephalopa-
finally the generation of reactive oxygen species. Thus, induc- thy. Typically, the concentrations are substantially lower than
tion of the mPT is part of the vicious circle of oxidative/ concentrations that relieve anxiety and appear to be too low
nitrosative stress and astrocytic dysfunction (Norenberg to produce coma. In controlled studies, patients given the
et al., 2009). benzodiazepine antagonist, flumazenil, are more likely to
improve than those given placebo. It is unclear whether ben-
Abnormalities of Neurotransmission. Since the early
zodiazepine displacement is the mechanism because these
1970s, a variety of hypotheses have suggested that HE is caused
patients do not usually have clinically significant blood levels
by disordered neurotransmission. Although early hypotheses
of benzodiazepines. This raises the possibility that any of
related to putative false neurotransmitters were disproved,
flumazenil’s beneficial actions may be related to other actions
there is still effort in this direction.
of the drug.
As a result of the false neurotransmitter hypothesis, it was
More recent theories have linked the presence of increased
shown that the ratio of plasma amino acids (valine + leucine
expression of peripheral types of benzodiazepine receptors
+ isoleucine) to (phenylalanine + tyrosine) was abnormal in
(currently called translocator protein (TSPO)) to HE. These
encephalopathic patients, leading to the development of
receptors are found on mitochondrial membranes and are
amino acid solutions designed to normalize this ratio, which
implicated in intermediary metabolism and neurosteroid syn-
are now commercially available. Although infusion of the
thesis. Hyperammonemia causes an increase in TSPO and
solutions normalizes the ratio and patients improve, the
thereby stimulates the production of neurosteroids such as
results of several controlled clinical trials were considered
allopregnanolone, which activates GABA and benzodiazepine
inconclusive as to whether the amino acids or the associated
receptor sites of the GABA-A receptor resulting in an increase
supportive care measures caused the improvement noted.
in GABA-ergic tone in the brain.
Substantial effort has been focused on potential abnor-
In addition, there are significant alterations in cerebral
malities of the GABA–benzodiazepine complex. Initial atten-
serotonin and dopamine metabolism and a reduction in post-
tion was directed at GABA itself. Early reports that GABA
synaptic glutamate receptors of the N-methyl-D-aspartate type.
concentrations were elevated in patients with encephalopathy
Thus, there is a substantial interest in the potential role of
have been disproved, and attention has shifted toward the
neurotransmitters in the pathogenesis of HE. As of yet, there
presence of benzodiazepines or benzodiazepine-like com-
is no unifying hypothesis and no rational therapeutic approach
pounds. A number of anecdotal reports have described dra-
based on altering neurotransmission.
matic improvements in patients who did not respond to more
conventional therapy after they were given flumazenil. Some Fatty Acids. Short-chain fatty acids affect a variety of meta-
of the patients in the reports had been given benzodiazepines bolic processes, including uncoupling oxidative phosphoryla-
during the course of their care; however, it is not always clear tion, altering the mitochondrial respiratory state and state
whether a patient has been given benzodiazepines, and very control mechanisms, and inhibiting the urea cycle, which may
low concentrations of benzodiazepines and their metabolites in turn lead to hyperammonemia. They work synergistically
with ammonia to produce coma in experimental animals. Treatment

Medium-chain fatty acid dehydrogenase activity deficiency 84
may lead to the development of a clinical syndrome similar Ideally, the management of cirrhosis should involve a coop-
to Reye syndrome. Indeed, many early cases of Reye syndrome erative effort between hepatologists, surgeons, neurologists,
may have been caused by this metabolic deficiency. and psychologists, with additional input from nurses and
dieticians. Practice guidelines published by the European and
Mercaptans. Mercaptans are thioalcohols. In this class of the American Association for the Study of the Liver (EASL/
compounds, the −OH group is replaced by an −SH group. AASL) recommend a four-pronged approach to management
Methanethiol, the principal mercaptan in humans, is formed of HE: (1) provision of supportive care, (2) identification and
by the catabolism of methionine and occurs in measurable treatment of precipitating factors, (3) search for and treatment
amounts in blood and exhaled air, causing fetor hepaticus. of concomitant causes of encephalopathy, and (4) commence-
Injecting or inhaling mercaptans produces coma in animals, ment of empirical HE treatment (Vilstrup et al., 2014).
and there were early reports of correlations between the con- Initial diagnostic and therapeutic efforts should be directed
centration of mercaptans in the blood and the severity of at the identification and mitigation of precipitating factors
encephalopathy in individual patients. Because mercaptans and reducing the nitrogenous load arising from the GI tract.
work synergistically with short-chain fatty acids, ammonia, or This is accomplished by a brief withdrawal of protein from
both to produce coma, synergistic effects may be of impor- the diet and the administration of cleansing enemas, followed
tance in humans. by the use of lactulose. Antibiotics such as rifaximin, metroni-
Manganese. Blood manganese levels are increased in patients dazole, or neomycin may be used as an alternative or add-on
with liver cirrhosis due to an impairment of biliary manga- to lactulose. Rifaximin has the advantage of showing no sys-
nese excretion. Manganese deposition within the brain temic side effects (Bass et al., 2010). After the acute phase of
increases with predominance in the basal ganglia. These man- HE, patients should receive the maximum amount of protein
ganese deposits are considered to cause the brain MRI that is tolerated. Prolonged periods of protein restriction
signal alterations in patients with liver cirrhosis. Manganese should be avoided. Protein is required for the regeneration of
potentiates the toxic effects of ammonia. Moreover, manga- hepatocytes and prevention of a catabolic state and muscle
nese deposition per se results in neuronal loss, Alzheimer wasting.
type II astrocytosis, alteration of dopaminergic neurotrans- In patients who have cirrhosis without overt encephalopa-
mission, and expression of the “peripheral-type” benzodi- thy, diagnostic efforts should be directed toward identifying
azepine receptor (translocator protein) mentioned earlier patients with minimal encephalopathy and monitoring the
(Butterworth, 2010). effects of treatment. The inappropriate terms subclinical or
latent HE have been too commonly applied to patients with
minimal encephalopathy. Patients with minimal encephalop-
Neuropathology athy have a diminished quality of life and benefit from therapy,
The Alzheimer type II astrocyte is the neuropathological hall- typically lactulose. Follow-up testing is needed to monitor
mark of hepatic coma. An account of the original descriptions treatment.
of this change was provided in translation by Adams and Foley Lactulose. Lactulose is a mainstay for the treatment of both
in 1953. In this report, they presented their own findings of acute and chronic forms of HE. It has been used for the treat-
this astrocyte change in the cerebral cortex and the lenticular, ment of overt HE for decades despite sparse data from rand-
lateral thalamic, dentate, and red nuclei, offering the tentative omized placebo-controlled trials. Its utility in the secondary
proposal that the severity of these changes might be correlated prevention of HE was supported by a recent open-label
with the length of coma. The cause of the astrocyte change was placebo-controlled study of patients who had recovered from
established by studies that reproduced the clinical and patho- an initial episode of HE (Sharma et  al., 2009). In the lactulose-
logical characteristics of HE in primates by continuous infu- treated group, 19.6% developed recurrent HE during a 1- to
sions of ammonia. In studies of rats with portacaval shunts, 14-month follow-up compared to 46.8% in the placebo group
astrocyte changes become evident after the fifth week. Before (P = 0.02). Lactulose is a synthetic disaccharide metabolized
coma develops, astrocytic protoplasm increases and endoplas- by colonic bacteria to produce acid and causes an osmotic
mic reticulum and mitochondria proliferate, suggesting that diarrhea. A widely held but incorrect theory concerning the
these are metabolically activated cells. After the production of mechanism of action of lactulose centers on its ability to
coma, the more typical signs of the Alzheimer type II change acidify the colon. Acidification presumably trapped ammonia
became evident as mitochondrial and nuclear degeneration as the charged and nonabsorbable ammonium ion, thereby
appeared. Norenberg (2007) suggested that HE is an astrocytic preventing ammonia absorption. This theory has been ques-
disease, although oligodendroglial cells are affected as well. tioned because lactulose treatment does not increase the fecal
More recent evidence from his laboratory has shown that ammonia concentration or the total amount of ammonia
ammonia affects a wide variety of astrocytic functions and excreted. The effect of lactulose is attributable to its role as a
aquaporin-4. substrate in bacterial metabolism, leading to an assimilation
The neuropathological-neurochemical link between astro- of ammonia by bacteria or reducing deamination of nitroge-
cytes and the production of hyperammonemic coma is nous compounds. It is probably the single most important
strengthened by immunohistochemical studies that localized agent in the treatment of acute and chronic encephalopathy.
glutamine synthetase to astrocytes and their end-feet. Similar The usual dose of lactulose is 20 to 30 g, 3 or 4 times a day,
findings for glutamate dehydrogenase have been described. or an amount sufficient to produce 2 or 3 stools per day. Lac-
Long-standing or recurrent HE may lead to the degen tulose also can be given as an enema.
erative changes in the brain characteristic of nonWilson
hepatocerebral degeneration. Brains of these patients have Amino Acids. The hypothesis that altered plasma amino acid
polymicrocavitary degenerative changes in layers five and six ratios (discussed earlier), especially the (valine + leucine +
of the cortex, underlying white matter, basal ganglia, and cer- isoleucine)–to–(phenylalanine + tyrosine) ratio, affect brain
ebellum. Intranuclear inclusions that test positive by periodic neurotransmitter pools has led to attempts to treat encepha-
acid-Schiff are also seen, as are abnormalities in tracts of the lopathy by normalizing the blood amino acid profile
spinal cord. with branched-chain amino acids. After preliminary open
trials suggested a possible therapeutic benefit, a number of symptoms. This concept implies that there may be a steadily
controlled trials were undertaken, with contradictory results. increasing risk for developing permanent neurological damage
A recent meta-analysis of randomized controlled trials, how as toxin hypersensitivity evolves.
ever, indicated that oral BCAA-enriched formulations improve
the manifestations of episodic HE whether overt or minimal
HE (Gluud et al., 2013).
Acute Liver Failure
Acute liver failure (ALF) is usually the result of massive necro-
Antibiotics. Nonabsorbable antibiotics such as neomycin
sis of hepatocytes and is defined as a syndrome in which the
were among the initial treatments for HE but have been aban-
signs of encephalopathy develop within 8 weeks of the onset
doned because of their renal and ototoxicity. In 2010, the US
of the symptoms of liver disease in a patient with a previously
Food and Drug Administration (FDA) approved oral rifax-
normal liver. HE in patients with acute liver failure and HE in
imin, 550 mg, twice daily for the treatment of HE. This non-
patients with cirrhosis share many symptoms. However, due
absorbable antibiotic had a relatively long history of use for
to the different time course and extent of the metabolic alter-
the treatment of traveler’s diarrhea. Its efficacy was shown in
ations, there are some significant differences. In contrast to
a multicenter randomized, placebo-controlled, double-blind
patients with cirrhosis, patients with ALF frequently develop
clinical trial involving 299 patients who were in remission
irritability, agitation, seizures, and brain edema, whereas
after sustaining at least two episodes of HE (Bass et al., 2010).
extrapyramidal and cerebellar symptoms, which are frequent
A breakthrough episode of HE occurred in 22.1% of the
in patients with cirrhosis, are lacking in ALF. In patients with
patients in the rifaximin group and in 45.9% of the patients
ALF, blood ammonia levels may extremely increase, and have
in the placebo group, yielding a hazard ratio of 0.42 (95%
been shown to correlate with intracranial pressure (ICP),
confidence interval 0.28–0.64; P < 0.001). There was also a
severity of clinical presentation, and death by brain hernia-
significant reduction in a secondary endpoint, the probability
tion (Bernal et al., 2007; Bernal and Wendon, 2013). Recently,
of rehospitalization. It is important to note that more than
it was shown that persistent hyperammonemia above
90% of the patients in this trial were already receiving and
122 µmol/L for 3 days is accompanied with an increased risk
continued to receive lactulose. Thus, this should be considered
to develop brain edema, seizures, and death. Brain edema is
to be an add-on therapy.
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
Complications and Prognosis recent retrospective analysis of cases from King’s College,
Although studies done over 2 decades ago demonstrated that London, the percentage of patients with intracranial hyper-
patients with hepatic coma were more likely to survive with tension significantly decreased between 1973 and 2008 from
minimal residua, this disorder still carries a substantial risk of 76% to 20% (Bernal et al., 2013). Nevertheless, brain edema
death. Transplant-free survival at 1 year is less than 50% after is one of the leading causes of mortality in ALF, while both
an initial episode and less than 25% at 3 years. To aid in the diagnosis and treatment are difficult. The diagnosis is
selection of patients for transplantation, a simple rating impeded by the fact that the patients are intubated and
system or MELD (Model for End-stage Liver Disease) score mechanically ventilated, and thus a clinical neurological
has been developed and validated to predict mortality. The assessment is impossible. Repeated brain imaging is not fea-
MELD score is based on the bilirubin, serum creatinine, and sible. In addition there is no strong correlation between ICP
the international normalized ratio (INR). The higher the and CCT results. Therefore, occasionally continuous monitor-
MELD score, the worse the prognosis. An online MELD calcu- ing of ICP is recommended, but not without controversy,
lator and a pediatric equivalent can be found at the United since these patients with altered hemostasis may develop
Network for Organ Sharing web site (http://www.unos.org/ intracranial hemorrhages. In a series of 324 patients with
resources/MeldPeldCalculator.asp?index=98). Currently the acute hepatic failure, 28% underwent ICP monitoring. In a
use of the MELD score is controversial. While the mortality subset of these, 10.3% had radiographic evidence of an intra
on the waiting list for liver transplantation decreased cranial hemorrhage, half of which were incidental findings
since introduction of the MELD score as a means for organ (Vaquero et al., 2005).
allocation, the mortality after transplantation continuously Basic treatment of patients with ALF aims to reduce plasma
increased. ammonia levels and systemic cytokine levels, and to hold
The incidence of HE is probably underestimated, mainly plasma sodium levels within the normal range. Therefore,
because neurologists are not usually the primary physicians of patients are treated prophylactically with antibiotics and anti-
these patients, and early subtle signs of cerebral dysfunction fungals as well as early renal support. Of note, lactulose has
may be missed. It is important to establish the diagnosis of not shown a significant effect in ALF, neither with regard to
HE promptly and proceed with vigorous treatment. Although plasma ammonia levels nor with survival. Brain edema is
HE is potentially completely reversible, prolonged or repeated treated with mannitol infusion given either every 6 hours (1 g
episodes risk transforming this reversible condition into non- mannitol/kg body weight) or in patients with ICP monitoring
Wilson hepatocerebral degeneration, a severe disease with as a response to ICP increases above 20–25 mmHg. A precon-
fixed or progressive neurological deficits including dementia, dition is that serum osmolality is <320 mOsm/L and patients
dysarthria, gait ataxia with intention tremor, choreoathetosis, have not yet developed acute renal dysfunction. Based on
and—most frequently—parkinsonism (Tryc et al., 2013). clinical observations, moderate hypothermia (32–34°C) has
Other patients may develop evidence of spinal cord damage, been recommended to reduce ICP in patients with uncon-
usually manifested by a spastic paraplegia. This complication trolled intracranial hypertension who are awaiting emergency
may be a part of the spectrum of hepatocerebral degeneration. liver transplantation. However, a randomized, controlled,
Differentiating correctly between early myelopathy or hepa- multi-centre study has not confirmed these observations.
tocerebral degeneration and the motor abnormalities that Besides supportive care, the quick identification of those
characterize reversible encephalopathy may not always be patients who will need liver transplantation is important. Risk
possible in a first visit but can be done with follow-up factors considered for this decision are the grade of encepha-
examinations. lopathy and coagulopathy, age, bilirubin and creatinine
Patients with HE may develop toxin hypersensitivity, plasma levels, and pH. Substantial research efforts have been
wherein previously innocuous levels of toxins cause devoted to the development of artificial livers or cell-based
perfusion systems designed to remove toxins from circulating patients with impaired renal function due to increased
blood. But none of the systems has shown significant effect plasma levels. 84
on survival (Bernal and Wendon, 2013; Lee, 2012; Shawcross The diagnosis of uremic encephalopathy is made in the
and Wendon, 2012). presence of the characteristic symptoms in a patient with
ALF has been described as “metabolic chaos” because of severe renal dysfunction after exclusion of other possible
coexisting acid–base, renal, electrolyte, cardiac, and hemato- causes. The diagnosis is proven if symptoms disappear with
logical abnormalities, usually culminating in GI bleeding, successful renal replacement therapy. EEG, CSF, and brain
ascites, sepsis, and often death. Due to continuous improve- imaging produce unspecific results. The EEG shows a general-
ment in intensive care management and emergency liver trans- ized slowing with excess theta and delta activity. Sometimes
plantation, mortality of ALF decreased from about 80% in the bilateral spike-wave complexes are found. EEG correlates with
1970s to currently about 40%. clinical findings: with progression of encephalopathy EEG
becomes slower, but normalizes with successful therapy. CSF
is often abnormal, and shows increased protein levels (<1 g/L)
Uremic Encephalopathy and a slight pleocytosis (<25 cells/mL). In contrast to patients
Neurological disorders in patients with renal failure may with liver cirrhosis, in patients with renal dysfunction brain
present more problems for the neurologist than are found in imaging is completely unspecific, showing just a decrease in
patients with failure of other organ systems. This is primarily brain volume.
because of the complexity of the clinical status of many of Uremic encephalopathy can successfully be treated by the
these patients. Many of the disorders that lead to the develop- initiation of renal replacement therapy. Symptoms usually
ment of renal failure (e.g., hypertension, systemic lupus ery- regress within days or weeks after the initiation of dialysis, but
thematosus, diabetes mellitus) are frequently associated with mild symptoms may persist. Successful renal transplantation
disorders of the nervous system that are independent of a results in resolution of symptoms within days.
patient’s renal function. Thus, it may be difficult to determine Cognitive dysfunction in patients with end-stage renal
whether new neurological problems are caused by the primary disease has several possible causes in addition to the
disease or by the secondary effects of uremia. Similarly, it is accumulation of uremic toxins; these include chronic renal
frequently difficult to determine whether neurological prob- anemia, hyperparathyroidism, or obstructive sleep apnea
lems are the consequence of the progression of renal disease (here, independent of a patient’s weight!). Improvement of
and progressive azotemia, the treatment of renal failure by cognitive function can be achieved by increasing a patient’s
measures such as dialysis and its associated disequilibrium hemoglobin level to about 11–12 mg/dL or treatment of
and dementia syndromes, or a complication of transplanta- obstructive sleep apnea by using continuous positive airway
tion and immunosuppression. With increasing numbers of pressure ventilation similar to obstructive sleep apnea in
renal transplants and improved treatment designed to prevent obese patients (Brouns and DeDeyn, 2004; Seifter and
rejection, it is likely that the complexity of these issues will Samuels, 2011).
continue to increase. For these reasons, good cooperation
and communication between neurologists and the nephrolo-
gists and transplant teams who care for these patients are
Twitch Convulsive Syndrome
important. The twitch convulsive syndrome was first described by Victor
Uremic encephalopathy is considered to be caused by and Adams in 1977. They observed patients with end-stage
uremic toxins, in particular guanidino compounds, that accu- renal function who showed varying degrees of muscle twitch-
mulate due to renal dysfunction. These compounds interfere ing and fasciculations, arrhythmic tremors, random and asyn-
with both glutamatergic and GABA-ergic neurotransmission, chronous jerking of the limbs, myoclonus, asterixis, and
finally leading to an enhanced excitability. In addition, distur- seizures. The motor symptoms were associated with various
bance of the dopaminergic neurotransmission has been degrees of mental dysfunction, some were mentally unaltered,
observed in experimental animals (uremic rats) and was others showed a delirium. Guadino compounds are consid-
related to impairment of motor activity. Secondary hyperpar- ered to play a major role in the development of these symp-
athyroidism is suggested as leading to increased neuronal toms. Recently, dexmedetomidin substantially improved the
calcium levels and neuroexcitation. Experimental studies have clinical symptoms in a patient with twitch-convulsive syn-
shown a doubling of the brain calcium content and serum drome. Dose reduction led to a rapid increase of symptoms
parathyroid hormone levels within days of the onset of acute (Nomoto et al., 2011).
renal failure. EEG slowing correlates with elevations in the
plasma content of the N-terminal fragment of parathyroid
hormone. Treatment with 1,25-dihydroxyvitamin D leads to
Restless Leg Syndrome
improvements in the EEG and reductions in N-terminal frag- Restless leg syndrome (RLS) is quite frequent in patients with
ment parathyroid hormone concentrations. renal failure, especially in women. It is characterized by a need
Clinical symptoms range from emotional alterations, to move the legs, is worsened by periods of inactivity, and can
especially depression, and slight attention and memory defi- be relieved by walking or stretching. Thus, patients suffer espe-
cits to severe alterations of consciousness and cognition cially during the night. RLS is considered to result from a
including (mostly agitated) confusion, psychosis, seizures, decrease in dopaminergic modulation of intracortical excita-
and coma. Slight neuropsychiatric symptoms are present in bility. Iron deficiency plays a major role in the development
about 30% of patients on dialysis therapy. The advanced of RLS since iron is a co-factor for the enzyme tyrosine hydrox-
grades of uremic encephalopathy with confusion or coma are ylase, the rate-limiting step in the biosynthesis of dopamine.
currently predominantly observed in patients in whom a Accordingly, treatment includes the application of dopamine
decision has been made not to start dialysis. Action tremor, receptor agonists, levodopa combined with dopa decarboxy-
asterixis, and myoclonus, as well as hyperreflexia, are charac- lase inhibitors, and the adjustment of any iron deficit. These
teristic features of uremic encephalopathy. Occasionally, treatments are often combined with the application of benzo-
choreatic movements have been described. Both asterixis and diazepines, opioids, or gabapentin. RLS often persists after the
myoclonus may be provoked by several drugs such as opioids, initiation of dialysis therapy, but resolves after kidney trans-
antiepileptic drugs, phenothiazines, or metoclopramide in plantation (Seifter and Samuels, 2011).
Wernicke Encephalopathy phosphate binders to treat hyperphosphatemia, and thus has

been referred to the neurotoxicity of aluminum. Most cases
Another possible cause of encephalopathy in hemodialysis were observed in the 1970s. Dialysis encephalopathy is cur-
patients is thiamine deficiency due to poor intake caused by rently reported only sporadically. Clinical features are dysar-
decreased appetite and increased loss of this water-soluble thria, aphasia, apraxia, myoclonus, seizures, and cognitive
vitamin in the dialysis procedure. The significance of thiamine decline. Deferoxamine is the treatment of first choice.
deficiency in patients with renal replacement therapy who
develop brain dysfunction, became evident in a study that
showed a 33% prevalence of thiamine deficiency in 30 dialysis METABOLIC DISTURBANCES
patients who presented with clinical symptoms of encepha- Disorders of Glucose Metabolism
lopathy (Hung et al., 2001). Brain imaging is mandatory in
order to exclude intracranial bleeding. The determination of Under normal conditions, glucose is the exclusive fuel for the
thiamine levels, however, can be omitted, since substitution brain, which unlike other organs such as the liver and skeletal
of thiamine can be done without any significant side effects, muscle, is able to store only trivial quantities of glucose as
although there are some reports of allergic reactions. glycogen. Because brain glucose concentrations are normally
low (i.e., ≈ 25% of the plasma concentration) and the cerebral
metabolic rate for glucose is high, the brain is highly vulner-
Mild Cognitive Impairment/Dementia in Chronic able to interruptions in the supply of glucose. Hyperglycemia
Renal Disease is tolerated by the brain better than hypoglycemia, but it also
Several studies provide evidence that patients with chronic produces neurological symptoms, largely due to osmotic
renal disease develop cognitive dysfunction from mild impair- effects.
ment to frank dementia (Bugnicourt et al., 2013; Elias et al.,
2013; Tryc et al., 2011). The frequency of dementia in patients Physiology
of old age undergoing dialysis therapy has been estimated as Glucose Homeostasis. After food is ingested, blood glucose
about 4%, with predominance of multi-infarct dementia. levels begin to climb, which, in concert with a number of
Multi-infarct dementia is about 7 times more frequent in complex factors, leads to the release of insulin from the pan-
dialysis patients than in the general elderly population. creas. Insulin has the combined effects of suppressing hepatic
Neuropsychological studies showed alterations especially glucose production and fostering the storage of glucose, par-
of attention, concentration, and memory, even in some ticularly as glycogen in the liver. After carbohydrate absorption
patients who appeared normal in a clinical examination. is complete, homeostasis is maintained by hepatic glycogenol-
Among 374 dialysis patients, 55 years of age or older, who ysis. The liver normally contains sufficient glycogen stores to
were tested in the domains of memory, executive function, maintain the blood glucose concentration at 80 to 90 mg/dL
and language, only 12.7% were normal. Almost 14% had mild for 24 to 36 hours. After this time, gluconeogenesis becomes
impairment, 36.1% had moderate impairment, and 37.3% the principal mechanism for maintaining adequate plasma
had severe impairment (Murray et al., 2006). Event-related glucose levels. Alanine and glutamine are the amino acids
potential studies applying an oddball experiment showed, as that, along with lactate and pyruvate, are the most important
in patients with hepatic encephalopathy, an increase in P300 glucose precursors. Initially, most gluconeogenesis takes place
latency and a decrease in P300 amplitude in patients with in the liver, but with extended starvation, the kidney begins to
chronic kidney disease but no clinical symptoms of brain produce glucose, accounting for roughly half of the glucose
dysfunction compared to controls. The pathophysiology is produced. Approximately half of the glucose produced in the
multifactorial: uremic toxins, hypertension, microangiopathic postabsorptive state is metabolized by the brain. Because
lesions, anemia, hyperparathyroidism, and others may play the metabolic processes of glucose homeostasis, including
a role. insulin release, glycogen breakdown, and gluconeogenesis, are
complex and involve the pancreas, liver, and other organs, it
CNS Symptoms Associated with Dialysis Therapy is not surprising that an extensive list of conditions may mani-
fest as hypoglycemia.
Dialysis Dysequilibrium Syndrome
Cerebral Glucose Metabolism. Under normal conditions,
Dialysis disequilibrium syndrome is especially observed after with a mean CBF of 50 mL/100 g of brain per minute and a
the initiation of renal replacement therapy. Rapid normaliza- glucose concentration of approximately 5 mmol/L, large
tion of electrolytes, urea, and creatinine result in water influx amounts of glucose are presented to the brain at all times. As
into brain cells because the intracellular osmolyte levels blood traverses the cerebral capillary bed, approximately 10%
cannot be normalized as fast as the intravascular levels. As a of the glucose is transported across the blood–brain barrier
consequence, cerebral edema evolves and presents with head- by a glucose transporter enzyme (GLUT1) that exhibits
ache, nausea, vomiting, confusion, and seizures. The diagnosis Michaelis–Menten kinetics. GLUT1 further facilitates the
of dialysis disequilibrium syndrome can be made only by glucose uptake into glial cells while the neuronal glucose
exclusion of other possible causes of brain dysfunction. Of uptake is mediated by the glucose transporter 3 (GLUT3),
special interest are hypertensive encephalopathy (or posterior which has a higher transport rate than GLUT1 (Mergenthaler
reversible encephalopathy syndrome, PRES) and intracranial et al., 2013). The local glucose utilization rate is driven by
bleeding as a complication of hypertension and anticoagula- functional activity that allows imaging of the cerebral glucose
tion with hemodialysis. Dialysis disequilibrium syndrome utilization via PET using an 18F-labeled glucose analog, fluoro-
responds to a decrease of dialysis length to 2–3 hours, deoxyglucose (FDG), to visualize brain regions with increased
daily dialysis, and reduced dialysis efficacy (Seifter and or decreased neuronal activity.
Samuels, 2011).
Clinical Aspects of Hypoglycemia
Dialysis Encephalopathy Diagnosing hypoglycemia on the basis of clinical symptoms
Dialysis encephalopathy has been observed especially with the is fraught with hazards. Although the majority of symptoms
use of aluminium-containing dialysate and aluminum-based are attributable to nervous system dysfunction, they are
extremely varied, nonspecific, and not always present even to drive, make critical decisions, and the like while in an
when blood glucose levels are very low. Because of the close impaired state. 84
link between the symptoms of hypoglycemia and the brain, Some special problems are associated with detecting
some authors use the term neuroglycopenia to refer to sympto- hypoglycemia in neonates and children, centering on the
matic hypoglycemia. There are three syndromes: acute, subacute, various nonspecific symptoms (e.g., pallor, irritability, and
and chronic. feeding difficulties) and on the variable sensitivities of indi-
The acute syndrome most commonly develops as the result vidual children to a given plasma glucose concentration. As
of the action of insulin preparations or oral antihyperglyc- with adults, the diagnosis is most likely to be made when the
emics and begins with vague symptoms of malaise, feeling physician consciously keeps his or her index of suspicion high
detached from the environment, restlessness associated with and when glucose measurements are done routinely when
hunger, nervousness that may lead to panic, sweating, and there is any doubt about a diagnosis. The risk of missing the
ataxia. Patients may recognize these symptoms. The symptoms diagnosis and having irreversible neuronal injury develop in
respond quickly to oral or parenteral glucose. An EEG per- the patient justifies liberal use of screening measures and, in
formed during this period may reveal nonspecific abnormali- some cases, presumptive treatment with parenteral glucose.
ties. Attacks may end spontaneously or proceed rapidly to The increasing use of home glucose test devices should help
generalized seizures and coma, with the attendant risk of per- minimize risks to these patients.
manent brain injury. These patients may arrive in the emer- Because of the complexity of glucose homeostasis, the
gency department in a coma with no history. causes of hypoglycemia are many and varied, and a detailed
The subacute syndrome is the most common form and discussion is beyond the scope of this chapter. In general, most
occurs in the fasting state. Most of the symptoms listed for the authors present a physiological classification as shown in
acute syndrome are absent. In their place is a slowing of Box 84.1.
thought processes and a gradual blunting of consciousness Drugs are an important cause of hypoglycemia. In some
with a retention of awareness, although amnesia for the cases, the effect of a drug may be potentiated by a restriction
episode is common. The diagnosis may be difficult to estab- of food intake. Age-varying causes have been found and
lish until the possibility of hypoglycemia is considered or should aid in the diagnosis of the disorder. In the newborn
routine testing uncovers the abnormality. Hypothermia is period, maternal administration of sulfonylureas and other
encountered frequently in this form of the disorder, and unex- possible hypoglycemic agents that appear in breast milk domi-
plained low body temperatures always should be followed by nate as a cause of hypoglycemia. From newborn to 2 years of
a blood glucose measurement.
Chronic hypoglycemia is rare and, if confirmed, suggests a
probable insulin-secreting tumor or obsessively good control
by a diabetic. Plasma hemoglobin A1c levels are helpful in
making this differential diagnosis. This syndrome is character- BOX 84.1 Causes of Hypoglycemia
ized by insidious changes in personality, memory, and behav-
POSTPRANDIAL HYPOGLYCEMIA (REACTIVE)
ior that may be misconstrued as dementia. Unlike those of the
acute and subacute forms of hypoglycemia, these symptoms Postoperative rapid gastric emptying (alimentary hyperinsulinism)
are not relieved by administering glucose, suggesting the pres- Fructose intolerance
ence of neuronal injury. Clinical improvement after removal Galactosemia
of the source of the exogenous insulin is gradual, extending Leucine intolerance
over periods as long as a year. Idiopathic
The symptoms of sweating, tremor, and the sensation of FASTING HYPOGLYCEMIA
warmth may be attributed to activity of the autonomic nervous
Overuse of glucose
system. The inability to concentrate, weakness, and drowsiness
Elevated insulin levels
are attributable to neuroglycopenia. Hunger, blurred vision,
Exogenous insulin (therapeutic, factitious)
and other symptoms are of uncertain cause.
Oral hypoglycemic (therapeutic, factitious)
Diabetics may develop hypoglycemia without being aware
Islet cell disorders (adenoma, nesidioblastosis, cancer)
of the usual warning symptoms, a condition known as hypogly-
Excessive islet cell function (prediabetes, obesity)
cemia unawareness, which may occur in a complete or partial
Antibodies to endogenous insulin
form in up to 17% of all episodes in patients with type 1
Normal to low insulin levels
diabetes. The underlying mechanisms appear to be related to
Ketotic hypoglycemia
the occurrence of prior episodes of hypoglycemia, altered neu-
Hypermetabolic state (sepsis)
roendocrine responses that regulate blood glucose levels, and
Rare extrapancreatic tumors
central nervous system dysfunction that may interfere with
Carnitine deficiency
symptom detection and analysis. This is supported by studies
that show that patients with the syndrome exhibit a reduction UNDERPRODUCTION OF GLUCOSE
in β-adrenergic sensitivity. In these patients, the glucose con- Hormone deficiencies (growth hormone, glucagon,
centration needed to initiate counter-regulatory hormonal hypoadrenalism)
response was lower than normal. Imaging studies using Enzyme disorders
FDG and PET to measure neuronal activity in the subthalamic Glycogen metabolism (glycogen phosphorylase, glycogen
area, a site implicated as a glucose sensor, showed an abnor- synthetase)
mal response in patients with symptoms of hypoglycemia Hexose metabolism (glucose-6-phosphatase,
unawareness (McCrimmon, 2012). fructose-1,6-biphosphatase)
The presence of the unawareness syndrome poses a special Glycolysis, Krebs cycle (phosphoenolpyruvate carboxykinase,
challenge for these patients, their caregivers, and colleagues. pyruvate carboxylase, malate dehydrogenase)
Precautions should be taken to minimize the chance that Alcohol and probably other drugs
a patient with the syndrome might have a prolonged and Liver disease (cirrhosis, fulminant hepatic failure)
unrecognized period of hypoglycemia that could result in per- Severe malnutrition
manent injury to the brain; the patient should not be allowed
age, salicylate ingestion dominates. Surprisingly, alcohol pre- by anorexia, nausea, disorientation, and coma. On physical
dominated as a cause in the age group 2 to 7 years. Alcohol- examination, sustained hyperventilation is common, espe-
containing cough syrups and alcoholic beverages were cially in patients with severe acidosis. The diagnosis is fre-
responsible. Sulfonylureas and oral hypoglycemics again dom- quently suspected on the basis of clinical findings, but
inate in the age groups 11 to 30 years and 50 years and older. laboratory data including the plasma glucose, arterial blood
Alcohol predominated between the ages of 30 and 50 years. gases, electrolytes, and an appropriate test for ketone bodies
Significant numbers of patients in most age groups were are essential for confirming the diagnosis and management.
encountered in whom beta-blockade with propranolol was a In contrast, nonketotic hyperosmolar coma—currently
factor in masking the symptoms of developing hypoglycemia. also called hyperosmolar hyperglycemic state—is a feature of
The use of beta-blockers in patients receiving insulin or oral type 2 diabetes and is thus encountered in older patients,
hypoglycemic agents therefore should be avoided. A number commonly as the first manifestation of the disease. This syn-
of risk factors have been recognized that predispose to the drome evolves more slowly than DKA, and the period of
development of hypoglycemia. These include (in addition to polyuria is more prolonged, leading to much more severe
diabetes) decreased caloric intake (usually related to severity dehydration. Because glucose is a less effective dipsogen than
of some illness or disruption of dietary routines), uremia, liver other solutes, water-seeking behavior is not as strong in this
disease, infection, shock, pregnancy, neoplasia, and burns. group of patients as it is in patients with hypernatremic hyper-
Hypoglycemia is associated with a substantial morbidity. A osmolality, thus promoting the development of dehydration.
study of 600 patients with diabetes showed that the frequency Suppressed water-seeking behavior combined with the inhibi-
of severe hypoglycemia was 1.60 episodes per patient per year tory effect of hypertonicity on insulin release can lead to
and that it occurred twice as often in patients with the type 1 severe dehydration and hyperglycemia that can be in excess of
form of the disorder. The risk of severe hypoglycemia episodes 2000 mg/dL. The disorder’s signs and symptoms are those of
increases with the duration of the disease. Among patients with hyperosmolality, hypovolemia, and cerebral dysfunction, with
severe episodes of hypoglycemia, injuries and convulsions epileptic seizures occurring in some individuals. Precipitating
occurred at rates of 0.04 and 0.02 episodes per patient per year, factors include infection, gastroenteritis, pancreatitis, and
respectively. Five patients had automobile accidents caused by occasionally, treatment with glucocorticoids or phenytoin.
hypoglycemia. But, in general, patients with diabetes are not Because many total parenteral nutrition protocols use solu-
more prone to automobile accidents than subjects without tions with high glucose contents, hyperglycemia is a potential
diabetes. Patients with episodes of severe hypoglycemia were complication of their use.
more likely to have had prior severe episodes, were on insulin DKA is an insulin-deficient state, and insulin is the corner-
longer, and had lower hemoglobin A1c concentrations. A south- stone of therapy. In the absence of insulin, peripheral glucose
ern California medical examiner found 123 deaths caused by uptake and glycogen formation are reduced, and glycogenoly-
hypoglycemia in a series of 54,850 autopsies. According to data sis and lipolysis are accelerated, leading to the formation of
from the Diabetes Control and Complication Trial (DCCT) acidic ketone bodies and hyperglycemia. When plasma glucose
more than half of the hypoglycemia episodes occur during the levels exceed the renal threshold (usually approximately
night ([No authors listed], 1997). Recently the dead-in-bed- 180 mg/dL), glucosuria and a forced osmotic diuresis ensue.
syndrome—a term used to describe the sudden unexplained The treatment of diabetic ketoacidosis is designed to reverse
deaths of young people with type 1 diabetes—could be related these pathophysiological abnormalities and consists of admin-
to hypoglycemia-related autonomic failure. istering insulin to enhance glucose uptake, enhance glycogen
The risk of death is usually highest in patients with the formation by noncerebral tissues, and reduce the rate of ketone
most severe hypoglycemia and the largest number of risk body formation occurring during low-insulin, high-glucagon
factors. Among hospitalized patients, whites have the lowest states that promote the entry of fatty acids into mitochondria,
mortality rate (approximately 6%), whereas black and His- where they are converted to ketones. Ten to 20 IU/h regular
panic patients have mortality rates of 30% and 46%, respec- insulin are delivered intravenously until blood glucose levels
tively. Hypoglycemia is a medical emergency, and this diagnosis are below 200 mg/dL; thereafter, the dose is decreased to
should be considered among virtually all patients with an 5–10 IU/h. Intravenous insulin application aims mostly to
altered mental status of unknown cause. Most of these treat ketonemia, and must not be stopped before normaliza-
patients should be treated with parenteral glucose after tion of the anion gap. Acidosis (ph <7.0) should be treated
adequate blood samples are obtained for laboratory testing. with 50–100 mmol sodium bicarbonate. Replacing fluid and
It is prudent to draw extra blood so that insulin and electrolytes is also required, as is treatment of precipitating
hemoglobin A1c levels can be measured if indicated by the factors. It is important to remember that overly vigorous treat-
patient’s subsequent course. These measures are particularly ment with rapid restoration of plasma osmolality to normal
important in patients with obscure histories and in whom levels can lead to the development of cerebral edema (see
factitious hypoglycemia may be present. The total amount of Complications of Treatment) (Nyenwe and Kitabchi, 2011).
glucose administered may be of little consequence if the Neurologists may become involved in the diagnosis and
patient is found to have a normal or elevated plasma glucose management of nonketotic hyperosmolar coma when a
concentration. patient is brought to the emergency department with unex-
plained coma or seizures. Alterations of consciousness, sei-
zures, and focal neurological deficits are more frequent in
Clinical Aspects of Hyperglycemia patients with nonketotic hyperosmolar coma than in those
Although there are many causes of hyperglycemia, diabetic with DKA. Neurologists should be aware that stroke might
ketoacidosis (DKA), nonketotic hyperosmolar coma, and accompany a nonketotic hyperosmolar coma, either as a com-
iatrogenic factors such as parenteral hyperalimentation are the plication due to the procoagulant status or as precipitant.
most important. DKA is a relatively common disorder, pre- Two characteristic, though rare, complications of the nonke-
dominantly affecting patients with type 1 diabetes. It is fre- totic hyperosmolar state are epilepsia partialis continua
quently precipitated by an infectious process in a patient who (Kojewnikow) and hemichorea.
has been otherwise stable, develops over several days, and is Because hyperosmolality and the associated hypovolemia
heralded by polyuria and polydipsia caused by the osmotic are usually much more severe in this condition than in DKA,
diuresis produced by glucosuria. These symptoms are followed maintaining an adequate blood pressure and cardiac output
are the first priorities in treatment. One liter of normal saline

per hour should be given during the first 3 hours to restore
Case 1
84
blood volume and to begin to reduce plasma osmolality. If
serum sodium levels are above 150 mmol/L, 1–2 liters 0.45% 600 CSF 600
pressure
saline solution should be given, followed thereafter by 5% Glucose
glucose solution. Glucose 5% should be used as soon as the
blood glucose levels are lower than 11.2 mmol/L. Insulin 400 400
therapy should start with a bolus of 5–10 IU intravenously
followed by 3–7 IU/hour. Blood glucose levels should not
decrease more than 100 mg/dL/h; the optimum would be 200 200
50 mg/dL/h. In addition, blood glucose levels should be
maintained between 10 and 15 mmol/L for the first 24 hours
after initiation of treatment. If serum levels are 3.5–5.5  mmol/L,
20 mmol potassium chloride should be added to every liter Fig. 84.4 Blood glucose and intracranial pressure during treat-
of the infusion, and 40 mmol if serum levels are below ment of diabetic ketoacidosis. The untreated hyperosmolar state
3.5 mmol/L. Recent Joint British Diabetes Societies guidelines leads to the intracerebral accumulation of idiogenic osmoles. As blood
even recommend initiation of hypergylcemic hyperosmolar glucose and osmolality levels decrease during treatment, free water
status treatment with fluid replacement, exclusively, while enters the brain more rapidly than idiogenic osmoles are shed, leading
low-dose intravenous insulin (0.05 units/kg/h) is advocated to an increase in intracranial pressure from the swollen brain. This
only if significant ketonemia (3-OH Butyrate >1 mmol/L) or mechanism presumably operates in all cases in which hyperosmolality
ketonuria (>2+) is seen at presentation or if plasma glucose is is corrected rapidly. CSF, Cerebrospinal fluid. (Reprinted with permis-
falling at a rate of less than 5 mmol/h despite adequate fluid sion from Clements, R.S. Jr., Blumenthal, S.A., Morrison, A.D., et al.,
replacement (Gouveia, Chowdhury, 2013). 1971. Increased cerebrospinal fluid pressure during treatment of dia-
The patients may require intensive monitoring with arterial betic ketoses. Lancet 2, 671–675.)
and central venous catheters to monitor the circulatory system
status and avoid inducing a volume overload. The exact mech-
anisms leading to the development of the syndrome, particu-
thrombotic complications. Thus, heparin should be adminis-
larly the absence of ketosis, are not fully explained.
tered subcutaneously for prophylaxis of thrombosis.
Complications of Treatment Disorders of Water and Electrolyte Metabolism

Although treatment of DKA has improved, the mortality rate
Patients with abnormalities of water and electrolyte metabo-
is still appreciable. Amongst adults, the mortality rate of DKA
lism frequently exhibit signs and symptoms of cerebral
is estimated being about 1%. However, DKA remains a leading
dysfunction. Typically these patients have altered states of
cause of mortality in children and young adults with type 1
consciousness or epileptic seizures that herald the onset of the
diabetes. The majority of patients who succumb do so because
abnormality. The vulnerability of the nervous system to abnor-
of cardiovascular collapse or from complications of the pre-
malities of water and electrolyte balance arises from changes
cipitating factor. A small number of patients die unexpectedly
in brain volume, especially the brain swelling that may
when laboratory and clinical indicators all show initial
be associated with water intoxication; the abnormalities are
improvement.
symptomatic almost immediately because the brain is enclosed
Clinically, patients with DKA who die experience rapid
by the rigid skull. The role played by electrolytes is also impor-
neurological then cardiovascular deterioration. Postmortem
tant in maintaining transmembrane potentials, neurotrans-
examinations of the brain show lesions similar to those seen
mission, and a variety of metabolic reactions such as those
in acute asphyxia, including capillary dilation with perivascu-
involving the role of calcium and calmodulin. Although most
lar and pericellular edema. Death is heralded by a rapid evolu-
clinicians are aware of the importance of water and electrolyte
tion of signs and symptoms indicating an increase in ICP.
disturbances as a cause of brain dysfunction, the importance
About half of patients die during the initial episode of DKA.
of the brain in the control of water and electrolytes is less well
The rate and degree to which the plasma glucose level is
appreciated. Excellent reviews of these disorders have been
lowered is not a major risk factor for death.
written by Adrogué and Madias (2000a,b, 2012, 2014).
Some degree of cerebral edema attends the treatment of
most patients with DKA, occasionally to the high level of
600 mm H2O CSF pressure, as shown in Fig. 84.4.
Disordered Osmolality
The data suggest that at least mild clinically silent cerebral Osmotic Homeostasis. The serum, and hence whole-body
swelling may be much more common than is realized in cases osmolality, are regulated by complex neuroendocrine and
of DKA. Rare unknown factors appear to trigger a malignant renal interactions that control thirst and water and electrolyte
increase in intracranial pressure in a small number of patients. balance. When serum osmolality increases, the brain loses
Published experience suggests that if this diagnosis is made, volume; when osmolality falls, the brain swells. Events related
prompt aggressive treatment of cerebral edema is indicated, to water loss are illustrated in Fig. 84.5. The brain has little
preferably using ICP monitoring as a guide to therapy. Never- protection in terms of volume changes when osmotic stress is
theless, the associated mortality rate is high. acute. Examples of acute osmotic stress may be found in
The estimated mortality rate in patients with nonketotic patients with heat stroke, inadvertent solute ingestion (par-
hyperosmolar coma, ranging between 5% and 20%, is much ticularly in infants), massive ingestion of water (which may
higher than that of DKA. This difference is partially due to be psychogenic), hemodialysis, and diabetics with nonketotic
affected patients being older and with comorbid conditions coma. Recent reports also suggest that excessive water con-
that contribute to volume depletion more often than those sumption occurs in some marathon runners, leading to acute
with DKA. Available evidence suggests that hyperglycemic water intoxication. When osmotic stress is applied more
emergencies are associated with an inflammatory and proco- slowly over a longer period, the predicted volume changes
agulant state, which both contribute to an increased risk of are smaller than would be expected. The mechanisms that
Water loss BOX 84.2 Causes of Hyponatremia

COMBINED WATER AND SODIUM DEPLETION
(HYPOVOLEMIA)
Increased osmolality Brain adapts
Renal Loss
Primary renal disease
Osmotic diuresis (glucose, mannitol)
ADH release Thirst Adrenal insufficiency
Nonrenal Loss
Gastrointestinal (diarrhea, suction, vomiting)
Water retention Water intake Transcutaneous (sweating, burns)
Sequestration (ascites, peritonitis)
HYPONATREMIA WITHOUT WATER LOSS

Decreased osmolality Brain adapts Edema with water and sodium retention
Dilutional (iatrogenic, psychogenic)
Sick cell syndrome
Hyperosmotic (hyperglycemia or mannitol administration)
Syndrome of inappropriate antidiuretic hormone secretion
ADH inhibition Thirst inhibition
Artifact (laboratory error, hyperlipidemia)
Fig. 84.5 Water balance and the brain. A reduction in water (or an
increase in water loss or solute gain) stimulates thirst and vasopressin
release, leading to increased water conservation and intake, which in
turn reduces vasopressin levels and ends thirst. Excessive water intake
or excessive water loss leads to hypo-osmolality or hyperosmolality Great care must be taken when considering the diagnosis
and the loss or gain of osmotically active particles in the brain, respec- of SIADH in patients with subarachnoid hemorrhage. Patients
tively. Excessively rapid treatment of these conditions may lead with subarachnoid hemorrhage, hyponatremia, and reduced
to the development of neurological symptoms. ADH, Antidiuretic blood volume may not have true SIADH. In these patients,
hormone. fluid restriction may lead to further volume reduction and
cerebral infarcts during the period of the highest risk for vaso
spasm. The mechanisms underlying this phenomenon are
unclear but may be related to the complexity of the peptidergic
underlie these protective adaptations are not known com- neurotransmitter systems in the vicinity of the third ventricle
pletely but involve the gain of amino acids in the case of the and to the possibility that they are damaged by the ruptured
hyperosmolar state and the loss of potassium in the hypo- aneurysm. Damage is especially likely with an aneurysm on
osmolar state. Experimental studies have failed to identify all the anterior communicating artery.
of the osmotically active particles that must exist in the brain Hyponatremia occurs in approximately 1% of patients
after a given osmotic stress is applied. These unidentified mol- with recent surgical procedures. Because the symptoms are
ecules are called idiogenic osmoles. frequently mild or attributed to the surgery itself, this diag-
nosis may be missed. Typically, these patients seem to do
Hypo-osmolality and Hyponatremia. Hypo-osmolality is
well in the immediate postoperative period and then develop
almost always associated with hyponatremia. The diagnosis
symptoms and signs of encephalopathy. Men and postmeno-
usually is made by laboratory testing. Conditions associated
pausal women are less likely to develop postoperative
with hyponatremia are shown in Box 84.2. When hyponatremia
hyponatremia than women who are still menstruating. Com-
is encountered, a measurement of serum osmolality should
plications such as respiratory arrest are particularly likely to
be performed to differentiate true from pseudo hypo-
occur more frequently in menstruating women than in men
osmolality, which may be encountered in patients with
or menopausal women. Thus, it is important to be particu-
lipidemic serum or in neurological patients treated with
larly vigilant when evaluating younger women with postop-
mannitol.
erative encephalopathy.
Elevated osmolality may be encountered in patients with
hyponatremia due to elevated urea or ethanol concentrations, Clinical Features. The signs and symptoms of deranged
who are subject to the same risks as patients with hyponatremia osmolality depend on the severity of the disturbance and the
associated with reduced osmolality. length of time elapsed between onset and clinical presenta-
A large and diverse group of neurological conditions is tion. Often these syndromes are of insidious onset. Typical
associated with hyponatremia as a result of SIADH, as shown complaints are nonspecific and include malaise, nausea, and
in Box 84.3. SIADH is characterized by hyponatremia in the lethargy, leading to obtundation and coma. Headache, due to
face of normal or increased blood volume, normal renal func- brain swelling, and epileptic seizures may be encountered in
tion, and the absence of factors that normally operate to patients with hyponatremia, especially in patients with an
produce antidiuretic hormone release. The syndrome may be acute alteration of serum sodium levels. Although serum
relatively asymptomatic, in which case water restriction is the sodium levels below 120 mmol/L are considered serious,
treatment of choice. In more severe cases, hypertonic saline patients who develop this level of hyponatremia as a side
combined with a diuretic may be required. Overly zealous effect of diuretics or antiepileptic treatment over a long period
treatment may produce central pontine myelinolysis (see the of time may present with only minor, if any, symptoms.
upcoming section, Therapy). Chronic syndromes have been Minor symptoms include dizziness, cognitive dysfunction,
treated successfully with a variety of drugs including the tetra- gait disturbances, and falls. Since, in these chronic states of
cycline demeclocycline, which interferes with the action of hyponatremia, the brain can counteract cell swelling by release
antidiuretic hormone on the renal tubules. of endogenous osmolytes, severe symptoms often occur only
BOX 84.3 Causes of the Syndrome of Inappropriate Antidiuretic Hormone Secretion 84

MALIGNANT NEOPLASMS Vinca alkaloids
Small cell carcinoma of lung Thiazides
Pancreatic tumors Chlorpropamide
Thymoma Phenothiazines
Mesothelioma Carbamazepine
Lymphoma (lymphosarcoma, reticulum cell sarcoma, Hodgkin Clofibrate
disease) Nicotine
Bladder, ureter, prostate tumors Monoamine oxidase inhibitors
Duodenal tumors Tricyclic antidepressants
Ewing sarcoma Cyclophosphamide
Narcotics
CENTRAL NERVOUS SYSTEM DISORDERS
PULMONARY DISEASES
Infections (meningitis, encephalitis, abscess, Rocky Mountain
spotted fever) Tuberculosis
Trauma Other pneumonias
Subarachnoid hemorrhage Abscess or cavity
Infarction Empyema
Guillain–Barré syndrome Cystic fibrosis
Acute intermittent porphyria Obstructive airway disease
Hydrocephalus Pneumothorax
Neonatal hypoxia Asthma
Shy–Drager syndrome Positive pressure ventilation
Delirium tremens MISCELLANEOUS CAUSES
Systemic lupus erythematosus
Hypothyroidism
DRUGS Acute psychosis
Vasopressin Postoperative state
Oxytocin Idiopathic
after serum sodium levels have decreased below 110 mmol/L. no evidence-based guidelines, it is suggested that the total
However, patients in whom serum sodium levels decrease correction of serum sodium levels should not exceed
within a short time interval due to an acute overload of total 6–8 mmol/24 hours. In patients with severe hyponatremic
body water are prone to develop brain edema, alterations of symptoms, a correction of 4–6 mmol/L should be achieved
consciousness, and seizures. Children and young women are within the first 4–6 hours. The correction can be achieved by
particularly vulnerable to hyponatremic brain damage. Of continuous infusion of 3% saline combined with the applica-
note is that brain adaptation to low serum sodium levels tion of 20 mg furosemide. In case of emergency, instead of a
increases the risk of osmotic demyelination after rapid resolu- continuous infusion, a 100-mL bolus of this solution, with up
tion of hyponatremia. to two additional boluses given at 10-minute intervals, depend-
ing on clinical manifestations, has been proposed. However,
Therapy. The treatment of hyponatremia has always been considering the risk of osmotic demyelination, cautious man-
controversial and has become more so since the link between agement of hyponatremia is advisable. This holds true espe-
hyponatremia treatment and the subsequent development of cially for those patient groups who are known to be at high
central pontine myelinolysis was recognized and experimen- risk for developing this condition. These are patients with
tal replication of the syndrome achieved. Investigators in chronic hyponatremia of 110 mEq/L, alcoholism, hepatic
one study were unable to identify the rate at which serum failure, orthotopic liver transplantation, potassium depletion,
sodium concentration was corrected, the absolute magnitude and malnutrition. In these patients, correction of serum
of the correction, or the type of solution infused as a factor sodium should not exceed 6 mmol/L in any 24-hour period.
that predisposed to the development of central pontine In patients with euvolemic or hypervolemic hyponatremia,
myelinolysis. They noted that undoubtedly thousands of vaptans, which antagonize the effect of vasopressin, thereby
patients with symptomatic hyponatremia have been treated promoting aquaresis, can be administered.
successfully using a large number of protocols, but these Sodium replacement cannot be done without considering
cases have not been reported. This makes it impossible to potassium levels. Replacement of 1 mmol/L potassium affects
estimate the risk of central pontine myelinolysis associated serum sodium levels as much as 1 mEq of retained sodium.
with any given treatment regimen. However, because they The effect of a given infusate on the serum sodium concen-
were unable to identify any cases of central pontine mye- tration can be estimated from the formula ΔNa+ in serum =
linolysis among the 185 published examples of symptomatic [Na+ + K+] in infusion – [Na+] in serum/total body water +1,
hyponatremia (published since 1954) in which patients were where total body water is calculated as fraction of body
allowed to “self-correct” during a period of water restriction weight. This fraction is 0.6 in children, 0.55 in men, and 0.5
(as opposed to the infusion of saline solutions of varied con- in women. In case of substantial ongoing fluid loss, it is rec-
centrations), they suggested that the preferred therapy of ommended to combine this formula with the so-called “fluid
hyponatremia might be water restriction and discontinuing loss formula” (see Adrogué and Madias, 2012). In case of
diuretics. severe symptomatic hyponatremia, continuous monitoring of
Infusions of hypertonic saline may be required for the vital signs and repeated measurement (every 2 hours) of the
treatment of symptomatic hyponatremia. Although there are electrolyte levels is mandatory. Overcorrection of the serum
sodium level should be treated by prompt administration of nerable to developing hypercalcemia after a change in therapy.
5% glucose solution. Less severe hypercalcemia may cause altered consciousness,
with a pseudodementia syndrome and weakness. GI, renal,
Hyperosmolality. Hyperosmolality is less common than
and cardiovascular abnormalities also may be present.
hypo-osmolality but may manifest with similar symptoms or
Severe hypercalcemia is life threatening. Initial treatment
evidence of intracranial bleeding caused by the tearing of veins
consists of a forced diuresis using saline and diuretics. Because
that bridge the space between the brain and dural sinuses.
the volumes of saline that are required may be large, a central
Usually, hyperosmolality is diagnosed by laboratory findings
venous or Swan-Ganz catheter may be needed to monitor
of an elevated serum sodium level or, perhaps more com-
therapy. Once the initial phase of treatment is accomplished,
monly, hyperglycemia in diabetics. The syndrome frequently
further management is determined by the cause of the
is caused by dehydration (especially in hot climates), by
hypercalcemia.
uncontrolled diabetes with or without ketosis, and (less fre-
Hypocalcemia usually is associated with hypoparathy-
quently) by central lesions that reset the osmotically sensitive
roidism. The neurological symptoms are attributable to the
regions of the brain. As with hypo-osmolality, cautious correc-
enhanced excitability of the nervous system. Symptoms
tion of the defect is important. Replacement should be given
include paresthesias around the mouth and fingers, cramps
orally if possible. Treatment is based on the answers to two
caused by tetanic muscle contraction, and in more extreme
questions: What is the water deficit? and How rapidly should
cases, epileptic seizures. In more chronic hypocalcemia, head-
it be corrected? The deficit can be computed from the equation
ache secondary to increased intracranial pressure may occur,
deficit = current body water (Na+/140 − 1). Current body water
and extrapyramidal signs and symptoms such as chorea or
can be estimated as ranging from 50% to 60% of the lean body
parkinsonism may be encountered. These patients may have
weight. A safety factor of 10% has been suggested; therefore,
calcification of the basal ganglia, evident on computed tom-
current body water should be taken as about 45% of the lean
ography of the brain. The physical examination should include
body weight. Thus, a 70-kg person with a sodium concentra-
attempts to elicit Chvostek and Trousseau signs. Cataracts and
tion of 160 mEq/L would require about 4.5 L of free water. As
papilledema may be seen.
with hypo-osmolality, general clinical guidelines developed in
Severe hypocalcemia should be treated with infusions of
the pediatric age group suggest a rate of correction that does
calcium to treat or prevent epileptic seizures or laryngeal
not exceed 0.5 mEq/h.
spasms, both of which are life-threatening but unusual com-
Chronic hyperosmolality is associated with relative brain
plications. Chronic therapy usually involves administration
volume preservation as a result of the production of idiogenic
of calcium and vitamin D. Care must be taken to avoid
osmoles, as described earlier. Administering free water at a rate
hypercalcemia and hypercalciuria. Consultation with an
that exceeds the rate at which the brain is able to rid itself of
endocrinologist is prudent, but continued neurological care
idiogenic osmoles is associated with the development of para-
may be necessary, especially in patients with extrapyramidal
doxical brain edema that occurs at a time when serum glucose
syndromes, who may require specific treatment.
and electrolyte concentrations are normalized. This is illus-
trated by the data in Fig. 84.4, in which the CSF pressure was
measured continuously as hyperglycemia due to diabetes mel- Disorders of Magnesium Metabolism
litus was corrected. The increase in intracranial pressure is
Hypermagnesemia is an unusual condition because of the ease
undoubtedly caused by adapted brain cells imbibing free water
with which normal kidneys act to preserve magnesium home-
as serum osmolality decreases in response to therapy. If patients
ostasis. Hypermagnesemia is most commonly due to infu-
undergoing treatment for hyperosmolar states develop new
sions given to treat blood pressure and nervous system
neurological signs, including altered consciousness and sei-
dysfunction in patients with eclampsia. Care must be observed
zures, the diagnosis of brain swelling should be considered.
in administering magnesium to patients with renal failure.
Mannitol treatment to restore osmolality to the prior elevated
This group of patients is the most vulnerable and the most
level may be required to prevent death due to brain swelling.
likely to develop hypermagnesemia because the kidneys’
To avoid the production of brain edema, seizures, and
homeostatic function is impaired. Hypocalcemia potentiates
other complications, the rate of correction should not
the effects of excess magnesium. Severe hypermagnesemia is
exceed 0.5 mmol/L in any given hour, and no more than
life threatening, and concentrations in excess of 10 mEq/L
10 mmol/L/day.
must be treated. Discontinuation of magnesium preparations
usually suffices. When cardiac arrhythmias are present or cir-
Disorders of Calcium Metabolism culatory collapse is possible, calcium must be infused, espe-
Hypercalcemia and hypocalcemia both have diverse causes cially when hypocalcemia is present.
associated with disordered parathyroid gland function and a Isolated hypomagnesemia is unusual. Magnesium defi-
variety of other conditions. In normal circumstances, approxi- ciency usually occurs in patients with deficiencies of other
mately half of the total serum calcium is bound to proteins, electrolytes. Hypomagnesemia may result from a diet deficient
mainly albumin, and half is in the ionized form, the only form in magnesium, including prolonged parenteral alimentation
in which it is active. When there is doubt about the Ca2+ con- with insufficient or no magnesium replacement, malabsorp-
centration, as in patients with hypoalbuminemia, direct meas- tion, and alcoholism. Excess magnesium loss from the GI tract
urement of Ca2+ with ion-sensitive electrodes may be required. or the kidneys may also lead to calcium deficiency. Magnesium
Hypercalcemia is associated with hyperparathyroidism, deficiency is usually part of a complex electrolyte imbalance,
granulomatous diseases (especially sarcoidosis), treatment and accurate diagnosis and management of all aspects of the
with drugs including thiazide diuretics, vitamin D, calcium state are necessary to ensure recovery.
itself, tumors that have metastasized to bone, and thyroid Pure magnesium deficiency has been produced experimen-
disease. Many cases are idiopathic. tally and is expressed primarily through secondary reductions
The symptoms and signs of hypercalcemia may be protean. in serum calcium levels despite adequate dietary calcium
Severe hypercalcemia affects the brain directly, causing coma intake. Ultimately, anorexia, nausea, a positive Trousseau sign,
in extreme cases. In this group of patients, metastatic tumors weakness, lethargy, and tremor develop but are rapidly abol-
are common, especially multiple myeloma and tumors of the ished by magnesium repletion. Balance studies indicate that
breast and lung. Cancer patients seem to be particularly vul- magnesium deficiency causes a positive sodium and calcium
balance and a negative potassium balance. Magnesium is nec- on HE, there is increasing evidence that accumulation of
essary for proper mobilization and homeostasis of calcium this metal in the brain causes hyperintensities on T1-weighted 84
and the intracellular retention of potassium. Some of the MRI and may be associated with disorders of dopaminergic
effects of magnesium depletion are secondary to abnormali- neurotransmission.
ties of potassium and calcium metabolism.
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84 Toxic and Metabolic Encephalopathies

Karin Weissenborn, Alan H. Lockwood

CHAPTER OUTLINE consciousness reflect involvement of the reticular activating

TOXIC ENCEPHALOPATHIES HISTORY

Hepatic Encephalopathy Onset Usually acute Varies; may be insidious

hepatic enzymes, are abnormal. Products of normal hepatic

Liver Glutamine Skeletal

Nitrogen Urease amino

with ammonia to produce coma in experimental animals. Treatment

Wernicke Encephalopathy phosphate binders to treat hyperphosphatemia, and thus has

are the first priorities in treatment. One liter of normal saline

Complications of Treatment Disorders of Water and Electrolyte Metabolism

Water loss BOX 84.2 Causes of Hyponatremia

HYPONATREMIA WITHOUT WATER LOSS

BOX 84.3 Causes of the Syndrome of Inappropriate Antidiuretic Hormone Secretion 84

Disorders of Manganese Metabolism REFERENCES

Lockwood, A.H., Weissenborn, K., Butterworth, R.F., 1997. An image

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