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Acute toxic-metabolic encephalopathy in adults

Authors: Julio A Chalela, MD, Scott E Kasner, MD
Section Editor: Michael J Aminoff, MD, DSc
Deputy Editor: Janet L Wilterdink, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2021. | This topic last updated: Jun 16, 2020.

INTRODUCTION

Confusion is clinically defined as the inability to maintain a coherent stream of thought or

action. Delirium is a confusional state with superimposed hyperactivity of the sympathetic
limb of the autonomic nervous system with consequent signs including tremor, tachycardia,
diaphoresis, and mydriasis. Acute toxic-metabolic encephalopathy (TME), which
encompasses delirium and the acute confusional state, is an acute condition of global
cerebral dysfunction in the absence of primary structural brain disease [1]. An overview of
TME in hospitalized patients will be discussed here; a diagnostic approach to delirium is
presented separately. (See "Diagnosis of delirium and confusional states".)

TME is common among critically ill patients. Furthermore, TME is probably under-recognized
and undertreated, especially when it occurs in patients who require mechanical ventilation
[2-4]. TME is usually a consequence of systemic illness, and the causes of TME are diverse.
Most TME is reversible, making prompt recognition and treatment important. Certain
metabolic encephalopathies, including those caused by sustained hypoglycemia and
thiamine deficiency (Wernicke encephalopathy), may result in permanent structural brain
damage if untreated. Alcohol withdrawal syndromes must be excluded in patients with
suspected TME. (See "Management of moderate and severe alcohol withdrawal syndromes".)

PATHOPHYSIOLOGY

Normal neuronal activity requires a balanced environment of electrolytes, water, amino

acids, excitatory and inhibitory neurotransmitters, and metabolic substrates [5]. In addition,
normal blood flow, normal temperature, normal osmolality, and physiologic pH are required
for optimal central nervous system function [6]. Complex systems, including those mediating
arousal and awareness and those involved in higher cognitive functions, are more likely to
malfunction when the local milieu is deranged [5-7].

All forms of acute TME interfere with the function of the ascending reticular activating
system and/or its projections to the cerebral cortex, leading to impairment of arousal and/or
awareness [6]. Ultimately, the neurophysiologic mechanisms of TME include interruption of
polysynaptic pathways and altered excitatory-inhibitory amino acid balance [8,9]. The
pathophysiology of TME varies according to the underlying etiology:

● Cerebral edema contributes to acute fulminant hepatic encephalopathy and to hypo-

osmolar encephalopathies [7].

● Drug-induced delirium results from disruption of the normal integration of

neurotransmitters, including dopamine, acetylcholine, glutamate, gamma-aminobutyric
acid (GABA), and/or serotonin [7,10].

● Electrolyte derangements alter membrane excitability to produce TME [6,8].

● Nutritional disorders disturb cellular energy metabolism and may result in neuronal
death [5,6].

● Exogenous toxins, including carbon monoxide and cyanide, cause impaired oxygen
delivery and mitochondrial dysfunction [7].

In some patients, a disturbed blood-brain barrier leads to the accumulation of systemic

toxins, as well as normal plasma constituents, in the brain or cerebrospinal fluid (CSF)
interfering with neuronal function. Increased permeability of the blood-brain barrier is
evidenced by elevated protein in the CSF, a frequent finding in TME [1]. Recent studies
suggest that large neutral amino acids such as tryptophan and tyrosine are involved in the
pathogenesis of delirium in critically ill patients undergoing mechanical ventilation [11].
Interestingly, both very low and very high levels of large neutral amino acids may be
associated with delirium.

CLINICAL MANIFESTATIONS

Most clinical features of acute TME are nonspecific and do not reliably identify a particular
etiology. The term "intensive care unit (ICU) syndrome," or "ICU psychosis," has been used to
describe TME in patients in the ICU. However, this term can be misleading and should be
avoided, since TME in any hospitalized patient results from organic stress on the central
nervous system, rather than factors specific to the ICU setting [12].
TME is common among patients admitted to an ICU; older patients and those with
underlying dementia are at greatest risk. A single center study found that delirium was
present at ICU admission in 31 percent of patients older than 65 years of age [13].
Furthermore, 70 percent of this population developed delirium at some point during
hospitalization. Other possible risk factors for TME include nutritional deficiency, infection,
temperature dysregulation, and failure of multiple organ systems [14]. The presence of
delirium is an independent risk factor for six-month mortality and prolonged hospitalization
in patients receiving mechanical ventilation [3].

Mental status examination — The cardinal feature of confusion and delirium is impaired

attention; clinical findings can range from subtle cognitive difficulties to florid delirium or
coma. Impairments in attention are a relatively sensitive and specific marker of delirium.
Simple bedside tasks such as serial subtraction or naming the months of the year in reverse
can test attention. Marked fluctuations in mental status over time are characteristic [5]. (See
"The mental status examination in adults", section on 'Attention and concentration'.)

Other common findings include a disturbed sleep-wake cycle, decreased alertness,

hypervigilance, hallucinations, sensory misperceptions, impaired memory, and
disorientation [1,5-7]. The thought process is often disorganized, manifested by confused or
rambling conversation [5]. Paranoid ideation and excessive suspiciousness may occur. Affect
is also compromised in TME; most patients tend to be apathetic and withdrawn; some seem
anxious, agitated, and fearful; and others appear to be manic [6,7]. (See "Diagnosis of
delirium and confusional states".)

The level of alertness reflects the severity of the underlying condition; severely affected
patients are comatose. (See "Stupor and coma in adults", section on 'Metabolic coma'.)

Seizures — Seizures, usually generalized tonic-clonic, but sometimes focal, multifocal, and

partial complex, can be a manifestation of acute TME. (See "Evaluation and management of
the first seizure in adults", section on 'Acute symptomatic seizures'.)

In some patients, seizures are subtle, without overt motor manifestations, and require
electroencephalography (EEG) monitoring for their detection.

Cranial nerve examination — Almost all causes of TME manifest preservation of pupillary

function (even if the pupils are pinpoint) except anticholinergic drug or glutethimide
ingestion [1,5-7,15]. Ocular motility remains intact, but in comatose patients the eyes may
rove randomly and come to rest in a dysconjugate position with upward and outward gaze
deviation bilaterally (Bell's phenomenon) [6,7,15]. (See "Stupor and coma in adults", section
on 'Neurologic examination'.)
Other brainstem reflexes (eg, oculocephalic reflex, corneal reflex, gag) generally are only
affected in severe TME. Occasional patients with Wernicke encephalopathy or barbiturate
overdose may lose brainstem reflexes, which can mimic death by brain criteria [1,6,7,15].
(See "Diagnosis of brain death" and "Stupor and coma in adults", section on 'Neurologic
examination'.)

Motor examination — A variety of motor abnormalities may be observed in patients with

TME:

● Tremor is common; it is usually coarse and irregular at a rate of 8 to 10 cycles per

second [1,6,16]. (See "Overview of tremor", section on 'Physiologic tremor'.)

● Asterixis, first described in hepatic encephalopathy, is now appreciated to be common to

many forms of TME. It is almost always bilateral; unilateral asterixis (or any asymmetric
response) suggests an occult structural lesion [5,7].

● Multifocal myoclonus is common in TME and is characterized by sudden, nonrhythmic,

gross muscle twitching, particularly involving the face and proximal muscles. (See
"Symptomatic (secondary) myoclonus".)

● Other common abnormalities include paratonia, primitive reflexes, brisk deep tendon
reflexes, and extensor plantar responses. In severely obtunded subjects, decorticate and
decerebrate posturing can occur [7,15,17].

Cardiopulmonary examination — Autonomic instability, manifested as tachycardia,

hypertension, fever, or diaphoresis, is characteristic of delirium [5,6,18]. Respiratory
abnormalities, particularly Cheyne-Stokes respiration, may also occur [1,6,15]. (See
"Disorders of ventilatory control".)

SPECIFIC ETIOLOGIES

Septic encephalopathy — Septic encephalopathy is the most common cause of acute TME,

and its presence and severity correlate with increased mortality [7,16,19,20]. The
pathophysiology of septic encephalopathy is multifactorial. Microcirculatory abnormalities,
altered blood-brain barrier permeability, inflammatory cytokines, reductions in monoamine
neurotransmitters, and an increase in the concentration of the false neurotransmitter
octopamine may all play a role [1,16,19,21]. Ischemia secondary to in situ thrombosis is well
known to occur in other organs in sepsis and may also affect the brain and be visible on
magnetic resonance imaging (MRI) [22,23].

A lumbar puncture performed to exclude meningitis may be entirely normal or show an

elevated protein concentration. The electroencephalography (EEG) is usually diffusely slow;
as the encephalopathy worsens there may be triphasic waves, and a burst-suppression
pattern in severe cases [7,16,19]. Diffuse muscle weakness due to coexistent critical care
polyneuropathy is found in up to 70 percent of patients [16,19]. (See "Neuromuscular
weakness related to critical illness".)

Treatment consists primarily of control of the underlying infection, as well as the general
measures described above. (See "Evaluation and management of suspected sepsis and
septic shock in adults".)

Hepatic encephalopathy — Two forms of hepatic encephalopathy are recognized [7,24,25]:

● Acute hepatic encephalopathy associated with marked cerebral edema is seen in

patients with the acute onset of hepatic failure.

● Chronic hepatic encephalopathy occurs in subjects with chronic liver disease and
portosystemic shunting of blood.

The pathophysiology of hepatic encephalopathy is multifactorial, and increased ammonia

concentration, false neurotransmitters, endogenous benzodiazepine-like substances,
abnormal fatty acid metabolism, free radical damage, cerebral edema, and increased
mercaptans all have been implicated [6,7,24]. (See "Hepatic encephalopathy: Pathogenesis".)

Cerebral edema is found in 80 percent of patients with acute hepatic encephalopathy and is
due to both cytotoxic edema and increased permeability of the blood-brain barrier [7,25].
Common precipitants of chronic hepatic encephalopathy include a high protein intake,
gastrointestinal bleeding, diuretic use, benzodiazepine or opiate use, alcohol consumption,
infections, hypovolemia, and progression of the underlying hepatic disorder [7,24,25]. (See
"Hepatic encephalopathy in adults: Clinical manifestations and diagnosis".)

Clinical findings in hepatic encephalopathy vary with its severity. Initial manifestations are
subtle and may include irritability, reversed sleep-wake cycles, brevity of responses, apathy,
and postprandial confusion. In chronic hepatic encephalopathy, the findings tend to
fluctuate with periods of remission interspersed. In acute hepatic encephalopathy, an
explosive, progressive course develops after the acute insult to the liver [5,7,24,25]. Typically,
an agitated confusional state (known as stages 1 and 2) leads to stupor with preserved
arousal (stage 3), followed by coma (stage 4). Hyperventilation and hyperthermia are often
present.

Neurologic examination may reveal disorientation, inattention, difficulty with visuospatial

tasks, cortical blindness, asterixis, paratonia, tremor, and frontal release signs, while the
pupillary response to light is preserved [6,24]. However, if the patient is comatose, false
localizing signs such as hemiparesis, ocular bobbing, dysconjugate eye movements, and
tonic downward deviation of the eyes may appear, suggesting a focal or structural lesion
[6,7]. In deep coma, decerebrate posturing and agonal respirations may be present.

The diagnosis of hepatic encephalopathy is made primarily upon clinical grounds. Elevated
arterial ammonia concentrations are frequently documented, but a normal ammonia
concentration does not exclude the condition [24]. Cerebrospinal fluid (CSF) glutamine
determination is a very sensitive test, but lumbar puncture is often contraindicated because
of coagulopathy [7]. Abnormal liver function tests, abnormal coagulation parameters,
decreased albumin concentration, mild respiratory alkalosis, and mild hypoxemia are
common. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis".)

A noncontrast head computed tomography (CT) should be performed to exclude intracranial

hemorrhage, particularly in coagulopathic patients. Cerebral edema is often evident in
patients with acute hepatic encephalopathy. (See "Acute liver failure in adults: Management
and prognosis".)

The EEG is always abnormal in the setting of hepatic encephalopathy, usually with diffuse
slowing and disorganization of the background rhythm. Triphasic waves are common in
hepatic encephalopathy but also may occur in other forms of TME [26].

Treatment of hepatic encephalopathy begins with correction of coagulation parameters,

electrolyte abnormalities, volume depletion, hypoxemia, and identification and treatment of
potential infectious precipitants [7]. (See "Hepatic encephalopathy in adults: Treatment".)

Uremic encephalopathy — TME is a sign of advanced renal failure. Although the onset and
severity of encephalopathy generally parallel the severity of azotemia, there is appreciable
interpatient variation [17]. As examples, encephalopathy typically occurs later in younger,
otherwise healthy patients and sooner in older patients or those with underlying central
nervous system disease. Encephalopathy can also occur as a component of dialysis
disequilibrium syndrome after dialysis is initiated. (See "Dialysis disequilibrium syndrome".)

The dialyzable toxins responsible for uremic encephalopathy have not been unequivocally
identified [1]. In animal models of uremia, infusion of parathyroid hormone reproduces both
the clinical and the EEG findings of uremic encephalopathy [8]. Brain amino acid metabolism
also may be impaired, causing an imbalance between excitatory and inhibitory
neurotransmitters, or the accumulation of false neurotransmitters such as methylguanidine
and "middle molecules" [7,8]. (See "Uremic toxins".)

Early clinical features of uremic encephalopathy include lethargy, irritability, disorientation,

hallucinations, and rambling speech. Coma is unusual but may occur in patients with acute
renal failure [1,8]. Most uremic patients have mild diffuse weakness and show unsteadiness
in their movements [8]. Tremor, myoclonus, and asterixis are common and tend to vary in
parallel with mental status; tetany may be present. (See "The detailed neurologic
examination in adults".)

Rarely, focal signs such as hemiparesis or reflex asymmetry may occur [8]. Such focal signs
tend to be transient, alternate from side to side, and resolve with hemodialysis [1,8].
Generalized seizures may occur, particularly when uremia is acute, and myoclonus,
psychosis, and coma can also be seen [1,6,8]. (See "Seizures in patients undergoing
hemodialysis".)

The EEG in uremia reflects the severity of encephalopathy. The most common EEG finding is
prominence of slow waves. Intermittent frontal rhythmic theta activity and paroxysmal,
bilateral, high-voltage delta waves also are frequent, and triphasic waves may appear in the
frontal regions [26]. Epileptiform activity may be present in up to 14 percent of cases [8].
Neuroimaging may be required to exclude the presence of a subdural hematoma.

Acute uremic encephalopathy reverses with dialysis, although a lag time of one to two days
usually is required before mental status clears. Subtle cognitive difficulties may persist even
after dialysis in patients with chronic renal failure. Failure to improve substantially following
dialysis should alert the physician to other possible etiologies of encephalopathy. In most
cases of dialysis disequilibrium syndrome, neurologic recovery is rapid and complete [1,6-8].

Hyponatremia — Hyponatremia, a common cause of TME, is most often due to the

syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or a decrease in
effective circulating blood volume [27,28]. (See "Causes of hypotonic hyponatremia in
adults".)

Clinical manifestations depend upon the severity and rate of the development of
hyponatremia. Hyponatremia developing in less than 12 to 24 hours and to sodium
concentrations below 120 mEq per liter generally results in more severe symptoms [27,28].
Confusion, disorientation, agitation, delirium, lethargy, muscle cramps, and generalized
weakness are common. With advancing hyponatremia, the level of consciousness declines
and generalized tonic-clonic seizures appear. (See "Manifestations of hyponatremia and
hypernatremia in adults".)

Treatment of hyponatremia should be based upon the clinical symptoms and the
presumptive cause. Care should be taken not to correct hyponatremia too rapidly or to too
high a concentration in asymptomatic patients because of concern regarding the
development of osmotic demyelination. (See "Osmotic demyelination syndrome (ODS) and
overly rapid correction of hyponatremia".)

Hypernatremia — Hypernatremia is due to increased insensible water losses, decreased

thirst or access to water, infusion of large volumes of saline or bicarbonate, or diabetes
insipidus [28]. (See "Etiology and evaluation of hypernatremia in adults".)

Neurologic symptoms in hypernatremia are due to the hyperosmolar state that leads to
osmotic dehydration of the brain. If hyperosmolality develops slowly and persists for hours
or days, brain cells maintain their volume by generating new intracellular solutes termed
"idiogenic osmoles" (or osmolytes) [7,27,28]. Most patients remain alert until their osmolality
exceeds 350 mOsm/kg, after which drowsiness, confusion, and occasionally seizures occur.
Intracranial hemorrhage and venous sinus thrombosis are other rare neurologic
complications. Mortality in patients with sodium levels exceeding 160 mEq/liter may exceed
70 percent but is often due to the underlying condition [7,28]. (See "Manifestations of
hyponatremia and hypernatremia in adults".)

Treatment is determined by the underlying cause of hypernatremia. The patient's volume

status and neurologic condition dictate the urgency of correction. A rate of correction of 1 to
2 mEq/L per hour is recommended; higher rates may lead to fatal cerebral edema [27,28].
(See "Etiology and evaluation of hypernatremia in adults" and "Treatment of hypernatremia
in adults".)

Other electrolyte abnormalities — Other electrolyte abnormalities that can produce

encephalopathy include hypo- or hypercalcemia, hypomagnesemia, and hypophosphatemia
[7,18,28].

● Hypercalcemia manifests as drowsiness that can progress to coma, and is readily

reversible. (See "Clinical manifestations of hypercalcemia" and "Treatment of
hypercalcemia".)

● Hypocalcemia and hypomagnesemia frequently coexist and present with muscle

weakness, behavioral changes, hallucinations, seizures, and coma. Chvostek's and
Trousseau's signs may be present. (See "Clinical manifestations of hypocalcemia" and
"Hypomagnesemia: Evaluation and treatment".)

● Severe hypophosphatemia leads to muscle weakness with particular preference for the
diaphragm. Confusion, ataxia, nystagmus, and abducens palsy may occur. Patients on
parenteral nutrition are most prone to these disorders [7,28]. (See "Hypophosphatemia:
Evaluation and treatment".)

Hypoglycemia — Hypoglycemia can produce a myriad of neurologic signs and symptoms.

Hypoglycemia results from the use of insulin or hypoglycemic agents, alcoholism, and/or
liver disease [29]. An overall mortality of 11 percent has been associated with hypoglycemia
and is attributable primarily to underlying medical conditions [29].

Hypoglycemia usually presents with symptoms of increased epinephrine release (eg, tremor,
diaphoresis) followed by neurologic symptoms that correlate poorly with glucose
concentrations and include generalized seizures, bizarre behavior, coma, and focal deficits
[28,29]. Seizures may occur after sudden shifts in the glucose level [7,29]. Recovery has been
reported even after sustained hypoglycemic coma [1,6,29]. (See "Physiologic response to
hypoglycemia in normal subjects and patients with diabetes mellitus".)

In acute severe hypoglycemia, a bolus of 25 to 50 grams of dextrose should be administered

intravenously, followed by a continuous dextrose infusion [7,29]. Blood glucose
concentrations should be measured hourly. Reversal of neurologic symptoms may lag
behind normalization of glucose levels [28,29]. (See "Hypoglycemia in adults with diabetes
mellitus".)

Hyperosmolar hyperglycemia and diabetic ketoacidosis — Patients with hyperosmolar

hyperglycemic state (HHS) and diabetic ketoacidosis (DKA) will develop progressive
neurologic impairment with lethargy and progressive obtundation and, ultimately, coma.
Focal deficits and seizures can occur [30-33]. Some patients with HHS have prominent
hemichorea-hemiballism with associated high signal intensity in the contralateral striatum
on T1-weighted MRI [34-37]. (See "Overview of chorea", section on 'Other metabolic or
endocrine disturbances'.)

Neurologic deterioration is more common and occurs earlier in HHS than DKA, implying a
primary pathogenic role of hyperosmolarity, although a metabolic acidosis can also play a
role [38]. HHS and DKA typically occur in a patient with known diabetes and are often
precipitated by infection or medical noncompliance; however, TME may be a first
presentation of diabetes as well. (See "Diabetic ketoacidosis and hyperosmolar
hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on
'Neurologic symptoms'.)

The treatment of HHS and DKA are discussed in detail separately. (See "Diabetic ketoacidosis
and hyperosmolar hyperglycemic state in adults: Treatment".)

Wernicke encephalopathy — Wernicke encephalopathy is due to diencephalic and

mesencephalic dysfunction of central gray structures surrounding the third and fourth
ventricles secondary to thiamine deficiency. Occurring both in alcoholics and nonalcoholic
subjects, it probably is an underrecognized cause of encephalopathy in the intensive care
unit (ICU). Patients who are fasting, receiving parenteral nutrition, recovering from
gastrointestinal surgery, being fed after a period of starvation, undergoing hemodialysis, or
suffering from advanced cancer are particularly susceptible to this disorder [39]. (See
"Wernicke encephalopathy".)

Wernicke encephalopathy is characterized by a triad of confusion, ataxia, and

ophthalmoplegia. The full triad is rarely present, and variations from the classical description
occur commonly. Ocular signs are the hallmark of the disease, including horizontal
nystagmus, bilateral abducens palsy, complete ophthalmoplegia, and pupillary
abnormalities [39]. Apathy, impaired awareness, disorientation, mental sluggishness, and
restlessness characterize the encephalopathy. In extreme cases, coma may be the
presenting feature [39]. An agitated form that overlaps with alcohol withdrawal syndrome
has been described [7]. Ataxia results from vestibular and cerebellar dysfunction, and
hypothermia and hypotension may occur due to hypothalamic dysregulation [39].

Prompt treatment with intravenous thiamine can reverse Wernicke encephalopathy. The
ocular abnormalities are the first manifestation to respond to therapy. The ataxia and the
encephalopathy may take days to weeks to resolve, and there may be permanent memory
and cognitive impairment [39]. All debilitated patients at risk for Wernicke encephalopathy
should receive adequate thiamine supplementation. (See "Wernicke encephalopathy",
section on 'Treatment' and "Wernicke encephalopathy", section on 'Prevention'.)

Hypoxic-ischemic encephalopathy — Hypoxic-ischemic encephalopathy is usually a

straightforward diagnosis that follows an obvious precipitating event such as cardiac arrest
with prolonged resuscitation efforts. Hypotension or hypoxemia may also lead to hypoxic-
ischemic encephalopathy that can mimic TME of other etiology [1,5,7]. The duration and
severity of hypoxia or hypotension and the patient's preexisting neurologic status determine
the magnitude of the neurologic insult [40-42]. (See "Prognosis and outcomes following
sudden cardiac arrest in adults" and "Cardiac evaluation of the survivor of sudden cardiac
arrest".)

Clinical findings range from subtle memory difficulties to coma. When patients awaken from
coma, anterograde and retrograde amnesia and global confusion may be apparent,
resembling the amnestic syndrome seen in Korsakoff's psychosis [7]. Other common clinical
findings include cortical blindness, myoclonus, seizures, cerebellar ataxia, akinetic-rigid
syndromes, and bilateral arm weakness due to watershed-territory infarctions (man in a
barrel syndrome) [5-7]. In comatose patients, the presence of the pupillary light reflex, flexor
or extensor responses, and conjugate or orienting eye movements on initial examination
may be used to identify patients with a better prognosis [40,41]. (See "Hypoxic-ischemic
brain injury in adults: Evaluation and prognosis".)

Post-transplantation encephalopathy — Encephalopathy following transplantation may be

due to underlying conditions, operative procedures, immunosuppressive medications,
cranial radiation, or opportunistic infections.

● Complications of underlying disease – The disease that led to transplantation may be

responsible for the encephalopathy [43,44]. As examples, patients with chronic renal
failure may develop uremia or experience a perioperative stroke, and patients with end-
stage cardiomyopathy may develop cerebral hypoperfusion or cerebral embolism. In
liver transplant patients, encephalopathy present at the time of transplantation may
 continue if the transplant fails acutely. In pancreatic transplant patients, a reversible and
rare pancreatic encephalopathy has been described that presents with prominent
autonomic findings and closely resembles Wernicke encephalopathy [43,44].

● Medications – Most immunosuppressant medications used following transplantation

are capable of producing encephalopathy:

• Cyclosporine can cause somnolence, headache, dysarthria, depression, and visual

hallucinations. Risk factors for cyclosporine toxicity include low concentrations of
magnesium or cholesterol, hypertension, aluminum overload, and concomitant use
of corticosteroids. Neurologic complications of cyclosporine toxicity are often
associated with a characteristic posterior leukoencephalopathy, which is reversible.
This phenomenon, visible on T2-weighted MRI, probably reflects abnormal cerebral
vascular autoregulation as occurs in hypertensive encephalopathy. Cyclosporine's
propensity to produce this autoregulatory failure is probably due to more than one
factor, including the induction of hypertension by a sympathomimetic mechanism,
renal toxicity, and hypomagnesemia related to renal effects. (See "Pharmacology of
cyclosporine and tacrolimus".)

• Tacrolimus (FK 506) may also cause an encephalopathy characterized by anxiety,

tremor, vivid nightmares, and restlessness [43]. (See "Pharmacology of cyclosporine
and tacrolimus".)

• Corticosteroids can cause insomnia, irritability, impaired concentration, and mood

changes including a florid steroid psychosis. Treatment options include stopping the
drug, lowering the dose, substituting dexamethasone (the glucocorticoid least likely
to induce psychosis), and administering antipsychotic agents. Affective symptoms
may respond to lithium. (See "Major side effects of systemic glucocorticoids".)

• Patients receiving OKT3 monoclonal antibodies may develop acute aseptic

meningitis with seizures, fever, lethargy, increased muscle tone, myoclonus, and a
diffuse encephalopathy with cortical blindness. Imaging studies may show mild
cerebral edema. Antithymocyte and antilymphocyte globulins can produce a similar
encephalopathy [44].

• Cranial irradiation administered in conjunction with bone marrow transplantation

may cause an acute encephalopathy characterized by fever, headache, nausea,
somnolence, worsening of preexisting deficits, and seizures. TME induced by cranial
radiation results from diffuse cerebral edema and may respond to corticosteroids
[43,44]. (See "Acute complications of cranial irradiation".)
 ● Rejection – An encephalopathy of acute rejection is increasingly recognized, particularly
with acute renal allograft rejection, and is characterized by headache, confusion,
seizures, and papilledema [44]. CSF opening pressure may be increased, and CT reveals
diffuse cerebral edema. The EEG shows diffuse slowing in all cases and focal slowing in
25 percent of cases. The syndrome is ascribed to release of soluble immune mediators
[44].

● Infection – Five to 10 percent of all transplant recipients develop a central nervous

system infection; some may present with encephalopathy without meningeal signs or
focal deficits. Listeria, Toxoplasma, varicella-zoster virus, Strongyloides stercoralis, and
Cryptococcus neoformans tend to present with encephalitis, mimicking TME [43,44].

DIFFERENTIAL DIAGNOSIS

Acute TME is in some measure a diagnosis of exclusion within a broad differential diagnosis.
Alcohol withdrawal, meningitis, encephalitis, brain tumors, nonconvulsive seizures, central
venous thrombophlebitis, bacterial endocarditis, fat embolism, basilar artery thrombosis,
traumatic brain injury, and right hemisphere stroke can present with an acute confusional
state or other state of impaired consciousness that appears similar to TME [5,7]. The
differential diagnoses of acute confusional state and stupor are discussed in detail
separately. (See "Diagnosis of delirium and confusional states", section on 'Risk factors' and
"Diagnosis of delirium and confusional states", section on 'Precipitating factors' and "Stupor
and coma in adults", section on 'Etiologies and pathophysiology'.)

DIAGNOSIS

The diagnostic evaluation focuses on excluding other conditions that may cause an acute
confusional state or suppressed consciousness and identifying the potential etiologies of a
TME. Usually, some element from the history, physical examination, or review of medications
will aid in determining the etiology, although the cause of encephalopathy frequently
remains undetermined [5]. (See "Diagnosis of delirium and confusional states", section on
'Evaluation'.)

Laboratory studies — The laboratory investigation of TME includes a complete blood count,

coagulation studies, electrolyte panel, and examination of calcium, magnesium, phosphate,
glucose, blood urea nitrogen, creatinine, bilirubin, liver enzymes, ammonia, serum
osmolality, and arterial blood gases [1]. Toxicologic screening should be performed for
suspected intoxications, and blood and cerebrospinal fluid (CSF) cultures obtained if
infection appears present. Thyroid function tests and vitamin B12 and serum cortisol
concentrations should be assessed if endocrinopathy is considered [18].
Neuroimaging — Computed tomography (CT) or magnetic resonance imaging (MRI) of the
head is indicated when focal signs are present on physical examination or when subdural
hematoma is suggested by the history [1].

Electroencephalography — The electroencephalogram (EEG) can both confirm global

cerebral dysfunction and exclude subclinical seizures with greater sensitivity than clinical
examination alone [1,6,7,16,19]. The degree of diffuse slowing of the normal background
plus abnormal mixed rhythms in the EEG correlates with the severity of TME [7]. Slowing can
be categorized as follows:

● Mild, with a reduction in the normal alpha frequencies (8 to 13 Hz)

● Moderate, with theta frequencies (4 to 8 Hz)

● Profound, with delta frequencies (less than 4 Hz)

Triphasic waves are paroxysmal (or occasionally rhythmic) discharges that are common, but
nonspecific, findings in TME. The most extreme cases of TME can exhibit a burst-suppression
pattern. Burst suppression, which occurs in close to 40 percent of sedated intensive care unit
(ICU) patients, is associated with increased mortality; however, it is not clear if this is due to
oversedation or underlying brain injury [45].

Epileptiform discharges, including spikes, sharp waves, and others, may be superimposed
upon the pattern of background slowing. Up to 10 percent of critically ill patients with sepsis
may be experiencing subclinical seizures or have periodic epileptiform discharges on EEG
[46]. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".)

PREVENTION

TME and delirium are associated with worse outcomes particularly in older adult patients.
(See 'Prognosis' below and "Delirium and acute confusional states: Prevention, treatment,
and prognosis", section on 'Outcomes'.)

Medical complications that lead to TME and delirium should be anticipated and avoided
when possible. Other preventive interventions are discussed separately. (See "Delirium and
acute confusional states: Prevention, treatment, and prognosis", section on 'Prevention'.)

MANAGEMENT

The treatment of TME focuses primarily on correcting the underlying condition. (See 'Specific
etiologies' above.)
However, regardless of the cause of acute TME, a number of general measures should be
instituted. (See "Delirium and acute confusional states: Prevention, treatment, and
prognosis".)

These include [1,5-7,18]:

● Review of medication list and discontinuation of all drugs with potential toxicity to the
central nervous system, if possible ( table 1).

● Physical restraints should be used only as a last resort, if at all, as they frequently
increase agitation and create additional problems, such as loss of mobility, pressure
ulcers, aspiration, and prolonged delirium. In one study, restraint use among patients in
a medical inpatient unit was associated with a threefold increased odds of persistent
delirium at time of hospital discharge [3]. Alternatives to restraint use, such as constant
observation (preferably by someone familiar to the patient such as a family member),
may be more effective.

● Haloperidol may be given parenterally to treat severe agitation; older adult subjects
usually require only small doses, such as 0.5 mg twice per day. Intravenous haloperidol
has been associated with clinically significant QT prolongation requiring additional
precautions regarding its use. Short-term use is advised. (See "Delirium and acute
confusional states: Prevention, treatment, and prognosis", section on 'Antipsychotic
medications'.)

Haloperidol should be avoided in cases of alcohol withdrawal, anticholinergic toxicity,

and benzodiazepine withdrawal, and also in patients with parkinsonism. (See "Delirium
and acute confusional states: Prevention, treatment, and prognosis", section on
'Antipsychotic medications' and "Management of moderate and severe alcohol
withdrawal syndromes".)

● Thiamine should be administered to patients with a history of alcoholism, malnutrition,

cancer, hyperemesis gravidarum, or renal failure on hemodialysis. (See "Wernicke
encephalopathy".)

PROGNOSIS

While TME is a treatable condition, the clinical course may be quite protracted; neurologic
recovery often lags behind recovery of the underlying condition, particularly in older patients
and those with underlying neurologic disease [23].

Traditionally, clinicians have viewed TME as a fully reversible event. However, severe TME,
particularly coma, is a marker for significant morbidity and mortality. Underlying etiology,
severity, and duration of coma were found to be independently associated with outcome in a
series of 500 patients with medical causes of coma [47-49]. Hypoxic-ischemic coma was
associated with a 58 percent mortality and a 31 percent incidence of persistent vegetative
state or severe disability, while corresponding statistics for other metabolic causes were 47
and 21 percent, respectively. Clinical signs were found to be predictive of these poor
outcomes [48]:

● Absent corneal or pupillary response at 24 hours

● Motor response poorer than withdrawal at three days
● Absent roving eye movements at seven days

Patients with so-called good outcomes may not be unaffected. Among unselected patients
followed after discharge from intensive care units (ICUs), significant, persistent neurologic
and psychiatric disturbances are prevalent, in 32 percent [50]. Cognitive impairment is
usually diffuse, but more prominent in the areas of psychomotor speed, verbal fluency,
visual and working memory, and visuoconstruction abilities. Depression occurs in up to 36
percent of patients discharged from the ICU. Duration of delirium during the acute hospital
stay is longer among patients that develop neuropsychological impairment. Advanced age,
low premorbid intelligence, cerebrovascular and peripheral vascular disease, and hypoxia
are also risk factors [51]. (See "Delirium and acute confusional states: Prevention, treatment,
and prognosis", section on 'Outcomes'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Delirium and
confusional states in older adults" and "Society guideline links: Adult with altered mental
status in the emergency department".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Delirium (confusion) (The Basics)")

● Beyond the Basics topic (see "Patient education: Delirium (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Acute toxic-metabolic encephalopathy (TME) is an acute condition of global cerebral

dysfunction in the absence of primary structural brain disease.

● Normal neuronal activity requires a balanced environment of electrolytes, water, amino

acids, excitatory and inhibitory neurotransmitters, and metabolic substrates. The
neurophysiologic mechanisms of TME include interruption of polysynaptic pathways and
altered excitatory-inhibitory amino acid balance. (See 'Pathophysiology' above.)

● TME manifests clinically as a delirium with either an agitated confusion or somnolence.

Impaired attention is a cardinal feature. Other more variably appearing features include
tremor, myoclonus, and asterixis. In severe cases, posturing may occur and brainstem
reflexes may be impaired. (See 'Clinical manifestations' above.)

● TME is a diagnosis of exclusion within a broad differential diagnosis. Alcohol withdrawal,

meningitis, encephalitis, brain tumors, nonconvulsive seizures, central venous
thrombophlebitis, bacterial endocarditis, fat embolism, basilar artery thrombosis,
traumatic brain injury, and right hemisphere stroke can present with an acute
confusional state. Laboratory studies and brain imaging are required in most patients.
Some will need electroencephalography (EEG) and/or lumbar puncture. (See 'Diagnosis'
above.)

● While treatment focuses on the underlying etiology, some general tenets apply to all
patients. (See 'Management' above.)

• Drugs with potential toxicity to the central nervous system are discontinued if
possible.

● Some patients may require medications to control agitated behaviors that risk further
injury to themselves. (See "Delirium and acute confusional states: Prevention, treatment,
and prognosis".)

● Thiamine should be administered to patients with a history of alcoholism, malnutrition,

cancer, hyperemesis gravidarum, or renal failure on hemodialysis. (See "Wernicke
 encephalopathy".)

● While TME is traditionally viewed as a reversible event, it is associated with significant

morbidity and mortality. The duration of the encephalopathy, its severity, advanced age,
and preexisting neurodegenerative disease are risk factors for delayed and incomplete
recovery from TME. (See 'Prognosis' above.)

● Issues related to specific etiologies of TME are discussed above. See individual topic
headings.

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Topic 1661 Version 14.0

GRAPHICS

Common causes of delirium and confusional states

Drugs and toxins

Prescription medications (eg, opioids, sedative-hypnotics, antipsychotics, lithium, skeletal muscle relaxers, polypharmacy)

Nonprescription medications (eg, antihistamines)

Drugs of abuse (eg, ethanol, heroin, hallucinogens, nonmedicinal use of prescription medications)

Withdrawal states (eg, ethanol, benzodiazepines)

Medication side effects (eg, hyperammonemia from valproic acid, confusion from quinolones, serotonin syndrome)

Poisons:
Atypical alcohols (ethylene glycol, methanol)
Inhaled toxins (carbon monoxide, cyanide, hydrogen sulfide)
Plant-derived (eg, Jimson weed, Salvia)

Infections
Sepsis

Systemic infections; fever-related delirium

Metabolic derangements
Electrolyte disturbance (elevated or depressed): sodium, calcium, magnesium, phosphate

Endocrine disturbance (depressed or increased): thyroid, parathyroid, pancreas, pituitary, adrenal

Hypercarbia

Hyperglycemia and hypoglycemia

Hyperosmolar and hypoosmolar states

Hypoxemia

Inborn errors of metabolism: porphyria, Wilson disease, etc

Nutritional: Wernicke encephalopathy, vitamin B12 deficiency, possibly folate and niacin deficiencies

Brain disorders
CNS infections: encephalitis, meningitis, brain or epidural abscess

Epileptic seizures, especially nonconvulsive status epilepticus*

Head injury*

Hypertensive encephalopathy

Psychiatric disorders*

Systemic organ failure

Cardiac failure

Hematologic: thrombocytosis, hypereosinophilia, leukemic blast cell crisis, polycythemia

Liver failure: acute, chronic

Pulmonary disease, including hypercarbia and hypoxemia

Renal failure: acute, chronic

Physical disorders
Burns

Electrocution

Hyperthermia

Hypothermia

Trauma: with systemic inflammatory response syndrome, head injury*, fat embolism
CNS: central nervous system.
* Disorders that, while not truly systemic or "medical," may produce the clinical picture of delirium or confusional state in all other
aspects.

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