Version May 2024
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 healthy individuals 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".)
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 adverse 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.
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Scott E Kasner, MD, who contributed to an earlier version of this topic review.
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