Metabolic encephalopathy and metabolic coma …

General Neurology

Updated 04.22.2024
Released 07.17.2007
Expires For CME 04.22.2027

Metabolic encephalopathy and metabolic coma

Authors: Jinny O Tavee MD, Margaret Yu MD

See Contributor Disclosures

Editor: Douglas J Lanska MD MS MSPH

Metabolic encephalopathy and metabolic coma

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Introduction

Overview

Metabolic encephalopathy is a syndrome of global cerebral dysfunction that encompasses various clinical presentations ranging from mild executive dysfunction or agitated delirium to deep coma with decerebrate posturing. In this update, the most recent literature on the clinical manifestations, diagnostic evaluation, and management of metabolic encephalopathy are reviewed. This includes new insights into underlying mechanisms and key features of the diagnostic evaluation that can help point toward specific etiologies.

Key points

	• The initial phase of impairment of consciousness with metabolic encephalopathies is often delirium, with impairment of attention and fluctuations in alertness, clouding of consciousness, disturbances in the wake-sleep cycle, and, sometimes, agitation and restlessness.
	• The anatomic basis for metabolic encephalopathy and metabolic coma relates to diffuse, bilateral cortical dysfunction.
	• In conscious patients with metabolic encephalopathies, cognitive function typically fluctuates considerably, in contrast to dementia.
	• Specific neurologic symptoms, imaging, and EEG patterns may be seen with certain causes of metabolic encephalopathy.
	• Treatment should focus on correcting the underlying etiology, supportive reorientation, and avoidance of sedating medications if possible.

Historical note and terminology

The origin of the term “metabolic encephalopathy” has been attributed to Glaser, who in 1960 described its clinical manifestations in the setting of renal, pulmonary, and hepatic disorders as “acute and chronic disturbances of intellectual performance and motor and sensory activities ranging from mild confusional states to coma” (25; 78). This was followed by Plum and Posner’s classification of encephalopathy into two distinct subgroups: structural and toxic-metabolic, which was published in their monograph, The Diagnosis of Stupor and Coma (57). In clinical practice today, the term metabolic encephalopathy typically refers to global cerebral dysfunction that occurs in the absence of a CNS structural lesion and manifests as delirium or in more severe cases, coma (78).

In this discussion we refer to the “metabolic” conditions as those due to organ dysfunction, nutritional deficiencies, electrolyte imbalances, hypoglycemia, hyperglycemia, endocrine disorders, medications, and systemic sepsis; the following are excluded: metabolic encephalopathies due to inborn errors of metabolism, cardiac arrest and anoxic-ischemic encephalopathy, direct CNS infections, exogenous toxins (including recreational drugs, alcohol, and poisons), hematological conditions, immune-mediated CNS diseases, and direct and indirect effects of cancer on the nervous system.

Of note, metabolic encephalopathy is often due to multiple metabolic derangements rather than just one in isolation, reflecting the interaction among various organ systems. The term “acute encephalopathy” has been recommended by a consensus panel to describe a pathobiological process that develops in less than 4 weeks. Clinically, this may be manifested as (1) subsyndromal delirium (acute cognitive changes compatible with delirium but do not fulfill all DSM-5 delirium criteria), (2) delirium, or (3) coma, and can have additional features like seizures or extrapyramidal signs (68).

Clinical manifestations

Presentation and course

Metabolic encephalopathy often presents as a spectrum that ranges from very mild confusion to coma. Often, patients appear to have components of delirium, which is usually the earliest recognized brain malfunction ability to focus, sustain, or shift attention (80).

Table 1. Common Bedside Tests to Assess for Mental Status Abnormalities

• Orientation question: to self, place, and time
• Forward or reverse digit span
• Spelling WORLD forwards and backwards
• Reciting the days of the week backwards
• Reciting the months of the year backwards
• Serial 3s and 7s
• Vigilance A tasks: tapping the letter A as the examiner lists out a sequence of letters
(03)

Other features of delirium include abnormalities in psychomotor function that can be characterized as hypoactive, hyperactive, and mixed. With hypoactivity, there is decreased motor activity (hypokinesia), reduced alertness, and decreased speech production. Hyperactivity refers to an increased amount of motor activity such as tremor or purposeless movements, which are often seen with restlessness and agitation. Finally, patients may have both components in which they alternate between hypoactivity and hyperactivity (69).

Clinical progression of metabolic encephalopathy beyond delirium can further manifest as obtundation, stupor, and coma. Patients displaying clinical signs of obtundation will be withdrawn and lethargic. Eye opening requires verbal stimulation, and examination requires repetitive prompting and reorientation of attention. Patients are able to follow commands unreliably at times, and following examination, they withdraw into the lethargic state. Stuporous patients require noxious stimulation to promote eye opening and quickly withdraw back to a depleted stated of consciousness. Though focal findings are not present, patients are unable to follow commands and participation in the exam is limited. There may also be associated respiratory depression and upper airway obstruction. The comatose patient presents with the complete inability to stimulate eye opening both through verbal and noxious stimulation. In some patients, the examination may remain nonfocal, so the distinction between metabolic and destructive lesions can be difficult. Patients commonly have associated airway compromise and cardiovascular abnormalities. In such a clinical scenario, triage to a critical care unit is necessary.

Features of encephalopathy that are more characteristic of a metabolic cause rather than a structural lesion include the following:

Acuity of presentation. Structural lesions (like trauma, subarachnoid hemorrhage, ischemic strokes) tend to have an acute onset of symptoms with a static clinical presentation. Metabolic encephalopathy is typically fluctuating in nature and presents more subacutely, although in some cases could be acute.

Clinical setting. Often there is an overt metabolic derangement, a background of vital organ dysfunction, or administration of a medication prone to disrupt cerebral function and the metabolic milieu of the brain (30). There may also be clues from the general examination, including jaundice, hyperventilation, signs of chronic pulmonary or cardiac disease, hypothermia, or hyperthermia.

Vital signs. Specific vital sign abnormalities may be seen depending on the underlying patholophysiology. Myxedema coma and Wernicke encephalopathy commonly cause hypothermia, with temperatures below 35°C. Hypothyroidism slows both metabolism and respiratory rate, and is commonly reflected as a respiratory acidosis on blood gas analysis. Hepatic encephalopathy typically presents with hypothermia, respiratory alkalosis, and relative hypotension due to altered vascular mechanics. Cheyne-Stoke respirations may also occur or develop. Hyperthermia, hypertension, and tachycardia are commonly seen in thyrotoxicosis due to increased sympathetic tone. Metabolic acidosis from advanced sepsis, renal failure, diabetic ketoacidosis, or lactic acidosis can produce hyperventilation and may accompany hypoxemia (80).

Motor phenomenon. Abnormal movements such as tremor, asterixis, and multifocal myoclonus are suggestive of metabolic encephalopathy.

Tremor. Action-postural tremors are commonly seen in agitated delirium as in withdrawal states, uremia, and early phases of hepatic encephalopathy (17).

Asterixis. Also known as negative myoclonus, asterixis is a loss of postural tone that is best assessed by having the patient hold the arms outstretched, the wrists dorsiflexed, and the fingers extended. The “flapping tremor” then appears and is typically irregular and asynchronous. Asterixis may also affect axial muscles, causing the head or body to drop forward. If supported in a frog-leg position, the lower limbs may be affected as well. Although asterixis is commonly associated with hepatic encephalopathy, it may also be seen with hypoxia, hypercarbia, and electrolyte abnormalities, which include but are not limited to hypokalemia and hypomagnesemia (01).

Multifocal myoclonus. In contrast to tremor and asterixis, which are not seen in coma, multifocal myoclonus can be seen in all stages of encephalopathy associated with renal failure, hepatic disease, electrolyte disturbances, and hyperthyroidism, among other causes (36). The originator of the myoclonus is often cortical-subcortical, and onset is typically acute to subacute (61). The brief twitches occur in various muscles in an asynchronous, nonrhythmic fashion. They often involve the face and limbs and may migrate from one side to the other. Multifocal myoclonus may respond to levetiracetam and valproate, but it is often refractory to treatment unless the underlying cause is corrected. In the setting of hepatic coma, multifocal myoclonus is usually an ominous sign and portends a poor prognosis.

Chorea. Chorea has been described in hypernatremia, hyperosmolar hyperglycemic state, hyperthyroidism, hypercalcemia from hyperparathyroidism, and as side effects of some intoxications, eg, phenytoin and phencyclidine (64).

General examination. The stationary position of the patient on the bed and their breathing pattern should be observed. Any spontaneous/semipurposeful movements and motor behavior should be noted. Clues of trauma including bleeding, scars, track marks, and postoperative drainage are important. In the intensive care unit setting, all connected intravenous infusions should be checked for sedative agents and/or vasopressors (81). This allows interrogation into whether a drug or intervention influences the patient’s consciousness level.

Neurologic examination. The key focus of the neurologic examination is to identify the presence of focal neurologic deficits, which would be seen with a structural lesion. The key feature would be the presence of focal neurologic deficits, which would be seen with a structural lesion.

In metabolic encephalopathy, the pupillary reaction to light is usually preserved and symmetric whereas a structural lesion may cause significant asymmetry or ipsilateral loss of pupillary reactions. Although roving eye movements and rarely downward eye deviation can occur in metabolic encephalopathy, lateral gaze deviation, skew deviation, and disconjugate eye movements are more suggestive of structural pathology. However, hepatic encephalopathy can produce a variety of false localizing signs, including conjugate horizontal or vertical gaze deviations, dysconjugate downgaze, severe spasticity with sustained clonus, and a variety of abnormal postures including decortication to painful stimuli. Such signs may be a consequence of cerebral edema but can also occur purely due to metabolic dysfunction with normal intracranial pressure. In end-stage hepatic encephalopathy, the pupillary reaction eventually disappears due to progressive central brainstem displacement, eventually causing fixed mid-position pupils (80). Other well-known metabolic mimics of focal lesions include hypoglycemia and hyperglycemia. Hyperglycemia is also notorious for producing movement disorders, especially hemichorea. Wernicke encephalopathy, related to thiamine deficiency, commonly causes eye movement abnormalities including loss of the vestibulo-ocular reflex even with caloric stimulation. This relates to the site of “metabolic lesions,” which includes the vestibular nuclei at the floor of the 4th ventricle. Other cranial nerve reflexes are spared, thus providing a helpful diagnostic clue. Parenteral thiamine usually restores the vestibulo-ocular reflex in these patients. Finally, the autonomic nervous system can also be affected in metabolic encephalopathy leading to insomnia, cardiac arrhythmias, and respiratory abnormalities (45).

Prognosis and complications

Although most metabolic disorders are reversible, the clinical course can be protracted with varying recovery times. Potential complications include long-term disability and permanent cognitive impairment. The underlying etiology, presence of critical illness, severity of impaired consciousness, and duration of coma are all independent predictors of outcome (54). Sepsis-associated encephalopathy (SAE) affects up to 50% of patients during their hospitalization for sepsis. Those with renal, liver, or multiorgan failure are more frequently affected than the patients with sepsis who do not have organ dysfunction. The mortality rate of sepsis-associated encephalopathy is elevated at 26% to 49% (14). In other studies, the case-fatality associated with metabolic encephalopathy generally ranges from 15% to 20% (29).

For neurocritically ill patients, delirium and metabolic encephalopathy are more difficult to discern but are estimated to have a pooled prevalence of 12% to 43% (55). Delirium in these patients has been found associated with increased hospital length of stay as well as worse functional independence and cognition (55).

Clinical vignette

An 87-year-old woman was admitted to the hospital from a chronic care facility. She was found unarousable in her bed after she had failed to go to breakfast that morning. She briefly roused in the ambulance, but lapsed into coma by the time the ambulance arrived at the emergency room, where she was promptly intubated. Blood studies were obtained, and a CT scan of the head was performed. Because of a heavily calcified basilar artery, the neurologic service was consulted to consider thrombolysis for a basilar artery occlusion.

Heavily calcified basilar artery (CT)

CT scan shows a heavily calcified basilar artery near the arrow (movement artifact is present causing it to appear duplicated) with no obvious lumen. (Contributed by Dr. G Bryan Young.)

On examination, her blood pressure was 140/80. Her heart rate was regular at 80 per minute (sinus rhythm on the monitor). Oral temperature was 36.5°C. The respiratory rate was 15 breaths per minute. She roused very briefly to a shout in the ear, fixated on the examiner, and then again went into a sleep-like state. Her pupils were 3 mm and reactive; corneal and vestibulo-ocular reflexes were brisk. Cough and gag reflexes were present with endotracheal suctioning. The tone of her limbs was normal. Deep tendon reflexes were 2+, except for the ankle jerks, which were absent. On general inspection her skin was normal. There was no organomegaly. Heart sounds were normal, and the chest was clear to auscultation.

Laboratory data revealed a hemoglobin of 12 g/L, white blood cell count of 5.8x10^9/L, and a normal platelet count. Blood gas showed a pH of 7.18, PaO2 of 60 mm Hg, PaCO2 of 98 mm Hg, and a bicarbonate of 35 mmol/L. Serum potassium, sodium, chloride, glucose, calcium, magnesium, phosphate, and creatine kinase were normal. Serum urea and creatinine were only slightly elevated.

A diagnosis of acute carbon dioxide narcosis due to acute-on-chronic respiratory failure was made. The immediate cause was not apparent. While intubated, the patient recovered awareness and could establish communication by nodding or shaking her head. She denied any history of chronic pulmonary disease, heart failure, or opiate intoxication. A more careful inspection of her muscles failed to reveal wasting, fasciculations, or fatigable weakness. The presence of deep tendon reflexes made acute neuropathic process extremely unlikely.

Further investigation included nerve conduction studies and electromyography, which revealed normal motor and sensory conduction velocities and no evidence of neuromuscular junction pathology. With phrenic nerve stimulation, however, diaphragmatic action potential amplitude was reduced, and needle electrode studies revealed abundant fasciculations and fibrillation potentials. A diagnosis of neurogenic diaphragmatic weakness was made, for which motor neuron disease was considered as most likely underlying condition.

This case was instructive, proving that detailed neurologic examination can distinguish structural from metabolic lesions. In this case, the preservation of cranial nerve function and brisk motor exam quickly excluded basilar artery occlusion. With this realization, other causes of coma were considered. The elevated serum bicarbonate concentration made chronic respiratory failure a distinct possibility, and the elevated PaCO2 with a noncompensatory acidosis indicated an acute decompensation. Further testing established that the cause for respiratory failure was not central in nature, but rather peripheral from diaphragmatic weakness due to possible motor neuron disease.

Isolated diaphragmatic failure has been described as an unusual presentation of motor neuron disease but can also be seen in some myopathies and rarely in disorders of neuromuscular transmission (42; 37; 10). Such phenomena are also commonly seen after cardiac surgery due to phrenic nerve dysfunction in the setting of cardioplegia (11).

Biological basis

Etiology and pathogenesis

Table 2 lists the most commonly encountered metabolic encephalopathies in tertiary centers along with postulated mechanisms.

Table 2. Common Etiologies of Metabolic Encephalopathy

Category	Etiologies	Mechanism
Organ dysfunction	Hepatic disorders: • Acute hepatic encephalopathy • Chronic (portal-systemic encephalopathy) • Complications of hepatic encephalopathy	Liver metabolism of ammonia is impaired, which enters the astrocytes of the brain and combines with glutamate to form glutamine. Glutamine formation results in a generation of reactive oxygen species and subsequently causes astrocyte edema (16). Subsequently, there are changes in the GABA-ergic, dopaminergic, serotonergic, and glutaminergic neurotransmission (17).
	Uremic disorders: • Acute renal failure • Chronic renal failure • Complications of renal transplant • Urea cycle disorder	Neurotoxicity arises from accumulation of products of protein metabolism and the kidney’s inability to maintain homeostasis (65).
	Pulmonary disorders: • Hypercarbia • Hypoxemia	Hypoxia: increased blood-brain barrier permeability can lead to cerebral edema. Hypercarbia: excess CO2 affects the CNS through its influence on the CSF pH (65).
Systemic infection	Sepsis	Inflammatory signals from sepsis reach the brain through a compromised blood-brain barrier as well as activation of afferent fibers of the vagus nerve. Astrocytes are activated, and the continued infiltration of inflammatory cells/injury to endothelial cells causes derangement of cerebral perfusion. The brain also affects the peripheral inflammatory response by initiating the neural reflex and promoting the release of neurotransmitters, which contribute to decreased counts and abnormal responses of peripheral immune cells, leading to vicious cycle of sepsis-induced immunosuppression due to uncontrolled neuroinflammation (60).
Endocrine dysfunction	Thyroid disease: • Hyperthyroid • Hypothyroid	Excess or deficiency of thyroid hormones may have neurotoxic effects and have been associated with nonspecific reduced cerebral blood flow (56; 79; 80).
	Adrenal dysfunction	Excess cortisol may cause psychosis (04; 66) whereas adrenal crisis may lead to gastrointestinal symptoms, orthostatic hypotension, electrolyte abnormality (particularly hypoglycemia), and hypotensive shock (58). Cerebral edema has also been reported as a feature of adrenal crisis (80).
	Glucose abnormalities: • Ketoacidosis • Hyperglycemia • Hypoglycemia	The human brain is almost entirely reliant on glucose as an energy source, particularly in higher cortical functioning like the neocortex (08). In addition, hypoglycemia can destroy superficial cortical neurons or cause secondary cerebral cortical injury (67). In hyperglycemia induced ketoacidosis, the metabolic dysregulation during this state mediates neuroinflammation and cerebral oxidative stress, subsequently causing neuronal injury (76).
Nutritional deficiency	B1 deficiency (Wernicke encephalopathy) B12 deficiency	Inability of neuronal cells with low intracellular B1 to meet metabolic demand (75; 51). Synthesis and maintenance of myelin sheaths require B12 (73).
Electrolyte derangements	Sodium: • Hypernatremia • Hyponatremia Calcium: • Hypocalcemia • Hypercalcemia Magnesium: • Hypermagnesemia • Hypomagnesemia	Electrolyte imbalances lead to fluid shifts within glial cells, which play a significant role in development of encephalopathy (24).
Medications	• CNS depressants (benzos, nonbenzo sedative hypnotics, barbiturates) • Anticholinergics • Dopaminergics • Serotonergics	These medications commonly lead to neurotransmitter imbalances involving acetylcholine, dopamine, and gamma aminobutyric acid (GABA). Drug-induced delirium can be caused by a diffuse excess of brain dopaminergic activity, diffuse deficit in brain cholinergic activity, or both (02). Benzodiazepine withdrawal causes a decrease in GABAergic stimulation, which can contribute to encephalopathy. Agonists at the dopaminergic receptors (D1 and D2) increase risk of encephalopathy. Abnormal interactions between the cholinergic/dopaminergic/serotonergic systems can contribute to development of encephalopathy (31).
	Polypharmacy	Increased number of medications is associated with cognitive impairment in older patients, even when none of the medications are themselves clearly linked to delirium or confusional states. This may be due to adverse drug reactions or drug-drug interactions that may be further exacerbated by renal and hepatic dysfunction (44).
	Cefepime	Activates GABA class A receptor resulting in intracellular influx of chloride (09).

Differential diagnosis

Degenerative diseases. The clinical course is more rapid with metabolic encephalopathies than most degenerative disorders. Caveats include Creutzfeldt-Jakob disease (CJD), in which the progression is often subacute. Creutzfeldt-Jakob disease may be associated with focal signs, startle myoclonus, and lack of fluctuation, all of which would be atypical for a metabolic encephalopathy. Other key features of metabolic disturbance causing delirium are a fluctuating course, day-night reversal, and increased psychomotor agitation.

Infections. Primary infectious diseases of the brain may have an acute or subacute onset and are steadily progressive, which may help distinguish them from metabolic encephalopathy. Such patients usually present with fever, leukocytosis, and a systemic inflammatory response.

Extracerebral mass lesions. Subdural hematomas may cause fluctuations in level of consciousness, somewhat similar to metabolic encephalopathies. However, such lesions usually also produce focal signs, such as lateralized weakness, although some patients with acute confusional states associated with acute or chronic subdural hematomas do not have focal findings.

Structural brain lesions. Structural lesions may present with nonfocal symptoms such as confusion, memory problems, or personality changes, which can mimic metabolic encephalopathies (26). However, they often result in focal deficits such as hemiparesis and have a static rather than fluctuating clinical course. Midbrain, thalamic, or parietal lesions may occasionally cause asterixis; however, in such situations, asterixis would likely be focal as opposed to generalized. In parietal and thalamic lesions, asterixis is lateralized to muscles contralateral to the lesion (40).

Intoxications. Many intoxications present like metabolic encephalopathies, sparing the cranial nerve reflexes and producing a dose-dependent depression in the level of consciousness. There are some exceptions, however. Sedative drugs can selectively and reversibly abolish the vestibulo-ocular reflex (50). Hence, sedative drug intoxication should be considered in the differential diagnosis of Wernicke encephalopathy. Massive doses of barbiturates can abolish pupillary and other cranial nerve reflexes and cause apnea, mimicking brain death (52). Drugs with anticholinergic effects, including tricyclic antidepressants or atropine used during resuscitation, can transiently produce dilated, unreactive pupils to both light and accommodation (39). Hyperventilation (mimicking that of metabolic acidosis from renal failure, lactate accumulation, or diabetic ketoacidosis) can be produced by exogenous agents, such as methanol, ethylene glycol, and aspirin (acetylsalicylic acid). These can easily be screened for in the emergency room. Specifically, methanol is metabolized to formic acid (which is present as the formate ion) via formaldehyde, and ethylene glycol is metabolized to oxalic acid. Salicylate assays are available to screen for aspirin poisoning. Ethylene glycol (antifreeze) is often manufactured with a florescent tag that can be detected in the urine with a Wood’s (ultraviolet) lamp.

Diagnostic workup

History and examination. The first and most important step is to obtain an accurate, thorough history followed by a comprehensive examination. In comatose patients, the history is obtained from relatives, friends, or eyewitnesses, either in person or by phone if necessary. Obtaining collateral information from witnesses is very important, as often patients with metabolic encephalopathy are unable to provide an accurate recollection of preceding events. Specific details to ascertain include the acuity of the presentation as well as the patient’s baseline mental status, the latter of which is important to obtain for comparison purposes, especially in older patients who may have preexisting cognitive impairment. Other information that is integral in the evaluation includes the patient’s prior medical and social history. Did the patient have cancer, profound depression (raising the possibility of a drug overdose), or a history of drug or alcohol abuse? Is there an underlying illness, such as diabetes mellitus; pulmonary, hepatic or kidney disease; immunosuppression (either drug-induced or acquired)? What are the current and prior medications?

Blood studies. A comprehensive metabolic panel should be obtained that includes electrolytes (sodium, potassium, magnesium, phosphate, calcium), glucose, and kidney and liver function tests, especially ammonia. Thyroid function tests are essential, as both hyper- and hypothyroidism can cause an encephalopathy. Arterial or capillary blood gas determination can be very helpful in the presence of hyperventilation, hypoventilation, and for some toxidromes. A complete blood count should be obtained (eg, to exclude a leukocytosis). Blood cultures should be done in the presence of fever or hypothermia.

Urine studies. A urine drug screen should be ordered to assess the presence of toxic substances or their metabolites including alcohol, benzodiazepines, barbiturates, opiates, cocaine, amphetamines, tricyclic antidepressants, salicylates, and acetaminophen.

Neuroimaging. Imaging studies are helpful to rule out a structural lesion (eg, intracranial hematoma or mass lesion). In a study of patients with cancer presenting with altered mental status, a structural brain lesion was the sole cause of encephalopathy in 15% of the patients (77). In some cases of metabolic encephalopathy, there may be specific changes on MRI or CT that can help identify the underlying etiology (33; 15; 71; 72). See Table 3. Diffusion-weighted imaging has disclosed characteristic features of acute hepatic encephalopathy, including restricted diffusion in the thalamus and cortex bilaterally (18). Characteristic lesions in the putamen and globus pallidus can suggest methanol and carbon monoxide toxicity, respectively. Nuclear magnetic resonance spectroscopy shows an increase in glutamate and glutamine peaks (46). MRI can also be helpful in confirming Wernicke encephalopathy, with changes occurring in the mammillary bodies, periaqueductal gray matter, the collicular bodies, and the medial thalamus (70). Of note, diffusion-weighted changes involving the cortex appear to indicate irreversible damage, whereas white matter changes are reversible in hypoglycemic coma (43).

Table 3. Potential Imaging and EEG Findings in Different Metabolic Encephalopathy Etiologies

	CT findings	MRI findings	EEG findings
Sepsis	Usually normal	Vasogenic edema when autoregulation is disturbed	Triphasic waves
Hepatic encephalopathy	Usually normal	T1 hyperdensities in the globus pallidus Hyperammonemia can cause bilateral symmetric involvement of the insular cortex with restriction on DWI.	Triphasic waves
Uremic encephalopathy	Hypodense basal ganglia and capsules	FLAIR/DWI hyperintense basal ganglia and capsules	Triphasic waves or epileptiform activity in some, photic sensitivity
Wernicke encephalopathy	Hypodense paraventricular thalamic regions	FLAIR hyperintense periaqueductal and medial thalamic regions, minimized mammillary bodies, and the tectal plate	Sharp and slow wave complexes, periods of suppression in very advanced cases
Hypoglycemic	Enhancing hypodense basal ganglia, cortex, hippocampus	FLAIR hyperintense caudate/lentiform nuclei, cerebral cortex Bilateral T2 hyperintensities with restricted diffusion on DWI of the basal ganglia yields a less optimistic prognosis of this potentially reversible condition	Diffuse slowing of the waking background frequency
Hyperglycemic	Hyperdense putamen and/or caudate nucleus	Uni or bilateral T1 hyperintensity in striatum	Mixed faster frequency, and some focal epileptiform discharges. As the glucose level increases, diffuse delta activity with sporadic spikes above 400 mg/dL.
Hyponatremia	Usually normal	FLAIR/DWI hyperintense lesions in pons, thalamus, putamen, and lateral geniculate bodies, with early restriction on DWI followed by hyperintensities on T2-FLAIR	Diffuse delta activity, alpha rhythms may be interrupted by bursts of high-voltage rhythmic delta activity. May be central high voltage 6 Hz to 7 Hz activity with stimulation-induced delta waves and periodic lateralized epileptiform discharges.
Hypernatremia	Usually normal	FLAIR/DWI hyperintense lesion	Progressive slowing of background EEG frequencies
Hypocalcemia	May see basal ganglia calcifications in chronic	May see basal ganglia calcifications in chronic	Generalized spikes, sharp waves bursts of delta activity with sharp components; some have reported “absence status”
Hypercalcemia	Usually normal	Usually normal	May be excessive theta activity, fast activity, and bursts of delta and theta slowing. Can have increased background slowing with largely frontal/paroxysmal theta/delta bursts. Potential occipital spike-slow wave complexes.
Hypoadrenalism	Usually normal	Usually normal	Marked diffuse theta and delta activity. Decreased reactivity and bursts of frontal delta activity.
Hyperthyroidism	Usually normal	Usually normal	Increased alpha rhythmic frequency with prominent central beta activity. Sporadic theta/anterior bursts of delta activity. Can show slowing of the background activity with some superimposed fast activity. Sometimes triphasics are seen.
Hypothyroidism	Usually normal	Usually normal	Low voltage patterns predominate by theta frequencies. In coma, the EEG may show diffuse suppression with scant activity. Occasionally may show periodic sharp waves. Generalized nonconvulsive status epilepticus may be precipitated.
Cefepime toxicity	Usually normal	Usually normal	Triphasic waves
Adapted from (33; 15; 71; 22; 41).

EEG. The main clinical role of EEG is to evaluate for subclinical seizures, but it can also be used to grade the severity of encephalopathy. Metabolic dysfunction secondary to renal and hepatic failure have been identified as risk factors for nonconvulsive status (34). The presence of triphasic waves or generalized, frontally-predominant rhythmic delta activity (4 Hz or less) on a slow or low-voltage background are common EEG features of metabolic encephalopathies. As with imaging studies, however, there may be certain EEG abnormalities that point toward a particular cause (15). EEG is also helpful in differentiating epileptic from nonepileptic myoclonus.

Lumbar puncture. CSF analysis may be considered but is primarily used to exclude the possibility of subarachnoid hemorrhage or CNS infection, eg, encephalitis or meningitis. In some cases, it may be helpful in evaluating for a potential inflammatory, neoplastic, or paraneoplastic etiology.

MR brain spectroscopy. Though not commonly available, MR spectroscopy can also be used to detect specific causes of metabolic encephalopathy. For hepatic encephalopathy, decreased myo-inositol and choline intensity with increased intensity of the glutamate/glutamine signal has been reported (47).

Special considerations

Pregnancy

Acute liver failure in pregnancy associated with encephalopathy occurs in two contexts: severe pre-eclampsia and acute fatty liver of pregnancy (28). The most severe variant of preeclampsia is the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), which may result in multiorgan involvement and cerebral dysfunction most commonly in the second and third trimesters. On the other hand, acute fatty liver occurs subacutely in the third trimester of pregnancy with microvesicular steatosis of hepatocytes. Immediate delivery is indicated in both conditions and is essential for the survival of mother and child (28).

Hyperemesis gravidarum affects 0.3% to 3.6% of pregnant women and is defined by persistent and excessive vomiting that results in dehydration and weight loss. Patients with hyperemesis gravidarum can develop thiamine deficiency, leading to Wernicke encephalopathy and other electrolyte disturbances such as hyponatremia and hypokalemia (74).

Acute renal failure with encephalopathy is most commonly related to antepartum or postpartum hemorrhage, although puerperal sepsis and disseminated intravascular coagulation are other causes.

Gestational diabetes with hyperglycemia could potentially produce encephalopathy as well.

Anesthesia

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cognitive changes ranging from agitation to severe encephalopathy requiring aggressive sedation are seen in 31% to 65% of hospitalized patients with coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 (07; 63). The most common etiologies in one large series of 4491 hospitalized patients with COVID-19 (of which 12% had toxic-metabolic encephalopathy) were septic, hypoxic-ischemic, and uremic encephalopathy (19); sedation-related delirium, seizures, structural brain disease, and primary neurologic diagnoses were excluded from the study. Risk factors for the development of COVID-19-related encephalopathy include age, underlying cognitive impairment, prior psychiatric disease, need for intubation, and cerebrovascular disease (19; 05). In a multicenter cohort study involving 69 adult ICUs, 55% of patients had delirium for a median duration of 3 days (59). The exact mechanism is not well understood but is thought to be multifactorial due to hypoxia from respiratory compromise, metabolic derangements, and the systemic infection in association with the inflammatory cascade (21; 27). All of these factors may result in a toxic-metabolic encephalopathy in the absence of viral CSF penetration (21). Cytokine-mediated inflammation involving Il-1, Il-6, TNF-alpha, and others increase blood brain barrier permeability and hypercoagulability, leading to stroke, which in combination with ARDS-associated hypoxemia further results in downstream inflammation, neuronal ischemia, and necrosis (49). A spectrum of neuroimaging abnormalities has been reported in COVID-19, including acute or subacute infarcts, symmetric bilateral hemorrhagic thalamic lesions, leptomeningeal enhancement and T2/FLAIR signal changes in cortical/subcortical white matter, and a diffuse leukoencephalopathy (21; 27). Generalized slowing is often seen on EEG, reflecting a diffuse cortical process that may be driven by a metabolic and/or hypoxic encephalopathy (12; 13). In a meta-analysis of 12 studies that characterized EEG findings in 308 patients with COVID-19 infection, 96% demonstrated abnormal background activity, 92% had generalized slowing, and 20% had epileptiform discharges (38). With respect to management, low-potency neuroleptics and alpha-2 adrenergic agents are helpful in treating neuropsychiatric symptoms associated with COVID-19 (06).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Jinny O Tavee MD

Dr. Tavee of National Jewish Health received consulting fees from Argenx, a research grant from Kabafusion Infusion Services as an investigator, lecture fees from Alexion, and travel fees from CSL Behring as an external advisor.
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Margaret Yu MD

Dr. Yu of Northwestern University, Chicago, has no relevant financial relationships to disclose.
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Editor

Douglas J Lanska MD MS MSPH

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
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Former Authors

Gary R W Hunter MD
Katharina M Busl MD MS
Christopher Robinson DO MS

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: None
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Metabolic encephalopathy and metabolic coma

Associated Disorders

Electrolyte imbalance
Endocrine disorders
Folate deficiency
Global or multifocal cerebral ischemia (without neuronal death)
Hepatic encephalopathy
- Hypercalcemia
- Hyperemesis gravidarum
- Hyperglycemia
- Hypoglycemia
- Hyponatremia
- Hypophosphatemia
- Nutritional encephalopathies
- Organ failure (especially hepatic, pulmonary, and adrenal)
- Pulmonary failure
- Renal failure
- Sepsis
- Vitamin B12 deficiency
- Wernicke encephalopathy

Differential Diagnosis

degenerative diseases
Creutzfeldt-Jakob disease
infectious disease of the brain
extracerebral mass lesions
subdural hematomas
- subdural meningiomas
- structural brain lesions
- midbrain lesions
- thalamic lesions
- parietal lesions
- sedative drug intoxication
- barbiturate intoxication
- tricyclic antidepressant intoxication
- atropine intoxication
- methanol intoxication
- ethylene glycol intoxication
- aspirin (acetylsalicylic acid) poisoning

Also Relevant

EEG in encephalopathic conditions
Hepatic encephalopathy
Hypercalcemia
Hypoglycemia
Hypothyroidism
- Myoclonus

Clinical Categories

General Neurology

Metabolic encephalopathy and metabolic coma

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Common Bedside Tests to Assess for Mental Status Abnormalities

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 2. Common Etiologies of Metabolic Encephalopathy

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Table 3. Potential Imaging and EEG Findings in Different Metabolic Encephalopathy Etiologies

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

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Nystagmus

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Brain death/death by neurologic criteria

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Hepatic encephalopathy

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Bowel dysfunction in neurologic disorders

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