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Encephalopathy is a clinical state characterized by global cerebral dysfunction in the absence of structural brain disease. The causes are numerous and often multifactorial but include infections, metabolic disorders, mitochondrial disorders, brain tumor, increased intracranial pressure, chronic progressive trauma, poor nutrition, hypoxia, or prolonged exposure to toxic elements.1 When the etiology is known, then an etiology-specific term is used (ie. hepatic encephalopathy). Often there are multiple potential contributing factors and a more generic term is used (ie. metabolic encephalopathy).

Metabolic encephaopathy (ME) is one of the most common and broadly defined, diagnoses encountered by physicians in the neurological fields. ME is a group of neurologic disorders characterized by an alteration in mental status caused by the direct physiological consequences of a general underlying medical condition and/or pharmacogenetics. Clinical presentation can vary from subtle executive dysfunction to coma with decorticate or decerebrate posturing. Disturbances of consciousness are not fully accounted for by structural brain injury or any preexisting or evolving dementia.2,3,4,5

Acute confusional state, delirium and encephalopathy may be used interchangeably in clinical practice; however, distinction should be made between the three. Confusion is an alteration in mentation from baseline which may present as impairment in memory, attention or awareness. Importantly confusion is a symptom, not a diagnosis, and should prompt further investigation to determine etiology. Acute confusional state refers to an acute state of altered consciousness characterized by disordered attention and diminished clarity and coherence of thought.6 Delirium is a type of acute confusional state, resulting from transient disturbances of neuronal activity, which tends to fluctuate during the course of a day.7 Individuals experience a disturbance in attention and awareness not better explained by another neurocognitive disorder and does not occur with severely reduced level of arousal (i.e. coma). [8] Metabolic encephalopathy encompasses delirium and the acute confusional state.1


Causes of ME are diverse and multifactorial. Septic encephalopathy occurs in up to 70% of patients with bacteremia and is the most common type of ME. Hepatic encephalopathy as a consequence of liver function disturbance can affect up to 50% of patients with advanced cirrhosis. Uremic encephalopathy occurs from failure to clear toxic nitrogenous waste products. Severe electrolyte abnormalities such as hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypomagnesemia and hypophosphatemia, if untreated, can result in ME. Wernicke’s encephalopathy due to diencephalic and mesencephalic dysfuction of central gray structures surrounding the third and fourth ventricles presents with a classic triad of mental status changes, gait abnormalities, and visual distrubances and can occur as a consequence of thiamine depletion. Hypoxic-ischemic encephalopathy and post-transplantation encephalopathy are also relatively common causes of ME.

Epidemiology including risk factors and primary prevention

ME is common among critically ill patients as a consequence of systemic illness. Risk factors include acute systemic illness, advanced age, medical comorbitdiies, and pre-existing cognitive impairement. Treatments such as sedation, mechanical ventilation, or neuromuscular junction blockade may mask the manifestations of ME.

Most cases of ME are acute in onset, but portal systemic encephalopathy and uremic encephalopathy often develop insidiously with gradual decline in cerebral functions making it difficult to appreciate deficits. Unlike most ME, sustained hypoglycemia and thiamine deficinecy (Wernicke’s encephalopathy) may result in permanent damage, making immediate recognization and treatment critical.

ME is a diagnosis of exclusion and must be distinguished from structural injuries such as traumatic brain injury, stroke, or brain tumor, and from various acute confusional states such as alcohol withdrawal, meningitis, encephalitis, or non-convulsive seizures.


All forms of ME interfere with the functioning of ascending reticular activating system and its projections to the cerbral cortex, leading to impairement of arousal and awareness. The neurophysiologic mechanism of ME includes interruption of polysynaptic pathways and altered excitatory-inhibitory amino acid balance. Electrolyte imbalances can alter membrane excitability to produce ME. In septic encephalopathy there are multiple contributing factors, including: microcirculatory abnormalities, altered blood-brain barrier permeability and inflammatory cytokines.

Patho-physiology of hepatic encephalopathy (HE) is multifactorial. It is likely that ammonia plays a central role. Elevated blood ammonia levels correlate with the degree of severity of encephalopathy. Metabolic products formed from ammonia, including glutamine and alpha ketoglutramic acid, are elevated in cerebro-spinal fluid (CSF) in patients with liver disease. Other theories have been proposed in the developement of HE, including production of false neurotransmitters (out of favor), abnormal fatty acid metabolism, free radical damage, cerebral edema and increased mercaptans.

Specific secondary or associated conditions and complications

Neuromuscular complications are quite common in ICU patients who have concomittant encephalopathy. Such complications include critical-illness polyneuropathy, cachectic myopathy or myositis.



In acute ME, the confused patient may be unreliable/uncooperative. Reports from family/friends and a medical record review are often necessary to construct an accurate history. Important clues include medical history, recent febrile illnesses, a history of organ failure, current medications, toxin exposure, and history of alcoholism or drug abuse, to determine the etiology of ME.10 Slower chronic processes (chronic kidney disease or liver failure) may manifest more insidiously, starting with lethargy, irritable behavior, or disturbed sleep-wake cycle, progressing to disorientation, confusion and problems with attention and concentration. This more gradual decline may disguise the true nature and severity of encephalopathy from patients and family members.

Physical examination

It is difficult to perform a comprehensive physical examination on a confused or uncooperative patient; instead, a focal exam specifically concentrating on certain aspects such as vital signs, the state of hydration, skin condition and potential infectious foci may be performed. Thorough serial neurologic examination should be performed in all patients to rule our serious structural causes of encephalopathy.

The appearance of jaundice might suggest hepatic failure; breath may smell of uremic fetor or ketones. Hyperventilation, or in later stages Kussmal breathing, may be present during periods of metabolic acidosis.2 Tachycardia, sweating, flushing, dilated pupils from autonomic system activation might suggest alcohol withdrawal.

Preserved pupillary function is a hallmark of ME, as brain stem reflexes are generally preserved. Horizontal gaze nystagmus is the most common ocular finding in Wernick’s encephalopathy, though complete ophthalmoplegia may be present in severe cases.. [3]

On mental status examination, the patient might exhibit decreased level of arousal, disorientation, cognitive deficits, difficulty with attention, hypervigilance, hallucinations, sensory misperceptions, impaired memory, and disorganized thought processes.

Motor exam findings are typically generalized and may include: tremors, myoclonus and asterixis. Paratonia, primitive reflexes, brisk tendon reflexes and extensor plantar responses might also be present. Focal examination findings warrant further work-up and should alert the practitioner to the possibility of an underlying structural lesion.10

Functional assessment

Premorbid functional baseline, including cognitive status, level of independence, and current functional status should be assessed in order to ascertain severity of deficits seen on exam and aid in determining treatment plan and rehabilitation goals. Assessment of mood/affect, behavior, and cognition can help monitor progress and assist in setting realistic goals. Formal neuropsychological assessment may be indicated in some cases for a more nuanced appraisal of behavior, cognition and affect. Since ME is usually reversible, return to previous function is often possible.

Laboratory studies

Laboratory investigation includes a complete blood count along with coagulation studies and electrolyte panel: calcium, magnesium, phosphate, glucose, blood urea nitrogen (BUN), creatinine. Further studies should be selected based on clinical suspicion of underlying etiology.

If infection is suspected, then blood, urine, and cerebrospinal fluid (CSF) cultures should be obtained along with urinalysis. If hepatic encephalopathy is suspected, then liver function tests and ammonia levels should be checked. To assess possible or ongoing uremic encephalopathy serum osmolality, BUN and creatinine are appropriate. If endocrine or nutritional abnormalities are suspect, thyroid function tests, serum cortisol, thiamine, and Vitamin B12 levels can be checked. A toxicology screen for prescription and illicit drugs should be considered in the appropriate clinical context.


Neuroimaging should be used selectively rather than routinely, but may be necessary when diagnosis is not clear.2,3,4 Neuroimaging may not be required if there is an obvious treatable medical condition, no signs of trauma, no focal neurological signs, patient is arousable and able to follow commands, and the condition resolves with treatment.13

Neuroimaging is required if the condition does not improve despite appropriate treatment of underlying problem. Computed tomography (CT) or magnetic resonance imaging (MRI) of the head is indicated when focal signs are present on physical examination, and to exclude acute stroke and multifocal inflammatory lesions. In patients with suspected vasculopathy or vascular occlusion, perfusion imaging (CT or MRI) may be useful.3

Supplemental assessment tools

CSF analysis should be performed when there is a high suspicion for bacterial or aseptic meningitis and encephalitis and no other infectious foci is obvious in a febrile patient. CSF analysis might be the only diagnostic tool to identify meningitis. Lumbar puncture is part of a standard work-up when the cause of delirium is not obvious.

Electroencephalography (EEG) is useful to exclude seizures (subclinical or otherwise) as a cause of altered mental status, and in determining whether myoclonus has a cortical basis. EEG can also be used to diagnose certain ME or infectious encephalopathies that have characteristic EEG patterns and to detect global cerebral dysfunction. ME may show diffuse bilateral slowing of background rhythm, triphasic waves, and frontally predominant rhythmic delta activity. In extreme cases, burst-suppression pattern may be seen.2,3,10 Practitioners should have low threshold for EEG monitoring as seizures can increase ICP. Continuous EEG monitoring for 48 hours is recommended over spot EEG monitoring.

The Confusion Assessment Method for the ICU (CAM-ICU) scale is a standardized examination that identifies delirium or fluctuating levels of attentiveness with 83-100% sensitivity and 95-100% specificity. CAM-ICU must be used in conjunction with serial neurologic examinations to identify both encephalopathy and focal neurologic deficits as well as to narrow etiology.3,14,15

Early predictions of outcomes

Delirium and encephalopathy are linked with poor outcomes in ICU survivors including increased morbidity and mortality, prolonged length of stay, and increased hospital complications. ME was initially thought to be completely reversible, but up to 32% of patients develop persistent neurological and psychological disturbances, especially if the underlying condition persists. Additionally, neurologic recovery often lags behind recovery of the underlying condition. Thus, identification and treatment of underlying cause is of paramount importance. Significant cognitive impairment might be prevalent in some patients, especially affecting areas of psychomotor speed, verbal fluency, working memory and visuoconstruction abilities.3,16

Specific etiologies of ME are associated with distinct long-term sequelae. Permanent nystagmus and ataxia are common after Wernicke encephalopathy. Patients often develop Korsakoff syndrome, characterized by antero- and retrograde amnesia with confabulation. Survivors of hepatic encephalopathy may have permanent cognitive or motor deficits. Patient with hypoglycemic encephalopathy may incur cortical and meso-temporal injury with long-term memory impairment.3


Given the wide range of etiologies and heterogeneous nature of ME, environmental needs will vary; thus, each patient deserves an individualized plan. An individual with mild cognitive impairment may need additional time to perform daily tasks, while another individual with moderate impairment may need a structured daily routine, including a modified environment with appropriate supervision. See treatment guidelines for more information.

Professional Issues

Care of ME patients may include continuing life-sustaining treatment in the ICU setting, including prolonged mechanical ventilation, invasive procedures such as tracheostomy and percutaneous endoscopy gastric tube placement. Ethical dilemmas can arise as to whether or when to withdraw care in critically ill patients with a potentially untreatable underlying condition. In a rehabilitation setting, the ethical focus is on determining the decision-making capacity of the patient.


Available or current treatment guidelines

The treatment plan should be individualized for each patient based on etiology of ME as well as current and premorbid cognitive and physical impairments. Underlying etiology should be treated initially in an acute care hospital/ICU setting.

Given the overlap between delirium and encephalopathy, general recommendations for management of metabolic encephalopathy are similar to that for delirium management. A number of general measures should be initiated while still in a hospital setting:

  1. Placing patient in a low stimulation environment, including a quiet private room.
    2. Limiting limb and chest restraints. Consider placing a one-to-one sitter to ensure patient safety for agitated or impulsive individuals.
    3. Avoid factors known to cause or aggravate confusion, altered mentation, and/or delirium such as polypharmacy, dehydration, and sleep disturbance.
  2. Frequent reorientation
  3. Early mobilization and therapies17

Thorough medication review should be completed in all patients with suspected metabolic encephalopathy. This should include review of prescription medications taken for nonmedicinal or recreational use as well as over-the-counter supplements/vitamins. It is also important to review recently discontinued medications as withdrawal states may contribute to delirious states. Discontinue or avoid medications with anticholinergic activity, opiate narcotics, corticosteroids, sedatives and other medications with sedative activity (e.g., cyclobenzaprine and gabapentin). Treatment with antipsychotics is controversial as strong sedative effects can be beneficial in agitation but can precipitate encephalopathy. For severe agitation, atypical antipsychotics are suggested when safety of the patient and caregivers is at stake; minimize typical antipsychotics due to side effect profile.3,10,1

At different disease stages

  • Acute management (ICU, medical or surgical unit): Treatment primarily consists of treating underlying etiology. Intracranial pressure monitoring should be considered if cerebral edema is suspected.3
    • For septic encephalopathy, treatment consists of primarily controlling underlying infection.
    • Treatment of hepatic encephalopathy consists of correcting coagulation parameters, electrolyte abnormalities, volume depletion. Orthotopic liver transplant may be necessary when treatment of the underlying disease or emergency measures to lower ICP prove unsuccessful. 2
    • Acute uremic encephalopathy reverses with dialysis, although there may be a lag of 1-2 days before mental status clears and subtle cognitive deficits may persist.
    • Immediate thiamine replacement takes precedence over imaging or laboratory diagnosis in at-risk populations given high morbidity of delayed treatment. 3
    • Myoclonus can be treated symptomatically with Levetiracetam or Valproic acid.
    • Primary rehabilitation goals in ICU/acute care hospital setting should include: monitoring and treatment of agitation, maintenance of skin integrity with frequent turning and special mattresses, early mobilization with therapy team and nursing staff to prevent complications of prolonged bedrest/immobility, providing bedside range of motion exercises and proper positioning.
  • Subacute management is generally initiated in an inpatient rehabilitation setting and should consist of an inter-disciplinary rehabilitation team approach to promote optimal recovery. Balance, coordination, mobility, and cognitive/behavioral deficits should be addressed. Patients should still be monitored for agitation/confusion and managed accordingly.
  • Chronic management includes successful community re-entry and gradual return to pre-morbid level of function. This may involve ongoing cognitive rehabilitation to improve cognitive impairment and for support/counseling, as well as continued medical surveillance/follow-up to address underlying etiology of ME.

Coordination of care

Care coordination is vital for successful transition from an acute inpatient rehabilitation to home, and for community re-entry. Case managers and social workers should provide information regarding various options available to patient and family including: home PT/OT, day programs and cognitive rehabilitation programs.

Patient & family education

Educating the patient and family should include discussing the reversible nature of ME and general cognitive improvement over time. Family meetings should also address the expectations of the patient and family members regarding short-term and long-term recovery. Family may be enlisted to modify lifestyle choices to address the underlying condition and risk for recurrence of ME.


Cutting edge concepts and practice

Directed therapies targeting neurochemical and neurotransmitter pathways mediating encephalopathy are an important area of future research.


Gaps in the evidence-based knowledge

Literature on rehabilitative management of patients with ME is scant. Signs/symptoms of delirium, acute confusional states, and metabolic encephalopathy have considerable overlap with often unclear etiology and/or unknown pathophysiology thus data is often generalized to fit all diagnoses.


  1. Chen and G. Young, “Metabolic Encephalopathies,” in Baillere’s Clinical Neurology, London, Balliere Tindall, 1996, p. 577.
  2. J. Angel and G. B. Young, “Metabolic Encephalopathis,” Neurol Clin, vol. 29, pp. 837-882, 2011.
  3. A. Frontera, “Metabolic Encephalopathies in the Critical Care Unit,” Neurol, vol. 18, no. 3, pp. 611-639, 2012.
  4. Bathla and A. Hegde, “MRI and CT appearances in metabolic encephalopathies due to systemic diseases in adults,” Clinical Radiology, vol. 68, pp. 545-554, 2013.
  5. F. M. Wijdicks, “Metabolic Encephalophaty: Behind the Name,” Neurocritical Care, pp. 1-3, 5 January 2018.
  6. Adams, M. Victor and A. Ropper, “Delirium and other acute confusional states,” in Principles of Neurology, New York, McGraw-Hill, 1997, p. 405.
  7. R. Maldonado, “Acute Brain Failure Pathophysiology, Diagnosis, Management, and Sequelae of Delirium,” Critical Care Clinics, vol. 33 , p. 461–519, 2017.
  8. American Psychiatric Associateion, Diagnostic and Statistical Manual, 5th edition, Washington, DC: APA Press, 2013.
  9. Francis, “Delirium in older patients,” J Am Geriatr Soc, vol. 40, no. 8, pp. 829-838, 1992.
  10. Krishnan, L. Y. Leung and L. R. Caplan, “A neurologist’s approach to delirium: diagnosis and management of toxic metabolic encephalopathies,” European Journal of Internal Medicine, vol. 25, pp. 112-116, 2014.
  11. Bolton and G. Young, “Uremic Encephalopathy,” in Neurologic complications of Renal Disease, Stoneham, MA, Buttersworth, 1990, p. 44.
  12. Pandharipande, A. Morandi, J. Adams, T. Girard, J. Thompson, A. Shintani and E. Ely, “Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients,” Intensive Care Med, vol. 35, no. 11, p. 1886, 2009.
  13. Daroff, G. Fenichel, J. Jankovic and J. Mazziotta, “Toxic and Metabolic Encephalopathies,” in Bradley’s Neurology in Clinical Practice. 6th Edition, Phildelphia, PA, Elsevier/Saunders, 2012, pp. 1321-1339.

Original Version of the Topic

Phalgun Nori, MD. Metabolic encephalopathies. Original publication date: 1/30/14.

Author Disclosures

Rani Haley Lindberg, MD
Nothing to Disclose

Lindsay Mohney, DO
Nothing to Disclose