Wernicke-Korsakoff and metabolic encephalopathies

• A metabolic encephalopathy is a brain syndrome caused by a systemic chemical or energy problem rather than by a structural lesion in the brain itself.
• Wernicke encephalopathy is the neurologic emergency of thiamine deficiency; it is treated immediately with intravenous thiamine, before any glucose, and most features can improve within days. ^[3]
• Liver failure causes hepatic encephalopathy through ammonia and inflammation; lactulose aiming at two to three soft bowel movements a day is the cornerstone of treatment.
• Acute or chronic kidney failure below an estimated glomerular filtration rate of 15 mL/min can cloud consciousness, and dialysis is the definitive treatment.
• Rapid correction of hyponatraemia can strip myelin from the pons, so sodium correction in chronic hyponatraemia should stay within conservative daily limits.
• After cardiac arrest or other oxygen deprivation, brain injury is limited by restoring perfusion and preventing secondary hypoxia, fever, seizures and low blood pressure.

By the end of this page you should be able to:

1. Recognise the varied triggers of thiamine deficiency and the clinical picture of Wernicke encephalopathy, and know the point at which it progresses to Korsakoff memory loss.
2. State the thiamine dose, route and duration used by the major guidelines, and explain why glucose and magnesium matter.
3. Recognise hepatic encephalopathy, know the role of ammonia, precipitants, lactulose and rifaximin, and plan secondary prevention.
4. Recognise uraemic encephalopathy, its eGFR threshold and the indication for renal replacement therapy.
5. Explain why rapid sodium correction demyelinates the brain and apply the daily correction limits.
6. Describe the mechanisms and immediate treatment priorities in hypoxic-ischaemic brain injury, including temperature management and neuroprognostication.

A metabolic encephalopathy is a global brain dysfunction produced by a disorder of systemic metabolism, nutrition, toxins, electrolytes or oxygen. The brain itself may be structurally normal at first. The patient presents with clouded consciousness, confusion, inattention or coma, often with non-focal signs such as asterixis, myoclonus or seizures. This page groups the main metabolic encephalopathies encountered in adults: thiamine deficiency (Wernicke encephalopathy and its chronic aftermath, Korsakoff syndrome), hepatic encephalopathy, uraemic encephalopathy, osmotic demyelination from sodium correction, and hypoxic-ischaemic brain injury.

These conditions share a final pathway: a change in the chemical environment of neurones and glia that exceeds the brain's capacity to compensate. The differences lie in which chemical is at fault, how fast the change occurs and whether the process is reversible.

Wernicke encephalopathy is underdiagnosed. Lesions consistent with Wernicke encephalopathy are found at autopsy in 0.4% to 2.8% of the general population in developed countries, while clinical recognition is lower. The female-to-male ratio is about 1 to 1.7. Severe alcohol use disorder accounts for roughly half of cases, but non-alcoholic thiamine deficiency is increasingly recognised after bariatric surgery, prolonged vomiting, malnutrition and severe systemic illness. Bariatric surgery carries an estimated 18% prevalence of thiamine deficiency and neurological complications in about 1.3% of patients. ^[1]

Hepatic encephalopathy complicates cirrhosis and, in hospital practice, is the most common first decompensating event; national and international guidelines therefore treat every episode as a recurrence-risk signal. ^[7] Uraemic encephalopathy is common once renal function has fallen below 15 mL/min and is often the clinical reason to start dialysis. Osmotic demyelination is rare but devastating. Hypoxic-ischaemic brain injury is the dominant neurologic outcome after out-of-hospital cardiac arrest.

Thiamine deficiency usually develops after 4 to 6 weeks of inadequate intake or increased utilisation. Thiamine is absorbed in the jejunum, with a body store of only 30 to 50 mg, sufficient for about 3 to 4 weeks. The daily requirement is about 0.5 mg per 1000 kcal, roughly 1.4 mg daily in a healthy adult. Alcohol reduces intestinal absorption, impairs hepatic storage and increases demand, while illness, surgery, pregnancy and hyperthyroidism increase utilisation. Other causes include prolonged parenteral nutrition, severe malnutrition, liver disease, hyperemesis gravidarum, malignancy, immunodeficiency, severe anorexia nervosa, hyperthyroidism, dialysis, gastrointestinal fistula and refeeding. ^[1][3]

Hepatic encephalopathy follows liver failure (type A), portosystemic shunting (type B) or cirrhosis (type C). Precipitants include gastrointestinal bleeding, infection, constipation, sedatives, dehydration, electrolyte disturbance and high protein loads in the setting of a bleeding episode. ^[7]

Uraemic encephalopathy arises when kidney failure, acute or chronic, allows retention of uremic solutes in addition to disturbances of electrolytes, acid-base balance and blood-brain barrier transport. ^[4]

Osmotic demyelination arises mainly from overly rapid correction of chronic hyponatraemia, but also from liver transplantation, malnutrition, alcohol withdrawal without sodium change, severe hyperglycaemia and refeeding, often where thiamine deficiency coexists. ^[9]

Hypoxic-ischaemic brain injury results from cardiac arrest, asphyxiation, carbon monoxide poisoning, severe anaemia, shock or any global cessation of cerebral perfusion. ^[6][9]

Thiamine pyrophosphate is the active coenzyme for several enzymes in glucose metabolism, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase. Deficiency causes lactic acidosis, reduced ATP synthesis and glutamate accumulation, leading to cytotoxic oedema; blood-brain barrier dysfunction adds vasogenic oedema. Brain regions with high metabolic demand and thiamine turnover are affected first. ^[1]

Magnesium is a cofactor for thiamine-dependent enzymes, so hypomagnesaemia blocks the response to thiamine even when thiamine is given. Alcohol also deactivates thiamine diphosphokinase, reducing intracellular activation. ^[1]

Ammonia produced by gut bacterial metabolism is not cleared by the failing liver and, together with systemic inflammation, crosses a permeable blood-brain barrier. Astrocytes metabolise ammonia to glutamine, which swells the cell and disturbs neurotransmission. This produces a graded clinical picture from subtle cognitive slowing to coma. ^[7]

Urea is the most commonly measured marker but is only one of many retained solutes. Their accumulation, with electrolyte and acid-base disturbance, impairs neuronal function, vascular reactivity and blood-brain barrier transport. The process is at least partly reversible when solute load is removed. ^[4]

The brain adapts to chronic hyponatraemia by losing intracellular electrolytes and organic osmolytes, so cell volume returns towards normal. If serum sodium is then raised rapidly, electrolytes reaccumulate faster than osmolytes, which take days to regenerate. The resulting osmotic shrinkage injures astrocytes first and then oligodendrocytes, producing symmetrical, non-inflammatory demyelination of the central pons and extrapontine sites. Cerebral endothelial shrinkage and inflammatory mediator entry have also been proposed. ^[8][9]

The first phase is the primary insult: loss of oxygen and glucose delivery, failure of ATP-dependent pumps, neuronal depolarisation and calcium influx. The second phase is reperfusion injury: reactive oxygen species, mitochondrial dysfunction, nitric oxide and caspase activation drive delayed cell death. The brain is most vulnerable in areas with high metabolic demand. ^[6][9]

The European Federation of Neurological Societies (EFNS) diagnostic guideline requires at least two of four features: dietary deficiency, ophthalmoplegia, cerebellar dysfunction, or either altered mental status or mild memory impairment. ^[1] The classical triad of confusion, ocular signs and ataxia appears in only 16% of patients. ^[1]

• Confusion, inattention, apathy and memory disturbance are the most common findings.
• Ocular signs include horizontal nystagmus, ptosis and impaired gaze; complete ophthalmoplegia is rare.
• Gait ataxia arises from vestibular and cerebellar vermis involvement; limb ataxia is less common.
• Hypothermia or hyperthermia, deafness and seizures are uncommon.

Korsakoff syndrome is the chronic amnestic state: severe anterograde and retrograde memory loss, confabulation and preserved immediate recall. Wernicke and Korsakoff overlap and are called Wernicke-Korsakoff syndrome; Wernicke encephalopathy is preventable and the memory deficit is the part least likely to recover. ^[1][2] Brain damage persists after acute Wernicke in many patients, so any suspected case must be treated immediately.

Cirrhotic patients show a spectrum from covert (minimal) cognitive slowing detected by testing, through grade 1 disorientation and asterixis, to drowsiness, stupor and coma. Diagnosis is clinical. Tremor, fetor hepaticus, hyperventilation and constructional apraxia occur. In hospital, repeated review matters because infection, bleeding and drugs are common reversible precipitants. ^[7]

Onset may be insidious, with fatigue, anorexia, nausea, weight loss and subtle cognitive slowing as renal function declines. Acute renal failure produces abrupt confusion, delirium, disorientation, seizures, asterixis, hyperreflexia, papilloedema and nystagmus. The physical findings include memory and calculation defects. ^[4]

Symptoms start days after correction: dysarthria, dysphagia, pseudobulbar palsy, spastic or flaccid quadriparesis, ataxia and tremor. Severe demyelination can produce locked-in syndrome with preserved consciousness. Extrapontine disease may present with altered mental status, behaviour change, seizures or movement disorder. ^[8][9]

Level of consciousness varies from mild confusion to coma. Seizures, myoclonus and focal deficits occur. Pulse, blood pressure and temperature control are clinical priorities. ^[6][9]

Before labelling a patient as having a single metabolic encephalopathy, exclude the frequent mimics: intracranial haemorrhage, stroke, meningitis or encephalitis, intoxication, epilepsy and sepsis. Wernicke in particular must be considered in delirious patients and in anyone with oculomotor or cerebellar signs. ^[1]

Wernicke encephalopathy has no specific laboratory test. If suspected, take blood for total thiamine (and lactate and pyruvate) before giving thiamine, but do not wait for the result. Magnetic resonance imaging is more sensitive than computed tomography and may show periventricular lesions; the brain changes are not consistently present. ^[1][2]

Hepatic encephalopathy is a clinical diagnosis; serum ammonia correlates poorly and should not guide treatment. Cultures of blood, urine and ascitic fluid, and a search for gastrointestinal bleeding, are routine because infection and bleeding are common precipitants. ^[7]

Uraemic encephalopathy has no confirmatory test. Marked elevation of urea and creatinine, urinalysis and acid-base and electrolyte panels are typical, while imaging excludes focal lesions. Electroencephalography shows non-specific slowing. If there is no improvement after several dialysis sessions, reconsider the diagnosis. ^[4]

Osmotic demyelination may be invisible on early magnetic resonance imaging; lesions typically appear 2 to 4 weeks later and show central pontine T2 hyperintensity. ^[8]

Hypoxic brain injury is investigated with computed tomography, which may be normal initially and show cerebral oedema or loss of grey-white distinction after a few days, and with diffusion-weighted magnetic resonance imaging. Continuous electroencephalography, somatosensory evoked potentials and serum neuron specific enolase support prognostication. ^[6][9]

The EFNS clinical criteria for Wernicke encephalopathy require two of four features and have been widely adopted; Caine's criteria (thiamine deficiency plus any one of memory loss, cerebellar signs or eye signs) are reported to have about 85% sensitivity in alcoholic patients but are not fully validated outside alcohol-related disease. ^[1] Histology of the resected or biopsied brain is not available in life.

Hepatic encephalopathy is graded by the West Haven criteria from covert impairment to coma; in practice, the American College of Gastroenterology guideline stresses that the episode is diagnosed clinically and that ammonia values alone cannot establish or grade it. ^[7]

Uraemic encephalopathy still has no diagnostic criteria and is diagnosed retrospectively when consciousness improves with renal replacement therapy. ^[4]

Airway and breathing support, correction of hypoglycaemia or hyperglycaemia, hypoxia, shock, hypothermia and sepsis, and a review of all drugs come first. Neuroimaging is used when the diagnosis is uncertain or when focal signs suggest a structural problem. If thiamine deficiency is possible, give thiamine before glucose and do not delay treatment for imaging. ^[1][2]

There is no universally accepted dose. The EFNS 2010 guideline (the edition cited by the reviews) recommends 200 mg intravenous thiamine every 8 hours, continued until no further improvement, together with a normal diet; thiamine should be given before any carbohydrate. ^[1][2] The Royal College of Physicians tradition from the United Kingdom recommends 500 mg intravenously three times a day for 2 to 3 days, then 250 mg once a day for 5 days or until improvement plateaus, then oral thiamine 50 to 100 mg daily. ^[1][2] StatPearls lists the Royal College and United Kingdom guidelines as 500 mg intravenously every 8 hours for 3 days, then 250 mg intravenously or intramuscularly once daily, often for a further 3 to 5 days, followed by oral thiamine 50 to 100 mg daily; and the EFNS position as 200 mg intravenously every 8 hours until no further improvement. ^[2] These differ, and clinicians must follow local protocol. Newer trial data have shown no clear benefit of high-dose over intermediate or low-dose thiamine, so patient-specific treatment with correction of magnesium deficiency is recommended. ^{[1] [3][5]}

Thiamine is given intravenously in most acute cases, diluted in 100 mL of normal saline or 5% glucose over about 30 minutes. ^[1][2] Oral absorption is limited in alcohol dependence and malnutrition, so intravenous treatment is preferred in acute disease. ^[1] Glucose oxidises thiamine, so carbohydrate is always preceded by thiamine. ^[1][2]

Magnesium deficiency is frequent, especially in chronic heavy alcohol use, and it prevents thiamine from working; give magnesium while awaiting levels. ^[1][2]

In the United States, a common empirical regimen is 100 mg parenterally daily for 3 to 7 days, then oral thiamine for as long as alcohol is consumed. ^[1] For bariatric surgery patients, the EFNS guideline recommends follow-up of thiamine status for at least 6 months with parenteral supplementation, and oral treatment should be continued for life in many protocols. ^[1][2] Prophylaxis in heavy drinkers or post-bariatric patients follows local and guideline protocol; StatPearls cites 100 mg orally three times daily in low-risk and 250 mg intramuscularly daily for 3 to 5 days in high-risk post-bariatric patients. ^[2]

Thiamine is very safe; reactions are rare. ^[1]

Management rests on treating the precipitant and reducing ammonia absorption. Lactulose is first-line for an overt episode and is titrated to 2 to 4 soft bowel movements daily. Rifaximin is added for acute episodes because a randomized trial showed higher reversal rates, shorter stay and lower mortality than lactulose alone, and it is strongly recommended as add-on therapy when episodes recur. ^[7] Outpatient secondary prophylaxis is lactulose aiming at 2 to 3 soft bowel movements daily after the first episode, with rifaximin added for breakthrough recurrence. ^{[7] [9]}

Dosing for lactulose is titration-based rather than a single fixed dose, so local guidance supplies volumes. Protein is not restricted; target 1.2 to 1.5 g/kg/day, with branched-chain amino acids if dietary intake is inadequate. ^[7] Rifaximin is given twice daily at a dose of 550 mg. ^[9]

Exclude precipitants vigorously: infection, bleeding, electrolyte disturbance, constipation and dehydration. Acute overt confusion expected to improve within 24 to 48 hours; lack of improvement after 48 to 72 hours should prompt reassessment and brain imaging for alternative causes. ^{[7] [8]}

A late-evening snack and the zinc supplementation in persistent low-zinc states are supported in the guideline; rifaximin prophylaxis is started 14 days before an elective transjugular intrahepatic portosystemic shunt and continued for at least 6 months. ^[7] Patients with recent overt hepatic encephalopathy should be advised not to drive, especially within 3 months. ^[7]

Uraemic encephalopathy is an absolute indication to start renal replacement therapy. Improvement is expected after initiation of dialysis, although recovery may take days to weeks and EEG changes may need months. Management is simultaneous care of chronic kidney disease: anaemia correction, calcium and phosphate control and nutritional support. Intermittent haemodialysis clears solutes better than continuous ambulatory peritoneal dialysis but carries a risk of dialysis disequilibrium syndrome. Mannitol 25 g before the first few sessions reduces that risk. ^{[4] [2]}

Haemodialysis should start gently, with low blood and dialysate flow rates and shorter sessions initially, to limit osmotic shifts and cerebral oedema. Treat hypokalaemia, hyponatraemia and hypoglycaemia, and consider lumbar puncture if there is no response. ^[4]

There is no specific treatment. Care is supportive, and rehabilitation is essential; up to 25% to 30% of severe cases suffer permanent disability and roughly 30% to 50% of cases recover substantially. ^[9] If an overcorrection is recognised, lowering serum sodium with desmopressin may reduce risk. ^[5] Prevention is therefore the treatment.

Chronic hyponatraemia adapts over 48 hours, so correction limits are applied for 24- and 48-hour windows. The 2026 review summarises average-risk target as a rise of 4 to 8 mmol per litre per day, not exceeding 10 mmol per litre in 24 hours and no more than 18 mmol per litre in 48 hours; high-risk patients should not exceed 8 mmol per litre in 24 hours, targeting a rise of 4 to 6 mmol per litre per day. High-risk features include very low baseline sodium (especially 105-110 mmol per litre or below), alcohol use disorder, advanced liver disease, malnutrition and hypokalaemia. ^[8] Older and more conservative guidance puts the limit at 8 mmol per litre per 24 hours for average risk and 6 mmol per litre for high risk; the StatPearls figure is not more than 8 to 12 mEq per litre per 24 hours. ^[5] Guidelines therefore differ, but conservative correction in chronic hyponatraemia is prudent. ^[5][8][9]

In severe symptomatic hyponatraemia, 3% saline in 100 to 150 mL boluses over 10 to 20 minutes, repeated up to two or three times, can raise sodium by 4 to 6 mmol per litre, relieve cerebral oedema and is limited by the same 24-hour caps once the immediate danger is past. ^[8]

Treatment is supportive and aimed at the cause: excellent initial resuscitation, optimising perfusion, oxygenation and carbon dioxide levels, blood pressure and glucose, treating seizures and preventing hyperthermia and infection. Core principles from the 2026 review are to maintain normoxia and normocapnia, target a mean arterial pressure of 65 mmHg, prevent fever, control seizures and start rehabilitation. ^[9]

Targeted temperature management means maintaining temperature at or below 36 degrees Celsius for at least 24 hours; therapeutic hypothermia uses 32 to 34 degrees Celsius in suitable patients. Rewarming should not exceed 0.5 degrees Celsius per hour, and ideally 0.25 degrees Celsius per hour. Shivering may require sedation or neuromuscular blockade, with continuous EEG when paralysis is used. ^{[6] [9]}

Neuroprognostication after cardiac arrest is deferred to at least 72 hours after return of spontaneous circulation and is multimodal, never based on one variable. The 2026 review quotes the European Resuscitation Council and European Society of Intensive Care Medicine criteria: poor outcome is predicted when at least two of the following are present: no pupillary and corneal reflexes at 72 hours or more, bilaterally absent N20 somatosensory evoked potential wave at 24 hours or more, highly malignant EEG pattern after 24 hours, serum neuron specific enolase over 60 microg per litre at 72 hours, status myoclonus within 72 hours, or extensive anoxic injury on CT or MRI. ^[9] Indicators of good prognosis include early continuous and reactive EEG, low neuron specific enolase and absence of diffusion change on MRI. ^[9] StatPearls notes that bilateral median nerve somatosensory evoked potential absence of the N20 response in the first week implies no outcome better than persistent vegetative state. ^[6]

Special groups: neonatal hypoxic-ischaemic encephalopathy is a related but distinct condition with therapeutic hypothermia as standard; it is not covered in detail here. ^[6]

Pregnancy: hyperemesis gravidarum is a classic cause of thiamine deficiency and Wernicke encephalopathy, affecting both maternal and fetal brain, so thiamine should precede glucose in any vomiting pregnant patient. ^[1]

Bariatric patients need lifelong supplementation and follow-up because of malabsorption and vomiting. ^[1][2]

Older adults with alcohol-related brain damage may already have poor nutrition and reduced reserve, so lower prophylactic doses given orally can be reasonable in lower-risk patients, but any sign of Wernicke requires parenteral high dose. ^[2]

Intravenous thiamine should be given whenever Wernicke encephalopathy is suspected, even where laboratory testing or imaging is unavailable; treatment should not wait for confirmation. ^[1][2] If parenteral thiamine is unavailable, oral treatment is inadequate but may be better than nothing, and urgent transfer is preferable. Ensure magnesium and diet correction alongside thiamine. ^[1]

Hepatic encephalopathy can be managed with lactulose titration by bowel movement and precipitant search even without ammonia assays. Uraemic encephalopathy requires dialysis; low blood and dialysate flows reduce risk if equipment is available. ^[4] Osmotic demyelination and hypoxic injury are largely prevented rather than treated, so careful sodium notation and basic critical care are the key interventions. ^[5][8][9]

• Metabolic encephalopathy is global brain dysfunction from a systemic chemical or energy problem; structure may be normal at first.
• Wernicke encephalopathy is an emergency of thiamine deficiency: treat with intravenous thiamine, before carbohydrate, and do not wait for imaging or laboratory results.
• EFNS 2010 recommends 200 mg intravenously every 8 hours to improvement; Royal College of Physicians practice reports 500 mg intravenously three times daily for 2 to 3 days then 250 mg daily. Guidelines differ, so use local protocol.
• EFNS clinical diagnosis requires two of four features and the classical triad appears in only 16% of patients.
• Maximise absorption by slow intravenous infusion in 100 mL of normal saline or 5% glucose over about 30 minutes, and add magnesium early. ^[2]
• Korsakoff syndrome is the chronic, largely irreversible memory disorder that may follow inadequately treated Wernicke's.
• Hepatic encephalopathy uses lactulose to 2 to 4 bowel movements daily plus precipitant treatment; rifaximin is added for recurrence, protein is not restricted and driving is avoided for about 3 months.
• Uraemic encephalopathy appears below an eGFR of about 15 mL/min and is an absolute indication for dialysis. ^[4]
• Osmotic demyelination follows rapid correction of chronic hyponatraemia: prevention is the treatment and correction limits must be followed.
• Average-risk hyponatraemia correction should not exceed 10 mmol/L in 24 hours, ideally targeting 4 to 8 mmol/L per day; high-risk patients should not exceed 8 mmol/L in 24 hours.
• Hypoxic brain injury management focuses on cause, perfusion, normoxia, normocapnia, mean arterial pressure of 65 mmHg, seizure control and fever prevention.
• Therapeutic hypothermia or targeted temperature management should be started after cardiac arrest in eligible patients, with slow controlled rewarming.
• Neuroprognostication is deferred to at least 72 hours and is multimodal.

• Brainstem and metabolic coma; alcoholic liver disease and cirrhosis; chronic kidney disease and dialysis access; sodium disorders and hyponatraemia; post-cardiac arrest care; and cognitive disorders including Korsakoff syndrome and dementia.