Wernicke-Korsakoff syndrome

Background

• Wernicke's Encephalopathy (WE): acute neurologic syndrome caused by thiamine deficiency
• Korsakoff's Psychosis (KS): chronic neuropsychiatric syndrome caused by thiamine deficiency
• Wernicke-Korsakoff Syndrome (WKS): presence of Wernicke's Encephalopathy + Korsakoff's Psychosis simultaneously
• First described by Carl Wernicke in 1881; remains one of the most underdiagnosed and undertreated neurologic emergencies

Epidemiology

• Autopsy prevalence ~2% in the general population; up to 12.5% in patients with alcohol use disorder
• Only ~20% of cases are identified before death; failure of diagnosis leads to ~20% mortality and ~75% permanent neurologic damage
• Classic triad (encephalopathy, oculomotor dysfunction, ataxia) is present in only ~10% of patients
• ~80% of patients with untreated WE progress to Korsakoff syndrome
• Not limited to alcoholics — increasingly recognized post-bariatric surgery (~10% prevalence), in hyperemesis gravidarum, cancer, and critically ill patients

Pathophysiology

• Thiamine (vitamin B1) is a cofactor for enzymes critical to cerebral energy metabolism:
  • Energy production pathways: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, transketolase (Krebs cycle, pentose phosphate pathway)
    • Deficiency leads to impaired ATP production → lactic acidosis, neuronal/astrocytic injury, and altered brain metabolism
    • Brain regions with high metabolic demand are most vulnerable
  • Lipid metabolism (including myelin sheath formation)
    • Alterations in myelination leads to peripheral neuropathy
• Thiamine half-life is only ~96 minutes; body stores are depleted within 2-3 weeks without intake
• Brain lesions/atrophy usually occur in (bilateral, symmetric):
  • Mammillary bodies (nearly all cases — involvement is pathognomonic)
  • Medial thalamus
  • Periaqueductal gray matter
  • 3rd/4th ventricle walls
  • Tectal plate
  • Cerebellum (especially vermis)
  • Frontal lobe (atypical)

Causes

• Thiamine (vitamin B1) deficiency caused by:
  • Insufficient intake
    • Chronic alcoholism (most common cause in Western countries)
    • Starvation/anorexia/eating disorders
    • Severe vomiting/diarrhea/hyperemesis gravidarum
    • Unbalanced or thiamine-deficient TPN
    • Self-imposed dietary restriction
  • Malabsorption
    • Post-bariatric surgery (especially Roux-en-Y gastric bypass)
    • Post-gastrectomy
    • IBD, celiac disease
    • Pancreatitis
    • Intestinal obstruction
  • Increased metabolic requirements
    • Malignancy/cancer chemotherapy
    • Thyrotoxicosis
    • Sepsis, critical illness
    • Refeeding syndrome
    • Carbohydrate loading (iatrogenic — can unmask subclinical deficiency)
  • Thiamine losses
    • Hemodialysis/peritoneal dialysis
  • Miscellaneous: AIDS, chronic liver disease, prolonged ICU admission, magnesium depletion (magnesium is a cofactor for thiamine-dependent enzymes)

Thiamine deficiency types

• Wernicke-Korsakoff syndrome
• Beriberi

Clinical Features

Wernicke's Encephalopathy

• Classic triad: encephalopathy, oculomotor dysfunction, gait ataxia
  • Classic triad present in only ~10% of cases — do NOT rely on complete triad to make diagnosis
• werNICke mnemonic:
  • Nystagmus/ophthalmoplegia
    • Horizontal nystagmus is the most common ocular finding (not complete ophthalmoplegia)
    • Other ocular findings: bilateral 6th nerve palsy, conjugate gaze palsy, pupillary abnormality, retinal hemorrhage, ptosis
    • May progress to complete ophthalmoplegia
  • Incoordination/ataxia
    • Legs affected more than arms (vestibular + cerebellar dysfunction)
    • Primarily affects gait; arms and speech usually spared
  • Confusion/memory impairment
    • Delirium/encephalopathy is the most consistent clinical feature
    • May present as apathy, inattention, disorientation, or progress to coma
• Other symptoms:
  • Hypotension, tachycardia, ECG abnormalities
  • Dyspnea on exertion, CHF symptoms (cardiac beriberi)
  • Hypothermia
  • Peripheral neuropathy (paresthesias, especially distal lower extremities — dry beriberi)
  • Vestibular dysfunction (without hearing loss)
  • Coma

Korsakoff's Psychosis

• Usually develops as a consequence of untreated or inadequately treated WE
• Anterograde > retrograde amnesia (disproportionate to other cognitive functions)
• Confabulation (often spontaneous)
• Confusion, disorientation, apathy
• Lack of insight into deficits
• Largely irreversible

Differential Diagnosis

Ethanol related disease processes

• Ethanol toxicity
• Alcohol use disorder
• Alcohol withdrawal
  • Alcohol withdrawal seizures
  • Delerium tremens
• Electrolyte/acid-base disorder
  • Alcoholic ketoacidosis
  • Beer potomania syndrome
  • Beriberi
  • Thiamine deficiency
  • Wernicke-Korsakoff syndrome

Vitamin deficiencies

• Vitamin A deficiency
• Vitamin B deficiencies
  • Vitamin B1 deficiency (Thiamine)
    • Beriberi
    • Wernicke-Korsakoff syndrome
  • Vitamin B3 deficiency (Pellagra)
  • Vitamin B9 deficiency (Folate)
  • Vitamin B7 deficiency (Biotin)
  • Vitamin B12 deficiency
• Vitamin C deficiency (Scurvy)
• Vitamin D deficiency (Rickets)
• Vitamin E deficiency
• Vitamin K deficiency
• Zinc deficiency
  • Acrodermatitis enteropathica
• Other diagnoses to consider:
  • Stroke/cerebellar infarction (can mimic entire triad — ophthalmoplegia, ataxia, AMS)
  • Hepatic encephalopathy
  • Hypoglycemia
  • Sepsis-associated encephalopathy
  • Meningitis/encephalitis
  • Metronidazole-induced encephalopathy (similar MRI findings; can coexist in malnourished patients on metronidazole)
  • Creutzfeldt-Jakob disease (CJD — may have similar thalamic/basal ganglia signal changes on MRI, but spares mammillary bodies)
  • Carbon monoxide poisoning
  • Central pontine myelinolysis
  • Delirium tremens

Evaluation

Axial MRI FLAIR image showing hyperintense signal in the mesial dorsal thalami, a common finding in Wernicke encephalopathy

Workup

• WE is a clinical diagnosis — do NOT delay treatment for workup
• Labs (to exclude alternative diagnoses and identify co-morbid conditions):
  • BMP— electrolytes, glucose, renal function, hepatic function
  • CBC
  • Magnesium level — critical; hypomagnesemia causes resistance to thiamine therapy
  • Lactate — may be elevated (thiamine is a cofactor for pyruvate dehydrogenase)
  • Blood alcohol level
  • Serum thiamine level (whole blood thiamine preferred over serum/plasma):
    • Draw before administering thiamine if possible, but never delay treatment to obtain
    • Normal range generally 70-180 nmol/L, but sensitivity and specificity are poorly defined
    • A normal thiamine level does NOT exclude WE
  • Other labs as clinically indicated: TSH, ammonia, lipase, toxicology screen, blood cultures
• Consider lumbar puncture if meningitis/encephalitis suspected — CSF in WKS typically shows normal or mildly elevated protein without pleocytosis

Imaging

• CT head: sensitivity only ~13% for WE; primary role is to exclude other pathology (hemorrhage, mass, infarct)
• MRI brain (best imaging modality if obtained):
  • Sensitivity ~53%, specificity ~93%, positive predictive value ~89%
    • MRI is better at confirming the diagnosis than ruling it out
    • A normal MRI does NOT exclude WE — do not withhold treatment based on normal imaging
  • Classic findings: bilateral, symmetric T2/FLAIR hyperintensities in:
    • Mammillary bodies (most distinctive finding; contrast enhancement may be pathognomonic)
    • Periventricular/medial thalamus
    • Periaqueductal gray matter
    • Tectal plate
    • Cerebellar vermis (atypical but recognized)
  • DWI may show restricted diffusion (helps differentiate vasogenic vs cytotoxic edema)
  • Findings may normalize within days of starting thiamine therapy
• Communicate suspected diagnosis to radiologists so protocols optimized for mammillary bodies, thalami, and periaqueductal region are used

Diagnosis

• Clinical diagnosis — maintain high index of suspicion
• Caine criteria (operational diagnostic criteria; ~85% sensitive when ≥2 present):
  • Nutritional deficiency (any state, not just alcoholism)
  • Ocular findings (ophthalmoplegia, nystagmus)
  • Cerebellar dysfunction (ataxia)
  • Altered mental status or mild memory impairment
• Per EFNS guidelines, clinical diagnosis of WE in alcoholics requires at least 2 of the following:
  • Dietary deficiencies
  • Ocular findings (ophthalmoplegia, nystagmus)
  • Cerebellar dysfunction (ataxia)
  • Mental status change or mild memory impairment

Management

If you suspect, then treat! Confirming diagnosis is difficult, treatment is low risk and effective, and morbidity/mortality is high if untreated

Acute Treatment

• Thiamine — IV administration is critical; oral absorption is unreliable in at-risk patients
  • Royal College of Physicians / UK guideline (widely adopted):
    • 500 mg IV over 30 min TID x 2-3 days → then 250 mg IV/IM once daily x 3-5 days → then 100 mg PO daily until patient no longer at risk
  • EFNS guideline:
    • 200 mg IV TID (diluted in 100 mL NS or D5W, infused over 30 min)
  • 100 mg/day (e.g., banana bag dose) is likely insufficient — especially in patients with alcohol use disorder
  • Thiamine has a short half-life (~96 min); multiple daily doses are more effective than once-daily dosing
  • Overall safety of thiamine is very good; anaphylaxis risk with IV thiamine is rare

Key Principles

• Give thiamine BEFORE glucose in any at-risk patient requiring dextrose
  • Glucose without thiamine can precipitate or worsen WE by driving remaining thiamine intracellularly
  • If both are urgently needed (e.g., symptomatic hypoglycemia), give them simultaneously — do not withhold glucose to wait for thiamine
• Give magnesium
  • Magnesium is a cofactor for thiamine-dependent enzymes
  • Hypomagnesemia may cause resistance to thiamine therapy
  • Replete magnesium early and aggressively
• Replete other vitamins/electrolytes as indicated (folate, multivitamin, pyridoxine)
• Monitor for refeeding syndrome in severely malnourished patients
• Treatment response can take days to weeks; lack of immediate improvement does not exclude WE

Treatment Response (Expected Timeline)

• Oculomotor dysfunction: often begins improving within hours to days
• Confusion/encephalopathy: may take days to weeks
• Ataxia: slowest to improve; may be permanent
• Korsakoff psychosis: largely irreversible once established

Common Pitfalls

Pitfall	Correct Approach
Believing WE only affects alcoholics	Any nutritionally deficient state can cause WE — consider post-bariatric surgery, cancer, hyperemesis, critical illness
Waiting for the complete classic triad	Triad present in only ~10%; any component + risk factor should prompt treatment
Using 100 mg IV thiamine (banana bag) as treatment dose	100 mg is prophylactic, not therapeutic; treatment requires 200-500 mg IV TID
Relying on labs/imaging to confirm before treating	Clinical diagnosis; normal thiamine levels and normal MRI do NOT exclude WE
Withholding glucose to wait for thiamine	If hypoglycemia is symptomatic, give both simultaneously; do not delay glucose
Forgetting to check/replete magnesium	Hypomagnesemia impairs thiamine utilization; always co-replete
Confusing WE with cerebellar stroke	Both present with ophthalmoplegia, ataxia, AMS — always consider WE in differential

Medication Dosing

Thiamine 500mg IV over 30min TID x 2-3 days, then 250mg IV/IM daily x 3-5 days, then 100mg PO daily IV — 100mg (banana bag dose) is prophylactic only, NOT therapeutic; treatment requires 200-500mg IV TID

Disposition

• Admit (inpatient medicine or neurology service)
  • Ensures continued IV thiamine and magnesium administration
  • Observation for development of Korsakoff syndrome
  • Evaluation for cardiovascular beriberi
  • Address underlying cause of thiamine deficiency
• <25% of patients show full recovery, ~50% show partial recovery, the remainder show no response despite treatment
• ~80% of patients with untreated WE develop Korsakoff syndrome
• Refer patients with alcohol use disorder to cessation programs; monitor for alcohol withdrawal

Prevention

• Give parenteral thiamine to all at-risk patients presenting to the ED — do not wait for symptoms
• After bariatric surgery: follow thiamine status for at least 6 months; supplement parenterally as needed

Vitamin Prophylaxis for Chronic alcoholics

• At risk for thiamine deficiency, but no symptoms: thiamine 100mg PO q day
• Give multivitamin PO; patient at risk for other vitamin deficiencies

Banana bag

The majority of chronic alcoholics do NOT require a banana bag

• Thiamine 100mg IV
• Folate 1mg IV (cheaper PO)
• Multivitamin 1 tab IV (cheaper PO)
• Magnesium sulfate 2mg IV
• Normal saline as needed for hydration

See Also

• Thiamine deficiency
• Beriberi
• Alcohol withdrawal
• Alcoholic ketoacidosis
• Refeeding syndrome

Ethanol related disease processes

• Ethanol toxicity
• Alcohol use disorder
• Alcohol withdrawal
  • Alcohol withdrawal seizures
  • Delerium tremens
• Electrolyte/acid-base disorder
  • Alcoholic ketoacidosis
  • Beer potomania syndrome
  • Beriberi
  • Thiamine deficiency
  • Wernicke-Korsakoff syndrome

External Links

• Emergency Care BC: Wernicke's Encephalopathy Diagnosis and Treatment
• EMCrit IBCC: Thiamine Deficiency and Wernicke Encephalopathy
• StatPearls: Wernicke Encephalopathy