Wernicke encephalopathy and Korsakoff syndrome

Wernicke encephalopathy is an acute, reversible condition caused by severe thiamine (vitamin B₁) deficiency, often due to chronic heavy alcohol use. Inadequate intake, impaired absorption, or increased excretion of thiamine can also cause Wernicke encephalopathy. The classical triad of confusion, oculomotor dysfunction, and gait ataxia is seen in about a third of patients. Chronic thiamine deficiency, especially in patients with alcohol use disorder, frequently progresses to Korsakoff syndrome, which is characterized by irreversible personality changes, anterograde and retrograde amnesia, and confabulation. The diagnosis of both Wernicke encephalopathy and Korsakoff syndrome is clinical, but laboratory tests confirming thiamine deficiency and brain imaging may be considered in ambiguous cases. Wernicke encephalopathy is an emergency and requires immediate high-dose IV thiamine therapy followed by long-term thiamine supplementation. Abstaining from alcohol is vital in both conditions. While the prognosis in Wernicke encephalopathy is good if treated accordingly, that in Korsakoff syndrome is generally poor.

• Wernicke encephalopathy and Korsakoff syndrome are caused by a severe deficiency of thiamine (vitamin B₁).
• Thiamine deficiency can be due to:
  • Chronic heavy alcohol use (most common): due to inadequate intake, absorption, and hepatic storage of thiamine
  • Inadequate intake
    • Thiamine-deficient diets
    • Anorexia nervosa, starvation
  • Malabsorption
  • Increased demand (hypermetabolic states)
    • Pregnancy and lactation
    • Hyperthyroidism
    • Systemic diseases
    • Malignancy
  • Increased loss
    • Diarrhea
    • Hyperemesis
    • Dialysis

References:^[1]

• Thiamine pyrophosphate (TPP) is the active form of thiamine.
• TPP is a cofactor for important enzymes involved in cerebral glucose and energy metabolism (see glycolysis and gluconeogenesis).
• The brain requires a constant source of thiamine to function properly.
• Thiamine deficiency → decreased cerebral glucose metabolism and mitochondrial dysfunction → depleted ATP and increased free radicals → injury of neuronal elements; (e.g., myelin sheaths, blood-brain-barrier, decreased neurotransmitters, etc.) → impaired axonal conduction → symptoms of Wernicke encephalopathy and Korsakoff syndrome
• In patients with Korsakoff syndrome: long term thiamine deficiency → permanent damage to components of the limbic system (e.g., mammillary bodies, anterior thalamic nuclei) → atrophy of these components → memory loss, apathy, and disrupted emotional processing

Wernicke encephalopathy (acute, reversible)

• Should be suspected in any patient with a history of chronic heavy alcohol use who presents with one/more symptoms of the classic triad of Wernicke encephalopathy
  1. Confusion (most common)
  2. Oculomotor dysfunction
     • Gaze-induced horizontal/vertical nystagmus (most common)
     • Diplopia
     • Conjugate gaze palsy
  3. Gait ataxia: wide-based, small steps
• Other manifestations
  • Autonomic dysfunction: hypotension, syncope, hypothermia
  • Peripheral neuropathy: paresthesia, foot drop, decreased deep tendon reflexes
  • Cardiovascular dysfunction: tachycardia, exertional dyspnea
  • Diencephalic involvement: vegetative disorders (coma and stupor)

Korsakoff syndrome (chronic, irreversible)

Korsakoff syndrome is a late development in patients with persistent vitamin B1 deficiency. It is most often seen in thiamine deficiency due to chronic heavy alcohol use.

• Confabulation: Patients produce fabricated memories to fill in lapses of memory.
• Anterograde and retrograde amnesia (anterograde is more common than retrograde)
• Personality changes (in frontal lobe lesions): apathy, indifference, decrease in executive function
• Disorientation to time, place, and person
• Hallucinations

Wernicke's COAT: Confusion, Oculomotor dysfunction, Ataxia, and Thiamine administration (see Treatment section)
Korsakoff's CART: Confabulation, Anterograde and Retrograde amnesia, and altered Temper

Although often grouped together as a single syndrome (Wernicke-Korsakoff syndrome), the two conditions are distinct entities with different presentations, and, while both are due to severe chronic thiamine deficiency, Wernicke encephalopathy is reversible whereas Korsakoff syndrome is not.

References:^[1][2]

• Usually a clinical diagnosis
• In ambiguous cases:
  • Laboratory tests
    • ↓ Serum thiamine levels
    • ↓ Erythrocyte transketolase activity (thiamine dependent)
    • ↑ Serum lactate and pyruvate
    • Evidence of alcohol-related liver dysfunction in patients with chronic heavy alcohol use
  • Brain MRI: T2-weighted hyperintense lesions in the mammillary bodies, midbrain tectal plate, dorsomedial nuclei of the thalamus, cerebellum, and around the aqueduct and the third ventricle

MRI signs of periventricular hemorrhage and/or atrophy of mammillary bodies is a frequent finding in both Wernicke encephalopathy and Korsakoff syndrome.

Laboratory tests or imaging should not delay treatment!

References:^[1]

• Petechial lesions and small vessel hemorrhage in the mesencephalon, mammillary bodies, ventricle walls, and dorsomedial nucleus of thalamus
• Atrophy of anterior thalamic nuclei and mammillary bodies (both are part of the limbic system)
• Microscopic spongiosis, capillary proliferation, and hemosiderin deposits (due to recurrent bleeding)

References:^[1][3]

• Wernicke encephalopathy (conditions that manifest with an acute onset of delirium/ataxia)
  • Cerebellar stroke
  • Hypoxia/hypercarbia (post cardiac arrest)
  • Postictal state
  • CNS infections (e.g., meningitis)
  • Tabes dorsalis
• Korsakoff syndrome (conditions that present with amnesia, disorientation)
  • Alzheimer disease
  • Dementia with Lewy bodies
  • Parkinson disease

References:^[1]

The differential diagnoses listed here are not exhaustive.

• Wernicke encephalopathy
  • Immediate IV administration of high-dose vitamin B₁/thiamine upon suspicion of Wernicke encephalopathy until symptoms recede, followed by a lower dose
  • Thiamine must be administered before IV glucose infusions because glucose administration without thiamine can worsen encephalopathy.
  • Long-term oral replacement of vitamin B₁, vitamin B₆, vitamin B₁₂, and folic acid (vitamin B complex)
  • Abstinence from alcohol
• Korsakoff syndrome
  • Oral thiamine supplementation to prevent further progression to irreversible complications
  • Abstinence from alcohol
  • Psychiatric and psychological therapy
  • Memory strengthening exercises and aids
  • The use of signs and arrows at home can help with orientation.
  • Acetylcholinesterase inhibitors (e.g., donepezil) are suggested to have beneficial effects on cognitive functioning. ^[4]

Because glucose increases thiamine demand and will worsen encephalopathy, IV glucose infusions must be administered AFTER thiamine!

References:^[5]

• Wernicke encephalopathy: Generally, oculomotor function resolves within hours, ataxia within days, and confusion within weeks.
• Korsakoff syndrome: Symptoms are often irreversible.