Key Facts

Wernicke encephalopathy (WE) is a medical emergency resulting from acute thiamine deficiency. It is grossly under-diagnosed: post-mortem studies show that ~80% of cases are missed clinically. Prompt parenteral thiamine can prevent progression to the irreversible Korsakoff syndrome.

Epidemiology

• Post-mortem prevalence: 1-3% of the general population; up to 12.5% of chronic alcohol misusers
• Clinical diagnosis rate: only ~20% of cases identified ante-mortem
• Alcohol misuse is the most common cause in developed countries, but non-alcoholic causes account for up to 20% of cases
• No sex or ethnic predilection when adjusted for alcohol consumption

Aetiology

• Alcohol-related: chronic misuse → poor dietary intake + impaired GI absorption + reduced hepatic storage + increased metabolic demand
• Non-alcoholic causes: hyperemesis gravidarum, prolonged vomiting, anorexia nervosa, bariatric surgery, cancer (especially post-chemotherapy), prolonged IV glucose without thiamine, dialysis, AIDS, refeeding syndrome
• Thiamine stores are limited (body stores ~30 mg); depletion occurs within 2-3 weeks of zero intake

Pathophysiology

• Thiamine is a cofactor for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase — key enzymes in aerobic metabolism
• Deficiency → impaired oxidative metabolism → cytotoxic oedema and energy failure in metabolically active brain regions
• Vulnerable areas: mammillary bodies, medial thalami, periaqueductal grey, superior cerebellar vermis, cranial nerve nuclei (III, VI)
• Glucose administration without thiamine → increased metabolic demand → accelerated depletion of remaining thiamine → clinical deterioration

Classic Triad (present in only ~16%)

1. Ophthalmoplegia/oculomotor abnormalities (~29%)
   • Lateral rectus (CN VI) palsy — most common
   • Conjugate gaze palsy
   • Nystagmus (horizontal > vertical)
   • Complete ophthalmoplegia in severe cases
2. Ataxia (~23%)
   • Broad-based gait ataxia (cerebellar vermis involvement)
   • Truncal ataxia > limb ataxia
   • May be unable to stand or walk
3. Confusion/altered mental state (~82%)
   • Global confusional state
   • Apathy, disorientation, inattention
   • Memory disturbance (early feature)
   • May progress to stupor and coma

Other Features

• Hypothermia: due to posterior hypothalamic involvement
• Hypotension: autonomic dysfunction
• Peripheral neuropathy: concurrent thiamine-deficiency polyneuropathy
• Vestibular dysfunction: vertigo, nausea

Caine Criteria (more sensitive — requires 2 of 4)

1. Dietary deficiency
2. Oculomotor abnormalities
3. Cerebellar dysfunction
4. Altered mental state or mild memory impairment

Red Flags

• Any confused patient with history of alcohol misuse — assume Wernicke until proven otherwise
• Administration of IV glucose without thiamine — may precipitate or worsen Wernicke encephalopathy
• Post-bariatric surgery patients with vomiting and confusion
• Hyperemesis gravidarum with neurological symptoms
• Rapid deterioration of cognition suggesting progression to Korsakoff syndrome

Bedside

• Clinical diagnosis: Caine criteria (2 of 4: dietary deficiency, oculomotor abnormalities, cerebellar signs, altered mental state)
• Capillary blood glucose: exclude hypoglycaemia
• Neurological examination: cranial nerves (especially III, VI), cerebellar signs, gait assessment
• Nutritional assessment: BMI, signs of malnutrition

Bloods

• Red cell transketolase activity: most specific test for thiamine status; rarely available acutely — do not delay treatment
• Serum thiamine level: can be measured but poor sensitivity; results take days
• FBC: macrocytosis, anaemia
• LFTs: assess liver function; coagulopathy
• U&Es: electrolyte abnormalities
• Magnesium: often low; magnesium is a cofactor for thiamine-dependent enzymes — must be corrected
• Serum lactate: may be raised due to impaired aerobic metabolism
• Blood alcohol level: assess recent intake

Imaging

• MRI brain (investigation of choice):
  • Mammillary body signal changes (most specific, ~58% sensitivity)
  • Periaqueductal grey matter hyperintensity
  • Medial thalamic changes
  • Tectal plate involvement
  • FLAIR and DWI sequences most sensitive
• CT head: usually normal in Wernicke; useful to exclude other pathology (subdural, stroke)

Special Tests

• Neuropsychological testing: if progression to Korsakoff syndrome suspected
• Nerve conduction studies: if concurrent peripheral neuropathy
• EEG: non-specific diffuse slowing; helps exclude non-convulsive status epilepticus

Non-pharmacological

• Immediate hospital admission: medical emergency
• Nutritional rehabilitation: dietitian involvement, oral supplementation once tolerating oral intake
• Refeeding risk assessment: Wernicke patients are high-risk for refeeding syndrome (NICE CG32)
• Alcohol cessation support: once acute phase managed

Pharmacological

• IV Pabrinex (first-line — immediate treatment, do not wait for investigations):
  • Suspected Wernicke: 2 pairs of IV ampoules (each pair = 250 mg thiamine) TDS for 3-5 days minimum
  • EFNS guideline recommendation: thiamine 500 mg IV TDS for 3-5 days, then 250 mg IV OD for 3-5 days, then oral thiamine 100 mg TDS indefinitely
  • Administer before any glucose-containing fluids
  • Anaphylaxis risk with IV Pabrinex is rare (~1:5 million) — resuscitation facilities should be available but risk should not delay treatment
• Magnesium replacement: IV magnesium sulphate 20 mmol over 4 hours — magnesium is essential cofactor for thiamine utilisation
• Oral thiamine: following IV course, continue 100 mg TDS long-term if ongoing risk
• Alcohol withdrawal management: concurrent chlordiazepoxide reducing regimen if withdrawing
• Correct other deficiencies: folate, B12, potassium, phosphate as indicated

Surgical

• Not applicable

Referral Criteria

• All suspected cases: acute medical admission for IV Pabrinex
• Neurology: atypical presentation, failure to respond to treatment, consideration of alternative diagnosis
• Neuropsychology: if Korsakoff syndrome develops — assess capacity and rehabilitation potential
• Alcohol services: after acute episode for relapse prevention
• Social services: if Korsakoff develops — may require long-term supported accommodation

Outcomes

• Untreated: mortality approximately 17-20%
• With treatment: oculomotor abnormalities improve within hours to days of thiamine; ataxia improves in ~40%; confusion improves in ~50%
• Progression to Korsakoff syndrome: approximately 80% of untreated and ~56% of treated cases
• Complete recovery: only ~20% with full treatment
• Residual deficits: gait ataxia persists in >50%; nystagmus may be permanent

Complications

• Korsakoff syndrome: irreversible anterograde amnesia with confabulation; requires long-term care
• Permanent cerebellar damage: chronic ataxia
• Peripheral neuropathy: may persist despite thiamine replacement
• Recurrence: high risk if ongoing alcohol misuse and poor nutrition
• Death: from cardiovascular collapse or concurrent complications if diagnosis delayed

Caine Criteria for Wernicke Encephalopathy

Pabrinex Content (per pair of ampoules)

Thiamine Replacement Summary