Medicine chapters
Vitamin B12 deficiency (subacute combined degeneration), Wernicke encephalopathy and Korsakoff syndrome
How vitamin B12 deficiency damages the spinal cord, nerves and brain, and how thiamine deficiency in alcohol misuse causes Wernicke encephalopathy and Korsakoff syndrome, with the other neurological effects of alcohol.
- B12 deficiency damages the dorsal columns, lateral corticospinal tracts and peripheral nerves (subacute combined degeneration): lost vibration and position sense, absent ankle jerks with extensor plantars.
- Wernicke encephalopathy is acute thiamine deficiency: confusion, ophthalmoplegia/nystagmus and ataxia; it is an emergency treated with IV thiamine before glucose.
- Untreated, it leaves Korsakoff syndrome: severe anterograde amnesia with confabulation, from damage to the mammillary bodies and thalamus.
On this page
Overview
Two vitamin deficiencies cause important, preventable and treatable neurological disease:
- Vitamin B12 (cobalamin) deficiency causes subacute combined degeneration of the cord (SACD), peripheral neuropathy, optic atrophy and dementia.
- Thiamine (vitamin B1) deficiency, usually from alcohol misuse, causes Wernicke encephalopathy and Korsakoff syndrome.
Both are under-diagnosed. Both respond to early treatment and leave permanent damage if treatment is late.
Part 1: Vitamin B12 deficiency
Physiology in brief
- B12 comes only from animal foods (meat, fish, eggs, dairy). The body stores 2–3 mg, mainly in the liver, enough for 2 years or more after intake or absorption stops.
- Absorption: B12 binds intrinsic factor (from gastric parietal cells) and is absorbed in the terminal ileum; it is carried in blood on transcobalamin II.
- B12 is a cofactor for methionine synthase (homocysteine → methionine; needed for DNA synthesis and myelin) and methylmalonyl-CoA mutase. Deficiency raises homocysteine and methylmalonic acid (MMA); the myelin defect explains the neurology.
Causes
| Site | Causes |
|---|---|
| Diet | Strict vegans, poor diet |
| Stomach | Pernicious anaemia (commonest in adults), gastrectomy, atrophic gastritis |
| Small bowel | Terminal ileal resection or Crohn disease, blind loop with bacterial overgrowth, fish tapeworm (Diphyllobothrium), tropical sprue |
| Drugs | Metformin, long-term PPIs (mild); nitrous oxide abuse or repeated anaesthesia (inactivates B12, so serum level can be normal) |
Pernicious anaemia: autoimmune atrophic gastritis with loss of parietal cells and intrinsic factor. Commoner in older people, women and those with other autoimmune diseases (thyroid disease, vitiligo, Addison disease). Parietal cell antibodies are present in about 90% but are not specific; intrinsic factor antibodies are found in only about half but are specific. Carries a higher risk of gastric cancer.
Subacute combined degeneration of the cord
"Combined" means posterior (dorsal) columns plus lateral corticospinal (pyramidal) tracts; a peripheral neuropathy is usually added.
| Structure damaged | Result |
|---|---|
| Dorsal columns | Loss of vibration (often first) and joint position sense; sensory ataxia; positive Romberg test |
| Lateral corticospinal tracts | Spastic weakness, brisk knee jerks, extensor plantars |
| Peripheral nerves | Symmetrical tingling of fingers and toes (often the presenting symptom), glove-and-stocking loss, absent ankle jerks |
| Optic nerves | Optic atrophy, central scotoma |
| Brain | Memory loss, depression, psychosis, dementia ("megaloblastic madness") |
The classic SACD combination is absent ankle jerks with extensor plantars (and often brisk knee jerks), with lost vibration and position sense.
Other causes of absent ankle jerks + upgoing plantars: SACD, Friedreich ataxia, taboparesis (syphilis), MND, and conus lesions, or diabetic neuropathy with a stroke.
Neurological damage can occur without anaemia or macrocytosis, especially if folic acid has been given. A normal blood count does not exclude SACD.
Other features of B12 deficiency: lemon-yellow pallor (anaemia plus mild jaundice from ineffective erythropoiesis), glossitis, angular stomatitis, weight loss.
Investigations
- Full blood count: macrocytic anaemia (high MCV), sometimes pancytopenia; film shows oval macrocytes and hypersegmented neutrophils.
- Serum B12 low (neurological damage is usual with very low levels); holotranscobalamin ("active B12").
- Raised MMA and homocysteine: useful when B12 is borderline but suspicion is high.
- Bone marrow (rarely needed): megaloblastic.
- Raised bilirubin (unconjugated) and LDH.
- Intrinsic factor and parietal cell antibodies for pernicious anaemia.
- MRI spine: high T2 signal in the dorsal columns (inverted "V") in SACD.
- Nerve conduction: axonal neuropathy.
Treatment
- Hydroxocobalamin intramuscularly: 1000 μg injections over the first 2 weeks, adding up to 5–6 mg in all, then 1000 μg every 3 months for life (for pernicious anaemia). With neurological involvement, injections are usually given more often at first.
- Do not give folic acid alone before B12 is known to be normal: it can correct the anaemia but precipitate or worsen SACD. In a very ill patient give both.
- Watch for hypokalaemia in the first days (potassium moves into new cells) and iron deficiency as production recovers.
- Response: reticulocytes rise in 2–3 days and peak at 5–7 days; peripheral nerves improve over 6–12 months, but long-standing cord and brain damage may not recover.
- Oral B12 is suitable for dietary deficiency and can work in malabsorption if adherence is good.
Hydroxocobalamin 1000 μg per injection, total loading 5–6 mg over 2 weeks
5–6 mg ÷ 1 mg per injection = 5–6 injections in the first 2 weeks
Then 1 mg every 3 months = 4 injections a year for life
Part 2: Alcohol and thiamine deficiency
Thiamine basics
- Thiamine pyrophosphate is a cofactor for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and transketolase. Without it, brain cells cannot use glucose properly.
- Body stores are small, so deficiency develops within weeks of poor intake.
- Glucose loads use up thiamine: giving glucose (or refeeding) to a deficient person can precipitate Wernicke encephalopathy.
Causes: chronic alcohol misuse (commonest; poor diet, poor absorption and storage), hyperemesis gravidarum, anorexia nervosa, starvation, gastric cancer or bariatric surgery, prolonged vomiting, dialysis, parenteral nutrition without vitamins, and refeeding.
Beriberi (dietary deficiency, e.g. polished-rice diets): dry = symmetrical sensorimotor neuropathy with lost ankle jerks; wet = high-output heart failure with oedema.
Wernicke encephalopathy
An acute, reversible brain disorder from thiamine deficiency. Lesions (haemorrhage and necrosis) lie around the third ventricle, aqueduct and fourth ventricle: mammillary bodies, medial thalamus, periaqueductal grey and oculomotor nuclei.
Classic triad:
| Feature | Details |
|---|---|
| Confusion (encephalopathy) | Disorientation, apathy, drowsiness; can progress to stupor and coma |
| Eye signs (ophthalmoplegia) | Nystagmus (commonest), bilateral lateral rectus (VI) palsy, conjugate gaze palsies |
| Ataxia | Broad-based, unsteady gait (truncal), from cerebellar vermis and vestibular involvement |
Other features: hypothermia, hypotension, peripheral neuropathy.
Only a minority have the full triad. Any confused or ataxic person with alcohol misuse or malnutrition should be treated as Wernicke without waiting.
Diagnosis: clinical. Red cell transketolase activity is low (rarely available); MRI may show high signal around the third ventricle and mammillary bodies. Do not delay treatment for tests.
Treatment (emergency):
- High-dose parenteral (IV) thiamine for several days, then oral thiamine. Give it slowly; anaphylaxis is rare.
- Give thiamine before (or with) any glucose in a patient at risk.
- Correct magnesium (a cofactor; low magnesium blunts the response), fluids and other vitamins.
- Eye signs improve within hours to days; ataxia and memory recover more slowly and often incompletely.
Prevention: oral thiamine (for example 300 mg daily) for heavy drinkers; parenteral thiamine for at-risk drinkers admitted to hospital, especially if malnourished or in withdrawal.
In any unconscious or confused patient with alcohol misuse: IV thiamine first, then glucose.
Wernicke = "COAT": Confusion, Ophthalmoplegia, Ataxia, give Thiamine.
Korsakoff syndrome (Korsakoff psychosis)
The chronic, often irreversible amnestic state that follows untreated or inadequately treated Wernicke encephalopathy (together: Wernicke-Korsakoff syndrome).
- Severe anterograde amnesia (cannot lay down new memories) with variable retrograde amnesia.
- Confabulation: fills memory gaps with invented stories, without intending to deceive.
- Lack of insight, apathy.
- Other cognition and consciousness are relatively preserved: alert, attentive, can hold a conversation; working memory (digit span) is normal.
- Lesion: mammillary bodies and dorsomedial thalamus (Papez circuit).
Treatment: thiamine, abstinence, nutrition and structured supportive care; many need long-term care.
| Feature | Wernicke encephalopathy | Korsakoff syndrome |
|---|---|---|
| Onset | Acute | Chronic, follows Wernicke |
| Consciousness | Confused, drowsy | Clear |
| Main feature | Triad: confusion, eye signs, ataxia | Amnesia + confabulation |
| Reversibility | Reversible if treated early | Largely irreversible |
Other neurological effects of alcohol
| Disorder | Key points |
|---|---|
| Acute intoxication | Ataxia, slurred speech, coma, hypoglycaemia; exclude head injury |
| Withdrawal | Tremor, sweating, anxiety within hours; withdrawal seizures |
| Delirium tremens | 1–3 days after the last drink: confusion, agitation, visual hallucinations (insects, small animals), tremor, fever, tachycardia; mortality if untreated. Treat with benzodiazepines (chlordiazepoxide or diazepam), fluids, electrolytes, parenteral thiamine |
| Alcoholic cerebellar degeneration | Atrophy of the anterior superior vermis: gait and leg ataxia, arms and speech relatively spared |
| Peripheral neuropathy | Painful, symmetrical, sensory-predominant, distal (alcohol toxicity plus thiamine deficiency) |
| Central pontine myelinolysis (osmotic demyelination) | Over-rapid correction of hyponatraemia: quadriparesis, dysarthria, dysphagia, "locked-in" |
| Alcohol-related dementia, cerebral atrophy | Frontal executive problems |
| Marchiafava-Bignami disease (rare) | Demyelination of the corpus callosum |
| Others | Subdural haematoma (falls), hepatic encephalopathy, stroke, myopathy |
Delirium tremens is a withdrawal state, appearing 1–3 days after stopping alcohol (often on day 2 of a hospital admission), not during drinking.
Expect: tracts involved in SACD (dorsal columns and lateral corticospinal) and the "absent ankle jerks with extensor plantars" pattern; earliest sign (lost vibration sense); pernicious anaemia antibodies; danger of folic acid alone; hydroxocobalamin regimen; B12 deficiency after ileal resection or with metformin; Wernicke triad, nystagmus and VI nerve palsy, thiamine before glucose, lesion around the third ventricle and mammillary bodies; Korsakoff amnesia with confabulation and preserved consciousness; delirium tremens timing and benzodiazepine treatment; central pontine myelinolysis.
Quick revision
- SACD = B12 deficiency damaging dorsal columns, corticospinal tracts and nerves: lost vibration/position sense, Romberg positive, absent ankle jerks, extensor plantars.
- Neurological damage can occur without anaemia; folic acid alone can worsen it.
- Pernicious anaemia: intrinsic factor antibodies specific, parietal cell antibodies sensitive.
- Hydroxocobalamin IM: loading 5–6 mg over 2 weeks, then 1 mg every 3 months for life; watch potassium.
- Wernicke: confusion + nystagmus/ophthalmoplegia + ataxia; IV thiamine before glucose; check magnesium.
- Korsakoff: anterograde amnesia, confabulation, clear consciousness; mammillary bodies and medial thalamus.
- Delirium tremens 1–3 days after stopping alcohol: benzodiazepines and thiamine.
- Alcohol also causes vermis atrophy (gait ataxia), neuropathy, and CPM if sodium is corrected too fast.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
Which reflex pattern is typical of subacute combined degeneration?
Absent ankle jerks (from peripheral neuropathy) with extensor plantar responses (from corticospinal tract damage), often with brisk knee jerks.
Why is thiamine given before glucose to a patient with alcohol misuse?
Glucose metabolism consumes thiamine, so a glucose load in a deficient patient can trigger or worsen Wernicke encephalopathy.
Is Korsakoff syndrome the same as dementia?
No. Korsakoff mainly affects memory, with confabulation, while attention and other thinking skills are relatively preserved; dementia affects several domains.
Can B12 injections reverse subacute combined degeneration?
Peripheral nerve damage often improves over months, but long-standing spinal cord and brain damage may be permanent, which is why early treatment matters.