Wernicke-Korsakoff Syndrome

Wernicke-Korsakoff syndrome is a spectrum of disease resulting from thiamine deficiency, usually related to alcohol abuse. Wernicke's encephalopathy was originally described by German neurologist Karl Wernicke in 1881 as a classic triad of symptoms (mental confusion, ataxia and ophthalmoplegia). Korsakoff's psychosis is the late manifestation of the condition, where Wernicke's encephalopathy has not been adequately treated.¹

Incidence

• 1/1000 population in USA.²
• A survey of new long-stay mental hospital patients in Scotland found that 9% had a diagnosis of alcohol-related brain damage.³
• Peak onset is seen in males 40-59 years, females 30-49 years.
• Approximately 2% of alcohol abusers develop syndrome.
• Much greater risk in continuous rather than binge drinking.
• No racial predilection is observed.
• The condition affects males slightly more frequently than it affects females.

Chronic alcohol consumption can result in thiamine deficiency by causing:

• Inadequate nutritional thiamine intake
• Decreased absorption of thiamine from the gastrointestinal tract
• Impaired thiamine utilisation in the cells

People differ in their susceptibility to thiamine deficiency, however, and different brain regions also may be more or less sensitive to this condition.⁴

Thiamine is a cofactor required by three enzymes in pathways of carbohydrate metabolism:

• A reduction in thiamine can interfere with numerous cellular functions.
• Alcohol-related neuronal loss has been documented in specific regions of the cerebral cortex, hypothalamus and cerebellum.⁵
• No change is found in basal ganglia, nucleus basalis, or serotonergic raphe nuclei.

Many of these regions which are normal in uncomplicated alcoholics are damaged in people with Wernicke-Korsakoff syndrome (WKS).

Chronic subdural haematoma has been documented as a cause of WKS:
The symptoms persisted after resolution of the haematoma as a result of organic atrophic changes of both the frontal and temporal lobes due to long-term compression.⁶

It has also been reported following nutritional stress e.g. laparotomy for small bowel obstruction, followed by total parenteral nutrition for one month,⁷ bariatric surgery or rapid weight-loss.⁸

Other chronic conditions that may cause a thiamine deficiency include AIDS, hyperemesis gravidarum, thyrotoxicosis, cancers that have spread throughout the body, long-term dialysis and congestive heart failure (when treated with long-term diuretic therapy).

Symptoms

• Vision changes:
  • Double vision
  • Eye movement abnormalities
  • Eyelid drooping
• Loss of muscle coordination:
  • Unsteady, uncoordinated walking
• Loss of memory, can be profound
• Inability to form new memories
• Hallucinations

Signs

• Examination of the nervous system may show polyneuropathy.
• Reflexes may be decreased (or of abnormal intensity), or abnormal reflexes may be present.
• Gait and coordination are abnormal on testing.
• Muscles may be weak and may show atrophy.
• Eyes show abnormalities of movement - nystagmus, bilateral lateral rectus palsy and conjugate gaze palsy.
• Blood pressure and body temperature may be low.
• Pulse may be rapid.
• The person may appear cachectic.

In addition there are the following cognitive features:

• Confabulation:
  • Falsification of memory in clear consciousness.
  • Very characteristic of the syndrome.
  • Can answer questions promptly with inaccurate and sometimes bizarre answer.
• Memory loss:
  • Anterograde amnesia is the main feature of syndrome.
  • This is loss of memory for events occurring after the onset of the disorder.
  • Unable to learn and repeat simple pieces of information or learn new tasks.
  • Often disorientated in time and place.
• Retrograde amnesia:
  • Loss of memory for events before onset of disorder.
  • Some memory of distant events may be preserved.
  • Telescoping of events is characteristic e.g. says something happened recently when it took place many years ago.
• Patient usually mentally alert with vocabulary, comprehension, motor skills, social habits and naming ability maintained.

Encephalopathy

At least two of the four following criteria should be present to diagnose encephalopathy:^9,10

1. Dietary deficiencies,
2. Oculomotor abnormalities
3. Cerebellar dysfunction
4. Either an altered mental state or mild memory impairment.

Subclinical episodes can occur.^11,12

• Alcohol abuse
• Drug abuse
• Alcoholic ketoacidosis
• Delirium tremens
• Dementia
• Chronic hypoxia
• Closed head injury
• Hepatic encephalopathy
• Post-ictal state
• Cerebral ischaemia
• Brain tumour

Diagnosis is based mainly on the history and physical examination, and if the condition is suspected, treatment should not be delayed whilst waiting for test results.

• FBC particularly looking at the MCV
• U&E's (to exclude hypernatraemia, hypercalcaemia, and uraemia)
• Liver function tests
• Glucose
• Blood arterial gases (to rule out hypercarbia and hypoxia)
• Cholesterol
• Serum B₁ levels may be low
• Pyruvate is elevated
• Red cell transketolase activity is decreased in thiamine deficiency, but are not usually necessary to diagnose the condition
• Lumbar puncture may be needed to exclude non-focal CNS infections

If the history is significant for chronic (long-term) alcohol abuse, serum or urine alcohol levels may be elevated.

Imaging

CT head scan may be useful in the acute phase,¹³ but is likely to be less sensitive than MRI.¹⁴ Diffusion-weighted imaging (an enhanced view based on local water diffusion properties) can improve MRI sensitivity.¹⁵

Other procedures

EEG may be required to rule out convulsive or non-convulsive status epilepticus.¹⁶

• Peripheral neuropathy
• Paraesthesia
• Malnutrition
• Liver disease
• Delirium tremens (around 10%)
• Beriberi (about 5%)

General principles

Address problem of alcohol abuse and diet. Treat as a medical emergency if symptoms are acute. Patients presenting with altered mental state or pre-coma may need oxygen and intravenous rehydration. Comatose patients may require intubation to maintain airway patency.

Pharmacological

• Thiamine orally (IM or IV may be used in secondary care) plus vitamin B complex or multi-vitamins should be given indefinitely.¹⁷Treatment with thiamine is often started under specialist care, although when deficiency is suspected, it should be started in primary care:
  • Some improvement has been seen in 50-75% of cases after starting thiamine, complete remission in 20%.¹⁸
  • A Cochrane review found there was insufficient evidence from randomised controlled clinical trials to guide clinicians in the dose, frequency, route or duration of thiamine treatment of WKS due to alcohol abuse.¹⁹ Although more recent work states that the route of administration and dose depends on the severity of dependence and overall physical health of the patient.²⁰
  • Most people with alcohol dependance (who are in reasonable health) should receive 200–300 mg oral thiamine per day, taken in divided doses (to aid absorption), while they are undergoing detoxification, or during periods they are drinking very excessively.¹⁷
  • The CSM (1989) advised that there is a small risk of serious allergic (anaphylactic) reactions occurring during or shortly after the administration of parenteral thiamine:
    • It recommends that use is restricted to people in whom parenteral treatment is essential.
    • Intravenous injections should be given slowly, over 10 minutes.
    • Facilities for treating anaphylaxis should be available when it is administered.
    • The magnesium level should be checked and corrected if low, as this can prevent the therapeutic effects of parenteral thiamine.¹⁶
• Memantine, a NMDA antagonist,(10 mg) has been reported as safe and well tolerated in small clinical trials:
  • The preliminarily findings of a study with 16 patients suggested that memantine was effective in the treatment of dementia in Wernicke-Korsakoff syndrome.
  • A mini mental state examination demonstrated a significant and clinically relevant benefit for memantine relative to placebo.²¹

A percentage of patients with Wernicke's encephalopathy develop Korsakoff syndrome. Only 20% of such patients recover completely, and a significant number require long term care.² One study suggested that the development of Korsakoff syndrome may be dependent on the degree of alcohol-related neurotoxicity that occurs before thiamine prevention is instituted.¹
• Korsakoff psychosis can develop in untreated or under-treated Wernicke's encephalopathy. One study in Glasgow found an increase in incidence which was thought to be related to a reduction by physicians in the use of parenteral thiamine after the CSM warning.²²
• Symptoms of alcohol withdrawal syndrome (tremors, hallucinations, convulsions) can complicate the picture.
• Recurrence of encephalopathy can recur in patients who continue to drink alcohol and fail to maintain their thiamine intake, and in non-alcoholics with persisting thiamine deficiency due to non-compliance or untreated secondary disease.¹⁶
• Congestive heart failure may be a complication and appears to be related to intracellular oedema and fibrosis of the cardiac muscle.²³
• Vertical nystagmus may resolve slowly, but fine horizontal nystagmus may persist indefinitely in up to 60% of cases.² Most other ocular symptoms resolve rapidly.
• Ataxia may persist in 40% of patients, who continue to suffer from a slow shuffling gait.²
• Global confusion state may be slow to resolve, and there may be persisting learning difficulties and memory impairment.

Prognosis depends on the stage of disease at presentation and on prompt treatment:

• Full recovery of ocular function generally occurs.
• Fine horizontal nystagmus can persist in as many as 60% of cases.
• Approximately 40% of patients have complete recovery from ataxia.
• Only 20% of patients recover completely from amnestic deficit.

The mortality rate is 10-20% in Wernicke-Korsakoff syndrome.²

Patients with significant alcohol dependency should be given thiamine supplementation. Identifying which patients are at risk is not always easy, but retrospective studies based on Accident and Emergency Department attendances which formed part of the Royal College of Physician's report 'Alcohol - Can the NHS Afford It?' suggest that homeless patients with inadequate social support are at greatest risk. Institution of adequate discharge and follow-up arrangements for such individuals may be as important as thiamine replacement.²⁴

• Vitamins
• Alcohol avoidance