Wernicke's Encephalopathy

Wernicke's encephalopathy was first identified by German neurologist Karl Wernicke in 1881 in three patients. Two had alcoholism and one had sulfuric acid poisoning. Three key symptoms were described - mental confusion, ataxia and ophthalmoplegia (the 'classic triad').^1,2

The causative factor was found to be thiamine deficiency. Thiamine is important in the function of the enzyme transketolase, which is involved in the maintainance of myelin sheaths. Thiamine is also involved in the metabolism of lipids and glucose, GABA metabolism and the electrical stimulation of neurones.
Research has shown that the classic triad of symptoms is not always present, and that subclinical episodes can occur. ^3,4

A late manifestation of the condition is memory problems and confabulation (filling in the gaps in one's memory with false information which one believes to be true). It is then known as Wernicke-Korsakoff syndrome.

Information is not widely available but American autopsy reports suggest an incidence in the general population of 0.8-2.8%. The incidence is thought to be much higher in alcoholics (approximately 12.5%). It is also common in individuals with nutritional deficiencies such as AIDS patients, pregnant women suffering from hyperemesis gravidarum, patients undergoing haemodialysis, and those suffering from malignancy. There is also a high incidence in underdeveloped countries where nutritional problems and vitamin deficiencies are common.⁵

Korsakoff's syndrome is not always preceded by Wernicke's encephalopathy. A retrospective analysis of 160,000 admissions to a hospital in Glasgow between 1990 and 1995 found 47 new cases of Korsakoff's syndrome of which only 7 were preceded by Wernicke's encephalopathy.⁶

The classic triad of confusion, ataxia, and ophthalmoplegia occurs in only 10% of cases.
Since most cases occur in alcoholics, who may already be confused and ataxic, the diagnosis may not be easy.⁷
Difficulties in diagnosis may also be compounded by the fact that alcohol intoxication or withdrawal and common concurrent morbidities such as head injuries also share many of the features of Wernicke's encephalopathy. These can include acute mental impairment, obtundation (a dulled or reduced level of consciousness), precoma and coma and occur in 82% patients with Wernicke's encephalopathy.
Wernicke's encephalopathy is therefore underdiagnosed but a high index of suspicion should be maintained for any patient with chronic alcohol abuse who also exhibits acute confusion, decreased level of consciousness, ophthalmoplegia, ataxia, memory disturbance, hypothermia with hypotension or delirium tremens.⁵
The conclusion of one study of 28 alcoholic patients was that at least two of the four following criteria should be present to diagnose Wernicke encephalopathy patients:
(1) dietary deficiencies, (2) oculomotor abnormalities, (3) cerebellar dysfunction, and (4) either an altered mental state or mild memory impairment.⁸
Ocular signs include nystagmus, bilateral lateral rectus palsy and conjugate gaze palsy.
Sometimes, pupil abnormalities can be seen such as ptosis, sluggish reaction to light and accommodation, and anisocoria (unequal size of the pupils).
Mental state examination may reveal global confusion, distraction, and disinterest.
Gait ataxia is sometimes present and results in the patient walking with a broad-based gait. In severe cases, walking may be completely impossible. The ataxia may relate to a combination of cerebellar damage and polyneuropathy. Vestibular dysfunction may also contribute to gait disturbance. Hearing is not usually affected.

The involvement of the temperature regulating centre in the brainstem commonly results in hypothermia, and the involvement of the efferent sympathetic outflow may cause hypotension.
The development of Korsakoff's psychosis (also known as Korsakoff's amnesic syndrome) may be signalled by retrograde amnesia (difficulty in recalling information), antegrade amnesia (difficulty in storing new information), apathy and lack of initiative and confabulation.⁹
Other signs of thiamine deficiency may be present including heart failure and oedema (wet beri beri) or nutritional polyneuropathy (a feature of dry beri beri, with burning pains in the feet and hands, distal weakness and wasting, dry hair and shiny skin).¹⁰

• Alcohol Abuse
• Drug Abuse
• Alcoholic Ketoacidosis
• Delirium Tremens
• Dementia
• Ischaemic Stroke
• Chronic hypoxia
• Closed head injury
• Hepatic encephalopathy
• Postictal state

Laboratory Investigations

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.
The following, however may be helpful:⁵

• Full blood count to rule out anaemia and leukaemias as a cause of altered mental state.
• Urea and Electrolytes to exclude hypernatraemia, hypercalcaemia, and uraemia as causes of altered mental state.
• Serum glucose level to rule out hypoglycaemia or hyperglycaemia.
• Blood arterial gases to rule out hypercarbia and hypoxia.
• Toxicology to check whether drugs of abuse may be causing altered mental state.
• Red cell transketolase levels detect thiamine deficiency but are not usually necessary to diagnose Wernicke encephalopathy.
• Lumbar puncture may need to be performed to exclude non-focal CNS infections.

Imaging

CT head scan may be useful in the acute phase,¹¹ but is likely to be less sensitive than MRI.¹² Diffusion-weighted imaging (an enhanced view based on local water diffusion properties) can improve MRI sensitivity.¹³

Other Procedures

EEG may be required to rule out convulsive or non-convulsive status epilepticus.⁵

Chronic alcoholism and substance abuse, HIV, starvation and overfeeding after starvation (carbohydrate overloading can deplete marginal thiamine stores). Any condition that causes persistent vomiting including hyperemesis gravidarum, malabsorption (sprue), chronic renal failure, and congenital transketolase function abnormalities.⁵

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.
Once the diagnosis is apparent, thiamine should be given intravenously. In the UK this comes in an ampoule in combination with ascorbic acid, anhydrous glucose, nicotinamide, pyridoxine hydrochloride, riboflavine, and thiamine hydrochloride 250 mg/10 mL . The injections come in paired ampoules and are given at a dose of 2-3 every 8 hours.¹⁴ Serious anaphylactic reactions have occurred, and the CSM warn that the parenteral route should only be given when absolutely necessary. The injection should be given slowly over a period of ten minutes, and facilities for treating anaphylaxis should be available.¹⁴The magnesium level should be checked and corrected if low, as this can prevent the therapeutic effects of parenteral thiamine.⁵
Parenteral therapy should be continued for 3-5 days after which oral therapy can be instituted, usually at a dose of 100-300mg.¹⁴
Milder cases or patients who continue to have poor nutrition after the acute phase should go on oral therapy at a dose of 10-25mg a day. Other vitamins, mainly of the B group, may also be required.

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.⁶
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.⁵
Congestive heart failure may be a complication and appears to be related to intracellular oedema and fibrosis of the cardiac muscle.¹⁵
Vertical nystagmus may resolve slowly, but fine horizontal nystagmus may persist indefinitely in up to 60% of cases.¹⁶ Most other ocular symptoms resolve rapidly.
Ataxia may persist in 40% of patients, who continue to suffer from a slow shuffling gait.¹⁶
Global confusion state may be slow to resolve, and there may be persisting learning difficulties and memory impairment.

The mortality rate is 10-20%. Death can result from infection, hepatic failure, or the direct result of thiamine deficiency.⁵
A percentage of patients develop Korsakoff syndrome. Only 20% of such patients recover completely, and a significant number require long term care.¹⁶ 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.¹⁷

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.¹⁸
Early detection of at-risk patients and adequate treatment with intravenous thiamine (250mg for at least 3 days), followed by intramuscular or oral thiamine maintenance combined with other B group vitamins is important. Fortified foods and beer have been instituted in America, and consideration is being given to introducing similar measures in the UK.¹⁷