Wernicke-Korsakoff syndrome

Notes

Overview

Wernicke-Korsakoff syndrome refers to two distinct neurological syndromes resulting from thiamine (Vitamin B1) deficiency.

Wernicke-Korsakoff syndrome (WKS) refers to a disease spectrum causing two classical neurological syndromes as a result of thiamine (vitamin B1) deficiency:

  • Wernicke encephalopathy (WE): an acute encephalopathy characterised by a triad of confusion, ataxia, and oculomotor dysfunction
  • Korsakoff syndrome (KS): a chronic amnesic syndrome characterised by defects in both anterograde and retrograde memory

The syndromes are most commonly observed in chronic alcoholism because of poor dietary intake, although other factors are involved including a possible genetic element. WKS is not restricted to chronic alcoholism and may be observed in other conditions (e.g. anorexia nervosa).

KS is essentially the late neuropsychiatric manifestation of WE if it goes unnoticed or untreated. Once KS has been established, patients rarely recover. This means early recognition and treatment of WE with high dose B vitamins (e.g. Pabrinex®) is critical to prevent permanent neurological damage.

Epidemiology

The majority of epidemiological data on Wernicke-Korsakoff syndrome comes from autopsy studies.

At autopsy, typical lesions associated with WE are found in up to ~2.8% of patients with the majority having been alcohol dependent. These studies also suggest that WE is under-recognised clinically.

Aetiology

Wernicke-Korsakoff syndrome predominantly occurs in the setting of chronic alcoholism.

The most common cause of Wernicke-Korsakoff syndrome is chronic alcoholism. In alcohol dependency, the combination of dietary thiamine deficiency, reduced gastrointestinal absorption, reduced hepatic uptake, and impaired utilisation all contribute to the development of the syndrome.

Other causes of Wernicke-Korsakoff syndrome occur from conditions that result in poor dietary intake or malabsorption of thiamine relative to metabolic requirements. Examples include:

  • Prolonged fasting or starvation
  • Anorexia nervosa
  • Hyperemesis gravidarum
  • Systemic malignancy
  • End-stage renal failure: on haemodialysis or peritoneal dialysis
  • Gastrointestinal disease & malabsorption

Pathophysiology

Thiamine is an essential cofactor for several metabolic reactions in the body.

Dietary requirements

Thiamine is present in most foods, but specifically in whole grains, poultry, nuts, peas, brown rice, and fortified food. Once absorbed from the gastrointestinal tract it is stored in the liver. However, storage occurs for a maximum of 18 days meaning a moderate consumption of thiamine is needed to maintain stores.

Recommended daily intake of thiamine (adults >18):

  • Men: 1.2 mg/day
  • Women: 1.1 mg/day
  • Pregnancy: 1.4 mg/day

Physiological function

Three enzymatic reactions are reliant on thiamine including acting as a cofactor for pyruvate dehydrogenase, which produces acetyl-CoA that can enter the citric acid cycle for the generation of the energy currency ATP. Thus, it has an important role in deriving energy from carbohydrates.

Role in disease

In Wernicke-Korsakoff syndrome, thiamine deficiency leads to neuronal injury. Deficiency causes areas of the brain with high metabolic activity to undergo neuronal injury that may be precipitated by the administration of intravenous glucose before thiamine supplementation.

On autopsy, typical findings in acute WE include vascular congestion, microglial proliferation, and petechial haemorrhage. In chronic disease, there is evidence of neuronal loss, most notably in the medial thalamus. Several other histological findings are typical of the syndrome.

Thiamine deficiency may also lead to a condition known as beriberi, which is discussed further below.

Beriberi

Beriberi refers to two classic syndromes known as ‘dry’ and ‘wet’ that result from thiamine deficiency.

Wernicke-Korsakoff syndrome is not the only manifestation of thiamine deficiency. Beriberi may also develop due to thiamine deficiency. Adult beriberi is divided into two distinct syndromes:

  • Dry beriberi: symmetrical motor and sensory peripheral neuropathy
  • Wet beriberi: causes a high-output cardiac failure (fluid overload, cardiomyopathy, tachycardia, warm extremities) due to peripheral vasodilatation from a build-up of pyruvate and lactate

Clinical features

Wernicke encephalopathy and Korsakoff syndrome are two clinically distinct syndromes.

Wernicke encephalopathy

WE is characterised by a triad of clinical manifestations that can be remembered by the mnemonic CAN:

  • Confusion
  • Ataxia: poor coordination of movement. Predominantly affects gait
  • Nystagmus: uncontrolled eye movement

This triad of features is only seen in up to one-third of patients.

Nystagmus may be seen as part of a wider number of abnormalities collectively termed oculomotor dysfunction, which can include:

  • Lateral rectus palsy (CN VI palsy)
  • Conjugate gaze palsies: inability to move both eyes in a single horizontal
  • Nystagmus

Korsakoff syndrome

KS is characterised by profound memory defects. Interestingly, long-term memory is relatively preserved in the condition.

  • Memory deficit: anterograde and retrograde
  • Confabulation: stories made up to fill gaps in memory
  • Poor insight: unaware of their illness
  • Global cognitive dysfunction: seen in some patients. Significant impairment in mental function with the development of dementia

Diagnosis

Wernicke-Korsakoff syndrome is primarily a clinical diagnosis.

The diagnosis of Wernicke-Korsakoff syndrome is usually clear cut in a patient with known chronic alcoholism and classic clinical features. However, the condition may present more subtly especially when the alcohol history is unknown. There may also be a low index of suspicion in non-alcoholic patients.

Patients with WE may lack one or more of the classic signs leading to underdiagnosis. An improvement with empirical thiamine replacement may help confirm the diagnosis.

Cane criteria

Diagnostic criteria proposed for WE. Based on the presence of ≥2 of the following criteria in patients with chronic alcoholism:

  • Dietary deficiency
  • Oculomotor abnormalities
  • Cerebellar dysfunction
  • Altered mental status or mild memory impairment

Investigations

No specific blood test is useful for the diagnosis of Wernicke-Korsakoff syndrome. Thiamine deficiency can be detected by performing erythrocyte thiamine transketolase activity before and after the addition of thiamine, but this test is not routinely available.

Neuroimaging (e.g. CT/MRI) is commonly performed in patients with Wernicke-Korsakoff syndrome to exclude an alternative cause of confusion. A number of typical findings can be identified on imaging in both conditions

Management

The principal treatment of WE is thiamine replacement, however, patients with established KS rarely recover.

Wernicke’s encephalopathy

Patients with established WE require treatment with intravenous thiamine. This is a relatively cheap, safe, and effective treatment. The principal treatment is Pabrinex®. There should be a low threshold for initiating Pabrinex® in suspected or at-risk cases.

Pabrinex® is prescribed as a ‘pair’ with each ampoule containing different vitamins:

  • Ampoule 1: Thiamine-B1 (250 mg), Riboflavin-B2 (4 mg), Pyridoxine-B6 (50 mg)
  • Ampoule 2: Ascorbic acid-C (500 mg), Nicotinamide-B3 (160 mg), Glucose (1000 mg)

Patients should be given 2-3 pairs up to three times a day for 3-5 days. This can be followed by 1 pair daily for as long as there is an improvement. Importantly, thiamine should be administered before, or alongside, any glucose infusions to prevent the precipitation of WE.

After completion of parenteral (i.e. intravenous) treatment patients should be prescribed oral thiamine replacement that is usually combined with vitamin B co-strong. This should be continued until patients are no longer at risk.

Patients at risk of WE should be given Pabrinex® prophylactically. This includes patients presenting with alcohol-related complications (e.g. withdrawal), severe malnutrition, or those at risk of refeeding syndrome. One pair once or twice a day is usually sufficient in this setting.

Korsakoff syndrome

Unfortunately, KS is a chronic condition with permanent neurological damage and patients rarely recover. This is why it is so important to recognise and treat WE early.

There is no specific treatment for KS and patients may require assistance with their activities of daily living (e.g. carers).

Complications

Without treatment, most patients with WE will progress to coma and death.

Prompt administration of high-dose thiamine (i.e. Pabrinex®) will lead to neurological improvement in WE. However, some patients may be left with permanent neurological sequelae:

  • Permanent horizontal nystagmus
  • Inability to walk
  • Deficits in learning and memory
  • Korsakoff syndrome

Without initial recognition and treatment of acute WE, patients will develop a progressive depressed level of consciousness and ultimately lead to coma and death.

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