Wernicke-Korsakoff’s Syndrome (WKS)

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Wernicke’s Encephalopathy (WE) –

Wernicke’s encephalopathy is an acute potentially reversible neuropsychiatric disorder caused by a deficiency in or depletion of thiamine, of which chronic alcohol use is one cause.

Other causes include:

Gastric bypass surgery
Gastric and colon cancer
Hyperemesis gravidarum
Recurrent vomiting and diarrhoea
Long-term parenteral feeding
Poor nutrition
Systemic diseases: e.g. AIDS, Renal disease, Graves disease
Cancer and chemotherapy
Magnesium depletion as magnesium is a cofactor in converting thiamine into the active form of thiamine pyrophosphate.

Wernicke’s encephalopathy is a medical emergency. Untreated, it leads to death in up to 20% of cases.

Wernicke’s encephalopathy (confirmed at autopsy) had been missed by routine clinical examination in 75–80% of cases in adults and about 58% of cases in children. [Sechi & Serra, 2007]

Thiamine deficiency in alcohol dependence occurs because of poor absorption of thiamine from the GI tract, impaired thiamine storage and reduced thiamine phosphorylation in the brain, reducing the amount of active thiamine in the brain. (Thiamine Pyrophosphate)

Thiamine deficiency leads to brain lesions in vulnerable regions of high thiamine turnover, such as mamillary bodies, within 2 to 3 weeks. It takes about 18 days for thiamine stores to be depleted, and after 3 weeks of deficiency, thiamine blood levels also fall. [Sechi & Serra, 2007]

Pathophysiology: [Sechi & Serra, 2007]

Thiamine is converted to thiamine pyrophosphate by neuronal and glial cells in the brain.
Thiamine pyrophosphate is necessary for several biochemical pathways in the brain, such as intermediate carbohydrate metabolism (for energy production by ATP synthesis), lipid metabolism (for production and maintenance of myelin sheath), and production of amino acids and glucose-derived neurotransmitters (e.g., glutamic acid; GABA).
Thiamine also plays a role in acetylcholinergic and serotoninergic synaptic transmission and axonal conduction.
The initial stage of thiamine deficiency (after 4 days ) is characterised by reduced α-ketoglutarate-dehydrogenase activity in astrocytes.
After 7-10 days, there is decreased transketolase activity in astrocytes and increased nitrous oxide (NO) from endothelial cell dysfunction. In addition, there is a diffuse decrease in glucose use in the brain, which impairs many neuronal and astrocytic functions leading to glutamate excitotoxicity, blood-brain barrier disruption and oedema.
After 14 days, apoptotic cell death occurs due to increased lactate concentrations, oxidative stress, free radicals and cytokines, and mitochondrial and endothelial dysfunction.

Clinical Features:

Triad consists of

Oculomotor abnormalities – lateral rectus palsy, nystagmus, ophthalmoplegia (29% of patients)
Cerebellar dysfunction – Ataxia (23% of patients)
Altered mental state – confusion (82% of patients)

Two of the above signs with dietary deficiencies improve the diagnostic specificity of Wernicke’s encephalopathy. [Caine et al., 1997].

The above criteria were adopted by the European Federation of Neurological Societies (EFNS). (see later)

Uncommon symptoms or signs at presentation

Stupor
Hypotension and tachycardia
Hypothermia
Bilateral visual disturbances and papilloedema
Epileptic seizures
Hearing loss
Hallucinations and behavioural disturbances

Late-stage symptoms

Hyperthermia
Increased muscular tone and spastic paresis
Choreic dyskinesias
Coma

Clinical Pearls –

Only 20% of patients may show the full triad in clinical practice.
Patients with alcoholism with hepatic encephalopathy have a high risk of additional Wernicke’s encephalopathy, and these patients might benefit from treatment with parenteral thiamine. [Caine et al., 1997]

The European Federation of Neurological Societies (EFNS) recommends a presence of 2 of the following four signs as evidence of Wernicke’s encephalopathy [EFNS] –

Dietary deficiency
Oculomotor abnormality
Mild memory impairment
Altered mental status

Treatment of acute WE –

Thiamine 500 mg IV TDS for 2-3 days and 250 mg daily for the next 3-5 days
Thiamine 100 mg PO TDS for rest of hospital stay
Multivitamins
Replace Mg
Replace fluid and electrolyte losses
Thiamine must be given before or concomitantly with intravenous glucose administration because glucose alone can precipitate Wernicke’s encephalopathy.

Clinicians suspecting Wernicke’s encephalopathy in a patient should treat it as an emergency and provide optimum intravenous treatment in order to avoid permanent brain damage. (BNF)

Prophylactic treatment for patients at risk of WE – Thiamine 200-300mg IM daily for 3-5 days.

Specifically, patients who have signs indicative of Wernicke’s encephalopathy should be treated empirically with a minimum of 500 mg thiamine hydrochloride (dissolved in 100 ml of normal saline), given by infusion over a period of 30 min, three times per day for 2–3 days. Where there is no response, supplementation may be discontinued after 2–3 days.

Where an effective response is observed, 250 mg thiamine given intravenously or intramuscularly daily for 3–5 days, or until clinical improvement ceases, should be continued.

Doses of thiamine between 100 mg and 250 mg per day apparently may not restore vitamin status, improve clinical signs, or prevent death.

In particular, when patients with Wernicke’s encephalopathy are inappropriately treated with low doses of thiamine, the biochemical abnormalities caused by thiamine deficiency can lead to irreversible brain damage.

This damage may lead to death, with an estimated mortality rate of about 20%, or to the chronic irreversible form of the encephalopathy (Korsakoff’s syndrome) in 85% of survivors.

Recent data from a controlled study into the therapeutic benefits of thiamine in alcohol-dependent patients without clinically apparent Wernicke’s encephalopathy indicate that at least 200 mg of parenteral thiamine may be required to improve neurological symptoms.

Prophylactic treatment—intramuscular administration of 250 mg thiamine once daily for 3–5 consecutive days—should be used in all people with severe alcohol withdrawal, poorly nourished patients, and people with poor diet and signs of malnutrition. [Sechi & Serra, 2007]

Korsakoff’s Syndrome:

Undiagnosed and untreated WE can lead to Korsakoff’s syndrome in 80% of cases.

Clinical features of Korsakoff’s Syndrome:

First described by Victor (1971)

An abnormal mental state in which memory and learning are affected out of all proportion to other cognitive functions in an otherwise alert and responsive patient

Anterograde amnesia (impaired ability to acquire new episodic memories)
Confabulation
Retrograde amnesia
Lack of insight
Disorientation in time and place
Executive dysfunction
Sequelae of WE

MRI findings in WKS-

Mamillary body atrophy
Neuronal loss in the anterior principal and mediodorsal nuclei of the thalamus and the basal forebrain

The most obvious neuroradiological sign of acute WE, regardless of etiology, is bilateral hyperintensity on late-echo MRI, generally occurring in gray matter tissue of the mammillary bodies, anterior and medial nuclei of the thalamus, periventricular gray matter, inferior and superior colliculi.

Image from Case courtesy of Dr Lee-Anne Slater, Radiopaedia.org. From the case rID: 12151