Wernicke Encephalopathy and Korsakoff Syndrome

Overview

Definition

Wernicke encephalopathy and Korsakoff syndrome are neurologic conditions that arise because of thiamine (vitamin B₁) deficiency. Wernicke encephalopathy is an acute, reversible condition. Korsakoff syndrome is an irreversible syndrome that is caused by more severe or prolonged thiamine deficiency and occurs after incomplete recovery from Wernicke encephalopathy.

Epidemiology

• Incidence of Wernicke lesions: 0.8%–2.8% of autopsies in general population 
• Korsakoff syndrome impacts up to 12.5% of chronic alcohol abusers.
• Men are more commonly affected than women.
• Average age at onset of Wernicke encephalopathy: 50 years

Etiology

Wernicke encephalopathy and Korsakoff syndrome are caused by a severe deficiency of thiamine. This deficiency is most commonly due to:

• Chronic alcohol use:
  • Inadequate intake
  • Poor absorption
  • Decreased hepatic storage
  • Improper utilization 
• Inadequate intake of thiamine:
  • Anorexia
  • Starvation
  • Thiamine-deficient diets 
• Increased loss of thiamine:
  • Diarrhea
  • Hyperemesis
  • Dialysis 
• Malnutrition can also cause thiamine deficiency.

Pathophysiology

• Thiamine is an essential coenzyme used for numerous bodily functions:
  • Glucose metabolism
  • Neurotransmitter synthesis
  • Lipid metabolism
• Thiamine is converted into its more active form, thiamine diphosphate (TDP).
• Thiamine deficiency is most often caused by alcoholism and malnutrition.
• Thiamine deficiency leads to: 
  • Oxidative damage
  • Cellular apoptosis 
• Deficiency of ATP and increase in harmful free radicals causes damage to myelin sheaths and decreases neurotransmitter production, resulting in impaired axonal conduction. 
• Wernicke lesions are most often found in the periventricular region, diencephalon (thalamus, hypothalamus, epithalamus, subthalamus), and midbrain.
• In Korsakoff syndrome, long-term damage to components of the limbic system leads to memory loss and apathy. 
• Petechial lesions and small-vessel hemorrhage are seen in the mesencephalon, mammillary bodies, ventricle walls, and the dorsomedial nucleus of the thalamus.
• Damage to the medial dorsal nucleus leads to memory deficit. 
• Atrophy of the limbic system, including anterior thalamic nuclei and mammillary bodies is seen after prolonged periods of deficiency.
• The location of the lesions affects the symptoms of disease:
  • Hypothalamus lesions lead to autonomic dysfunction.
  • Medulla lesions lead to ataxia.
  • Mammillary body lesions cause amnestic syndrome.

Clinical Presentation

History

• Suspected in individuals with a history of: 
  • Chronic excessive alcohol consumption
  • Malnutrition/malabsorption:
    • History of bowel resection
    • History of bariatric surgery
    • History of inflammatory bowel disease
• History often provided by caregivers, family, first responders:
  • Amnesia, both anterograde and retrograde
  • Disorientation 
  • Confabulation (memory fabrication to make up for memory lapses)
  • Personality changes, including apathy, indifference, and executive function 
  • Hallucinations
• In alcohol abusers, may present with acute withdrawal symptoms and/or delirium tremens

Examination

• Wernicke encephalopathy presents with a classic triad of examination findings: 
  • Encephalopathy: 
    • Profound disorientation
    • Indifference
    • Inattentiveness
  • Oculomotor dysfunction: 
    • Nystagmus
    • Lateral rectus palsy
    • Diplopia
  • Gait ataxia: 
    • Wide-based, slow gait
    • Short-spaced steps
    • In severe cases, inability to walk
• Additional examination findings in Korsakoff syndrome:
  • Confabulation
  • Amnesia
• Other signs: 
  • Vestibular dysfunction 
  • Fatigability
  • Apathy
  • Drowsiness
  • Impaired vision and hearing loss
  • Peripheral neuropathy involving lower extremities
  • Cardiovascular signs and symptoms:
    • Tachycardia
    • Exertional dyspnea
    • Elevated cardiac output
    • Hypertension 
  • Hypothermia
  • Sleep apnea
  • Tremor
  • Seizure
  • Delirium tremens

Diagnosis

Wernicke encephalopathy and Korsakoff syndrome are primarily clinical diagnoses.

• Wernicke encephalopathy and Korsakoff syndrome should be suspected in any individual with chronic alcohol abuse or any form of malnutrition.
• Wernicke encephalopathy may be diagnosed with the presence of 2 of 3 prototypical symptoms:
  • Ophthalmoplegia
  • Ataxia
  • Confusion
• Individuals with only 1 of these symptoms may be treated empirically. 
• Imaging and laboratory measurements are not sufficient for diagnosis.
• Laboratory tests: 
  • Reduced serum thiamine levels
  • Reduced erythrocyte transketolase activity
  • Increased serum lactate and pyruvate 
  • Consider serum alcohol level to evaluate for signs of intoxication.
  • Consider metabolic workup for alcoholic ketoacidosis.
  • Consider CBC, liver function tests, and measurement of serum chemistry levels to evaluate for stigmata of chronic liver disease.
  • Consider measurement of ammonia level to rule out hepatic encephalopathy.
• Additional testing: if diagnosis of delirium or confusion is uncertain
  • Urine/blood toxicity screen
  • Drug levels of selected prescribed medications
  • Thyroid function tests
  • Vitamin B12 level
  • Urinalysis/urine culture
  • Blood gas testing
  • Chest X-ray
• Neuroimaging may show:
  • Cytotoxic edema (bilateral and symmetric)
  • Contrast enhancement of the thalamus and mammillary bodies 
• MRI findings are highly specific; however, CT has little value.

Management

In addition to treatment of the presenting encephalopathy, the clinician should also have a high clinical suspicion for acute alcohol intoxication, hepatic encephalopathy, alcohol withdrawal syndrome, and alcoholic ketoacidosis.

Wernicke encephalopathy

Treatment should be prompt because memory deficits may be irreversible.

• Thiamine supplementation as soon as possible:
  • Route: IV or IM
  • Duration: Continue treatment until symptoms resolve.
• Laboratory studies evaluating thiamine level and other vitamin/mineral levels (e.g., magnesium)
• Hypoglycemic individuals should be given both glucose and thiamine because glucose will deplete the remaining store of thiamine.
• Long-term vitamin replacement therapy can be given with oral vitamin supplements.
• Educate about the importance of lifestyle changes (e.g., diet, abstinence from alcohol).
• Referral for community social support:
  • Psychiatrist/addictionologist
  • Substance abuse counselor
  • Provide a list of local Alcoholics Anonymous meetings/contact info.

Korsakoff syndrome

Korsakoff syndrome is serious and may require a high level of care for life, as memory deficits are often permanent.

• Thiamine (IV or IM)
• Psychiatric evaluation
• Rehabilitation services
• Acetylcholinesterase inhibitors may be considered to improve cognitive functioning. 
• Absolute abstinence from alcohol
• Referral for community social support:
  • Psychiatrist/addictionologist
  • Substance abuse counselor
  • Provide a list of local Alcoholics Anonymous meetings/contact info.

Differential Diagnosis

• Cerebellar stroke: cerebrovascular event leading to impaired perfusion of O₂ to the posterior fossa of the brain. Cerebellar strokes account for 1%–4% of all strokes and can be thromboembolic or hemorrhagic in nature. Symptoms include headache, vomiting, vertigo, unilateral hearing loss, and contralateral sensory loss (pain and temperature). Diagnosis is clinical and confirmed by neuroimaging. Acute thrombolytic therapy can be used in selected acute cases. Long-term management consists of risk factor modification of further ischemic events. 
• Delirium tremens: severe form of ethanol withdrawal characterized by tremor, anxiety, nausea, vomiting, insomnia, auditory hallucinations, vomiting, diaphoresis, and severe hypertension. Diagnosis is clinical but supported by laboratory evaluation and neuroimaging. Treatment includes IV fluids for rehydration, thiamine and magnesium supplementation, and benzodiazepines for agitation and seizure prophylaxis. 
• Hepatic encephalopathy: altered mental status in the setting of chronic liver disease due to elevated ammonia levels. May be associated with ataxia, personality changes, and altered level of consciousness. Diagnosis is clinical but supported by evidence of hepatic decompensation and elevated serum ammonia. Lactulose is the mainstay of acute management for lowering ammonia levels. Long-term management consists of efforts to stabilize hepatic function and hepatic transplantation. 
• Lewy body dementia: condition associated with deposition of Lewy bodies (clumps of protein) in the cortical region of the brain. Lewy body dementia is a progressive disease that presents with dementia, cognitive decline, and visual hallucinations. Diagnosis is based on the clinical presentation. The time frame of symptom onset is an important piece of the history, as this entity presents more gradually than Wernicke/Korsakoff syndrome. There is no cure for Lewy body dementia. Treatment is supportive and aimed at reducing behavioral changes.