Wernicke's encephalopathy is a disease state arising from thiamine deficiency, where the failure of thiamine to act as a co-factor in gucose metabolism results in neuronal damage. Characteristic features are delirium, gait disturbance, nystagmus and some sort of oculomotor prblem like a gaze palsy. This condition has appeared in the SAQs several times:

Usually, the candidates were given both a characteristic history and a biochemical picture of hyponatremia hypoglycaemia and high cholesterol.

The summary which follows is constructed from a blend of the UpToDate article, an excellent review by Thompson et al (2005) and a paper by Flynn et al (2015)

Pathophysiology Wernicke's encephalopathy

  • Thiamine is a cofactor in the synthesis of ATP from glucose
  • Thiamine requirements depend on metabolic rate
  • If it is deficient, the metabolically active tissue is unable to synthesise ATP, and is damaged thereby (in a manner similar to the damage from hypoxia or glycoepenia)
  • This tends to happen in states of high metabolic demand and high glucose intake
  • The result is a symmetrical pattern of lesions characterized by vascular congestion, microglial proliferation, and petechial hemorrhages.
  • Cytotoxic oedema develops and the blood-brain barrier becomes dysfunctional.

Causes of Wernicke's encephalopathy

  • Alcoholism (impaired absorption of thiamine)
  • Chronic liver disease (impaired storage of thiamine)
  • Malnutrition (low dietary thiamine intake)
    • Starvation
    • Weird diet
    • Anorexia nervosa
    • TPN without supplemental thiamine
    • Hyperemesis gravidarum
    • Abdominal surgery
  • Hypercatabolic states (extensive metastatic malignancy, terminal AIDS)
  • Genetic disorders (disorder of thiamine metabolism and utilisation)
  • Haemodialysis (increased clearance of thiamine by the circuit)
  • Diuretics (decreased reabsorption of thiamine in the tubule)

Association of Wernicke's encephalopathy with glucose replacement

The administration of glucose to a patient who has a thiamine deficiency tends to precipitate an acute Wernicke's encephalopathy. Watson et al (1981) presented a case series of non-alcoholic malnourished patients all of whom developed the encephalopathy after having a bolus of dextrose.

There is some concern about giving glucose to the hypoglycaemic patient at risk of Wernicke's. This is patently absurd, as the complications of neuroglycopenia will be much more damaging in the long run than the manifestations of Wernicke's , given that the former are reversible and mild, whereas the latter are irreversible and severe (Gussow et al, 2007).

Clinical features of Wernicke's encephalopathy

Clinical signs of thiamine deficiency develop when cerebral thiamine levels drop to 20% below baseline (Isenberg-Grzeda et al, 2012). It can be rapid in onset: four days of low thiamine is enough.

  • Encephalopathy
    • Rarely, stupur and coma
    • Most often, confusion and impaired memory
  • Ataxia
    • Usually, there are no upper limb or speech cerebelar signs
    • This is because only the anterior and superior vermis are affected
    • The lower limb cereballar signs conspire with vestibular damage and thiamine-associated polyneuropathy(i.e. "I can't feel my legs").
  • Eye signs
  • Hypothermia
    • due to impairment of thermoregulation: the hypothalamus is damaged
  • Hypotension
    • due to heart failure, "wet Beri-Beri"

Diagnostic criteria for Wernicke's encephalopathy

Royal College Criteria

  • Alcoholism, AND one other :
    • Acute confusion
    • Decreased level of consciousness
    • Memory problems
    • Ataxia
    • Ophthalmoplegia
    • Hypothermia with hypotension

European Federation of Neurologic Societies

  • Any two of:
    • Dietary deficiencies
    • Eye signs
    • Cerebellar signs (ataxia)
    • Either altered mental state or mild memory impairment

Laboratory features  of Wernicke's encephalopathy

Wernicke's encephalopathy is a clinical diagnosis. However, thiamine deficiency is readily diagnosed by the levels of red cell transketolase.  One may test the levels before and after thiamine supplementation. A low transketolase level along with a >25% rise in level following thiamine supplementation is diagnostic of thiamine deficiency.

Management of  Wernicke's encephalopathy

The treatment consists of some IV thiamine. The college answer to Question 13.3 from the second paper of 2013 suggests 100mg IV daily is a big enough dose. However, there is disagreement as to ho much is enough. A Cochrane review (Day et al, 2013) was not able to reach any sensible conclusions about the dosage, siting methodological problems in the one and only trial which met the inclusion criteria (Ambrose et al, 2001). This trial found a relationship between dose and response (more was better: 200mg vs 100mg daily).  It may be reasonable to give large amounts; Cook et al (1998) recommended 1g daily. Locally, 300mg IV three times a day is given. UpToDate recommends the largest dose, 500mg three times a day. The rationale for such massive doses is the theoretical benefit of producing a steep blood-to-brain thiamine concentration gradient, to facilitate its passive diffusion into the neurons.

References

Flynn, Alexandra, et al. "Wernicke’s Encephalopathy: Increasing Clinician Awareness of This Serious, Enigmatic, Yet Treatable Disease." The primary care companion for CNS disorders 17.3 (2015).

Thomson, Allan D., and E. Jane Marshall. "The natural history and pathophysiology of Wernicke's encephalopathy and Korsakoff's psychosis." Alcohol and Alcoholism 41.2 (2006): 151-158.

Gussow, Leon. "Myths of toxicology: thiamine before dextrose." Emergency Medicine News 29.4 (2007): 3-11.

Isenberg-Grzeda, Elie, Haley E. Kutner, and Stephen E. Nicolson. "Wernicke-Korsakoff-syndrome: under-recognized and under-treated." Psychosomatics 53.6 (2012): 507-516.\

Watson, A. J. S., et al. "Acute Wernickes encephalopathy precipitated by glucose loading." Irish journal of medical science 150.1 (1981): 301-303.

Kissoon, Niranjan. "Thiamine before glucose to prevent Wernicke encephalopathy: examining the conventional wisdom." JAMA 279.8 (1998): 583.

Day, Ed, et al. "Thiamine for prevention and treatment of Wernicke‐Korsakoff Syndrome in people who abuse alcohol." The Cochrane Library (2013).

Ambrose, Margaret L., Stephen C. Bowden, and Greg Whelan. "Thiamin Treatment and Working Memory Function of Alcohol‐Dependent People: Preliminary Findings." Alcoholism: Clinical and Experimental Research 25.1 (2001): 112-116.

Cook, Christopher CH, Phillip M. Hallwood, and Allan D. Thomson. "B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse." Alcohol and Alcoholism 33.4 (1998): 317-336.