AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Wernicke encephalopathy is a serious disorder caused by thiamine (vitamin B-1) deficiency. Dr Carl Wernicke, a Polish neurologist, described it in 1881 as a triad of acute mental confusion, ataxia, and ophthalmoplegia. Korsakoff amnestic syndrome is a late neuropsychiatric manifestation of Wernicke encephalopathy with memory loss and confabulation; hence, the condition is referred to as Wernicke-Korsakoff syndrome or psychosis. It is most often seen in alcoholics, but it can be seen in disorders associated with malnutrition and also in patients on long-term hemodialysis or with AIDS. The disease is frequently unrecognized and is likely more prevalent than commonly supposed.

Pathophysiology

Thiamine in its metabolically active form, called thiamine pyrophosphate (TPP), is vital in the metabolism of carbohydrates. It serves a critical role in 3 enzyme systems: (1) conversion of pyruvate to acetyl coenzyme A by pyruvate dehydrogenase, (2) conversion of a-ketoglutarate to succinate by a-ketoglutarate dehydrogenase in the Krebs cycle, and (3) catalysis by transketolase in the pentose monophosphate shunt. In the presence of thiamine deficiency, these cellular systems dependent on thiamine begin to fail, leading eventually to cell death.

Diminished transketolase activity results in failure of the maintenance of the myelin sheaths in the nervous system, metabolism of lipids and glucose, and production of branched chain amino acids.

Lack of a-ketoglutarate dehydrogenase activity in the Krebs cycle alters cerebral energy utilization. If cells with high metabolic requirements have inadequate stores of thiamine to draw from, energy production drops, and neuronal damage ensues. Increased cell death then feeds the localized vasogenic response (Buscaglia, 2005). Additionally, the reduced production of succinate, which plays a role in GABA metabolism and the electrical stimulation of neurons, leads to further CNS injury.

Increased lactic acid production ensues in the absence of pyruvate dehydrogenase function, as the reduced conversion of pyruvate to acetyl coenzyme A results in less efficient oxidative phosphorylation.

Frequency

United States

Autopsy series identifying typical brainstem lesions of Wernicke encephalopathy have placed the incidence between 0.8% and 2.8% of the general population. However, the incidence can be as high as 12.5% in a population of alcoholics. It has been described in many other situations where nutrition has been compromised. These cases include patients with AIDS, individuals receiving hemodialysis, hyperemesis gravidarum, and malignancy with or without chemotherapy.

International

Although it may not be diagnosed as frequently in third and fourth world nations, the incidence is probably higher in areas where there is more malnutrition and less vitamin supplementation.

Mortality/Morbidity

Studies suggest that up to 80% of patients with Wernicke encephalopathy may not be diagnosed, which makes estimates of mortality unreliable. Wernicke encephalopathy is a significantly disabling and potentially lethal condition that can be prevented or reversed if treated early. Established Wernicke encephalopathy can have major long-term consequences among patients requiring permanent institutional care.

Race

No racial predilection is known to exist for Wernicke encephalopathy.

Sex

The male-to-female ratio is 1.7:1, likely owing to alcoholism being 3-4 times more frequent in men than in women.

Age

Average age at onset is 50 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The 3 components of the classic triad of Wernicke encephalopathy are encephalopathy, ataxic gait, and some variant of oculomotor dysfunction. All 3 features of the triad are recognized in only about one third of cases.

• Consideration for Wernicke encephalopathy should be given to patients with any evidence of long-term alcohol abuse or malnutrition and any of the following: acute confusion, decreased conscious level, ataxia, ophthalmoplegia, memory disturbance, hypothermia with hypotension, and delirium tremens.
• Wernicke encephalopathy should be considered when any patient with long-term malnutrition presents with confusion or altered metal status. Significant overlap exists between Wernicke encephalopathy and Korsakoff psychosis, in which patients experience delayed and potentially irreversible anterograde and retrograde amnesia. For this reason, the two entities have been described together as Wernicke-Korsakoff syndrome. Bariatric surgery, human immunodeficiency virus, hyperemesis gravidarum, and other disorders associated with grossly impaired nutritional status have been associated with Wernicke-Korsakoff syndrome.
• Additionally, infantile thiamine deficiency with manifestations of Wernicke syndrome has been reported in infants fed formula that was deficient in thiamine (Fattal-Valevski, 2006).

Physical

• Ocular abnormalities are the hallmarks of Wernicke encephalopathy. The oculomotor signs are nystagmus, bilateral lateral rectus palsies, and conjugate gaze palsies reflecting cranial nerve involvement of the oculomotor, abducens, and vestibular nuclei. Less frequently noted are pupillary abnormalities such as sluggishly reactive pupils, ptosis, scotomata, and anisocoria.
• Encephalopathy is characterized by a global confusional state, disinterest, inattentiveness, or agitation. Stupor and coma are rare.
• Gait ataxia is likely to be a combination of polyneuropathy, cerebellar damage, and vestibular paresis. Vestibular dysfunction without hearing loss is a common finding. In less severe cases, patients walk slowly with a broad-based gait. However, gait and stance may be so impaired as to make walking impossible. Cerebellar testing in bed with finger-to-nose and heel-to-shin tests may not illicit any notable deficit; thus, it is important to test for truncal ataxia with the patient sitting or standing. This finding is due to focal midline degeneration of the superior division of the vermis as opposed to global cerebellar dysfunction.
• Hypothermia is common because of the involvement of the temperature-regulating center in the brainstem.
• Hypotension, caused by a defect in efferent sympathetic outflow and decreased peripheral resistance, may be present. Hypotension can also be the result of significant alcoholic liver disease.
• • Coma is rarely the sole manifestation of Wernicke encephalopathy.
  • Of patients surviving Wernicke encephalopathy, a large percentage have Korsakoff psychosis, characterized by the following: retrograde amnesia (inability to recall information), anterograde amnesia (inability to assimilate new information), decreased spontaneity and initiative, and confabulation.
  • Other manifestations of thiamine deficiency involve the cardiovascular system (wet beri beri) and peripheral nervous system (nutritional polyneuropathy).
• Manifestations of thiamine deficiency in infants are constipation, agitation, apathy, vomiting, lack of appetite, and later, diarrhea, grunting, nystagmus, convulsions, unconsciousness, and cardiomyopathy (Fattal-Valevski, 2005).

Causes

• Long-term alcohol abuse is the most common cause of Wernicke encephalopathy. In long-term alcoholics, malnutrition can reduce intestinal thiamine absorption by 70%, decreasing serum levels of thiamine from between 30% and 98% below the lower level established for normal subjects. Alcohol alone can also decrease absorption by 50% in one third of patients who are not malnourished.
• Other less common etiologies are forced or self-imposed starvation, protein-energy malnutrition resulting from inadequate diet or malabsorption (from sprue), conditions associated with protracted vomiting (eg, hyperemesis gravidarum), chronic renal failure, carbohydrate loading in the presence of marginal thiamine stores (feeding after starvation), bariatric surgery and other gastric bypass surgeries, absence of thiamine from the diet (in the case of infants fed formula without the addition of thiamine), and congenital transketolase function abnormalities.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Psychosis
Normal pressure hydrocephalus
Cerebrovascular accident
Chronic hypoxia
Closed-head injury
Hepatic encephalopathy
Postictal state

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Patients with Wernicke encephalopathy present with altered mental status and other neurologic abnormalities. Careful history, physical examination, laboratory workup, and radiographic evaluation are essential to exclude other causes of CNS dysfunction. No specific laboratory test is available for diagnosing Wernicke encephalopathy. Wernicke encephalopathy is a clinical diagnosis, and normal electrolyte levels may only give false reassurance and delay therapy. This is particularly the case where malnutrition is likely to be present. The motto should be "If in doubt, treat," as administration of thiamine does not pose potential harm.
• The history and initial evaluation guide selection of laboratory and radiographic tests. Although Wernicke encephalopathy remains a clinical diagnosis with no characteristic abnormalities in diagnostic studies, it remains important to exclude alternate or coexisting medical conditions.
• Complete blood count (CBC) rules out severe anemias and leukemias as causes of altered mental status.
• Alterations in serum electrolytes, such as hypernatremia or hypercalcemia, can cause altered mental status and must be excluded.
• Determine serum glucose level to exclude hypoglycemia and hyperglycemia.
• Obtain pulse oximetry and/or arterial blood gases (ABGs) to exclude hypoxia and hypercarbia.
• Obtain arterial blood gases (ABGs) to exclude hypoxia and hypercarbia.
• Perform toxic drug screening to exclude some causes of drug-induced altered mental status.
• Consider lumbar puncture (LP) to exclude CNS infections if indicated.
• Erythrocyte transketolase levels reliably detect thiamine deficiency but are not necessary for the diagnosis of Wernicke encephalopathy. In the erythrocyte transketolase activity assay, the extent of thiamine deficiency is expressed in percentage stimulation compared with baseline levels (the thiamine pyrophosphate effect). Normal values range from 0-15%; a value of 15-25% indicates thiamine deficiency, and greater than 25% indicates severe deficiency (Fattal-Valevski, 2005).
• Elevated blood lactate levels are nonspecific but may reflect thiamine deficiency.

Imaging Studies

• A head computed tomography (CT) scan is a vital initial test for emergency diagnosis of focal neurologic disease. In patients who are comatose, CT scan can detect not only intracranial lesions but also fractures of the skull and minute amounts of blood.
• In Wernicke encephalopathy, the CT scan may be normal or it may show symmetric low-density abnormalities in periventricular areas, the diencephalon, and the midbrain. Such symmetric lesions are uncommon in other disorders.
• Magnetic resonance imaging is more sensitive than CT and is probably the imaging modality of choice when the diagnosis is suspected. The appearance of Wernicke encephalopathy on MRI, specifically on fluid-attenuated inversion recovery scans, demonstrates abnormal hyperdensity of the mammillary bodies and peri-aqueductal gray matter with associated abnormal enhancement on T1-weighted images (Kaineg, 2005).

Other Tests

• Consider an electroencephalogram (EEG) if nonconvulsive status epilepticus is suspected as a potential cause of coma and altered mental status.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Because patients with Wernicke encephalopathy present with altered mental status in the prehospital setting, focus prehospital care on stabilizing the airway, ensuring oxygenation, and maintaining blood pressure and euvolemia.

Emergency Department Care

Wernicke encephalopathy must be viewed as a medical emergency, even if other competing diagnoses of CNS processes are being considered. Because the condition is potentially reversible, institution of treatment is indicated in patients exhibiting any combination of symptoms and signs, particularly if the patient is in a high-risk population. Onset of the disease may be acute, subacute, or chronic.

Although as little as 2 mg of thiamine may be enough to reverse symptoms, the dose of thiamine required to prevent or treat Wernicke encephalopathy in most alcoholic patients may be as high as greater than 500 mg given once or twice daily parenterally. Thiamine solution should be fresh, since old solutions may be inactive. Ataxia and acute confusional state may resolve dramatically, although improvement may not be noted for days or months.

• Treat all poorly nourished patients with large doses of parenteral thiamine, particularly if intravenous glucose administration is necessary, even in the absence of symptoms and signs of Wernicke encephalopathy. Administering dextrose in a thiamine-deficient state exacerbates the process of cell death by providing more substrate for biochemical pathways that lack sufficient amounts of coenzymes (Buscaglia, 2005).
• Start thiamine prior to or concurrently with treatment of intravenous glucose solutions, and continue until the patient resumes a normal diet.
• Patients with Wernicke encephalopathy are likely hypomagnesemic and should be treated empirically with parenteral magnesium sulfate, as they may be unresponsive to parenteral thiamine in the presence of hypomagnesemia. After correction of hypomagnesemia in conjunction with thiamine repletion, the blood transketolase activity can return to normal and clearing of the clinical signs may occur.

Consultations

Consult a neurologist for further evaluation and treatment of altered mental status or other neurologic deficit. A physiatrist may be helpful in evaluating comorbid psychiatric conditions.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The cornerstone of therapy for prevention or treatment of Wernicke encephalopathy in most alcoholic patients is thiamine until the patient resumes a normal diet.

Drug Category: Nutrients

The primary objective is to replenish vitamin B-1 stores. In adults, 60-180 mEq of potassium, 10-30 mEq of magnesium, and 10-40 mmol/L of phosphate per day appear necessary to achieve optimum metabolic balance.

Drug Name	Magnesium sulfate
Description	Cofactor in a number of enzyme systems; also involved in neurochemical transmission and muscular excitability. Persons with long-term alcoholism and patients who are malnourished usually have inadequate magnesium stores.
Adult Dose	2-4 g IV mixed with initial IV fluid bolus; followed by 1-4 g IV q4h prn Alternatively: 1-4 g/h continuous infusion
Pediatric Dose	25-50 mg/kg/dose IV q4-6h mixed with initial fluid bolus for 3-4 h; not to exceed single dose of 2 g; also may be administered and repeated if hypomagnesemia persists
Contraindications	Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis
Interactions	Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade seen with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants, betamethasone, and cardiotoxicity of ritodrine
Pregnancy	A - Safe in pregnancy
Precautions	May alter cardiac conduction leading to heart block in digitalized patients; monitor respiratory rate, deep tendon reflex, and renal function when electrolyte is administered parenterally; caution when administering, since may produce significant hypertension or asystole; in overdose, 10% calcium gluconate solution 10-20 mL IV can be administered as antidote for clinically significant hypermagnesemia

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Depending on mental status and ability to protect his or her airway, admit patients with suspected or confirmed Wernicke encephalopathy to an internal medicine or neurology service.
• Admission ensures that the patient receives continued intravenous thiamine and magnesium administration, observation for possible development of Korsakoff psychosis, and evaluation for possible cardiovascular beri beri.

Further Outpatient Care

• Refer patients with alcoholism to alcohol-cessation programs and monitor for signs of alcohol withdrawal.
• Patients who are malnourished, whether from alcohol or other causes, should continue to receive thiamine supplementation on an outpatient basis.

In/Out Patient Meds

• Administer daily oral thiamine (100 mg) on a long-term outpatient basis.
• Inpatient therapy of infants with thiamine deficiency involves administration of high-dose thiamine 50 mg/day for 2 weeks (Fattal-Valevski, 2005).

Deterrence/Prevention

• Patients should avoid alcohol consumption and other behaviors that predispose to thiamine deficiency.
• In the United States, many foods (but not alcoholic beverages) are supplemented with multiple vitamins and minerals. Some health policy experts have hypothesized that fortifying alcoholic beverages with thiamine would lower healthcare costs.

Complications

• Korsakoff psychosis
• Alcohol withdrawal
• Acute precipitation of Wernicke encephalopathy
• Congestive heart failure
• The administration of dextrose in the setting of thiamine deficiency can be harmful because glucose oxidation is a thiamine-intensive process that may drive the insufficient circulating vitamin B-1 intracellularly, thereby precipitating neurologic injury (Fattal-Valevski, 2005).

Prognosis

• Patients with Wernicke encephalopathy have a significant morbidity and mortality rate, especially if no early signs of neurologic improvement are present after repletion of thiamine.
• Of patients surviving Wernicke encephalopathy, a percentage will develop Korsakoff psychosis.
• Of patients with Korsakoff psychosis, a significant number do not recover and require long-term institutionalization. Only about 20% eventually recover completely during long-term follow-up care.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider Wernicke encephalopathy as a cause of altered mental status.
• Acute Wernicke encephalopathy may be precipitated rapidly in high-risk patients after instituting intravenous therapy with glucose-containing solutions, resulting in rapid changes in cognitive function and ocular characteristics.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Azim W, Walker R. Wernicke's encephalopathy: a frequently missed problem. Hosp Med. Jun 2003;64(6):326-7. [Medline].
• Blass JP, Gibson GE. Abnormality of a thiamine-requiring enzyme in patients with Wernicke- Korsakoff syndrome. N Engl J Med. Dec 22 1977;297(25):1367-70. [Medline].
• Buscaglia J, Faris J. Unsteady, unfocused, and unable to hear. Am J Med. Nov 2005;118(11):1215-7. [Medline].
• Fattal-Valevski A, Kesler A, Sela BA, et al. Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-based formula. Pediatrics. Feb 2005;115(2):e233-8. [Medline].
• Henry GL. Coma and altered states of consciousness. In: Emergency Medicine. 4th ed. 1996:225-233.
• Hoffman RS. Thiamine hydrochloride. In: Goldfrank's Toxicologic Emergencies. 5th ed. 1994:825-6.
• Hung SC, Hung SH, Tarng DC, et al. Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. Nov 2001;38(5):941-7. [Medline].
• Kaineg B, Hudgins PA. Images in clinical medicine. Wernicke's encephalopathy. N Engl J Med. May 12 2005;352(19):e18. [Medline].
• Marx JA. The varied faces of Wernicke's encephalopathy. J Emerg Med. 1985;3(5):411-3. [Medline].
• Reuler JB, Girard DE, Cooney TG. Current concepts. Wernicke''s encephalopathy. N Engl J Med. Apr 18 1985;312(16):1035-9. [Medline].
• Thomson AD, Cook CC, Touquet R, et al. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke's encephalopathy in the accident and Emergency Department. Alcohol Alcohol. Nov-Dec 2002;37(6):513-21. [Medline].
• Victor M. Persistent altered mentation due to ethanol. Neurol Clin. Aug 1993;11(3):639-61. [Medline].
• Willett WC, Stampfer MJ. Clinical practice. What vitamins should I be taking, doctor?. N Engl J Med. Dec 20 2001;345(25):1819-24. [Medline].

Article Last Updated: Oct 24, 2006