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

In 1881, Carl Wernicke first described an illness that consisted of paralysis of eye movements, ataxia, and mental confusion in 3 patients. The patients, 2 males with alcoholism and a female with persistent vomiting following sulfuric acid ingestion, demonstrated these findings with progression to coma and death. Wernicke detected punctate hemorrhages affecting the gray matter around the third and fourth ventricles and aqueduct of Sylvius. He felt these to be inflammatory and therefore named the disease polioencephalitis hemorrhagica superioris.

S.S. Korsakoff, a Russian psychiatrist, described the disturbance of memory in the course of long-term alcoholism in a series of articles from 1887-1891. He termed this syndrome psychosis polyneuritica, believing that these typical memory deficits, in conjunction with polyneuropathy, represented different facets of the same disease. In 1897, Murawieff first postulated that a single etiology was responsible for both syndromes.

The term Wernicke encephalopathy is used to describe the symptom complex of ophthalmoplegia, ataxia, and an acute confusional state. If persistent learning and memory deficits are present, the symptom complex is termed Wernicke-Korsakoff syndrome.

Pathophysiology

A deficiency of thiamine (vitamin B-1) is responsible for the symptom complex manifested in Wernicke-Korsakoff syndrome, and any condition resulting in a poor nutritional state places patients at risk. Heavy, long-term alcohol use is the most common association with Wernicke-Korsakoff syndrome. Alcohol interferes with active gastrointestinal transport, and chronic liver disease leads to decreased activation of thiamine pyrophosphate from thiamine, as well as a decreased capacity of the liver to store thiamine. Thiamine is converted to thiamine pyrophosphate, which serves as a cofactor for several enzymes that function in glucose utilization. These enzymes include transketolase, pyruvate dehydrogenase, and alpha ketoglutarate.

Thiamine deficiency results in a diffuse decrease in cerebral glucose utilization. However, symptoms are attributed to focal areas of damage. Ocular motor signs are attributable to lesions in the brainstem affecting the abducens nuclei and eye movement centers in the pons and midbrain. These lesions are characterized by a lack of significant destruction to nerve cells, which accounts for the rapid improvement and degree of recovery observed with thiamine repletion. Ataxia is a manifestation of damage to the cerebellum, particularly the superior vermis. The cerebellar changes consist of a degeneration of all layers of the cortex, particularly the Purkinje cells. The loss of neurons leads to persistent ataxia of gait and stance. In addition to cerebellar dysfunction, the vestibular apparatus also is affected.

Vestibular paresis, confirmed by abnormal results on caloric testing, is observed in the early stages of disease and generally improves with treatment. The amnestic component is related to damage in the diencephalon, including the medial thalamus, and connections with the medial temporal lobes and amygdala. The slow and incomplete recovery of memory deficits suggests that amnesia is related to irreversible structural damage.

The mechanism by which thiamine deficiency leads to damage in these specific areas is not fully understood. Proposed mechanisms include altered cerebral energy metabolism resulting from decreases in transketolase, pyruvate, and acetylcholine; diminished nerve-impulse transmission at synapses; and impaired DNA synthesis. Variations in clinical presentations and the fact that not all patients with thiamine deficiency develop Wernicke-Korsakoff syndrome has raised the possibility that a genetic predisposition may exist in some patients.

McEntee and colleagues (1980) have demonstrated decreased levels of a metabolite of norepinephrine (3-methoxy-4-hydroxyphenolglycol or MHPG) in the cerebrospinal fluid (CSF) of some patients with Wernicke-Korsakoff syndrome. They point out that the diencephalic lesions are located within monoamine-containing pathways. Clonidine, an alpha-noradrenergic agonist, seemed to improve the memory disorder of their patients. They have postulated that damage to these pathways may be the basis for the amnestic features of Wernicke-Korsakoff syndrome. These results have not been reproduced in any large prospective study. Patients with permanent Korsakoff psychosis are not treated routinely with clonidine.

Frequency

United States

Long-standing alcohol use is the most common association with development of Wernicke-Korsakoff syndrome, although poor nutrition can also be an important factor. Prevalence data have come primarily from necropsy studies, with rates of 1-3%, and have indicated that prevalence at autopsy exceeds recognition in life. The rate has been found to be significantly higher in specific populations, ie, homeless people, older people (especially those living alone or in isolation), and psychiatric inpatients, where alcohol use and poor nutritional states predominate.

International

International and US rates of occurrence essentially are the same.

Mortality/Morbidity

The mortality rate is 10-20%. Prognosis depends on the stage of disease at presentation and on prompt treatment.

• In general, full recovery of ocular function occurs. Fine horizontal nystagmus can persist in as many as 60% of cases.
• Approximately 40% of patients have complete recovery from ataxia.
• Only 20% of patients recover completely from amnestic deficit.

Race

No racial predilection is observed.

Sex

The condition affects males slightly more frequently than it affects females.

Age

Age of onset is evenly distributed from 30-70 years.

CLINICAL

Section 3 of 10  

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

History

• Ocular/visual disturbances
• • Painless vision abnormalities
  • Diplopia (double vision)
  • Strabismus
• Gait abnormalities
• • New wide-based, short-stepped gait
  • Inability to stand or walk without assistance
• Mental status changes
• • Apathy, indifference, paucity of speech
  • Hallucination, agitation
  • Confabulation: Patient fills in gaps of memory with data that can be recalled at that moment. Debate remains as to whether this action represents a deliberate attempt by the patient to hide his memory deficits or if it is an unconscious mechanism.

Physical

• Ocular abnormalities: The diagnosis of Wernicke encephalopathy is made most reliably on the basis of the following ocular abnormalities, which can occur singly or in combination:
• • Nystagmus, vertical and horizontal
  • Weakness or paralysis of lateral rectus muscles - Occurs bilaterally but can be asymmetric and is accompanied by diplopia and internal strabismus
  • Weakness or paralysis of conjugate gaze
  • Nonreacting miotic pupils and complete loss of ocular movements (in advanced cases)
  • Ptosis, small retinal hemorrhages, involvement of near-far focusing mechanism, and optic neuropathy (occasionally)
  • Papilledema (very rare)
• Ataxia is manifested as an abnormality of both stance and gait. Vestibular paresis also plays a role in ataxia in the early stages of disease.
• • Mildest form evident on tandem walking only
  • Wide-based stance
  • Slow and uncertain short-stepped gait
  • In the most severe form, inability to walk without support
  • Abnormal results on caloric testing (indicates vestibular paresis)
• Mental status changes: Alterations in consciousness can present simultaneously with ophthalmoplegia and ataxia but more commonly follow these signs and symptoms by days to weeks. These changes are present in 90% of patients and present in various forms.
• • Mental Status Examination
    • General description: Patients with long-term alcoholism are likely to present disheveled and unkempt, but appearance on presentation can range to a well-kept individual.
    • Mood and affect: Patients' mood can range from calm and blunted or apathetic affect to stupor, as well as acute delirium tremens in a patient with alcohol withdrawal. The rare patient presenting in the Korsakoff amnestic state will be alert and oriented but lack the ability to provide adequate history.
    • Speech: No characteristic speech pattern exists.
    • Perceptual disturbances: No characteristic disturbances exist, but those of delirium tremens are present if it coexists.
    • Thought: Form and content will vary depending on patient presentation.
    • Stupor involves no speech and a global confusional state—minimal spontaneous or provoked speech indicative of disorientation.
    • An amnestic state involves appropriate form and content with apparent loss of certain details.
    • Sensorium and cognition will vary with level of consciousness.
    • Suicidal ideation generally is not associated with this disorder, although any person in the midst of delirium can become self-injurious.
  • A global confusional state is the most common early manifestation and is characterized by apathy, inattentiveness, and indifference to surroundings. Spontaneous speech is minimal, and provoked speech indicates general disorientation to time, place, and purpose. Prompt administration of thiamine often results in increased attentiveness and orientation.
  • Stupor or coma can be observed in more severe cases but is rare as an initial presentation. If patients remain untreated, the condition will progress to death, as in the initial cases described by Wernicke.
  • Patients may present with varying degrees of alcohol withdrawal. Alcohol use is the most common etiology leading to a poor nutritional state that results in Wernicke-Korsakoff syndrome.
  • Korsakoff amnestic state
    • The Korsakoff amnestic state is observed in a small number of patients. Individuals present alert and responsive. On examination, they demonstrate the amnestic features of Korsakoff psychosis as the only manifestation of mental confusion. This state appears after the initial confusional state begins to resolve with thiamine administration and persists to some degree in the most severely affected individuals.
    • The Korsakoff state is characterized by both anterograde (ie, learning) and retrograde (ie, memory of past events) amnesia. Anterograde amnesia is severe but incomplete. This is demonstrated by patients' ability to repeat a series of numbers or objects as they are stated but not after a recall period. Retrograde amnesia is demonstrated by gaps in patients' memories of recent and remote past that antedate the onset of illness. These gaps in memory are what lead to the characteristic feature of confabulation. Confabulation represents filling in of memory gaps with data the patient can readily recall. Debate continues as to whether this action represents a deliberate attempt of patients to hide their memory deficits. In either case, confabulation is a fascinating defense mechanism.
• Other manifestations
• • Hypothermia presents secondary to damage in temperature regulating centers.
  • Associated peripheral neuropathy is found in 80% of patients.
  • Cardiovascular dysfunction may be observed. Overt signs of beriberi heart disease are rare in patients with Wernicke-Korsakoff syndrome. The following symptoms may be observed and generally improve with administration of thiamine:
    • Postural hypotension
    • Tachycardia
    • Syncope

Causes

• Chronic alcoholism
• Persistent emesis
• • Hyperemesis gravidarum
  • Gastric malignancy
  • Intestinal obstruction
  • Bariatric surgery – Usually presents within 8-15 weeks but can occur as early as 6 weeks postoperatively. Recovery typically occurs within 3-6 months of initiation of therapy but may be incomplete if not recognized promptly and treated.
• Systemic diseases
• • Malignancy
  • Disseminated tuberculosis
  • Acquired immunodeficiency syndrome
  • Uremia
• Starvation
• • Anorexia nervosa
  • Prisoners of war
• Iatrogenic
• • Intravenous hyperalimentation
  • Refeeding after starvation
  • Chronic hemodialysis

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Wernicke encephalopathy should be differentiated from acute delirium secondary to hypoxia, hypercarbia, CNS infections, and postictal state (seizure). Ataxic disorders also can result from cerebellar infarction. Ocular disorders also can result from vasculitis or infarction.

The differential diagnosis of Korsakoff psychosis includes the following:

Temporal lobe epilepsy
Temporal lobe infarction
Concussive head injury
Transient global amnesia
Anoxic encephalopathy
Alzheimer disease
Third ventricle tumor
Herpes simplex virus sequela

WORKUP

Section 5 of 10  

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

Lab Studies

• Electrolytes: Initial laboratory studies are directed at the differential diagnostic possibilities that can be identified and corrected rapidly. Electrolyte studies are used to rule out an acute metabolic derangement causing mental confusion.
• Complete blood count: Rule out an acute infectious process, thrombocytosis, or erythrocytosis predisposing to thrombosis and infarction.
• Coagulation panel: Evaluate for a potential bleeding diathesis.
• Arterial blood gas: Evaluate for hypoxemia, hypercarbia, acidosis, or alkalosis.
• Serum/urine toxic drug screen: Rule out acute toxic ingestion. This is most helpful if results are available rapidly.
• Liver-associated enzymes: This may provide evidence of alcohol abuse or liver dysfunction.

Imaging Studies

• CT brain scan (noncontrast): CT scan can help in rapid assessment for hemorrhage, mass effect, edema, and large subacute stroke.
• MRI of the brain with contrast: MRI demonstrates acute lesions of Wernicke-Korsakoff syndrome in medial thalamic and periaqueductal regions. This can be a useful diagnostic procedure in patients presenting with suggestive history and stupor or coma, where ataxia and ophthalmoplegia are not detectable.

Procedures

• Lumbar puncture/CSF analysis: Seriously consider this procedure for any confused patient with fever and/or headache, particularly elderly patients, to rule out infectious etiology. Patients with Wernicke-Korsakoff syndrome have a protein content that is within the reference range or mildly elevated without pleocytosis on CSF analysis.

TREATMENT

Section 6 of 10  

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

Medical Care

Wernicke encephalopathy is a medical emergency. Prompt recognition of the symptom complex and a high index of suspicion are crucial to ensure early treatment. Intravenous thiamine (50-100 mg) is the treatment of choice. Early treatment can rapidly reverse the ophthalmoplegia and improve ataxia/dysequilibrium and early mental confusion, as well as prevent development of the amnestic state. In advanced cases, where severe prolonged deficiency has led to permanent structural damage, permanent deficits most often are manifested as the amnestic state and severe ataxia.

After the initial IV dose, continue daily doses of thiamine (50-100 mg) as IV, IM, or oral doses depending on patient status. Supplementation of electrolytes, particularly magnesium and potassium (often low in people with alcoholism), may be required in addition to thiamine. In patients who are chronically malnourished, the remainder of the B vitamins also should be supplemented. Administration of intravenous glucose to patients who are severely malnourished can exhaust their supply of thiamine and precipitate Wernicke-Korsakoff syndrome. Thus, good practice demands administration of thiamine prior to glucose infusions in patients at high risk for Wernicke-Korsakoff syndrome.

Consultations

Long-term alcohol use is the most common etiology for Wernicke-Korsakoff syndrome, and abstinence provides the best chance for recovery. Referral to an alcohol recovery program should be part of the treatment regimen. Base disposition to inpatient versus outpatient rehabilitation on the individual. Several other risk factors for Wernicke-Korsakoff syndrome are recognized (see Causes). Patients with these risk factors also could benefit from referral or consultation to help prevent future episodes.

Diet

A balanced diet should be resumed as early as possible. Vitamin and electrolyte supplementation should be adhered to in addition to a well-balanced diet initially, and supplementation can be tapered as the patient resumes normal intake and demonstrates symptomatic improvement.

Activity

Due to gait abnormalities, unassisted ambulation is discouraged during the initial phase of treatment. Patients may require physical therapy evaluation for gait assistance. Gait abnormalities may be permanent, depending on the severity at initial presentation and the timeliness of therapy.

MEDICATION

Section 7 of 10  

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

Wernicke-Korsakoff syndrome is a result of thiamine deficiency. The treatment is replacement of this essential vitamin.

Drug Category: Nutrients

In treating this disorder, the 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, it also is involved in neurochemical transmission and muscular excitability. Patients with chronic alcoholism and patients who are malnourished usually have inadequate magnesium stores.
Adult Dose	2-4 g IV at rate of 1 g/h initially, switch to PO when tolerated; dose is determined by level of deficiency
Pediatric Dose	Not established
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 observed 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	Possible alteration of cardiac conduction, leading to heart block in digitalized patients; monitor respiratory rate, deep tendon reflex, and renal function when electrolyte is administered parenterally; magnesium may produce significant hypertension or asystole, so caution is needed when administering dose; in overdose, calcium gluconate, 10-20 mL IV of 10% solution, can be administered as antidote for clinically significant hypermagnesemia

Drug Name	Potassium acid phosphate (K-Phos)
Description	Essential for transmission of nerve impulses, contraction of cardiac muscle, maintenance of intracellular tonicity, skeletal and smooth muscles, and maintenance of normal renal function. Gradual potassium depletion occurs via renal excretion, through GI loss, or because of low intake. Patients with chronic alcoholism and patients who are malnourished usually have inadequate nutrient stores. Potassium depletion sufficient to cause a 1-mEq/L drop in serum potassium requires a loss of about 100-200 mEq of potassium from the total body store.
Adult Dose	10 mEq/h IV, switch to PO when tolerated; dose is determined by level of deficiency
Pediatric Dose	Not established
Contraindications	Hyperkalemia; renal failure; conditions in which potassium retention is present; oliguria or azotemia; crush syndrome; severe hemolytic reactions; anuria; adrenocortical insufficiency
Interactions	Concurrent use with ACE inhibitors may result in elevated serum potassium concentrations; potassium-sparing diuretics and potassium-containing salt substitutes can produce severe hyperkalemia; in patients taking digoxin, hypokalemia may result in digoxin toxicity; caution if discontinuing potassium administration in patients maintained on digoxin
Pregnancy	A - Safe in pregnancy
Precautions	High plasma concentrations may cause death due to cardiac depression, arrhythmias, or arrest; plasma levels do not necessarily reflect tissue levels; monitor potassium replacement therapy whenever possible by continuous or serial ECG

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Evaluation for progression or recovery from Wernicke-Korsakoff syndrome symptom complex is the primary reason for further inpatient care. Patients also require monitoring for alcohol withdrawal and the potential cardiac manifestations of Wernicke-Korsakoff syndrome.

Further Outpatient Care

• Recovering patients will require outpatient follow-up care to evaluate for continued progress or relapse.
• Patients with long-term alcoholism may benefit from further inpatient or outpatient rehabilitation, depending on the likelihood of compliance.

In/Out Patient Meds

• Patients should continue taking thiamine supplementation, as well as other vitamins and electrolytes, until a well-balanced diet can be maintained. Long-term supplementation may be required in patients who cannot maintain adequate nutritional intake, whether from noncompliance or the underlying disorder.

Deterrence/Prevention

• Long-term alcohol use is the most common etiology for development of Wernicke-Korsakoff syndrome. Abstinence from alcohol provides the best chance for recovery, in conjunction with thiamine replacement. Refer patients for alcohol abuse counseling on an individual basis to deter future use and prevent future episodes.

Complications

• Ocular complications
• • Patients who recover generally do so in a particular sequence. Improvement of ocular abnormalities is the earliest and most dramatic, usually occurring within hours of the initial thiamine dose. Failure of ocular abnormalities to respond to thiamine in this manner should raise doubt as to the veracity of the diagnosis.
  • Vertical nystagmus may persist for months. Fine horizontal nystagmus may persist indefinitely in as many as 60% of patients, but patients completely recover from sixth nerve palsies, ptosis, and vertical gaze palsies.
• Ataxic complications
• • Approximately 40% of patients recover completely from their ataxic symptoms. The remainder has varying degrees of incomplete recovery, with a residual slow, shuffling, wide-based gait and the inability to tandem walk.
  • Vestibular dysfunction generally responds to a similar degree.
• Mental status complications: The symptoms of global confusional state often resolve gradually after treatment is initiated. If an amnestic deficit is present, it will manifest as the early signs of apathy and global confusion resolve. Only 20% of patients who demonstrate signs of the amnestic state after treatment has been initiated have complete recovery. The remaining patients have varying degrees of persistent learning and memory impairment. Maximum recovery may take 1 or more years and depends on abstinence from alcohol. According to reports, once patients with Korsakoff psychosis have recovered, they do not demand alcohol, but they will accept it if offered.

Prognosis

• The mortality rate is 10-20%. The most common etiologies are infection and hepatic failure, but some deaths are directly attributable to irreversible defects of severe and prolonged thiamine deficiency.

Patient Education

• In alcohol-related Wernicke-Korsakoff syndrome, abstinence from alcohol and maintenance of a balanced diet offer the best chance for recovery and prevention of future episodes.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Maintain a high level of suspicion for thiamine deficiency to avoid iatrogenic precipitation of the Wernicke-Korsakoff syndrome. Heightened awareness should lead to prophylactic supplementation in at-risk patients.
• • This syndrome most commonly is observed in patients with alcoholism, so, when these patients present to an emergency department, they routinely are administered thiamine prior to glucose infusion.
  • Several other categories of patients are at increased risk for thiamine deficiency, including inpatients receiving total parental nutrition, which necessitates vigilant monitoring for indicative signs and symptoms to insure prompt treatment.

Special Concerns

• Alcohol use is the most common etiology for Wernicke-Korsakoff syndrome. Health care providers usually need to treat varying degrees of withdrawal symptoms in any patient who presents with Wernicke-Korsakoff syndrome.

REFERENCES

Section 10 of 10

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

• Adams RD, Victor M, Ropper AH. Diseases of the nervous system due to nutritional deficiency. In: Principles of Neurology. 6th ed. New York, NY:. McGraw Hill Text;1997:1138-1145.
• Al-Sanouri I, Dikin M, Soubani AO. Critical care aspects of alcohol abuse. South Med J. Mar 2005;98(3):372-81. [Medline].
• Berger JR. The neurologic complications of bariatric surgery. Arch Neurol. 2004;61:1185-1189.
• Diamond I. Nutritional disorders of the Nervous System. In: Cecil RL, Goldman L, Bennett JC, eds. Cecil Textbook of Medicine. 19th ed. Philadelphia, Pa:. WB Saunders Co;1992:2125-2128.
• McEntee WJ, Mair RG. Memory enhancement in Korsakoff''s psychosis by clonidine: further evidence for a noradrenergic deficit. Ann Neurol. May 1980;7(5):466-70. [Medline].
• Nautiyal A, Singh S, Alaimo DJ. Wernicke encephalopathy--an emerging trend after bariatric surgery. Am J Med. Nov 15 2004;117(10):804-5. [Medline].
• Reuler JB, Girard DE, Cooney TG. Current concepts. Wernicke''s encephalopathy. N Engl J Med. Apr 18 1985;312(16):1035-9. [Medline].
• Rotman P, Hassin D, Mouallem M, et al. Wernicke''s encephalopathy in hyperemesis gravidarum: association with abnormal liver function. Isr J Med Sci. Mar 1994;30(3):225-8. [Medline].
• US Pharmacopeial Convention. Thiamine. In: Drug Information for the Health Care Professional. 18th ed. Micromedex;1998:2824-2826. [Full Text].
• Victor M, Martin JB. Nutrional and metabolic diseases of the nervous system. In: Eugene Braunwald, ed. Harrison's Principles of Internal Medicine. 13th ed. New York, NY:. McGraw Hill Text;1994:2328-2331.
• Zubaran C, Fernandes JG, Rodnight R. Wernicke-Korsakoff syndrome. Postgrad Med J. Jan 1997;73(855):27-31. [Medline].

Article Last Updated: Sep 1, 2005