eMedicine Specialties > Psychiatry > Adult

Wernicke-Korsakoff Syndrome

Author: Glen L Xiong, MD, Assistant Clinical Professor, Department of Psychiatry and Behavioral Sciences, Department of Internal Medicine, University of California Davis School of Medicine; Attending Psychiatrist, Sacramento Mental Health Treatment Center; Attending Physician, Sacramento County Primary Care Clinic
Coauthor(s): G Patrick Daubert, MD, Assistant Professor, Assistant Medical Director, Sacramento Division, California Poison Control System; Director of Clinical and Medical Toxicology Education, Department of Emergency Medicine, University of California, Davis Medical Center
Contributor Information and Disclosures

Updated: Nov 23, 2009

Introduction

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, exhibited these findings, developed coma, and eventually died. On autopsy, 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 clinical triad of confusion, ataxia, and nystagmus (or ophthalmoplegia). When persistent learning and memory deficits are present, the symptom complex is often called Wernicke-Korsakoff syndrome. Clinically, this term is best conceptualized as 2 distinct syndromes with acute/subacute confusional state and often reversible findings of Wernicke encephalopathy versus persistent and irreversible findings of Korsakoff dementia. 

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 absorbed from the duodenum. The body has approximately 18 days of thiamine stores. Thiamine is converted to its active form, thiamine pyrophosphate, in neuronal and glial cells. Thiamine pyrophosphate serves as a cofactor for several enzymes, including transketolase, pyruvate dehydrogenase, and alpha ketoglutarate, that function in glucose use. The main function of these enzymes in the brain is lipid (myelin sheath) and carbohydrate metabolism, production of amino acids, and production of glucose-derived neurotransmitters. Thiamine appears to have a role in axonal conduction particularly in acetylcholinergic and serotoninergic neurons. A reduction in the function of these enzymes leads to diffuse impairment in the metabolism of glucose in key regions of the brain resulting in impaired cellular energy metabolism.

Within 2-3 weeks of decreased intake and thiamine depletion, areas of the brain with the highest thiamine content and turnover will demonstrate cellular impairment and injury. The main consequence of these metabolic changes is the loss of osmotic gradients across cell membranes. The earliest biochemical change is the decrease in a -ketoglutarate-dehydrogenase activity in astrocytes. Additional findings include increased astrocyte lactate and edema, increased extracellular glutamate concentrations, increased nitric oxide from endothelial cell dysfunction, DNA fragmentation in neurons, free radical production and increase in cytokines, and breakdown of the blood brain barrier. Thiamine appears to have a role in acetylcholinergic and serotoninergic synaptic transmission and axonal conduction.
 
Symptoms of Wernicke-Korsakoff syndrome are attributed to these 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 is also affected. In addition, chronic alcohol consumption results in a 35% decrease in transketolase activity within the cerebellum, which is likely due to thiamine deficiency.

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.

McEntee and colleagues 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 postulated that damage to these pathways may be the basis for the amnestic features of Wernicke-Korsakoff syndrome.¹ These results have not been reproduced in any large prospective study. Patients with permanent Korsakoff psychosis are not routinely treated 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 clinical detection. 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 are essentially the same. In a survey of neuropathologists from several countries (Australia, Austria, Belgium, Czechoslovakia, France, Germany, Norway, United Kingdom, and United States), prevalence ranged from 0-2.8%. Prevalence did not correlate with per capita alcohol consumption in each country.²

Mortality/Morbidity

The mortality rate is up to 10-15% in severe cases. Since the presentation is variable and often clinically missed, the exact mortality rate is difficult to estimate. Prognosis depends on the stage of disease at presentation and 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

History

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) does not consider Wernicke-Korsakoff syndrome as a distinct entity. However, if dementia is prominent, for Axis I purposes, dementia due to [General Medical Condition] (294.1) may be used for coding purposes. If acute confusion is prominent, then the code for delirium [due to medical condition] (293.0) may be considered.

The International Statistical Classification of Diseases and Related Health Problems (ICD-9) code includes (291.1) Alcohol-induced persisting amnestic disorder; Wernicke-Korsakoff Syndrome (alcohol). Since the ICD-9 codes link the diagnosis to alcohol-related conditions, non-alcohol associated Wernicke-Korsakoff syndrome would require other nonspecific codes, eg, (265.1) Other and unspecified manifestations of thiamine deficiency; Other vitamin B-1 deficiency states.

• 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.

Physical

• The classical triad of confusion, ataxia, and nystagmus is only present in about 16-38% of patients.³
• 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 agitation in acute delirium and tremens in a patient with alcohol withdrawal. The rare patient presenting in the Korsakoff amnestic state is alert and oriented but lacks the ability to provide adequate history.
    • Speech: No characteristic speech pattern exists. Vocal tremor may be present in a patient undergoing alcohol withdrawal. Reduced verbal content may occur in those with apathy.
    • Perceptual disturbances: No characteristic disturbances exist, but those of delirium tremens are present if it coexists.
    • Thought: Form and content vary depending on patient presentation. Themes may include a lack of concern about current health status or state of affairs.
    • Sensorium and cognition vary with level of consciousness. A state of altered sensorium, with decreased attention and concentration (inability to perform "serial 7's" or spell "WORLD" backwards); disorientation is present in the acute state, consistent with other delirium (or encephalopathy). For a patient who is not in delirium, impaired recall or orientation to date or location may occur. Knowledge of historical facts (eg, naming of presidents) is often impaired for those with Korsakoff syndrome. A patient may cover up the memory deficit by confabulating information.
    • Suicidal or homicidal ideation is generally not associated with this disorder, although any person in the midst of delirium can become self-injurious or violent.
    • 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 able to recall the registered information after 3-5 minutes. 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.
  • Confabulation is classically described in Korsakoff dementia, although it may be present in other dementias and is not necessarily present to make the diagnosis.
    • In actual patient scenarios, the patient often greets the examiner cordially as if he knows the examiner from the past (although the examiner has never met the patient).
    • When asked about prior encounters, the patient tells the examiner that they met 2 weeks ago in the hospital but does not recall exactly the topic of the conversation. The patient then proceeds to tell the examiner that currently he is doing well and is able to give basic history about current symptoms and uncertainty about where he will live. However, when asked about the year and the president, the patient replies (usually without hesitation) that it is 1955 and the president is Eisenhower. The actual year is 2005 and the president is G.W. Bush. In this case, the examiner may not have detected any deficits until specific orientation questions are asked. Other aspect of conversation generally lacks specificity and/or depth.
• 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
• Nutritional deficiency
• Thiamine-deficient formula⁴
• Persistent emesis
  • Hyperemesis gravidarum: In a study of 49 cases of Wernicke encephalopathy in pregnancy, pregnancy loss attributable to Wernicke encephalopathy was nearly 48%.⁵
  • Gastric malignancy
  • Intestinal obstruction
  • Bariatric surgery: Wernicke encephalopathy can present as early as 2 weeks after surgery. Recovery typically occurs within 3-6 months of initiation of therapy but may be incomplete if this syndrome is not recognized promptly and treated. The highest risk is in young women with vomiting.⁶
• Systemic diseases
  • Malignancy
  • Disseminated tuberculosis
  • Acquired immunodeficiency syndrome (AIDS)⁷
  • Uremia
• Starvation
  • Anorexia nervosa (see the Medscape Resource Center on Eating Disorders)
  • Prisoners of war
  • Schizophrenia⁸ (see the Medscape Resource Center on Schizophrenia)
  • Terminally ill cancer patient⁹
• Iatrogenic
  • Intravenous hyperalimentation
  • Refeeding after starvation
  • Chronic hemodialysis¹⁰

• Search for CME/CE on This Topic »

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• Wernicke Encephalopathy (Emergency Medicine)
• Alcohol-Related Psychosis (Psychiatry)
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