Wernicke-Korsakoff syndrome

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Photo by: Yurok Aleksandrovich

Definition

Wernicke-Korsakoff syndrome is a severe memory disorder usually associated with chronic excessive alcohol consumption, although the direct cause is a deficiency in the B vitamin thiamin.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), the professional handbook that aids clinicians in diagnosing patients' mental disorders, refers to Korsakoff syndrome as alcohol-induced persisting amnestic disorder and includes it under the category of substance-induced persisting amnestic disorders .

Description

The disorder was first identified in the late nineteenth century. The first phase of the condition, called Wernicke's encephalopathy, was described by German neurologist and psychiatrist Karl Wernicke in 1881. He noted three key symptoms in three patients—two with alcoholism and one who had swallowed sulfuric acid. These patients suffered from mental confusion, eye movement disorders , and ataxia (poor motor coordination). A few years later, S. S. Korsakoff, a Russian psychiatrist, began publishing reports describing a syndrome of anterograde amnesia—an inability to form new memories—and confabulation in individuals with severe alcoholism or certain medical illnesses. (Confabulation refers to the practice of filling in gaps in memory by fabrication.) By 1900, researchers and clinicians studying alcoholism recognized a connection between the two conditions. The typical syndrome begins with acute Wernicke's encephalopathy, with Korsakoff syndrome emerging when the acute phase resolves. The symptoms of Wernicke's encephalopathy appear suddenly. The most prominent symptom initially is mental confusion including memory problems. On examination, patients have difficulty moving their eyes to follow a visual stimulus due to paralysis of the muscles controlling eye movements. For instance, a patient may have trouble looking upward or to the side with one or both eyes. Problems maintaining balance while standing or walking, a condition known as ataxia, are frequently observed as well. If left untreated, most of these symptoms may resolve spontaneously, but the severe memory disorder characteristic of Korsakoff syndrome remains.

The typical person with Korsakoff syndrome appears fairly normal on first impression. Intelligence is intact, and individuals with the syndrome can carry on a conversation quite naturally. They are usually able to recall and talk about incidents that took place before the onset of the disorder and recognize family members and old friends without much difficulty. The ability to form new memories is nearly absent, however. In the course of conversation, people with Korsakoff syndrome may repeat comments or questions several times. They will fail to recognize people they met minutes before or greet a friend with excitement and surprise after a brief trip to another room. These are the characteristics of anterograde amnesia . Research shows that anterograde amnesia results from a failure of memory formation and storage. New information is processed normally, but almost immediately forgotten, never making it into the regions of the brain where memories of the past are stored. People with Korsakoff syndrome thus have no memories of events that happened after the onset of the illness. Many previously stored memories are still available, however, explaining why individuals with Korsakoff syndrome can usually remember the distant past quite well.

Causes and symptoms

Causes

Wernicke-Korsakoff syndrome is caused by thiamin deficiency. It is most commonly observed in people with alcoholism since heavy drinkers often eat poorly, and alcoholism interferes with absorption of nutrients from the digestive system. It can also occur in people who are malnourished for other reasons. Thiamin helps produce energy needed to make neurons function properly. Insufficient thiamin can lead to damage or death of neurons.

Thiamin deficiency damages regions of the brain, particularly the thalamus and the mammillary bodies. The thalamus is a structure deep within the brain that serves many important functions. It is often called the major relay station of the brain, and many neurons make connections in the thalamus. The mammillary bodies are part of the hypothalamus, located just below the thalamus. The mammillary bodies receive many neural connections from another part of the brain called the hippocampus, which appears to be the primary part of the brain involved in the formation of memories. Neurons in the mammillary bodies make connections with the thalamus, which in turn makes connections with the cortex of the brain, where long-term memories are stored. This may explain why damage to the mammillary bodies and thalamus can lead to anterograde amnesia. Memories formed in the hippocampus are never stored since connections between hippocampus and cortex are disrupted.

Eye movement disorders observed in the acute phase of the condition are probably due to damage to other nearby brain regions that make connections to the nerves controlling eye muscles. These nerves emerge from the brainstem located right below the thalamus and mammillary bodies. Nerves involved in balance also make connections with other nerves in the brainstem, but a separate part of the brain called the cerebellum may also contribute to ataxia. Reasons why some regions of the brain are selectively affected by thiamin deficiency are not yet fully understood, but selective vulnerability of certain neurotransmitters is suspected.

Symptoms

Mental confusion, eye movement disturbances, and ataxia are the primary symptoms of Wernicke's encephalopathy—the first, acute stage of Wernicke-Korsakoff syndrome. At first glance, confusion and ataxia may resemble the effects of severe alcohol intoxication, but they persist after intoxication wears off. Some patients with Wernicke's encephalopathy will recover completely without residual memory deficits, particularly if they are treated quickly with thiamin.

The chronic stage of Wernicke-Korsakoff syndrome, sometimes called Korsakoff psychosis , is distinguished by anterograde amnesia, and most untreated patients with Wernicke's encephalopathy will develop this severe memory disorder, which prevents them from forming lasting memories of events or information encountered after the onset of the initial symptoms. Symptoms of Korsakoff syndrome may also develop spontaneously in many patients who never show signs of Wernicke's encephalopathy. Once patients develop Korsakoff's amnesia, recovery is unlikely.

Loss of memory for past events is called retrograde amnesia. Many people with Korsakoff syndrome have some retrograde amnesia in addition to anterograde amnesia, particularly for events that occurred shortly before the onset of illness, but most can recall the distant past without difficulty.

Immediate memory is not affected. For instance, an individual with Korsakoff syndrome could repeat a sentence or string of numbers immediately after hearing them, although this information would likely be forgotten within half a minute. Preservation of immediate memory allows individuals with Korsakoff syndrome to interact with others and respond to questions. Implicit memory is also preserved, so people with Korsakoff syndrome can learn new motor skills or develop conditioned reactions to stimuli. For example, individuals who play computer games can show improved performance each time they play, even if they cannot explicitly remember having played the game before.

Confabulation is another striking feature of Korsakoff syndrome, although it is not always observed. Confabulation refers to falsification of memory. The individual appears to be making up stories to cover up for inability to remember. Confabulation often seems to involve a confusion of the past and present. For example, if patients with Korsakoff syndrome are asked why they are in the hospital, they may say they just had a baby, are recovering from pneumonia, undergoing medical tests, or even applying for a job.

Patients with Wernicke-Korsakoff syndrome may also show signs of apathy and a lack of spontaneous behavior. Emotional expression may be lacking as well.

Interestingly, autopsies often reveal brain lesions characteristic of Wernicke-Koraskoff syndrome in alcoholic patients who showed general cognitive problems like those seen in dementia , but who never developed anterograde amnesia. These findings suggest that onset may be gradual in some patients.

Demographics

When diagnosis is based on postmortem findings, the estimated prevalence of Wernicke-Korsakoff syndrome is between 1 and 2% of the population. The classic presentation with acute onset of Wernicke's encephalopathy is fairly rare, about 0.05% of all hospital admissions, although this does not account for patients who do not seek medical attention. Wernicke-Korsakoff syndrome usually follows many years of chronic alcoholism or malnutrition and is seldom seen among people under 20. Most patients are 40 years of age or older. The disorder is apparently more common in alcoholic individuals who are particularly vulnerable to malnutrition such as indigent or homeless people.

Diagnosis

Wernicke's encephalopathy is diagnosed when patients seek medical attention and have the classic trio of signs: mental confusion, eye movement disorders, and ataxia. The diagnosis of Korsakoff syndrome is given when anterograde amnesia is present in an individual with a history of chronic, heavy drinking or malnutrition. When Korsakoff syndrome follows Wernicke's encephalopathy, the entire Wernicke-Korsakoff syndrome diagnosis is appropriate. The diagnosis is supported by neuroimaging or autopsy findings showing degeneration of the thalamus and mammillary bodies and loss of brain volume in the area surrounding the fourth ventricle—a fluid-filled cavity near the brainstem.

Although DSM-IV-TR criteria for alcohol-induced persisting amnestic disorder apply to most people with Wernicke-Korsakoff syndrome, there are some differences between the two diagnoses. Despite research findings suggesting that severe amnesia is not a necessary symptom of Wernicke-Korsakoff syndrome, the DSM-IVTR requires the presence of either anterograde or retrograde amnesia for a diagnosis of alcohol-induced persisting amnestic disorder. One additional cognitive symptom is also required. Symptoms listed in the DSM-IV-TR include language disturbance (aphasia), inability to carry out motor activities (apraxia), inability to recognize objects (agnosia), or deficits in planning, initiation, organization and abstraction (executive functions). Individuals with Wernicke-Korsakoff syndrome frequently demonstrate problems with executive functions that contribute to the symptoms of confabulation and apathy. Aphasia, apraxia, and agnosia are not common signs of Wernicke-Korsakoff syndrome.

The DSM-IV-TR also requires that memory impairment must significantly impair a person's ability to perform normal activities and functions, and it must represent a decline from a previous level of functioning. Amnesia cannot occur exclusively during states of delirium , alcohol intoxication, or withdrawal, or be exclusively associated with a dementia. Both of the these requirements are consistent with the usual presentation of Wernicke-Korsakoff syndrome.

Finally, the DSM-IV-TR requires evidence that amnesia is caused by use of alcohol. Such evidence can include an extensive history of heavy drinking; or physical examination or laboratory findings revealing other signs of heavy alcohol use, such as abnormal liver function tests. Despite this DSM-IV-TR requirement, Wernicke-Korsakoff's syndrome can occur in the absence of heavy alcohol use. Emergence of the disorder in people without alcoholism is much less common today than it was in the past, however, since vitamins are now added to many foods. In practice, most people who show the hallmark symptoms of Wernicke-Korsakoff syndrome also qualify for the DSM-IV-TR diagnosis.

Treatments

Nutritional

Individuals with signs of Wernicke's encephalopathy should be treated with thiamin immediately. In many cases, prompt administration of thiamin reverses the symptoms and prevents amnesia from developing. Thiamin can be administered intravenously or directly into the digestive system. Unfortunately, thiamin is less effective in the chronic phase of the condition. Based on autopsy findings suggesting the presence of Wernicke-Korsakoff syndrome in people with milder cognitive problems who do not show the classic signs of the disorder, researchers have examined the usefulness of thiamin treatment in people with alcohol dependence who are at risk of developing the syndrome. Results suggest that thiamin treatment improves performance on memory tests in this group, and that higher thiamin doses are associated with better performance. These findings suggest that thiamin treatment can help prevent Wernicke-Korsakoff syndrome in heavy drinkers.

Medication

Recent reports suggest that donepezil and rivastigmine , drugs used to treat Alzheimer's disease , may improve memory in patients with Wernicke-Korsakoff syndrome. Both drugs prevent the breakdown of the neurotransmitter acetylcholine, which is important for the formation of memories. Patients treated with these drugs showed improvements on memory tests and were more able to recognize hospital staff and family members. Although improvements appear to be rather modest, these drugs may be useful for patients who do not respond to thiamin. Antidepressants that increase levels of serotonin may also be helpful, although the reasons why are not clear since these drugs are not effective with other memory disorders.

Conditioning

The fact that implicit memory is not affected by Wernicke-Korsakoff syndrome has led some researchers to explore the use of classical conditioning procedures in helping patients to remember specific people. In classical conditioning, animals and people learn to associate a stimulus with an outcome. The most famous example is the pairing of a ringing bell with food. Dogs naturally salivate when given food. In a famous experiment, Ivan Pavlov rang a bell immediately before serving food to dogs. After doing this repeatedly, Pavlov found that the dogs salivated upon hearing the bell ring even when the food was not presented. This form of learning does not rely on the hippocampus and cortex but appears to involve neurons in other parts of the brain. Patients with Wernicke-Korsakoff syndrome who are given specific rewards for correctly choosing a picture of a face that matches a face they have seen previously are more able to choose the correct face than those who do not receive the rewards. Although these individuals do not explicitly remember the face they saw previously, they are still able to make the correct choice. Training patients in this way could enable them to recognize familiar people and differentiate them from strangers.

Prognosis

The prognosis for full recovery from Wernicke-Korsakoff syndrome is poor. Once chronic Korsakoff's amnesia ensues, approximately 80% of patients will never fully recover the ability to learn and remember new information. Because they cannot learn from experience, individuals with Wernicke-Korsakoff syndrome almost always require some form of custodial care. They are usually unable to work, although some can perform simple tasks they learned prior to onset of the condition if closely supervised.

Prevention

Wernicke-Korsakoff syndrome can be prevented with a nutritious diet containing sufficient thiamin. Because severe chronic alcoholism is the most common cause of thiamin deficiency, treatment of alcohol dependence is extremely important. In order to prevent Wernicke-Korsakoff syndrome among people who are unable to stop drinking or among particularly vulnerable individuals like homeless drinkers, some researchers and clinicians have advocated supplementing alcoholic beverages with thiamin.

See also Alcohol and related disorders ; Amnestic disorders ; Brain ; Dementia ; Executive function

Resources

BOOKS

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edition, text revised. Washington, DC: American Psychiatric Association,2000.

Hochhalter, Angela K., Whitney A. Sweeney, Lisa M. Savage, Bruce L. Bakke, and J. Bruce Overmier. "Using animal models to address the memory deficits of Wernicke-Korsakoff syndrome." In Animal Research in Human Health: Advancing Human Welfare Through Behavioral Science, edited by Marilyn E. Carroll and J. Bruce Overmier. Washington, DC: American Psychological Association, 2001.

Mesulam, M.-Marsel. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press, 2000.

Nolte, John. The Human Brain: An Introduction to Its Functional Anatomy. 5th edition. St. Louis: Mosby, 2002.

Walsh, Kevin and David Darby. Neuropsychology: A Clinical Approach. 4th edition. Edinburgh: Churchill Livingstone,1999.

PERIODICALS

Ambrose, Margaret L., Stephen C. Bowden, and Greg Whelen. "Thiamin treatment and working memory function of alcohol-dependent people: Preliminary findings." Alcoholism: Clinical and Experimental Research 25, no. 1 (2001): 112-116.

Angunawela, Indira I. and Andrew Barker. "Anticholinesterase drugs for alcoholic Korsakoff syndrome." International Journal of Geriatric Psychiatry 16 (2001): 338-339.

Harding, Antony, Glenda Halliday, Diana Caine, and Jillian Kril. "Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia." Brain 123 (2000): 141-154.

Iga, Jun-Ichi, Makoto Araki, Yasuhito Ishimoto, and Tetsuro Ohmori. "A case of Korsakoff's syndrome improved by high doses of donepezil." Alcohol and Alcoholism 36, no. 6 (2001): 553-555.

ORGANIZATIONS

Family Caregiver Alliance. 690 Market Street, Suite 600, San Francisco, CA 94104. <http://www.caregiver.org/> .

Medical Council on Alcohol. 3 St. Andrew's Place, Regent's Park, London, UK NW1 4LB. <http://www.medicouncilalcol.demon.co.uk> .

National Institute on Alcohol Abuse and Alcoholism (NIAAA). Willco Building, 6000 Executive Boulevard, Bethesda, MD 20892. <http://www.niaaa.nih.gov> .

OTHER

Memory Loss and the Brain Newsletter, Memory Disorders Project, Rutgers University, 197 University Avenue, Newark, NJ 07102 <http://www.memorylossonline.com/> .

Danielle Barry, M.S.