Wernicke-Korsakoff Syndrome

Updated: Sep 27, 2023
  • Author: Glen L Xiong, MD; Chief Editor: David Bienenfeld, MD  more...
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Overview

Practice Essentials

Wernicke-Korsakoff Syndrome (WKS) classically, but not always, presents with the clinical triad of confusion, ataxia, and nystagmus. [1] It is best conceptualized as 2 distinct syndromes, with one being characterized by an acute/subacute confusional state and often reversible findings of Wernicke encephalopathy (a type of delirium) and the other by persistent and irreversible findings of Korsakoff dementia. A deficiency of thiamine (vitamin B-1) is responsible for the symptom complex manifested in WKS, and any condition resulting in a poor nutritional state places patients at risk.

Signs and symptoms

The classical triad of confusion, ataxia, and nystagmus is only present in about 16-38% of patients. [2]

Ocular/visual disturbances may include the following:

  • Painless vision abnormalities

  • Diplopia (double vision)

  • Strabismus

Gait abnormalities include the following:

  • New, wide-based, short-stepped gait

  • Inability to stand or walk without assistance

Mental status changes include the following:

  • Apathy, indifference, paucity of speech

  • Hallucination, agitation

  • Confabulation - Patient fills in gaps of memory with data that can be recalled at that moment

Diagnosis

The primary focus should not necessarily be an accurate diagnosis, but to prevent harm from worsening Wernicke-Korsakoff syndrome in vulnerable patients. If there is clinical uncertainty, patients should be empirically treated while additional evaluations are undertaken.

Management

Wernicke-Korsakoff syndrome (unlike acute Wernicke encephalopathy) is often a long-term condition. It should be treated aggressively as Wernicke encephalopathy in the acute setting, but with the understanding that it is rare for the Korsakoff amnestic state to fully reverse with treatment. After a course of treatment with high-dose parenteral thiamine and reversal of the acute effects of Wernicke encephalopathy, if there is no improvement in the Korsakoff amnestic state or other mental status abnormalities for 7 days, then a strategy of secondary harm prevention should be pursued. This includes maintenance with oral thiamine to prevent further insult, as well as consideration for rehabilitation, treatment of comorbid deficiencies and medical conditions, and consideration of the need for long-term residential care or supportive accommodation.

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Background

Wernicke-Korsakoff Syndrome (WKS) classically, but not always, presents with the clinical triad of confusion, ataxia, and nystagmus. [1] It is best conceptualized as 2 distinct syndromes, with one being characterized by an acute/subacute confusional state and often reversible findings of Wernicke encephalopathy (a type of delirium) and the other by persistent and irreversible findings of Korsakoff dementia. (See Clinical and Workup.)

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.

Sergei Korsakoff, a Russian psychiatrist, described the disturbance of memory in the course of long-term alcoholism in a series of articles from 1887 to 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. (See Etiology.)

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Etiology

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. The structural lesions associated with Wernicke-Korsakoff syndrome are more likely to manifest in patients with malnutrition. [3] However, it is crucial to recognize that Wernicke-Korsakoff syndrome also appears in patients without exposure to alcohol. The occurrence of WKS in patients without alcohol use disorders is well described in the literature and cited in the section below. [4]

The following are associated with Wernicke-Korsakoff syndrome:

  • Chronic alcoholism - There may be a synergistically destructive effect of alcohol and thiamine deficiency that contributes to the 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 decreased capacity of the liver to store thiamine. [5, 6, 7]

  • 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) [8, 9]

  • Nutritional deficiency and certain diets [10]

  • Starvation - Persons with anorexia nervosa, [11] schizophrenia, [12] or terminal cancer [13] ; prisoners of war

  • Thiamine-deficient formula [14]

  • Hyperemesis gravidarum - In a study of 49 cases of Wernicke encephalopathy in pregnancy, pregnancy loss attributable to Wernicke encephalopathy was nearly 48% [15]

  • Gastric malignancy, [16, 17] inflammatory bowel disease [18]

  • Intestinal obstruction, including abdominal abscess [19]

  • Plastic surgery - Panniculectomy [20]

  • Systemic diseases - Malignancy, [21, 22] disseminated tuberculosis, acquired immunodeficiency syndrome (AIDS), [23] uremia, stem cell transplantation [24]

  • Iatrogenic - Intravenous hyperalimentation (without thiamine supplementation), refeeding after starvation, chronic hemodialysis [25]

  • Encephalitic infections or infarctions affecting the mammillary bodies or hippocampus Rare reports - Rare reports [26]

  • Infants breastfed by mothers with inadequate intake of thiamine [27]

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Pathophysiology

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 demonstrate cellular impairment and injury. The earliest biochemical change is the decrease in α-ketoglutarate-dehydrogenase activity in astrocytes. Acute thiamine deficiency leads to mitochondrial dysfunction and therefore oxidative toxicity in areas of the brain starting with areas with the highest metabolic activity. The exact mechanism of neuronal cell death remains to be elucidated. [28]

Additional findings include increased astrocyte lactate and edema, increased extracellular glutamate concentrations, increased nitric oxide from endothelial cell dysfunction, deoxyribonucleic acid (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. [29] They pointed 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. These results have not been reproduced in any large prospective study. Patients with permanent Korsakoff psychosis are not routinely treated with clonidine.

Variants in the gene coding for the high-affinity thiamine transporter protein SLC19A2 in neurons may also contribute to the susceptibility of Wernicke-Korsakoff syndrome. Patients with a functional impairment in the ability to effectively transport thiamine may have impaired ability to cope with thiamine deficiency or respond to thiamine replacement.

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Epidemiology

Eighty-five percent of the survivors of the acute phase of Wernicke encephalopathy who remain untreated go on to develop Wernicke-Korsakoff syndrome. [30]

Occurrence in the 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 occurrence

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, United States), prevalence ranged from 0-2.8%. Prevalence did not correlate with per capita alcohol consumption in each country. [31] In one study of 131 patients with post-mortem findings Wernicke’s encephalopathy, only 20% of the patients had a recorded diagnosis of the nutritional disorder. [32]

Sex-, age-, and race-related demographics

The condition affects males slightly more frequently than it affects females. Age of onset is evenly distributed from 30-70 years.

Studies have reported Wernicke encephalopathy in the pediatric population, often in association with malignancy. However, because of the prevalent role of alcohol in Wernicke-Korsakoff syndrome, it is very rarely reported in children. One report describes Wernicke-Korsakoff–like syndrome in a 10-year-old child who contracted herpesvirus encephalitis through an unrelated cord blood transplantation. The symptoms resolved with treatment of the virus, implying it had attacked the mammillothalamic system. [33]

While many clinicians empirically assume that age and the length of alcohol abuse are correlative with the risk of developing Wernicke-Korsakoff syndrome, there does not appear to be any controlled study evaluating this. Although studies have compared memory deficits in patients with Alzheimer dementia and Korsakoff syndrome (see the work of Michael D. Kopelman from the 1980s and 1990s), there do not appear to be studies looking at the impact of age-related atrophy or comorbid Alzheimer dementia as risk factors for Wernicke-Korsakoff syndrome.

The epidemiology of Wernicke-Korsakoff syndrome generally follows rates of alcoholism. There do not appear to be studies investigating or suggesting a genetic susceptibility of one racial group or sexual predisposition.

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Prognosis

As many as 25% of patients with Wernicke-Korsakoff syndrome require long-term supervised care or institutionalization. [34] Patients depending on long-term care usually have comorbidity in more than one domain (somatic and psychiatric). [35]

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 have 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.

Mortality

Mortality may be secondary to infections and hepatic failure, but some deaths are directly attributable to irreversible defects of severe and prolonged thiamine deficiency (eg, coma).

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. Unspecified infections were the cause of death in 77% of one cohort of Wernicke-Korsakoff patients. [36]

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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.

Patients who have undergone gastric bypass surgery are recommended to adhere to a balanced diet and continue vitamin supplementation.

Family education and support is an important component of taking care of anyone with a dementia illness, including Wernicke-Korsakoff syndrome. Patients with persistent dementia usually require 24-hour supervision, because they usually have poor insight into their illness and significant functional impairments in activities of daily living. Some patients with alcohol dependence may continue to prefer alcohol use, despite their cognitive deficits. In severe cases, private or public guardianships (or conservatorships) may need to be sought from the courts.

Some helpful Web sites for patients include the following:

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