Wernicke-Korsakoff Syndrome 

Updated: May 16, 2018
Author: Glen L Xiong, MD; Chief Editor: David Bienenfeld, MD 

Overview

Background

Wernicke-Korsakoff Syndrome (WKS) classically, but not always, presents with the clinical triad of confusion, ataxia, and nystagmus. 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 1887-1891. 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.)

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.[1] 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.{ref53]

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.[2, 3, 4]

  • 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)[5, 6]

  • Nutritional deficiency and certain diets[7]

  • Starvation - Persons with anorexia nervosa,[8] schizophrenia,[9] or terminal cancer[10] ; prisoners of war

  • Thiamine-deficient formula[11]

  • Hyperemesis gravidarum - In a study of 49 cases of Wernicke encephalopathy in pregnancy, pregnancy loss attributable to Wernicke encephalopathy was nearly 48%[12]

  • Gastric malignancy,[13, 14] inflammatory bowel disease[15]

  • Intestinal obstruction, including abdominal abscess[16]

  • Plastic surgery - Panniculectomy[17]

  • Systemic diseases - Malignancy,[18, 19] disseminated tuberculosis, acquired immunodeficiency syndrome (AIDS),[20] uremia, stem cell transplantation[21]

  • Iatrogenic - Intravenous hyperalimentation (without thiamine supplementation), refeeding after starvation, chronic hemodialysis[22]

  • Encephalitic infections or infarctions affecting the mammillary bodies or hippocampus Rare reports - Rare reports[23]

  • Infants breastfed by mothers with inadequate intake of thiamine[24]

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.[25]

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.[26] 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.

Epidemiology

Eighty-five percent of the survivors of the acute phase of Wernicke encephalopathy who remain untreated go on to develop Wernicke-Korsakoff syndrome.[27]

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.[28] 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.[29]

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.[30]

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.

Prognosis

As many as 25% of patients with Wernicke-Korsakoff syndrome require long-term supervised care or institutionalization.[31] Patients depending on long-term care usually have comorbidity in more than one domain (somatic and psychiatric).[32]

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.[33]

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:

  • Family Caregiver Alliance, Wernicke-Korsakoff Syndrome

  • National Institute of Neurological Disorders and Stroke, Wernicke-Korsakoff Syndrome Information Page

  • Alzheimer's Association, Wernicke-Korsakoff Syndrome

 

Presentation

History

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

Other conditions that can be associated with Wernicke-Korsakoff syndrome include the following:

  • Weight loss or reduced body mass index

  • High starch/carbohydrate intake to the exclusion of a balanced diet

  • Intellectual impairment or autism with a diet restricted to one or a few foods.

  • Recurrent vomiting (eg, profound hyperemesis gravidum)

  • Comorbid malnutrition associated conditions such as pellagra, iron-deficiency anemia, amblyopia, and polyneuropathy from vitamin B-12 deficiency

Physical Examination

The classical triad of confusion, ataxia, and nystagmus is only present in about 16-38% of patients.[34]

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 asymmetrical 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

Ataxia is manifested as an abnormality of stance and gait. Vestibular paresis also plays a role in ataxia in the early stages of disease. The following characteristics are demonstrated by the patient:

  • 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

Alterations in consciousness can present simultaneously with ophthalmoplegia and ataxia but more commonly follow these signs and symptoms by days to weeks. These changes develop in 90% of patients and present in various forms.

Patients with long-term alcoholism are likely to present disheveled and unkempt, but appearance on presentation can range to a well-kept individual. No characteristic perceptual disturbances exist, but those of delirium tremens are present if it coexists.

The patient’s mood can range from calm and blunted or apathetic affect to stupor; agitation can occur in acute delirium and tremens can be found 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.

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.

Form and content of thought vary depending on patient presentation. Themes may include a lack of concern about the patient’s own current health status or state of affairs.

Sensorium and cognition vary with the level of consciousness. The patient may be in 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 in persons 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 with regard 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 as 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 anterograde (ie, learning) and retrograde (ie, memory of past events) amnesia. Anterograde amnesia is severe but incomplete. It is demonstrated by the ability of the patient to repeat a series of numbers or objects as they are stated, along with an inability to recall the registered information after 3-5 minutes.

Retrograde amnesia is demonstrated by gaps in patients' memories of the 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 by 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 does not necessarily need to be present for a diagnosis to be made.

In actual patient scenarios, the patient often greets the examiner cordially as if he or she knows the individual, despite having never met him or her. When asked about prior encounters, the patient may tell the examiner, for example, that he or she met the examiner 2 weeks ago in the hospital but does not precisely recall the topic of the conversation. The patient may then proceed to tell the examiner that currently he or she is doing well and provide a basic history about current symptoms, as well as express uncertainty about where he or she will live. However, when asked about the year and the president, the patient might reply (in many cases, without hesitation) that the year is 1955 and that the president is Dwight Eisenhower, even though the actual year is 2011 and the president is Barack Obama.

In such cases, the examiner may not have detected any deficits until specific orientation questions were asked. Other aspects of conversation generally lack 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[35] 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

 

DDx

Diagnostic Considerations

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

Several recent review papers have suggested routinely incorporating the Caine criteria, proposed in 1997. Because the classic textbook symptoms are rare and because the potentially treatable disorder is so often missed, these criteria may provide significant value in the general hospital and psychiatric hospital setting.[36]

These criteria suggest that a diagnosis of Wernicke encephalopathy can be made if 2 of the following are present in a patient with chronic alcoholism:

  • Eye signs (ocular abnormalities as described above)

  • Cerebellar signs (ataxia as described above)

  • Mild memory impairment of confusion without another etiology

  • Signs of malnutrition on physical or laboratory exam

While this broad definition would appear at first to be over-inclusive, in a follow-up study of a 106 alcoholic patients who underwent autopsy, the criteria had a sensitivity of 85% and a specificity of 100% for the diagnosis of Wernicke encephalopathy.[37]

In chronic alcoholic patients who meet the Caine criteria for Wernicke encephalopathy and have features of Korsakoff amnestic syndrome, a diagnosis of Wernicke-Korsakoff Syndrome should be presumed.

These criteria have not been validated in nonalcoholic patients and a high-index of suspicion for thiamine deficiency and Wernicke-Korsakoff syndrome needs to be maintained in vulnerable populations.

The British Royal College of Physicians guidelines are similar; they suggest treating everyone who has evidence of alcohol abuse and any one of the following:

  • Acute confusion

  • Decreased consciousness

  • Ataxia

  • Ophthalmoplegia

  • Memory disturbances

  • Hypothermia hypotension

The differential diagnosis of Korsakoff psychosis includes the following:

  • Temporal lobe epilepsy

  • Temporal lobe infarction

  • Concussive head injury

  • Dementia with Lewy bodies

  • Transient global amnesia

  • Anoxic encephalopathy

  • Alzheimer disease

  • Third ventricle tumor

  • Herpes simplex virus

Differential Diagnoses

 

Workup

Approach Considerations

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.

Initial laboratory studies are directed at the differential diagnostic possibilities that can be identified and corrected rapidly.

Maintain a high level of suspicion for thiamine deficiency to avoid iatrogenic precipitation of Wernicke-Korsakoff syndrome. Heightened awareness should lead to prophylactic supplementation in at-risk patients.

This syndrome is most commonly observed in patients with alcoholism. Consequently, when these patients present to an emergency department, they are routinely 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 ensure prompt treatment.

Laboratory Tests

Laboratory studies to detect various morbidities in the diagnosis of Wernicke-Korsakoff syndrome include the following:

  • Electrolytes - To rule out an acute metabolic derangement causing mental confusion

  • Lactic acidosis may occur as a result of thiamine deficiency and is often under-recognized. Supplementation with thiamine often leads to resolution of lactic acidosis[38, 39]

  • Magnesium level as it may explain impaired thiamine utilization[40]

  • Complete blood count (CBC) - To rule out an acute infectious process, thrombocytosis, or erythrocytosis predisposing to thrombosis and infarction

  • Coagulation panel - To evaluate for a potential bleeding diathesis

  • Arterial blood gas - To evaluate for hypoxemia, hypercarbia, acidosis, or alkalosis

  • Serum/urine toxic drug screen - To rule out acute toxic ingestion; this is most helpful if results are available rapidly

  • Liver-associated enzymes - May provide evidence of alcohol abuse or liver dysfunction

Serum thiamine levels

Serum thiamine levels have been used in case reports to confirm Wernicke-Korsakoff syndrome. However, studies have not directly examined the correlation between a critical serum thiamine level and the development of neurologic symptoms and Wernicke-Korsakoff syndrome itself. One small study did show that the serum thiamine level correlated well with cerebellar vermal atrophy.[41] For now, the role of serum thiamine levels remains uncertain, although it may eventually play a part in confirming the diagnosis of Wernicke-Korsakoff syndrome and/or monitoring adequacy of treatment.

Lumbar puncture/CSF analysis

Seriously consider this procedure for any confused patient with fever and/or headache, particularly elderly patients, to rule out an 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.

Imaging Studies

CT brain scan (noncontrast)

Computed tomography (CT) scanning can help in the rapid assessment for hemorrhage, mass effect, edema, and large, subacute stroke.

MRI of the brain with contrast

MRI can be a useful confirmatory in cases in which there is a clinical suspicion or a diagnostic procedure in patients presenting with a suggestive history and stupor or coma, in whom ataxia and ophthalmoplegia are not detectable. The possible diagnosis of Wernicke-Korsakoff syndrome should be communicated to the radiologists prior to ordering the scan to confirm that protocols suitable for the highest-yield imaging of the mammillary bodies, hippocampus, medial thalami, periaqueductal region, and the tectum of the midbrain are used. While specificity of MRI findings is high, the sensitivity is not; one study reported 53%.[42] Nevertheless, early diagnosis of WKS using MRI (T2 and FLAIR hyperintensities) in typical locations (thalami, mammillary bodies, tectal plate, and peraqueductal area) and atypical locations (cerebellum, cranial nerve nuclei, and cerebral cortex) has been proposed.[43]

As opposed to structural lesions and necrosis of the mammillary bodies, another study compared 9 patients with chronic Wernicke encephalopathy to 7 patients with Alzheimer disease and 37 controls. They found that 78% (7) of the chronic Wernicke patients had smaller mammillary bodies than 36 of 37 controls and 7 of 7 Alzheimer patients. The decrease was not related to age or ventricular size and is consistent with previous reports of autopsy findings.[44]

 

Treatment

Approach Considerations

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.

Dosing

Traditional regimens in the United States have used 100 mg of parental (intravenous or intramuscular) thiamine for 3-7 days (treatment period), followed by oral thiamine indefinitely as long as the patient is consuming alcohol. Because of case reports suggesting that much higher doses are needed (up to 1 g of parental thiamine) to obtain resolution of symptoms, some authorities such as the Royal College of Physicians have suggested 500 mg intravenously 3 times a day for 2-3 days.[45] If no response is noted, discontinue supplementation and assess for supportive care (unless the patient is comatose). If there is a partial response, continue at 250 mg parenterally for 5 days or as long as improvement continues in patients with neuropsychiatric symptoms.[34, 27]

Use of high-dose thiamine (500 mg TID intravenously) may be indicated given the detrimental consequence of untreated or undertreated WKS. A response to high-dose thiamine was reported as last as 30 days after initial recognition and treatment with thiamine at 100mg/day IV.[46] Monitoring of thiamine levels after treatment may be useful in guiding both route of administration and dosing.

After the patient’s response has plateaued, supplement with oral thiamine indefinitely until the patient is no longer at risk (eg, as long as they are drinking alcohol).

Absorption

Most recommendations for the initial use of parental thiamine are based on the poor bioavailability of oral thiamine, which is estimated to be between 3.7% and 5.3%.[47] Studies have suggested that 8.3 mg is the maximum that can be absorbed from a single oral thiamine dose, suggesting an absorption pathway that is easily saturated.[48] This seemed to be confirmed when another study showed very little thiamine is excreted in urine when oral doses greater than 2.5 mg are given.[49]

The most prominent study was in 52 prisoners of war in a report published in 1947. All developed Wernicke-Korsakoff syndrome during a period of starvation and/or nutritional deficiency (eg, living on white rice). Fifteen patients were treated with oral thiamine only and 67% (10 patients) died. Of the 37 who received intramuscular thiamine, 11 died, a mortality rate of 30%.[50]

Recent studies have challenged this and demonstrated that high-dose oral thiamine (500-1500 mg) can achieve correspondingly high blood levels in healthy subjects.[51] However, these studies have generally been in healthy subjects without comorbidities and no measurement has been made of the biological effect or tissues absorption of thiamine, especially in the brain. Until clinical studies have been undertaken on high-dose oral thiamine, the strong recommendation is that parental thiamine be the first line for the initial treatment of Wernicke-Korsakoff syndrome.

Adverse reactions

Allergic/anaphylactic reactions to thiamine do occur, but it does not appear to be at a rate to justify specific concern, despite a case report in the nursing literature that appears to have impacted many hospital protocols for thiamine administration. One paper reported more than 300,000 patients treated with parental thiamine without anaphylaxis.[52]

The Royal College of Physician guidelines recommend that intravenous thiamine be given over 30 minutes. This usually involves adding the thiamine to intravenous rehydration solutions, often with a parenteral multivitamin (banana bag). However, this is an empiric recommendation and is not followed at all institutions.

Other considerations

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 or simultaneously with glucose infusion in patients at high risk for Wernicke-Korsakoff syndrome. However, emergency care for life-threatening hypoglycemia should not be withheld for thiamine administration.

Emergency psychiatric hospitalization and evaluation are indicated when the patient is having active psychotic symptoms that pose a danger to himself or herself or to others. Many such patients also meet the criteria of grave disability (ie, inability to provide basic needs, such as food and shelter). In such cases, however, the patient should generally be medically and neurologically stable prior to transfer to a psychiatric facility, where acute medical work-up and monitoring may be available (eg, IV access, neuroimaging, nutritionist, neurology consultation).

In most cases, patients with psychotic symptoms may require inpatient medical hospitalization and psychiatric consultation. Once medically stabilized, patients may need continued psychiatric care if severe psychotic symptoms persist.

In patients with comorbid acute alcohol withdrawal, treatment with IV/IM thiamine occurs concurrently with the indicated alcohol withdrawal procedures.

Other deficiencies

Supplementation of electrolytes, particularly magnesium and potassium (often low in people with alcoholism), may be required in addition to thiamine. Magnesium acts as a cofactor for many enzymes (eg, transketolase for the conversion of thiamine to thiamine pyrophosphate), and, therefore, its deficiency may lead to a refractory response to thiamine supplementation.[53] In patients who are chronically malnourished, the remainder of the B vitamins also should be supplemented with an intravenous or oral multivitamin supplement. In patients with clinical evidence of Wernicke-Korsakoff syndrome, vitamin B-12 levels should be measured.

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 (eg, congestive heart failure). Owing to the acuity of the confessional state and continued neuronal damage, inpatient treatment may be needed to ensure sufficient thiamine supplementation via either oral and parenteral routes.

Diet and Activity

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. Supplementation can be tapered as the patient resumes normal intake and demonstrates symptomatic improvement.

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.

Referral and Follow-Up Care

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. Inpatient treatment versus outpatient rehabilitation depends on the needs of the individual and risks of relapse.

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.

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 and Prevention

Long-term alcohol use is the most common etiology for the development of Wernicke-Korsakoff syndrome. Abstinence from alcohol, in conjunction with thiamine replacement, provides the best chance for recovery. Refer patients for alcohol abuse counseling, community alcohol abuse treatment programs (eg, Alcoholics Anonymous and other consumer support programs), and couples/family therapy on an individual basis to deter future alcohol use and prevent future episodes of Wernicke-Korsakoff syndrome.

In patients at risk for malnutrition (eg, after gastric bypass surgery), appropriate thiamine and other B-vitamin supplementation should be taken in accordance with a nutritionist’s advice.

In emergency management of patients with acute confusion and concurrent risk factors (eg, alcohol dependence and malnutrition), thiamine administration should be strongly considered, especially prior to glucose administration.[54] Generally, high-carbohydrate diets increase the demand for thiamine.[34]  Immediate intravenous thiamine supplementation is the standard of care in ER patients with alcohol use disorders and withdrawal, and should be strongly considered in anyone with malnutrition.

In a large, prospective study, the introduction of thiamine-enriched bread flour was shown to reduce the prevalence of Wernicke-Korsakoff syndrome in Australia.[55] However, whether thiamine fortification in general or additional supplementation in alcoholic beverages could reduce Wernicke-Korsakoff syndrome has not been systematically studied.

Neuropsychological Testing and Rehabilitation

After the acute clinical symptoms stabilize and adequate thiamine supplementation is established, persistent cognitive symptoms will likely stabilize and plateau. Neuropsychological testing should be considered in patients with persistent cognitive symptoms to delineate the various cognitive domains that are impaired. Most commonly, declarative memory, immediate recall, attention and concentration, and executive function are impaired.[56] Procedural learning and memory rehabilitation can be employed to help the patient compensate for certain cognitive deficits to improve quality of life and overall functional improvement.[57]

 

Medication

Medication Summary

Wernicke-Korsakoff syndrome results from thiamine deficiency. The treatment is replacement of this essential vitamin. Previously, the usual dose was 100 mg/day via oral, intravenous, or intramuscular administration. However, the US and International standard of care appears to be shifting towards high-dose thiamine (500 mg tid) for a brief period (2-3 days), then reassessing the patient for improvement. In cases in which the patient is alert and is demonstrating improvement, parental (intravenous/intramuscular) thiamine should continue as long as the patient continues to improve, usually at 250 mg daily.

In patients who are comatose, intravenous thiamine should be continued, but no clear recommendations have been determined.

In patients whose responses plateau, which happens with most patients with Wernicke-Korsakoff syndrome, oral thiamine should be administered at 50-100 mg/day to prevent further neurodestruction if the patient continues to drink or will be vulnerable to thiamine deficiency for any other reason.

It is worth noting that the above recommendations are based on the British Royal College of Physicians guidelines, themselves based on case studies that reported patients who required high doses to demonstrate improvement. Since these recommendations were adopted in the United Kingdom, several other international reports have described patients who required high-dose parental thiamine before Wernicke Encephalopathy symptoms resolved. This regimen is also increasingly recommended by gastroenterologists in the United States and is being adopted by academic medical centers in the United States, Europe, Australia, and New Zealand. The use of this regimen in Wernicke-Korsakoff syndrome is purely an extrapolation of these recommendations and case reports.

European guidelines are similar but suggest a dose of 200 mg of preferably intravenous thiamine 3 times a day until symptoms resolve.

In a systematic review from the Cochrane Database, Day et al only found 2 randomized studies that were of sufficient quality.[27] There was a significant difference in favor of 200 mg/day, as compared with 5 mg/d, when the outcomes were measure after 2 days. The review concluded that evidence is insufficient to support specific treatment recommendations with regard to dose, frequency, and duration of treatment.[36] Nevertheless, the Royal College of Physicians recommends thiamine at 500 mg intravenously 3 times per day for 3 days, followed by 250 mg intravenously or intramuscularly for 5 days or until clinical improvement plateaus.[45] The European Federation of Neurological Societies recommends 200 mg intravenous 3 times daily until symptoms resolve.[58]

The following case reports highlight the current trend and variability on thiamine usage. In a patient with anorexia nervosa, 600 mg/day was given for 6 months; this did not result in any changes from baseline Mini-Mental Status Exam of 27/30.[8] In a patient with pyloric stenosis, high-dose thiamine treatment (900 mg intramuscular daily with 600 mg orally daily for 5 days, and 900 mg intramuscular daily for 7 more days) resulted in rapid neurological and radiographic improvements, although cognitive impairment was still severe.[59] In a separate case report on a diabetic patient with Wernicke encephalopathy and central pontine myelinosis (and normal serum thiamin levels), 1000 mg/day (of fursultiamine) led to attenuation of neurological deficits on day 7.[60]

For persistent cognitive impairment (eg, Korsakoff dementia), cognitive enhancers such as acetylcholinesterase inhibitors and memantine have demonstrated some benefit.[61, 62] However, the findings were negative in a small comparison study with rivastigmine.[63]

Nutrients

Class Summary

In treating Wernicke-Korsakoff syndrome, 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.

Thiamine

Thiamine is a water-soluble vitamin that combines with adenosine triphosphate (ATP) to form the coenzyme thiamine pyrophosphate, which is necessary for carbohydrate metabolism. The B vitamins are readily absorbed from the gastrointestinal tract (except in cases of malabsorption syndromes). Alcohol inhibits the absorption of thiamine, which occurs primarily in the duodenum.

Magnesium sulfate

Magnesium sulfate is a 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.

Potassium acid phosphate (K-Phos)

Potassium is 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 gastrointestinal loss, or because of low intake. Patients with chronic alcoholism and those 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.

 

Questions & Answers

Overview

What is Wernicke-Korsakoff Syndrome (WKS)?

What causes the symptom complex of Wernicke-Korsakoff Syndrome (WKS)?

What causes Wernicke-Korsakoff Syndrome (WKS)?

What role does thiamine have in the pathophysiology of Wernicke-Korsakoff Syndrome (WKS)?

What is the pathophysiology of Wernicke-Korsakoff syndrome (WKS)?

What is the role of norepinephrine (3-methoxy-4-hydroxyphenolglycol, or MHPG) in the pathophysiology of Wernicke-Korsakoff syndrome (WKS)?

What is the role of genetics in the pathophysiology of Wernicke-Korsakoff syndrome (WKS)?

What is the prevalence of Wernicke-Korsakoff syndrome (WKS) in the US?

What is the global prevalence of Wernicke-Korsakoff syndrome (WKS)?

Which patient groups are at highest risk for Wernicke-Korsakoff syndrome (WKS)?

What is the prognosis of Wernicke-Korsakoff syndrome (WKS)?

What are ocular complications of Wernicke-Korsakoff syndrome (WKS)?

What are ataxic complications of Wernicke-Korsakoff syndrome (WKS)?

What are psychiatric complications of Wernicke-Korsakoff syndrome (WKS)?

What is the mortality of Wernicke-Korsakoff syndrome (WKS)?

How should patients be educated about Wernicke-Korsakoff syndrome (WKS)?

Presentation

What are the signs and symptoms of Wernicke-Korsakoff syndrome (WKS)?

What history findings suggest Wernicke-Korsakoff syndrome?

Which ocular abnormalities are characteristic of Wernicke-Korsakoff syndrome (WKS) on physical exam?

How is ataxia characterized in Wernicke-Korsakoff syndrome (WKS)?

Which mental status changes are characteristic of Wernicke-Korsakoff syndrome (WKS)?

When are stupor or coma typically observed in patients with Wernicke-Korsakoff syndrome (WKS)?

What is the amnestic state of Wernicke-Korsakoff syndrome (WKS)?

How is the Korsakoff amnestic state characterized?

What are cardiovascular manifestations of Wernicke-Korsakoff syndrome (WKS)?

DDX

How is Wernicke-Korsakoff syndrome (WKS) diagnosed?

What is the sensitivity and specificity of the Caine diagnostic criteria for Wernicke-Korsakoff syndrome (WKS)?

What are the British Royal College of Physicians guidelines for Wernicke-Korsakoff syndrome (WKS)?

What are the differential diagnoses of Korsakoff psychosis?

What are the differential diagnoses for Wernicke-Korsakoff Syndrome?

Workup

What should be included in the evaluation of Wernicke-Korsakoff syndrome (WKS)?

What is the role of lab tests in the evaluation of Wernicke-Korsakoff syndrome (WKS)?

What is the role of serum thiamine measurement in the evaluation of Wernicke-Korsakoff syndrome (WKS)?

What is the role of lumbar puncture and CSF analysis in the evaluation of Wernicke-Korsakoff syndrome (WKS)?

What is the role of imaging studies in the evaluation of Wernicke-Korsakoff syndrome (WKS)?

Treatment

What is the initial approach to treatment for Wernicke-Korsakoff syndrome (WKS)?

Which medications are used in the treatment of Wernicke-Korsakoff syndrome (WKS)?

What is the role of parental thiamine in the treatment of Wernicke-Korsakoff syndrome (WKS)?

What are adverse reactions to thiamine for the treatment of Wernicke-Korsakoff syndrome (WKS)?

What is the role of IV glucose in the treatment of Wernicke-Korsakoff syndrome (WKS)?

When is inpatient treatment indicated in the treatment of Wernicke-Korsakoff syndrome (WKS)?

What is the role of nutritional supplementation in the treatment of Wernicke-Korsakoff syndrome (WKS)?

What is included in inpatient care for Wernicke-Korsakoff syndrome (WKS)?

What diet and activity modifications are needed during the treatment of Wernicke-Korsakoff syndrome (WKS)?

What is included in long-term monitoring of patients with Wernicke-Korsakoff syndrome (WKS)?

How is Wernicke-Korsakoff syndrome (WKS) prevented?

When is neuropsychological testing and rehabilitation indicated in the management of Wernicke-Korsakoff syndrome (WKS)?

Medications

What are the medication recommendations for the treatment of Wernicke-Korsakoff syndrome (WKS)?

Which medications in the drug class Nutrients are used in the treatment of Wernicke-Korsakoff Syndrome?