INTRODUCTION — Wernicke-Korsakoff syndrome is the best known neurologic complication of thiamine (vitamin B1) deficiency [1]. The term refers to two different syndromes, each representing a different stage of the disease. Wernicke encephalopathy (WE) is an acute syndrome requiring emergent treatment to prevent death and neurologic morbidity. Korsakoff syndrome (KS) refers to a chronic neurologic condition that usually occurs as a consequence of WE.
In 1881, Carl Wernicke described an acute encephalopathy characterized by mental confusion, ophthalmoplegia, and gait ataxia and associated it with autopsy findings of punctate hemorrhages around the third and fourth ventricles and the aqueduct. A few years later, Russian psychiatrist Sergei Korsakoff described a chronic amnestic syndrome in which memory was impaired far out of proportion to other cognitive domains. While both observations were described in the context of chronic alcoholism, neither Wernicke nor Korsakoff initially recognized the relationship between the disorders, which was not appreciated until later by other investigators.
This topic will review WE. KS and other chronic neurologic complications of alcohol abuse, including alcohol withdrawal, are discussed separately. (See "Overview of the chronic neurologic complications of alcohol" and "Management of moderate and severe alcohol withdrawal syndromes".)
EPIDEMIOLOGY
Prevalence — Typical brain lesions of WE are observed at autopsy in 0.4 to 2.8 percent of the general population in the Western world, and the majority of affected patients are alcoholic [2,3]. The prevalence of WE lesions seen on autopsy was 12.5 percent of alcohol abusers in one report [4]. Among those with alcohol-related deaths, it has been reported to be even higher, 29 to 59 percent [5,6]. Autopsy studies have consistently revealed a higher incidence of Wernicke lesions in the general population than is predicted by clinical studies, suggesting that it is under-recognized clinically [1,7].
While cases of WE in men outnumber those in women, women appear to be more susceptible to developing WE than men. In several series, the female-to-male ratio for WE was higher than the ratio for alcohol dependence [1,7].
Associated conditions — While most often associated with chronic alcoholism, WE occurs also in the setting of poor nutrition caused by malabsorption, poor dietary intake, increased metabolic requirement (eg, during systemic illnesses), or increased loss of the water-soluble vitamin thiamine (eg, in renal dialysis). In one autopsy series, non-alcohol abusers accounted for 12 of 52 cases (23 percent) of WE [8]. Conditions associated with WE include:
●Chronic alcoholism
●Anorexia nervosa or other psychiatric illness leading to poor intake [9,10]
●Hyperemesis of pregnancy [11,12]
●Prolonged intravenous (IV) feeding without proper supplementation [13,14]
●Prolonged fasting or starvation, or unbalanced nutrition, especially with refeeding [15]
●Gastrointestinal disease or surgery (especially bariatric surgery) [10,13,16-21]
●Systemic malignancy [22-24]
●Transplantation [25]
●Hemodialysis or peritoneal dialysis [26-28]
●Acquired immunodeficiency syndrome [29-31]
One report also describes WE in the setting of a genetic disorder of thiamine metabolism [32].
PATHOPHYSIOLOGY — Thiamine is a cofactor for several key enzymes important in energy metabolism, including transketolase, alpha-ketoglutarate dehydrogenase, and pyruvate dehydrogenase [1]. Thiamine requirements depend on metabolic rate, with the greatest need during periods of high metabolic demand and high glucose intake. This is manifest by the precipitation of WE in susceptible patients by administration of intravenous (IV) glucose before thiamine supplementation [33].
Evidence for the role of thiamine in WE is supported by observations that the thiamine antagonist pyrithiamine causes experimental thiamine deficiency in rats, resulting in a sequence of ataxia, loss of the righting reflex, and convulsions [34,35]. In some cases, low levels of magnesium, an essential cofactor of thiamine into its active diphosphate and triphosphate forms, have been implicated with thiamine deficiency in WE [36].
Because of the role of thiamine in cerebral energy utilization, it has been proposed that its deficiency initiates neuronal injury by inhibiting metabolism in brain regions with high metabolic requirements and high thiamine turnover. Events such as blood-brain barrier breakdown, N-methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity, and increased reactive oxygen species have been implicated in thiamine deficiency-induced neurotoxicity [37].
Thiamine deficiency in alcohol abusers results from a combination of inadequate dietary intake, reduced gastrointestinal absorption, decreased hepatic storage, and impaired utilization [38].
Not all thiamine-deficient alcohol abusers develop WE. Greater susceptibility among identical rather than fraternal twins suggests a genetic predisposition [37]. Investigators have found that in alcohol abusers with WE, the thiamine-dependent enzyme transketolase has an altered affinity for thiamine [39-47]. Variants in the high-affinity thiamine transporter gene have also been implicated [48,49].
PATHOLOGY — Acute WE lesions are characterized by vascular congestion, microglial proliferation, and petechial hemorrhages. In chronic cases, there is demyelination, gliosis, and loss of neuropil with relative preservation of neurons. Neuronal loss is most prominent in the relatively unmyelinated medial thalamus [1,50]. Atrophy of the mamillary bodies is a highly specific finding in chronic WE and Korsakoff syndrome (KS) and is present in up to 80 percent of cases [1,51].
The lesions of WE occur in a characteristic, symmetric distribution in structures surrounding the third ventricle, aqueduct, and fourth ventricle [1,51]. The mamillary bodies are involved in virtually all cases, and the dorsomedial thalamus, locus ceruleus, periaqueductal gray, ocular motor nuclei, vestibular nuclei, and cerebellum are commonly affected. Lesions occur less frequently in the colliculi, fornices, septal region, hippocampus, and cerebral cortex, which may show patchy, diffuse neuronal loss and astrocytic proliferation.
In approximately one-half of cases, sagittal sections through the cerebellum reveal selective loss of Purkinje cells at the tips of the folia of the anterior superior cerebellar vermis. These changes are identical to those found in alcoholic cerebellar degeneration, where they can occur in the absence of other Wernicke lesions. (See "Overview of the chronic neurologic complications of alcohol", section on 'Alcoholic cerebellar degeneration'.)
CLINICAL MANIFESTATIONS
Classic signs — The classic triad of WE includes:
●Encephalopathy
●Oculomotor dysfunction
●Gait ataxia
Clinical recognition of WE is straightforward when an alcoholic presents with this classic triad. However, this may be the exception rather than the rule. Large case series, some with neuropathological data, have found that all features of the classic triad are present in only approximately one-third of patients; in most, only one or two elements of the clinical triad were apparent [1,10].
Absence of one or more of the classic symptoms likely leads to under-diagnosis [4,52]. In one series, WE was diagnosed premortem in only 26 of 131 patients whose brains revealed chronic WE lesions. All signs of the classic triad were recorded in 17 percent; none were recorded in 19 percent [52]. Clinical records documented a high incidence of mental status abnormalities (82 percent), but much lower incidences of ataxia (23 percent), ocular motor abnormalities (29 percent), and polyneuropathy (11 percent).
The symptoms may present more or less simultaneously. Often, however, ataxia precedes other symptoms by a few days or weeks [1].
●Encephalopathy – The encephalopathy is characterized by profound disorientation, indifference, and inattentiveness [1]. If these are less severe and permit higher cognitive testing, impaired memory and learning are also evident. Some patients exhibit an agitated delirium related to concomitant ethanol withdrawal. An initial presentation with depressed level of consciousness is uncommon, although the course in untreated patients will progress through stupor and coma to death [1,53]. In one autopsy series, patients with unrecognized WE frequently had lethargy or coma.
●Oculomotor dysfunction – Nystagmus, lateral rectus palsy, and conjugate gaze palsies reflect lesions of the oculomotor, abducens, and vestibular nuclei. Ocular abnormalities usually occur in combination rather than alone.
Nystagmus is the most common finding and is typically evoked by horizontal gaze to both sides [1]. Vertical nystagmus can also occur, usually an upbeat nystagmus at initial presentation, though it may convert later to a downbeat nystagmus [54]. Rotatory and vertical nystagmus alone are uncommon. Lateral rectus palsy is virtually always bilateral. Vertical gaze palsies are less common than conjugate gaze palsies, and isolated vertical gaze palsy, internuclear ophthalmoplegia, and complete ophthalmoplegia are rare. Pupillary abnormalities, usually sluggish or unequal pupils, may be present. A light-near dissociation is sometimes seen. In advanced cases, there may be complete loss of eye movements with miotic, nonreactive pupils. Ptosis is uncommon.
●Gait ataxia – Ataxia primarily involves stance and gait and is likely due to a combination of polyneuropathy, cerebellar involvement, and vestibular dysfunction [1,55]. When severe, walking is impossible. Less affected patients walk with a wide-based gait and slow, short-spaced steps. Gait abnormalities are appreciated only on tandem gait in some patients.
Cerebellar pathology is generally restricted to the anterior and superior vermis; thus, ataxia of the legs or arms and dysarthria or scanning speech are uncommon [1]. Vestibular dysfunction may be the major cause of acute gait ataxia in WE, also explaining the dissociation between gait and limb abnormalities [1,55,56]. These findings contrast with those reported in patients with alcoholic cerebellar degeneration, in whom lower extremity ataxia is common [57]. (See "Overview of the chronic neurologic complications of alcohol", section on 'Alcoholic cerebellar degeneration'.)
Other signs — In addition to the classic triad, stupor or coma, hypotension, and hypothermia were prominent findings in unsuspected cases [52]. Patients with WE may also present with the following findings:
●Evidence of protein-calorie malnutrition is observed frequently in patients with WE [1]. However, not all patients are malnourished; in Australia, some beer drinkers with WE were reported to be overweight [58].
●Vestibular dysfunction without hearing loss is a common finding [1,55,56,59]. In one study of 17 patients with acute WE, cold caloric responses were absent on at least one side in all, and abnormalities were bilateral in 11 [55]. The presence of spontaneous nystagmus with absent caloric responses appears to be a relatively specific finding in WE [56]. Vertigo is unusual. Some vestibular dysfunction is permanent after WE.
●Peripheral neuropathy is common and typically involves just the lower extremities [1]. Patients complain of the gradual onset of weakness, paresthesias, and pain affecting the distal lower extremities. In many patients there are no symptoms of neuropathy, but examination reveals diminished or absent ankle jerks and distal sensory loss.
●Hypothermia has been described in 1 to 4 percent of patients with WE who went to autopsy, and it has been noted in numerous case reports [1,52,60]. Hypothermia may cause unreactive pupils [61], a finding rarely encountered in normothermic patients with WE [1]. Lesions in the posterior and posterolateral hypothalamus were noted in two patients with WE and hypothermia in one report [62]. This location is consistent with the known thermoregulatory functions of the hypothalamus. Other signs of autonomic involvement may include hypotension and syncope. In one autopsy series, hypotension and hypothermia were prevalent in unsuspected cases of WE [52].
●While overt beriberi heart disease is rare in WE, other cardiovascular signs and symptoms are common and include tachycardia, exertional dyspnea, elevated cardiac output, and electrocardiogram (EKG) abnormalities [1]. These reverse with thiamine administration.
DIAGNOSIS — Although laboratory studies and neuroimaging studies can be helpful, WE is primarily a clinical diagnosis. The main barrier to diagnosis is a low index of suspicion in the nonalcoholic patient, especially when the classic triad of clinical symptoms is not present and the patient is not a known alcoholic. Institution of early thiamine replacement takes priority, and response to treatment may be diagnostic. (See 'Treatment' below.)
Differential diagnosis — WE should be considered in the differential diagnosis of all patients presenting with acute delirium or acute ataxia. It follows that other causes of delirium are considered in the diagnosis of a patient presenting with WE (table 1). In one case series of 36 hospitalized geriatric patients, thiamine deficiency was common and associated with delirium [63]. In another small series, thiamine deficiency appeared to contribute to postoperative confusion in older patients after hip surgery [64]. These results appear to be contradicted by a larger series of 118 older inpatients in which there was no association between thiamine deficiency and delirium; however, the inclusion of patients with dementia and a broader definition of delirium in this study may have influenced these results [65]. The evaluation of patients with delirium is discussed separately. (See "Diagnosis of delirium and confusional states".)
Also, structural diseases in the medial thalami, hippocampi, or inferior medial temporal lobes should be considered because of the neuroanatomic overlap with WE. These include top-of-the-basilar stroke, hypoxic-ischemic encephalopathy after cardiac arrest, herpes simplex encephalitis, and third ventricular tumors [66,67].
Clinical criteria — While autopsy studies likely underestimate the presence of classic signs that were not properly elicited, recognized, or recorded, it is clear that the diagnosis of WE can be missed when reliance is placed on the presence of all three of the typical symptoms [10]. Autopsy-based series suggest that many patients lack one or more elements of this triad, and in some, lethargy or coma is the only clinical feature [1,4,52].
Suggested criteria for the diagnosis of WE and Korsakoff syndrome (KS) in chronic alcohol abusers are based upon clinical-neuropathological correlation [3,68]. WE is diagnosed in patients with two of the following four Caine criteria:
●Dietary deficiency
●Oculomotor abnormalities
●Cerebellar dysfunction
●Either altered mental status or mild memory impairment
In one study of 106 autopsied alcohol abusers, the Caine criteria increased the diagnostic sensitivity for WE from 22 percent, using the classic triad, to 85 percent [68]. The Caine criteria are clearly more sensitive than the classic triad, but given the high morbidity and mortality associated with the disorder, they are not sensitive enough. Specificity is low, and these criteria were not intended to apply to nonalcoholics in whom the diagnosis is further impeded by a lower index of suspicion.
Laboratory testing — There are no laboratory studies that are diagnostic of WE. Thiamine deficiency can be most reliably detected by measurement of erythrocyte thiamine transketolase activity (ETKA) before and after the addition of thiamine pyrophosphate (TPP). A low ETKA, along with a more than 25 percent stimulation, establishes the diagnosis of thiamine deficiency [69]. This test is often not readily available, especially in the emergency setting. A serum thiamine or TPP level in serum or whole blood can also be measured by high-performance liquid chromatography [70,71]. (See "Overview of water-soluble vitamins", section on 'Vitamin B1 (thiamine)'.)
The sensitivity and specificity of these blood tests in symptomatic patients are unclear, as blood level may not accurately reflect brain thiamine level. A normal blood level does not exclude the possibility of WE [72].
Results from these measurements are not necessary for patient management. When the diagnosis of WE is entertained, immediate thiamine replacement takes precedence over laboratory diagnosis. (See 'Treatment' below.)
Patients with WE will likely also be tested for other toxic and metabolic conditions that can lead to delirium (see "Diagnosis of delirium and confusional states"). In the setting of fever or other suspicion for central nervous system infection, a lumbar puncture is required. In WE, the cerebrospinal fluid may be normal or may show a mild protein elevation [1]. Pleocytosis or protein >100 mg/dL suggest alternative diagnoses. An electroencephalogram (EEG) may be ordered if nonconvulsive seizures are suspected. In WE, only approximately half of patients will demonstrate EEG abnormalities, usually diffuse mild to moderate slow wave activity [1].
Imaging studies — Imaging studies are not necessary in all patients with suspected WE and should not delay treatment (see 'Treatment' below). However, diagnostic imaging can be helpful by providing evidence of WE in many patients and may rule out alternative diagnoses.
Abnormalities on computed tomography (CT) scans or magnetic resonance imaging (MRI) have been reported in patients with acute WE [73]. CT may show symmetric, low-density abnormalities in the diencephalon, midbrain, and periventricular regions that enhance after the injection of contrast [74-77]. Gross hemorrhages are uncommon in acute WE, but they have also been detected by CT [78]. These findings are uncommon in other disorders and, when present, should strongly suggest the diagnosis. However, CT is an insensitive test for WE.
MRI is more sensitive than CT in detecting acute diencephalic and periventricular lesions [79-81]. Typical findings include areas of increased T2 and fluid-attenuated inversion recovery (FLAIR) signals, decreased T1 signal, and diffusion abnormality surrounding the aqueduct and third ventricle and within the medial thalamus, dorsal medulla, tectal plate, and mamillary bodies (image 1 and image 2) [81-88]. Lesions may also be seen in areas such as the cerebellum, cranial nerve nuclei, dentate nuclei, caudate, red nuclei, splenium, and cerebral cortex [10,89]. Findings such as nonspecific cortical atrophy are also common, but are likely not directly related to WE [10].
In one report comparing 15 patients with acute WE with 15 asymptomatic alcohol abusers and 15 controls, the sensitivity and specificity of MRI were 53 and 93 percent, respectively [79]. Other series have reported a higher prevalence of MRI abnormalities in patients with acute WE [81,90]. Abnormal T2 signal disappears within as little as 48 hours after treatment with thiamine [90], and isolated mamillary body abnormality may rarely be the only finding on MRI [91].
Mamillary body atrophy is a relatively specific abnormality in patients with chronic lesions of WE [92]. A large decrease in the volume of the mamillary bodies can be identified by MRI in approximately 80 percent of alcohol abusers with a history of classic WE, and it is not found in controls, patients with Alzheimer disease (AD), or alcohol abusers without a history of WE [92-94]. Mamillary body atrophy can be detected within one week of the onset of WE [90]. Susceptibility-weighted imaging (SWI) may show petechial hemorrhages not seen on standard T2-weighted images [95].
TREATMENT — The diagnosis of WE is difficult to confirm and, untreated, most patients progress to coma and death. Therefore, diagnostic testing should not delay treatment, which should immediately follow consideration of the diagnosis. Fortunately, intravenous (IV) administration of thiamine is safe, simple, inexpensive, and effective [3,96]. Adverse reactions, including anaphylaxis and bronchospasm, are reported but are extremely rare; in the United Kingdom, there were four reported cases for every five million intramuscular (IM) doses used and one report for every one million IV doses used [97-100].
Patients with suspected WE require immediate parenteral administration of thiamine. A recommended regimen is 500 mg of thiamine IV infused over 30 minutes three times daily for two consecutive days and 250 mg IV or IM once daily for an additional five days, in combination with other B vitamins [98]. Administration of glucose without thiamine can precipitate or worsen WE; thus, thiamine should be administered before glucose. Because gastrointestinal absorption of thiamine is erratic in alcoholic and malnourished patients, oral administration of thiamine is an unreliable initial treatment for WE [38]. High-dose parenteral thiamine therapy is justified based on the failure of lower doses to produce clinical improvement in some patients with WE; however, there are no randomized studies to support a particular dosing regimen [97,98,100-102].
Although dietary requirements for thiamine are only 1 to 2 mg daily, absorption and utilization of thiamine are incomplete, and some patients have genetically determined requirements for much larger doses [40,103]. Daily oral administration of 100 mg of thiamine should be continued after the completion of parenteral treatment and after discharge from the hospital until patients are no longer considered at risk. Magnesium and other vitamins are replaced as well, along with other nutritional deficits if present.
By establishing a sufficiently low threshold for treatment, all patients with WE will receive thiamine, including those whose diagnosis is unsuspected. For practical purposes, all at-risk patients with undiagnosed altered mental status, oculomotor disorders, or ataxia should receive parenteral thiamine.
CLINICAL COURSE AND PROGNOSIS — Prompt administration of thiamine leads to improvement in ocular signs within hours to days [1]. If ocular palsies fail to respond, other diagnoses should be considered. In one report, recovery of vestibular function began during the second week after thiamine treatment; improvement in gait ataxia coincided with recovery of vestibular function [55]. Confusion subsides over days and weeks. Signal abnormality on magnetic resonance imaging (MRI) resolves with clinical improvement [90,104]. This early therapeutic response likely represents the recovery from a biochemical rather than a structural lesion.
In the largest cohort of patients reported on, residual deficits were the rule [1]. While gaze palsies recovered completely in most cases, 60 percent had permanent horizontal nystagmus. Only approximately 40 percent recovered from ataxia; remaining deficits ranged from inability to walk at all to a wide-based, slow, shuffling gait. As the acute encephalopathy and confusion receded, deficits in learning and memory became more obvious; the latter recovered completely or substantively in only approximately 20 percent; the remainder had a permanent amnestic syndrome. (See "Overview of the chronic neurologic complications of alcohol", section on 'Korsakoff syndrome'.)
Case reports and small case series suggest that prognosis may be less dismal [58,88,105]. One exceptional case reports near complete recovery in a severely affected patient whose treatment was delayed for four months [106].
PREVENTION — WE may be iatrogenically precipitated by glucose loading in patients with unsuspected thiamine deficiency [33]. To avoid this complication, it has become standard practice in emergency departments to administer thiamine prior to or along with glucose infusion, particularly in those who are at risk for thiamine deficiency [107]. (See 'Associated conditions' above.)
Patients at risk for WE should also receive thiamine supplementation in the absence of glucose loading (see 'Associated conditions' above). The dose, frequency, and route of administration are based on standard clinical practice, as there is little controlled evidence on which to base recommendations [101]. As an example, patients admitted for alcohol withdrawal should receive thiamine 100 to 250 mg daily, depending on their nutritional status and perceived risk of WE. (See "Management of moderate and severe alcohol withdrawal syndromes".)
The prevention of WE and Korsakoff amnestic syndrome (KS) might be possible through the widespread oral administration of thiamine to outpatients at risk. Enrichment of flour with thiamine decreased the autopsy prevalence of WE in Australia [108]. There is also interest in whether preventing thiamine deficiency would also reduce the high prevalence of cognitive deficits in alcohol abusers without known episodes of WE [109]. The low cost and safety of oral thiamine argue for widespread supplementation in alcohol abusers and others at risk for developing thiamine deficiency. Fortification of alcoholic beverages has also been proposed.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adult with altered mental status in the emergency department".)
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●Beyond the Basics topic (see "Patient education: Delirium (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS — Wernicke encephalopathy (WE) and Korsakoff amnestic syndrome (KS) are, respectively, acute and chronic brain disorders that result from thiamine deficiency.
●WE is often associated with alcoholism but can also occur in other situations including malabsorption, poor dietary intake, increased metabolic requirement, and in dialysis patients. (See 'Associated conditions' above.)
●WE produces petechial hemorrhagic necrosis in midline brain structures and corresponding deficits in mentation, oculomotor function, and gait ataxia. All three of these classic symptoms are present in only approximately one-third of patients. Any one of these, most often encephalopathy, may be seen in isolation. WE should be considered when one or more occur in at-risk patients. (See 'Clinical manifestations' above.)
●While laboratory measurements and neuroimaging are often abnormal in WE, there is no single test with sufficiently high diagnostic accuracy. The first imperative is to administer thiamine rather than confirm the diagnosis, whenever WE is considered. (See 'Diagnosis' above.)
●Untreated, WE leads to coma and death. Prognosis is improved by prompt administration of thiamine. Immediate parenteral administration of thiamine is required whenever the diagnosis of WE is entertained. A suggested treatment regimen is 500 mg intravenous (IV) infused over 30 minutes, repeated three times daily for two consecutive days, and 250 mg IV or intramuscular (IM) once daily for an additional five days. Oral thiamine and multivitamin supplementation are recommended thereafter as long as the patient remains at risk. (See 'Clinical course and prognosis' above.)
●WE may be precipitated by administration of IV glucose solutions to individuals with thiamine deficiency. In susceptible individuals, glucose administration should be preceded or accompanied by thiamine 100 mg IV (Grade 1A). (See 'Prevention' above.)
●Thiamine supplementation, along with other multivitamin supplementation, is recommended for patients at risk for thiamine deficiency. (See 'Prevention' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Michael E Charness, MD, who contributed to an earlier version of this topic review.
