Wernicke Encephalopathy Workup

Patients with WE present with altered mental status and other neurologic abnormalities. Obtaining a detailed patient history, performing a detailed physical examination with a focus on the neurological exam, laboratory workup, and radiographic evaluation are essential to exclude other causes of central nervous system (CNS) dysfunction.

The clinical diagnosis of WE in alcoholics requires two of the following four signs: (i) dietary deficiencies (ii) eye signs, (iii) cerebellar dysfunction, and (iv) either an altered mental state or mild memory impairment. Sensitivity of the classic triad was 23%, but rose to 85% if the patients had at least two of the four following features: dietary deficiencies, eye signs, cerebellar signs, and either mild memory impairment or an altered mental state. ^[1]

No specific laboratory test is available for diagnosing WE. WE is a clinical diagnosis, and normal electrolyte levels may give only false reassurance and delay therapy. This is particularly the case when malnutrition is likely to be present. The motto should be "If in doubt, treat," as administration of thiamine does not pose potential harm.

Moreover, neither a normal computed tomography (CT) scan nor a normal magnetic resonance imaging (MRI) scan of the brain rule out the presence of acute WE or chronic WKS. ^[13]

Although WE remains a clinical diagnosis with no characteristic abnormalities in diagnostic studies, the use of laboratory and radiographic tests remains important to exclude alternate or coexisting medical conditions. The patient’s history and initial evaluation guide the selection of these tests.

Biomarkers, including an assay for thiamine, are not typically available for timely diagnostic purposes. In addition, no study has clearly described the sensitivity, specificity, and accuracy of thiamine levels in relation to active disease. ^[15] However, the thiamine levels can help the clinician assuming care of the patient in ambiguous cases, and obtaining a thiamine level can be considered for diagnostic dilemmas. ^[5]

Complete discrimination of WE patients and controls has been reported for thiamine monophosphate, a dephosphorylation product of the coenzyme thiamine pyrophosphate. However, evidence is sparse, and thiamine assays have limited availability and usually do not allow for an immediate diagnosis. ^[7]

Alterations in serum electrolyte levels, such as hypernatremia or hypercalcemia, can cause encephalopathy and must be excluded.

One case series suggested that patients with WE may exhibit a distinctive acid-base pattern consisting of a primary metabolic acidosis in conjunction with a primary respiratory alkalosis. The primary metabolic acidosis is secondary to thiamine's role in aerobic metabolism and the Krebs cycle; without thiamine, aerobic metabolism cannot progress and metabolic products, including lactate and pyruvate, are produced, which result in an anion gap acidosis (see the Anion Gap calculator). The role of thiamine in causing a primary respiratory alkalosis is unclear. ^[15]

CT scanning

A head CT scan is an essential initial test for emergency diagnosis of focal neurologic disease, such as intracerebral hemorrhage. In patients who are comatose, CT scan can detect not only intracranial lesions but also fractures of the skull and minute amounts of blood. However, with a reported 13% sensitivity for WE, CT of the head does not appear to be useful in screening for WE. ^[13]

MRI

Thiamine is a cofactor of several enzymes involved in glucose metabolism and cerebral energy utilization, and its depletion results in the neuronal damage as seen on MRI, including T2 and fluid-attenuated inversion recovery hyper-intense signaling in the mammillary bodies, periventricular thalamus, and periaqueductal gray matter, as well as diffusion-weighted imaging to differentiate vasogenic from cytotoxic edema. ^[2]

The sensitivity and specificity of MRI has been reported at 53% and 93% with a positive predictive value of 89%; in other words, MRI is better at confirming the diagnosis of WE than ruling it out. ^[1]  MRI offers a technique to make a definitive diagnosis antemortem, but the sensitivity is poor, and obtaining an MRI for this indication is typically impractical and unnecessary in the emergency department (ED). ^[5]

Although the clinical evidence for the utility of MRI is based on a study in which the sample size was small, the reported sensitivity of MRI was 53% and the reported specificity was 93%, for acute and chronic WKS. Because of the low sensitivity of MRI for WE, particularly an acute presentation, and because many patients with WE may not exhibit diagnostic features on MRI, normal MRI results does not preclude the diagnosis of acute illness. ^[13]

The appearance of acute WE on MRI demonstrates abnormal hyper-density of the mammillary bodies and periaqueductal gray matter with associated abnormal enhancement on T1-weighted images. ^[16] In chronic WE and WKS, radiographic imaging, especially MRI, may be normal or may show mamillary body, cerebellar, and cerebral shrinkage, as well as symmetrical, low-density abnormalities in periventricular areas, the diencephalon, and the midbrain. ^[13] Such symmetrical lesions are uncommon in other cerebral encephalopathic disorders and are suggestive of WKS. ^[13]

Morphometric studies of MRI imaging confirm that patients with WKS show excessive mammillary body and cerebellar shrinkage, indicating that these are highly specific MRI findings for this kind of encephalopathy. ^[13]

The image below shows brain morphologic studies as demonstrated on MRI. A 60-year-old man presented with bilateral gaze-evoked nystagmus, severe ataxia, and memory impairment. Brain fluid-attenuated inversion recovery (FLAIR)–weighted MRI shows concurrent cytotoxic and vasogenic edema patterns. This case demonstrates cytotoxic and vasogenic edema that may occur at the same time in WE. These findings may result from different vulnerability of brain regions to thiamine deprivation and the corresponding time delay between the development of lesions. ^[17]

This MRI shows typical high signal intensities (SIs) in the medial thalamus (A), periaqueductal gray (B), mamillary bodies (C), cerebellar vermis (B, C, D), and paravermian superior cerebellum (D). All the lesions represent high SIs on the DWI (E–H). The ADC images of the cerebellar vermis (K, L) and paravermian superior cerebellum (L) show low SIs (arrowheads), whereas other described areas (I, J) show iso-SIs (arrows). Image courtesy of Neurology. Apr 8 2008;70(15):e48.

Tests to perform include the following:

• Complete blood count (CBC) - Rules out severe anemias and leukemias as causes of altered mental status.

• Serum glucose levels - To exclude hypoglycemia and hyperglycemia as causes of encephalopathy.

• Liver function tests and ammonia levels- To exclude hepatic and some medicinal causes of encephalopathy.

• Basic metabolic profile (BMP)- To exclude hyponatremia and uremia as causes of encephalopathy.

• Pulse oximetry and/or arterial blood gas (ABG) measurement - Exclude hypoxia and hypercarbia as causes of encephalopathy.

• Toxic drug screening - Excludes some causes of drug-induced altered mental status.

• Consider lumbar puncture (LP) - Consider LP to exclude CNS infections, such as meningitis and encephalitis, if indicated.

Erythrocyte transketolase levels

Erythrocyte transketolase levels reliably detect thiamine deficiency but are not necessary for the diagnosis of WE. In the erythrocyte transketolase activity assay, the extent of thiamine deficiency is expressed in percentage stimulation compared with baseline levels (the thiamine pyrophosphate effect). Normal values range from 0-15%; a value of 15-25% indicates thiamine deficiency, and a value of greater than 25% indicates severe deficiency. ^[3]  The erythrocyte transketolase activity assay including thiamine pyrophosphate effect has been replaced by direct measurement of thiamine and its phosphate esters in human blood by high-performance liquid chromatography. ^[1]  

Blood pyruvate and lactate measurements

Blood pyruvate and lactate measurements, although not specific for thiamine deficiency illnesses, are sensitive and helpful, as thiamine is a cofactor of the pyruvate dehydrogenase enzyme, an important enzyme in aerobic metabolism (i.e. the Kreb cycle). ^[3]

High-Performance Liquid Chromatography for Thiamine Detection

This thiamine assay is now commercially available in many countries. Adult normal range (60–220 nM) and the lowest detectable level (3–35 nM) are given. The sample (2 ml EDTA blood) should be taken before administration of thiamine and should be protected from light. ^[1] This assay has largely supplanted the erythrocyte transketolase assay.

Electroencephalogram

Consider an electroencephalogram (EEG) if nonconvulsive status epilepticus is suspected as a potential cause of coma and altered mental status.