Continuing Education Activity

Wernicke encephalopathy is an acute neurological condition characterized by a clinical triad of ophthalmoplegia, ataxia, and confusion. This disease is caused by thiamine deficiency, which primarily affects the peripheral and central nervous systems. This should be differentiated from Korsakoff syndrome, a neuropsychiatric disorder associated with confabulation and significant deficits in anterograde and retrograde memory. This activity reviews the pathophysiology and evaluation of Wernicke encephalopathy and highlights the role of the interprofessional team in the management of patients with this illness.

Objectives:

• Describe the pathophysiology of Wernicke encephalopathy.
• Identify the causes of Wernicke encephalopathy.
• Explain the treatment for Wernicke encephalopathy.
• Explain the importance of improving care coordination among interprofessional team members to enhance outcomes for patients affected by Wernicke encephalopathy.

Introduction

Wernicke encephalopathy (WE) is an acute neurological condition characterized by a clinical triad of ophthalmoparesis with nystagmus, ataxia, and confusion. This is a life-threatening illness caused by thiamine deficiency, which primarily affects the peripheral and central nervous systems. This disorder should be differentiated from Korsakoff syndrome which is preventable and is usually suspected as a consequence of at least one episode of Wernicke’s encephalopathy. Korsakoff syndrome is a neuropsychiatric disorder associated with memory disturbances in which there are significant deficits in anterograde and retrograde memory. Immediate memory is maintained, but short-term memory is diminished with intact sensorium. The disorder is associated with patients fabricating stories in the setting of clear consciousness. Confabulations can be spontaneous or provoked with provoked confabulation commonly seen in chronic Korsakoff syndrome and spontaneous confabulation usually noted in the acute Wernicke state.[1][2]

Etiology

Thiamine deficiency is characteristically associated with severe alcohol use disorder. Although Wernicke encephalopathy mostly affects people who have a thiamine deficiency due to chronic alcoholism, various other causes include severe malnutrition, hyperemesis gravidarum, prolonged parenteral nutrition, malignancies, immunodeficiency syndromes, liver disease, hyperthyroidism, and severe anorexia nervosa. Chronic alcohol consumption may cause thiamine deficiency due to impaired absorption of thiamine from the intestine, a possible genetic predisposition, inadequate diet, reduced storage of thiamine in the liver, and other nutritional deficiencies.[3][2][4]

A common inciting event that precipitates WE is an acute infection. Other triggers include prolonged carbohydrate or glucose loading in the presence of thiamine deficiency. In general, patients who receive glucose should also be administered thiamine at the same time.

Epidemiology

Prevalence data on Wernicke encephalopathy comes mainly from autopsy studies with rates ranging between 1% and 3%. Several studies indicate that prevalence rates via analysis of clinical records are lower in comparison to necropsy studies as the diagnosis is easily overlooked or missed. The incidence of Wernicke encephalopathy is believed to be higher in developing countries due to vitamin deficiencies and malnutrition. The female to male ratio for Wernicke encephalopathy is 1:1.7, and there are no studies that show a particular race predisposed to Wernicke encephalopathy.[5]

Pathophysiology

Thiamine, one of the first B vitamins to be discovered also known as Vitamin B1, is a coenzyme that is essential for intricate organic pathways and plays a central role in cerebral metabolism. This vitamin acts as a cofactor for several enzymes in the Krebs cycle and the pentose phosphate pathway, including alpha-keto-glutamic acid oxidation and pyruvate decarboxylation. Thiamine-dependent enzymes function as a connection between glycolytic and citric acid cycles. Therefore, deficiency of thiamine will lead to decreased levels of alpha-keto-glutarate, acetate, citrate, acetylcholine and accumulation of lactate and pyruvate. This deficiency can cause metabolic imbalances leading to neurologic complications including neuronal cell death. Neuronal death in the mammillary bodies and thalamus were implicated in multiple cases of Wernicke encephalopathy studied. Studies involving computed tomography (CT) and magnetic resonance imaging (MRI) of patients with Wernicke encephalopathy revealed lesions in the thalamus with dilated ventricles and volume loss in the mammillary bodies. The lesions are usually symmetrical in the midbrain, hypothalamus, and cerebellum.[6][7]

History and Physical

Wernicke encephalopathy should be suspected in any patient with chronic alcohol abuse or any form of malnutrition and any of the following: acute altered mental status, ophthalmoplegia, ataxic gait, delirium, and hypotension. The classic triad of Wernicke encephalopathy is altered mental status, ataxic gait, and ophthalmoplegia. The diagnosis is made based on clinical presentation, and a definitive diagnosis is complicated as the clinical triad may not be present in up to 90% of patients. 

The hallmark sign of Wernicke encephalopathy is ocular abnormalities especially nystagmus. Other oculomotor symptoms include cranial nerve involvement of oculomotor, abducens, and vestibular nuclei causing conjugate gaze palsies. Pupillary sluggishness, ptosis, and anisocoria are also common.

Gait ataxia is also a significant finding in Wernicke encephalopathy where patients will present with a broad-based gait. Also, gait can worsen, and in many cases, patients are unable to walk. Physical examination may include a complete neurological exam with cerebellar testing. Disorientation and altered sensorium characterize encephalopathy. Some patient can present with hyperactive delirium secondary to possible alcohol withdrawal symptoms alongside Wernicke encephalopathy. Less than 5% of patients with Wernicke encephalopathy can present with the severely depressed level of consciousness that will eventually lead to coma and death. Some other warning signs could include hyperthermia and hypotension. The patient could also present with peripheral neuropathy and commonly includes the lower extremity, and an examination would reveal distal sensory loss.

WE should be a consideration in a patient with long term malnutrition and episodes of confusion and altered mental status. Over the past few decades, bariatric surgery has been associated with WE and malnutrition; the key reason is that after surgery, there is limited intake of food and the stores of thiamine are rapidly depleted.

Evaluation

Evaluation should include a thorough patient history with a focused physical exam and laboratory workup with appropriate imaging. There are no specific laboratory tests for diagnosing Wernicke encephalopathy as it is a clinical diagnosis with the above mentioned classic signs and symptoms.

The clinical diagnosis of WE is present if the patient has two of the following features:

• Eye signs
• Dietary deficiency of thiamine
• Altered mental status
• Cerebellar dysfunction

However, a complete blood count and the comprehensive metabolic panel can be completed to exclude other causes of central nervous system abnormalities. Moreover, normal brain imaging cannot rule out Wernicke encephalopathy and therefore not very beneficial either. Caine et al. criteria were established in 1997 which is now 85% sensitive if patients have two or more of the classic features that include: ataxia, confusion, and ophthalmoplegia. Also, looking for risk factors helps in evaluating the patient as Wernicke encephalopathy was classically thought of as a disease exclusively due to alcoholism. However, in recent years Wernicke encephalopathy is also seen in patients that are chronically malnourished, post-bariatric surgery, hyperemesis gravidarum, liver disease, hyperthyroidism, and severe anorexia nervosa.[1][8][9]

MRI may reveal hyperintense signaling in the periventricular thalamus, mammillary bodies and the periaqueductal gray matter.

Erythrocyte transketolase levels can detect thiamine deficiency. Levels of lactate and pyruvate are often measured since thiamine is a cofactor for pyruvate dehydrogenase enzyme.

Treatment / Management

The aim of treatment is prompt and quick correction of the thiamine deficiency in the brain. Wernicke encephalopathy is a medical emergency and considered a reversible condition, therefore, requiring immediate emergent attention although the onset of the disease may be acute or chronic. Parenteral administration of thiamine is most effective and provides for rapid administration, however, in some cases, there are persistent neurological deficits, and the acute condition can progress to chronic Korsakoff syndrome. The preferred dose of thiamine treatment for Wernicke encephalopathy may be as high as 500 mg given one to three times daily parenterally. All malnourished patient may need higher doses of thiamine. Oral dosing is not reliable and not recommended.

There is some evidence that thiamine treatment can improve the confusional state, quick resolution of ataxia, ophthalmoplegia, and nystagmus. Thiamine is generally administered before or together with glucose solutions because the glucose oxidation can decrease thiamine levels thereby exacerbating the neurological symptoms of Wernicke encephalopathy. Patients with magnesium deficiency should also be treated as this can result in reduced recovery from Wernicke encephalopathy especially in patients with alcoholism.[10][11][12]

Most patients need to be admitted to ensure that they receive IV thiamine and magnesium.

Differential Diagnosis

Differential diagnoses include:

• Hepatic encephalopathy
• Stroke
• Alcohol withdrawal syndrome
• Delirium tremens
• Chronic hypoxia
• Normal pressure hydrocephalus 

Staging

Current Guidelines on Managing WE

1. Clinical diagnosis of WE should be considered in alcoholics if the individual has a dietary deficiency, cerebellar dysfunction, eye signs, and altered mental status
2. Total thiamine levels in the blood should be measured before treatment
3. MRI can be used to support the clinical diagnosis of WE
4. Thiamine should be given IV
5. After bariatric surgery, follow thiamine levels and supplement with thiamine for at least 6 months

Prognosis

WE is a serious life-threatening disorder with enormous disability. While thiamine can induce partial improvement, the neuropsychological deficits persist in many cases. The confusional state usually improves when IV thiamine is administered by the learning and memory deficits only improve partially. A small number of patients fail to have any improvement and may develop Korsakoff psychosis, which often requires institutionalization. Very few individuals recover at this point.

Complications

• Neurological injury
• Ataxia
• Korsakoff syndrome
• Ophthalmoplegia
• Heart failure
• Lactic acidosis

Consultations

• Internist
• Endocrinologist
• Psychiatrist
• Neurologist
• Intensivist

Enhancing Healthcare Team Outcomes

The management of WE is complex and usually requires a team approach. Because the disorder can present with various manifestations, the patient is best managed by a neurologist and an intensivist. Other specialists may be required according to organ involvement. The role of the nurse, dietitian, social worker, and pharmacist cannot be overemphasized. These patients are sick, frail and malnourished. A dietary consult should be done to assess the calorie needs and determine how to provide the food as well as thiamine. Since many WE patients are managed as outpatients, the pharmacist should encourage abstinence from alcohol. Since the cornerstone of therapy is thiamine, the importance of compliance is vital. At the same time, the electrolyte deficiencies should be corrected. Finally, the family should be educated about the prognosis of these individuals and make preparations for long-term care, in case the patient develops korsakoff syndrome. Close communication between members of the team is vital to ensure that the patient is receiving the current standard of care treatment. The ultimate goal is to improve the quality of life and lessen the burden on the family.[13][14] (Level V)

Outcomes

WE is a serious medical disorder which carries enormous morbidity and mortality. Even when the condition is managed with thiamine, the global confusion usually improves rapidly, but the ataxia and ophthalmoplegia may persist for some time. Patients who minimal or neurological signs have the best outcomes with thiamine supplement. However, survivors of WE may develop korsakoff psychosis and require long-term institutionalization. Of these, less than 10% will recover to be discharged from long-term care. A significant number of patients will have long-term neurological deficits like ataxia, nystagmus and korsakoff syndrome, which seriously diminishes the quality of life. Unfortunately, there are no long-term follow-up studies and anecdotal reports indicate that many of these patients do die prematurely. [15][16][17](Level V)