Wernicke’s Encephalopathy: An Underrecognized Risk of Using Semaglutide Medications

Wernicke’s encephalopathy (WE) is an acute neuropsychiatric condition caused by thiamine (vitamin B1) deficiency. WE is a clinical diagnosis characterized by a classical clinical triad of confusion, eye signs, and gait ataxia. (Only 16 percent of patients present with the entire triad.)

Pathophysiology

Thiamine is an essential vitamin with low body stores and a short half-life that can, therefore, be depleted in just a few weeks. Because thiamine serves several critical physiologic functions in the human body—including cell growth, myelin sheath maintenance, and energy production via the Krebs cycle—deficiency affects all organ systems, in particular the central nervous system.

If not corrected, thiamine deficiency rapidly progresses to WE, which can be fatal if untreated, or it can progress to Wernicke-Korsakoff syndrome (WKS), which is irreversible. Patients with WKS have permanent neurological and psychiatric impairments to the point that they may need assistance with activities of daily living or even full-time care. Patients with WKS have deficits in short-term memory and executive functions that can cause them to confabulate (that is, to fill in the blanks by fabricating memories). They typically also continue to have WE symptoms such as weakness, paresthesias, and balance issues, and they may need to use ambulatory assistive devices, such as walkers or wheelchairs.

Epidemiology

Since 1940, wheat flour has been fortified with thiamine in the United States. Breakfast cereals and infant formulas are also fortified. Foods rich in thiamine include seafood, pork, legumes, nuts, whole grains, seeds, and some vegetables. If it were not for fortified foods, however, thiamine deficiency would be rampant in the U.S. Forty-one percent of National Health and Nutrition Examination Survey (NHANES) respondents between 2009 and 2012 got less than 1.0 mg of thiamine from food daily. The recommended daily allowance is 1.1 mg/day for women, 1.2 mg/day for men, and 1.4 mg/day for pregnant or nursing women.

Alcohol use disorder and bariatric surgery are the most common groups at high risk of WE, but other patients with reduced nutritional intake or persistent vomiting are also at risk, such as those with hyperemesis gravidarum, sepsis, and more recently, patients taking appetite-suppressing medications, such as semaglutide (e.g., Ozempic or Wegovy).

WE was historically reported to occur in 0.4–2.8 people per 100,000 population, but recent autopsy studies have shown that the postmortem prevalence of WKS is as high as 1–2 percent of the population. Cases of WE have increased over the past two decades, concomitant with the rise in bariatric surgery. Not surprisingly, there has also been an increase in the number of medical malpractice lawsuits related to missed diagnosis or undertreatment of WE.

The rising concern is that we will see many more cases of WE with the explosion of usage of glucagon-like peptide-1 receptor agonists (GLP-1 RA), such as Ozempic or Wegovy, which are often prescribed for diabetes and weight loss. Patients taking these medications experience decreased appetite, early satiety, nausea, vomiting, and decreased gastric emptying.

Clinical Presentation and Diagnosis

Based on a 1997 histopathological paper, the widely adopted Caine criteria for WE diagnosis have a high sensitivity. The criteria require two or more of the following:

• Dietary deficiency.
• Eye signs, such as blurred vision or nystagmus.
• Cerebellar signs, such as gait ataxia.
• Altered mental status, such as confusion or mild memory impairment.

It is vitally important to recognize that WE is a clinical diagnosis based on history and physical examination alone—and it is a bona fide emergency. Radiological imaging of the brain with MRI with contrast (and fluid-attenuated inversion recovery, or FLAIR, images) may be confirmatory and also have some utility in excluding other diagnoses. Laboratory testing of whole blood thiamine is recommended, but treatment should not be delayed pending the result, which often takes five days to return. The best diagnostic test remains a trial of treatment with high-dose intravenous thiamine (500 mg IV three times a day) for at least three days and continue until there is no further improvement in symptoms, followed by oral thiamine (100 mg po daily) for long-term maintenance.

Medical and Surgical Weight Loss Patients

Although most reported cases of WE after bariatric surgery occur within the first three to four months, it can occur at any time. Vomiting is not normal or expected after bariatric surgery. If nausea and poor nutritional intake is persistent over several weeks, it becomes a vicious cycle, with nausea being both a cause and effect of thiamine deficiency. Vomiting can occur in the absence of any anatomic complications after bariatric surgery and is often due to thiamine deficiency itself. Interestingly, up to 30 percent of patients having bariatric surgery are thiamine deficient preoperatively.

Although the FDA has not issued a prescriber or black box warning related to the risk of thiamine deficiency from Ozempic and other GLP-1 RAs, thiamine deficiency has become a new and ubiquitous risk factor—especially because the drugs are being prescribed by practitioners who have received minimal nutritional education since graduating from training.

Prevention

Thiamine deficiency can be considered in the public health paradigm of primary, secondary, and tertiary prevention.¹

Primary prevention (prevent disease in susceptible populations). Ensure adequate thiamine intake from food, fortified foods, and vitamin supplements. For patients who are high risk, such as those with alcohol use disorder or who are expected to experience rapid weight loss from bariatric surgery or weight loss medications, give 50 mg to 100 mg of oral thiamine daily.

Secondary prevention (treat early when subclinical). For patients with decreased food intake, persistent vomiting, trauma, sepsis, or alcohol intoxication, give medium-dose (100 mg to 300 mg) parenteral thiamine daily (e.g., in an intravenous banana bag with vitamins, minerals, and electrolytes, or an intramuscular injection) for several days or until symptoms resolve and adequate intake is restored and risk factors resolved.

Tertiary prevention (reduce the severity of the disease). Once the Caine criteria for WE are met, treat with high-dose IV thiamine (500 mg/three times a day) for at least three days or until symptoms resolve, then continue oral thiamine.

This article is intended to raise awareness of WE and be a reminder to educate patients about the importance of sustaining adequate nutrition, including thiamine intake, despite reduced appetite, especially while on GLP-1 RAs, such as Ozempic.

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