Alcohol Alone Does Not Cause Wernicke-Korsakoff Syndrome

University of Toronto

Wernicke-Korsakoff syndrome is a neuropsychiatric disorder marked by an acute confusional state as well as other cognitive and neurological problems. Though rare, the prevalence of this syndrome is elevated in people with psychiatric or other medical illnesses (Scalzo et al., 2015).

Wernicke-Korsakoff syndrome—which is brought on by a severe deficiency in thiamine (vitamin B1)—has been at the receiving end of nearly 140 years of myth and misinformation, handed down from one generation of learners to the next, like a game of telephone. As a result, much of what we think we know about Wernicke-Korsakoff syndrome may be false.

Perhaps the most common myth that I encounter involves overstating alcohol’s role in the pathogenesis of Wernicke-Korsakoff syndrome. People are often surprised to learn that Carl Wernicke’s first case description, in 1881, was not of a patient with what would now be called alcohol use disorder (AUD), but rather a young woman who developed esophageal stricture and malnutrition following ingestion of a caustic substance (Thomson et al., 2008). Alcohol, when implicated in Wernicke-Korsakoff syndrome, is not a causative agent; it mediates its effects via thiamine deficiency (Isenberg-Grzeda et al., 2012).

Perpetuation of the myth that alcohol causes Wernicke-Korsakoff syndrome can, at least partly, be explained by the fact that vitamins were not discovered until 1911—30 years after Wernicke published his first case reports. In fact, neither Carl Wernicke nor Sergei Korsakoff, his contemporary, knew about thiamine—or each other’s eponym—during their lifetime (Isenberg-Grzeda et al., 2012). If they had (and had the internet existed then), they may have realized that they were mostly describing the same syndrome. In 1947 the first large case series strongly implicated thiamine in the pathogenesis and resolution of Wernicke-Korsakoff syndrome. This was long after the erroneous beliefs about alcohol as a causative agent had become deeply engrained in the collective psyche of the medical community (De Wardener et al., 1947).

To understand why patients without AUD develop Wernicke-Korsakoff syndrome, it is important to first understand the role of thiamine in the body. Thiamine is an essential nutrient—one that cannot be synthesized by the body—and is a co-factor for the enzymes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase (Isenberg-Grzeda et al., 2012). Both enzymes are required for the body to produce energy aerobically. For every 1,000 calories a person consumes, about 0.33 mg of thiamine is used under normal metabolic conditions. If ever this proportion is disturbed—whether due to a lack of thiamine or an overabundance of glucose—this metabolic machinery is at risk of slowing or shutting down. Energy-hungry neurons in the central nervous system depend on thiamine-derived energy to such an extent that a mere 10 to 14 days in a thiamine-deficient state can easily lead to neuronal cell death (Sechi et al., 2007).

To be clear, AUD is a significant risk factor for Wernicke-Korsakoff syndrome; chronic alcohol intake can reduce the absorption of thiamine into the body, and this deficiency is compounded by the generally poor dietary habits of people with AUD. But while the abundance of literature on Wernicke-Korsakoff syndrome to date is comprised of cases related to alcohol, I suspect this reflects a diagnostic blind spot rather than a true absence of evidence.

In essence, any illness state causing either an absolute deficiency in thiamine or a relative deficiency (for example, a surplus of glucose without a proportional increase in thiamine) can lead to Wernicke-Korsakoff syndrome. The former can occur in states of malnutrition or malabsorption (for example, head and neck cancers, inflammatory bowel disease, and chemotherapy-related nausea); the latter can occur in hypermetabolic states (for example, diabetes, hyperthyroidism, and following excess glucose load delivered via intravenous fluid) or a state of rapid cell growth (for example, hematologic malignancies) (Isenberg-Grzeda et al., 2016). Accordingly, studies have found high rates of thiamine deficiency among a number of medically ill patient populations including those with cancer, diabetes, and in the ICU (Isenberg-Grzeda et al., 2017). In addition, hundreds of case reports have been published on non-alcohol-induced Wernicke-Korsakoff syndrome in the medically ill (Scalzo et al., 2015).

With increased attention focused on non-AUD-related Wernicke-Korsakoff syndrome in certain medically ill populations (for example, those with cancer), we have seen an exponential increase in cases published over the past two decades (Isenberg-Grzeda et al., 2016). Despite an ever-growing body of evidence to the contrary, some authors have argued that Wernicke-Korsakoff syndrome cannot exist in the absence of AUD, which may explain why clinicians seem less likely to diagnose Wernicke-Korsakoff syndrome in patients without a history of AUD (Scalzo et al., 2015). To unwed associations between alcohol use and Wernicke-Korsakoff syndrome and hopefully alleviate the blind spot that some clinicians may encounter when their patients without AUD develop symptoms of Wernicke-Korsakoff syndrome, I recommend that we begin referring to this disorder as thiamine-related encephalopathy.

Because relying on the classic triad of thiamine-related encephalopathy symptoms (confusion, ataxia, and ophthalmoplegia) to diagnose the condition only captures about 16 percent of cases, I always use the operational diagnostic criteria developed by Clive Harper and colleagues (Caine et al., 1997). These criteria require two of the following four signs for a diagnosis of thiamine-related encephalopathy: dietary deficiencies, oculomotor abnormalities, cerebellar dysfunction, and either an altered mental state or mild memory impairment.

Blood tests for thiamine are not widely available, and MRI scans also fail to detect most cases, which means that thiamine-related encephalopathy remains a clinical diagnosis (Isenberg-Grzeda et al., 2016). In the absence of any serious toxicity, administering high dose intravenous thiamine is safe and effective for the prevention and treatment of thiamine-related encephalopathy, and delaying treatment or under-dosing thiamine may lead to long-term or even permanent cognitive sequelae (Galvin et al., 2010; Thomson et al., 2002).

As a psycho-oncologist and consultation-liaison psychiatrist working with the acutely medically ill, it is possible that most of the patients I treat are at risk for thiamine deficiency, that a majority of them may be thiamine deficient, and that a small minority of them may even have thiamine-related encephalopathy. I suspect it is only a matter of time until larger and higher-quality studies are published on this understudied condition. Until then, I typically recommend erring on the side over-treating whenever possible. ■