Historical Development of Korsakoff Syndrome

Written by Wong Hei Tung

Introduction

Amnesia refers to the neurological condition where the patient loses memories or has trouble forming new memories. People generally experience retrograde amnesia or anterograde amnesia, which is when one cannot recall from the past and when one cannot form new memories respectively (Amnesia, 2025). It is perhaps the most devastating when one experiences both in a severe way, which was what happened to Jimmie G., a patient described in one of Dr. Oliver Sack’s essays: “The Lost Mariner and the Self”. In his first encounter with Jimmie, Jimmie seemed like a charming, intelligent, middle-aged man. But upon further conversation, it appears that he believed that he was only 19 years old and lacked memories of the years after his 20th birthday. Worse, in their next meeting just a few minutes afterwards, Jimmy had already forgotten their previous interaction. There are many diseases with such symptoms, and the one that Jimmie was diagnosed with was Korsakoff syndrome (KS)  (Sacks, 2011).

Background 

Korsakoff syndrome is a chronic amnesia, including both anterograde and retrograde amnesia caused by thiamine (vitamin B1) deficiency (Wijnia, 2022). It usually develops as a residual disorder of Wernicke encephalopathy, an acute neurological disorder characterised by abnormal eye movement, ataxia, and confusion also caused by thiamine deficiency, is not treated properly or completely (Wernicke-Korsakoff Syndrome, 2024). It is listed under major neurocognitive disorder of the confabulating amnestic type in the DSM-5 criteria (Wijnia, 2022).

Thiamine is used to form thiamine diphosphate in the body. It acts as a cofactor for multiple enzymes in the body that are involved in glucose and energy metabolism in brain cells (Thomson et. al., 2012). It is also the biochemical processes that carry signals between neurons, especially for storing and retrieving memory. So if the body lacks thiamine, these processes are disrupted, leading to amnesia (Korsakoff Syndrome, n.d.). It is noted that the primary affected areas occur in the limbic system, with the most heavily affected being the mamillary bodies, amygdala, and anterior thalamus (Goldman & Schafer, 2012). 

Fig.1 The limbic system (Moini et. al., 2021)

Fig.2 Details of the anterior thalamic nucleus (Sitnikov et. al., 2018). Noted to likely be the critical lesion for the memory-related symptoms of KS (Arts et. al., 2017).

Those who First Observed KS 

The neurologist Robert Lawson is the first to detail the multiple symptoms of KS in 1878. However, KS is named after Sergei Korsakoff, a Russian neuropsychiatrist, as he was the one who provided a more comprehensive understanding of this syndrome. Initially, he called this collection of symptoms “polyneuritic psychosis or cerebropathia psychica toxaemica” as he found that KS was usually associated with peripheral nerve inflammation and thus believed that it was a result of a toxin. Korsakoff syndrome or “Korsakoff symptom complex” was coined later by the German psychiatrist Friedrich Jolly (Arts et. al., 2017).

Wernicke encephalopathy (WE) was detailed at a similar time period. A few years before, the characteristics of Wernicke encephalopathy, including the distinct abnormal eye movement, ataxia, and mental confusion (Wernicke-Korsakoff Syndrome, 2024), were first collectively described by the German psychiatrist Carl Wernicke. Similar to KS, the name “Wernicke encephalopathy” was only proposed afterwards and he initially called it “polioencephalitis superior haemorrhagica” (Arts et. al., 2017). 

To link WE and KS, it took a third person. The German neuropsychiatrist Karl Bonhoeffer was the first to claim this statement, as he observed that all WE patients soon developed KS in the long term or as a residual syndrome (Arts et. al., 2017). 

Changes in the Understanding of KS 

Yet, none of them were aware of how Wernicke encephalopathy and KS developed, as the concept of “vitamins” had yet to be popularized. As this syndrome mostly appears in alcohol-abusers, it was first assumed to be induced by alcohol (Arts et. al., 2017). 

But it still took quite some time from 1912, when the concept of “vitamins” had fully evolved, to 1952, when the etiology of WE and KS was completely understood. During which, thiamine was first isolated and synthesized in 1926 and 1936 respectively. Ever since the etiology has been cleared up, the survival rate of WS patients has increased tremendously and because of that the number of patients with residual symptoms i.e. KS has also increased by a large amount (Arts et. al., 2017). 

Currently, the reason as to why alcohol is the major cause of KS has been discovered. Alcohol irritates our digestive system, compromising thiamine transport systems. The liver damage alcohols causes will also affect thiamine storage and thus interfere with thiamine utilization. Therefore, not only does alcohol affect the absorption and transportation of thiamine, it also affects the availability of it to the brain (Thomson et. al., 2012). 

However, there has been much debate over the definition and diagnosing criteria of KS. According to Arts et. al. (2017), up until 2017, which was when their paper was published, the most commonly cited definition of KS is “ an abnormal mental state in which memory and learning are affected out of all proportion to other cognitive functions in an otherwise alert and responsive patient.” by Victor et. al. (1989) with an addition of “resulting from nutritional depletion, ie, thiamine deficiency.” by Kopelman et. al. (2009).

Genetics 

The body is incapable of synthesizing thiamine, therefore the two thiamine transporters: Thiamine Transporter-1 and Transporter-2 (produced by the genes SLC19A2 and SLC19A3 respectively) are vitally important. In an experiment where rats are fed sith alcohol, they found a reduction in carrier-mediated thiamine transport across the renal brush-border and basolateral membranes, also an inhibition of the expression of the two transporters. However, other than this recent study, only so few other genetics studies have been carried out and the findings have been controversial (Thomson et. al., 2012). 

Despite this, a consensus has reached that heritable susceptibility to thiamine deficiency is greater than other hereditary metabolic disorders (Thomson et. al., 2012). 

Conclusion 

In conclusion, this review of the historical development of Korsakoff syndrome highlights how the understanding of diseases changes as understanding in different fields advances and breakthroughs occur. However, it should be noted that more studies could be done to clarify the diagnosis of KS, especially when alcohol misuse is more common in marginalised and stigmatized groups who have less access to comprehensive health care and generally have less knowledge on adequate nutrient intake (Thomson et. al., 2012). 

References: 

Amnesia. (2025, February 7). Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/21455-amnesia

Arts, N. J., Walvoort, S. J., & Kessels, R. P. (2017). Korsakoff's syndrome: a critical review. Neuropsychiatric disease and treatment, 13, 2875–2890. https://doi.org/10.2147/NDT.S130078

A. R. Sitnikov, Yu A. Grigoryan, L. P. Mishnyakova. (2018). Bilateral stereotactic lesions and chronic stimulation of the anterior thalamic nuclei for treatment of pharmacoresistant epilepsy. 9:137. https://surgicalneurologyint.com/surgicalint-articles/bilateral-stereotactic-lesions-and-chronic-stimulation-of-the-anterior-thalamic-nuclei-for-treatment-of-pharmacoresistant-epilepsy-2/

Jahangir Moini, Nicholas G. Avgeropoulos, Mohtashem Samsam. (2021). Chapter 1 - Anatomy and physiology, Epidemiology of Brain and Spinal Tumors, Academic Press, Pages 3-40, ISBN 9780128217368. https://doi.org/10.1016/B978-0-12-821736-8.00002-9. 

(https://www.sciencedirect.com/science/article/pii/B9780128217368000029)

Kopelman MD, Thomson AD, Guerrini I, Marshall EJ. (2009) The korsakoff syndrome: clinical aspects, psychology and treatment. Alcohol Alcohol.

Korsakoff syndrome. (n.d.). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/korsakoff-syndrome

Lee Goldman and Andrew I. Schafer. (2012). Goldman's Cecil Medicine Book. Twenty Fourth Edition.

Sacks, O. (2011). The man who mistook his wife for a hat. Picador.

Thomson, A. D., Guerrini, I., & Marshall, E. J. (2012). The evolution and treatment of Korsakoff's syndrome: out of sight, out of mind?. Neuropsychology review, 22(2), 81–92. https://doi.org/10.1007/s11065-012-9196-z

Victor M, Adams RD, Collins G. (1989). The Wernicke-Korsakoff Syndrome and Related Neurologic Disorders Due to Alcoholism and Malnutrition. 2nd ed. Philadelphia: Davis

Wernicke-Korsakoff Syndrome. (2024, December 19). Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/22687-wernicke-korsakoff-syndrome

Wijnia, J. W. (2022). A Clinician’s View of Wernicke-Korsakoff Syndrome. Journal of Clinical Medicine, 11(22), 6755. https://doi.org/10.3390/jcm11226755