Peter R. Martin: Historical Vocabulary of Addiction
Wernicke-Korsakoff Syndrome
There is no actual definition of Wernicke-Korsakoff syndrome in the current electronic version of the Oxford English Dictionary (OED). Rather, listed separately are the names of two physicians, the German neurologist Karl Wernicke (1848–1905) and the Russian psychiatrist Sergei Sergeievich Korsakoff (1854–1900). These physicians are each considered to have described a distinct neuropsychiatric syndrome (“A concurrence of several symptoms in a disease; a set of such concurrent symptoms”) often found in patients with chronic alcoholism. The eponyms Wernicke and Korsakoff (also Korsakow, Korsakov) are typically used as nouns in the possessive form or attributively, e.g. Wernicke’s encephalopathy and Korsakoff psychosis.
Through clinical descriptions, neuropathological correlations and biochemical studies the etiological basis of the syndromes attributed to Wernicke and Korsakoff were demonstrated to be closely related (Victor, Adams and Collins 1971). In due course, Wernicke’s encephalopathy and Korsakoff psychosis were recognized to be two stages in the clinical course of the same disorder. It was finally proven that the pathogenesis of the disorder involved episode(s) of malnutrition associated with a specific deficiency of thiamine(vitamin B1), often exacerbated by the effects of chronic alcohol consumption. Therefore, half a century after these protagonists’ descriptions, their eponyms became joined forever in the English-speaking world as Wernicke-Korsakoff syndrome (WKS) (Anonymous 1970). However, Wernicke’s encephalopathy is not the eponym employed in French psychiatry. The name of the French ophthalmologist Alphonse-Charles Gayet (1833–1904) was attached to the disorder because of primacy of his description (Gayet 1875) over Wernicke’s (1881). Accordingly, encéphalopathie de Gayet-Wernicke is accepted usage, despite the fact that there still is no consensus that Gayet’s description referred to exactly the same pathological entity as that of Wernicke (Girard, Garde and Devic 1953; Victor, Adams and Collins 1971).
The noun Wernicke is defined in OED as: “An encephalopathy caused by vitamin B1 deficiency and characterized by mental confusion and uncontrolled movements, especially of the eyes. So, Wernicke–Korsakoff, [is] applied to Wernicke's syndrome and Korsakoff's syndrome when both are present in an individual.” Based on contemporary understanding (Caine, Halliday, Kril and Harper 1997), Wernicke’s syndrome is the acute, life-threatening stage of the avitaminosis. With repletion of thiamine, the neuropsychiatric residua of the acute brain insult can manifest as the chronic phase of the disorder, Korsakoff’s syndrome. Therefore, with recovery from the acute phase of WKS, the clinico-pathological features of both the acute and chronic phases can be simultaneously appreciated as expression of the natural history of the effects of thiamine deficiency on the nervous system. Accordingly, the eponym Wernicke is commonly associated with the noun encephalopathy, which in OED is defined simply as: “Disease of the brain in general.”
The noun Korsakoff is defined in OED as: “…denote[s] a type of psychosis, namely a syndrome, often the result of chronic alcoholism, which is characterized by disorientation, memory loss for recent events [anterograde memory], and consequent confabulation.” The verb confabulate (“To fabricate of imaginary experiences as compensation for loss of memory”) has been used in reference to Korsakoff psychosis, suggesting that many cognitive skills and certain aspects of memory are strikingly preserved despite the specific inability to acquire most new learning (Weingartner, Grafman, Boutelle et al. 1983). Psychosis is defined in OED as: “Originally: any kind of disordered mental state or mental illness. Later: specifically, severe mental illness, characterized by loss of contact with reality (in the form of delusions and hallucinations) and deterioration of intellectual and social functioning, occurring as a primary disorder or secondary to other diseases, drug ingestion, etc.” The characteristic parsing of mnemic (“The capacity which a substance or organism possesses for retaining after-effects of experience or stimulation undergone by itself or its progenitors”) functions in WKS has contributed substantially to understanding neuropsychological and brain mechanisms of learning and memory in health and disease (Talland 1965; Butters and Cermak 1980; Squire 1987).
In his Lehrbuch der Gehirnkrankheiten, Wernicke (1881) described three patients, of which two men had chronic alcoholism and a woman developed persistent vomiting after self-poisoning by drinking sulphuric acid, who all exhibited a clinical triad of acute mental confusion, ataxia and ophthalmoplegia. The patients died and neuropathologic examination showed punctate haemorrhages of the gray matter around the third and fourth ventricles and aqueduct, which Wernicke called “polioencephalitis haemorrhagica superioris” (Victor, Adams and Collins 1971). Other than a possible association with alcoholism and persistent vomiting, the etiology was unknown. The role of thiamine deficiency in etiopathogenesis of Wernicke’s encephalopathy was not established until experiments of thiamine deprivation were performed in animal models (Prickett 1934) and it was found that specific pathological signs and symptoms of the condition and associated biochemical abnormalities could be rectified in humans by adminstration of thiamine (Wortis, Bueding, Stein and Jolliffe 1942). Demonstration of clinico-pathologic findings of WKS in WWII prisoners-of-war in a Singapore hospital who were thiamine deficient due to dietary deprivation, provided strong evidence that WKS was a disease of malnutrition, not alcoholism (De Wardener and Lennox 1947).
In 1887 Korsakoff first described a syndrome characterized by subacute dysmnesia and confabulation in his paper “The disturbance of psychic activity in alcoholic paralysis and its relation to the disturbance of the psychic sphere in multiple neuritides of nonalcoholic origin” (Korsakoff 1955; Victor and Yakovlev 1955). He indicated that disturbed memory and neuropathic findings likely represented different aspects of the same disease process and, accordingly, proposed the name “psychosis polyneuritica.” In subsequent articles, Korsakoff expressed his thoughts about presentation and etiopathogenesis. He described subtle anterograde memory deficits and behavioral abnormalities, noting that neuropathic features may or not be present. Behavioral findings included apathy and social indifference, superficial and labile emotions, and lack of goal-oriented spontaneous activity with a surprising sparing of intellectual functions considering the level of incapacity. He described an association with alcoholism, but recognized that the disorder may also complicate a wide variety of other medical illnesses, such as puerperal sepsis, typhoid fever, intestinal obstruction with persistent vomiting and hyperemesis gravidarum (Victor, Adams and Collins 1971). Although the correct etiology escaped Korsakoff, he postulated that the cause of the disorder was an unknown toxic substance in the blood and coined the term “cerebropathia psychica toxaemica.”
Friedrich Jolly (1844–1904), a German neurologist and psychiatrist, first introduced the eponym Korsakoff’s syndrome (Jolly 1897). The conceptual linkage between Korsakoff’s syndrome and alcoholism was mightily reinforced by the German neurologist and psychiatrist Karl Bonhoeffer (1868-1948), who believed that the phenomenology of Korsakoff’s syndrome resembled delirium tremens. Accordingly, in his seminal textbook Acute Psychic Diseases of Habitual Drunkards he grouped Korsakoff’s syndrome with the alcoholic psychoses (Bonhoeffer 1901). Bonhoeffer was also one of the first to note amnesic features in Wernicke’s syndrome, indicating its overlapping phenomenology with Korsakoff psychosis (Bonhoeffer 1904).
The term Korsakoff psychosis is now mostly subsumed under Wernicke-Korsakoff syndrome. However, the eponym is still commonly employed when referring to the characteristic amnestic (“Causing loss of memory”) features, which are considered the hallmark of the syndrome. It is now evident that Korsakoff’s syndrome has very little to do with psychosis; however, if delirium emerges in a patient undergoing complicated alcohol withdrawal, the mistaken classification proposed by Bonhoeffer becomes understandable. In the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association (APA), the term Korsakoff psychosis has been mentioned in passing while the accepted nomenclature to designate the syndrome has continued to evolve (American Psychiatric Association 1980, 1987, 2013). For example, in the first version of the APA diagnostic criteria (DSM-I), the term used to denote Korsakoff psychosis was chronic organic brain syndrome. This term was changed in DSM-III to chronic organic mental syndrome or disorder, but the new multi-axial classification system raised the issue of whether this diagnosis was a psychiatric or medical disorder. In DSM-IV, alcohol-induced persisting amnestic disorder was introduced so as to be compatible with the International Statistical Classification of Diseases and Related Health Problems (ICD). Finally, in DSM 5, the descriptive alcohol-induced major neurocognitive disorder, amnestic-confabulatory type was introduced to represent the chronic phase of WKS. Of note, in DSM 5, the term alcohol-induced major neurocognitive disorder, nonamnestic-confabulatory type was also introduced, but whether it represents a distinctly different disorder or simply different phenomenology with related etiopathogenesis is still disputed (Wilkinson and Carlen 1980; Lishman 1981; Martin, Adinoff, Weingartner et al. 1986).
Since first described by Wernicke, the characteristic triad of clinical findings has been considered pathognomonic of the encephalopathic stage of WKS. However, Harper (1983) reported that only 20% of the 131 cases of WKS he diagnosed at autopsy had been recognized to have the syndrome on clinical examination. Such low accuracy of the clinical diagnosis of the encephalopathic stage of WKS represents a significant challenge because thiamine administration is typically such an effective treatment (Centerwall and Criqui 1978).
These misdiagnoses could be accounted for by evolution of presentation of the disorder in recent times and/or lack of reliability of the classical diagnostic criteria. Due to the current widespread administration of thiamine to alcoholic patients even if assymptomatic (Thomson, Cook, Touquet and Henry 2002), it has been proposed that fewer classical cases of Wernicke's encephalopathy are likely to be encountered. Furthermore, as a result, repeatedly treated subclinical episodes of thiamine deficiency may result in a progressive disorder in which the extent and tempo of recovery is the major determinant of the clinical presentation (Witt and Goldman-Rakic 1983).
For example, Alling and Bostrom (1980) found that the mamillary bodies, which are almost always affected in the neuropathology of WKS (Victor, Adams and Collins 1971), showed loss of myelinated fibers and decreased concentrations of cerebrosides, cholesterol and phospholipids compared to normal controls in male chronic alcoholics who had no previous history of WKS. Determination of the specificity of the classical diagnostic triad of Wernicke’s encephalopathy was conducted by Caine, Halliday, Kril and Harper (1997). Reproduciblity and validity of the clinical diagnosis in their sample of WKS patients examined at necropsy were optimised by setting the diagnostic criteria as either having the full classic triad or the presence of two of the following: 1) dietary deficiencies, 2) oculomotor abnormalities, 3) cerebellar dysfunction and 4) either an altered mental state or mild memory impairment. The reliability of the clinical diagnosis of WKS in their sample could be enhanced by adding a nutritional criterion to one or more of the signs of the triad. This actually supports the tremendous importance of nutritional deficiencies in alcoholics (Martin, Singleton and Hiller-Sturmhöfel 2003).
The frequent co-occurrence of alcoholism with WKS continued to confound understanding of etiopathogenesis well into the 20th century (Joyce 1994). The toxic effect of chronic alcohol consumption on nervous system functions has long been suspected, as suggested by a quotation from Sutton concerning delirium tremens (1813) “…as an affection of the brain in which some morbid change might be expected.” Courville’s influential monograph Effects of Alcohol on the Nervous System of Man (1955) is noted for its extensive and systematic neuropathological studies of chronic alcoholics presumed to have little evidence of the findings of WKS:
“Throughout the past quarter century… [the author] has been impressed by the fact that any noteworthy evidence of atrophy of the cerebral cortex occurring before the age of fifty years has, in the great majority of cases, proven to be the result of chronic alcoholism. In his earlier experience with other postalcoholic residuals, an occasional case of alcoholic pellagra was observed. Beyond these incidental observations, opportunity for the routine study of the central lesions in that complex which has eponymically described as Wernicke’s encephalitis was [only] occasionally afforded.”
These neuropathological findings suggested that atrophy of the cerebral cortex was the most relevant deficit associated with chronic alcoholism. The focus on cortical damage was supported by early neuroradiologic (Pluvinage 1954), electroencephalographic (Bennett, Dot and Mowrey 1956) and neuropsychological (Moore 1941) studies. Therefore, research on the neurotoxic effects of alcohol consumption in humans and as modelled in laboratory animals gained impetus (Freund 1973).
During this era, the neuropathological substrates underpinning brain dysfunction associated with alcoholism effectively shifted from the midline punctate haemorrhages of ventricular and periaqueductal gray matter and the cerebellar vermis due to thiamine deficiency to the relatively poorly understood and nonspecific pathogenesis of cortical atrophy. Neuropsychological studies of detoxified alcoholics “without clinical evidence of malnutrition” showed impairments in performance of visuospatial problem-solving tasks in 50-70% detoxified alcoholics suggesting frontal lobe deficits (Rankin 1975; Parsons 1977; Eckardt and Martin 1986). In parallel, newly implemented, non-invasive neuroimaging techniques began to be utilized to depict cortical atrophy and partial recovery with abstinence (Carlen, Wortzman, Holgate et al. 1978).
The fundamental mechanism(s) of cortical atrophy were revisited as every new neuroimaging technique, in turn, was applied to this issue that was never fully explicated, despite the fact that meaningful clinical correlates were identified (Berglund and Ingvar 1976; Martin, Rio, Adinoff et al. 1992; Martin, Gibbs, Nimmerrichter et al. 1995; Pfefferbaum, Sullivan, Rosenbloom et al. 1993; Parks, Dawant, Riddle et al. 2002). Several interacting factors associated with alcoholism (in addition to malnutrition) may contribute to the neurocognitive deficits found in a given patient (Martin, Adinoff, Weingartner et al. 1986).
For example, liver disease complicating alcoholism may result in brain deficits ranging from subtle neuropsychological abnormalities to fulminant encephalopathy, delerium and coma, often difficult to distinguish from WKS (Schenker, Henderson, Hoyumpa and McCandless 1980; Caine, Halliday, Kril and Harper 1997). Also, repeated head trauma and episodes of hypoxemia due to bronchopulmonary infections, exacerbated by sleep apnea and chronic obstructive pulmonary disease are frequent during intoxication, all with cumulative negative consequences on brain functioning over a lifetime of drinking (Weinstein and Martin 1995). Finally, co-occurring drug use and other psychiatric and neurological disorders may also contribute to neurocognitive deficits observed in chronic alcoholics.
As the pathogenesis of cerebral dysfunction and concomitant cortical atrophy in chronic alcoholism is multifactorial, the effects of malnutrition may be overshadowed if not suspected. This conundrum led to a heuristically useful dichotomization of severe chronic organic brain impairment, which eventually develops in about 10% of alcoholic patients, into amnestic and dementia syndromes — the former due to the effects of thiamine deficiency and the later to the neurotoxicity of alcohol consumption (Wilkinson and Carlen 1980; Lishman 1981; Martin, Adinoff, Weingartner et al. 1986). This hypothesis received considerable support, including distinctions in neuroimaging, neuropsychological functioning, and response to treatment (Martin, Adinoff, Eckardt et al. 1989).
More subtle and clinically difficult to recognize brain dysfunction may develop relatively early in life and is so prevalent among alcoholic patients that it may be considered a precursor to, or a consequence of alcohol consumption (Parsons 1977, Eckardt and Martin 1986). Nevertheless, alcoholism-associated brain disease over a broad range of severities share neurobiological and clinical similarities (Ryback 1971; Alling and Boström 1980). Therefore, clinical observations and pathophysiological constructs derived from investigation of alcoholics with severe neurocognitive disorders have contributed to our understanding of the very large population with lesser degrees of cerebral impairment and vice versa.
A question that has perplexed clinicians and scientists is why only some individuals develop the most severe forms of alcoholism-associated brain damage. Blass and Gibson (1977) first proposed that genetic abnormalities in the thiamine-requiring enzyme tansketolase may predispose alcoholics to develop WKS during periods of thiamine malnutrition which are so common during extended episodes of alcohol consumption. This hypothesis was supported by findings that a similar abnormality in transketolase was identified in genetically at risk sons of alcoholics prior to ever consuming alcohol (Mukherjee, Svoronos, Ghazanfari et al. 1987). When McCool, Plonk, Martin and Singleton (1993) demonstrated that there were no differences in the genetic sequence of transketolase in severe alcoholics with and without WKS, the putative role of a transketolase abnormality in predisposing individuals to progressive development of cerebral dysfunction due to repeated subclinical episodes of thiamine deficiency during a lifetime of drinking alcohol to excess had to be expanded. Thiamine deficiency in the etiopathogenesis of alcoholism-associated brain dysfuntion may involve various thiamine-related molecular processes and transporters required to make thiamine available to WKS-related brain regions (Singleton and Martin 2001; Abdul-Muneer, Alikunju, Schuetz et al. 2018; Bordia and Zahr 2020). Finally, the idea that any alcohol-induced toxicity acts through thiamine deficiency seems sensible because thiamine deficiency can be demonstrated in up to 80% of alcoholics even in affluent countries (Martin, Singleton and Hiller-Sturmhöfel 2003).
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June 3, 2021