Korsakoff syndrome is marked by remote memory impairment together with characteristic profound anterograde memory deficits, out of proportion to dysfunction in other cognitive domains, in a person who is fully alert and responsive. Korsakoff syndrome typically results from a deficiency of thiamine and then has a characteristic pathology, making it a specific disease condition, Korsakoff disease. Korsakoff disease is most commonly associated with chronic alcohol abuse, but it can also result from nonalcohol-related malnutrition or malabsorption. An inherited insensitivity to thiamine has been proposed as a risk factor for alcoholism and Wernicke-Korsakoff syndrome. Successful treatment of established Korsakoff disease is infrequent, and memory impairment may be profound and chronic. Clinically, similar disorders of memory can occur with other etiologies and pathologies (eg, head trauma, anterior communicating aneurysm rupture, herpes encephalitis), and these have been referred to with various terms (eg, Korsakowian syndrome, mental syndrome of Korsakoff, amnestic syndrome, etc.), but they could reasonably be included under the umbrella of Korsakoff syndrome (ie, as distinct from the specific disease entity, Korsakoff disease).
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• The main clinical characteristic of Korsakoff syndrome is a disproportionate impairment in memory in comparison to other cognitive functions.
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• Korsakoff syndrome typically results from a deficiency of thiamine and then has a characteristic pathology, making it a specific disease condition, Korsakoff disease.
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• Korsakoff disease is frequently associated with chronic alcohol abuse, but it has also been observed in the context of a number of other conditions that cause malnutrition or malabsorption.
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• Treatment with thiamine may partially improve the memory impairment in some patients with Korsakoff disease.
Historical note and terminology
Russian neuropsychiatrist Sergei Sergeievich Korsakoff (sometimes spelled Korsakov; 1853/1854-1900) described a persistent amnestic confabulatory state that became known as Korsakoff psychosis, or Korsakoff syndrome, the chronic state of the spectrum of the Wernicke-Korsakoff syndrome or Wernicke-Korsakoff encephalopathy (Korsakoff 1887; 79; 80; 78; 168; Victor and Adams 1971; 163; 84; 85; 86). In a series of 3 articles from 1887 to 1889, Korsakoff gave a comprehensive description of a cognitive disorder now known as Korsakoff psychosis, occurring in conjunction with peripheral polyneuropathy, a combination he initially labeled either as “psychosis associated with polyneuritis” or “polyneuritic psychosis” (Korsakoff 1887; 79; 80; 78; 168; Victor and Adams 1971; 84; 85; 86). Initially, in 1887, Korsakoff felt that the cognitive disorder and the polyneuropathy represented “two facets of the same disease…The pathologic cause provoking multiple neuritis may affect several parts of the nervous system, central as well as peripheral, and according to where this cause is localized there will be symptoms either of neuritis or of the brain” (85; 86). By 1889, Korsakoff recognized that the peripheral neuropathic symptoms “may be so slight that the whole disease manifests itself exclusively by psychic symptoms.” Therefore, he concluded that “one might also call it psychosis polyneurotica, but using this designation one must remember that an identical psychic disturbance may occur also in cases in which the symptoms of multiple degenerative neuritis may be very slight or even entirely wanting” (85; 86). The associated polyneuropathy would now be recognized as beriberi, a nutritional neuropathy caused by thiamine deficiency.
Sergei Sergeievich Korsakoff (1)
Russian neuropsychiatrist Sergei Sergeievich Korsakoff (1853/1854-1900) in 1885. (Courtesy of Wikipedia, a public domain.)
Sergei Sergeievich Korsakoff (2)
Russian neuropsychiatrist Sergei Sergeievich Korsakoff (1853/1854?-1900) in 1900. (Courtesy of the U.S. National Library of Medicine, a public domain.)
Korsakoff noted the characteristic problems in new learning (anterograde amnesia) as well as the deficits in remembering past events (retrograde amnesia), and he emphasized that these occurred in the context of clear attention and consciousness. Although the eponym of Korsakoff psychosis is now often used to indicate the combination of anterograde amnesia and confabulation (with or without neuropathy), Korsakoff originally described a much wider range of mental states in affected patients that often occurred sequentially and included an agitated delirium and an apathetic acute confusional state (85; 86). However, Korsakoff was particularly intrigued by the confabulatory amnestic state, which typically followed an agitated delirium (85; 86). Patients tended to confabulate, sometimes making up stories or events entirely, but more frequently confusing the temporal context of actually experienced events.
Korsakoff based his conclusions on at least 46 patients, about two thirds of whom were alcoholics, whereas the remainder suffered from a diverse group of disorders associated with protracted vomiting, including postpartum infections, intestinal obstruction, abdominal tumor, typhoid fever, and jaundice. Korsakoff believed the diverse underlying medical conditions that were associated with the disorder could all be “reduced to an incorrect constitution of the blood, developing under their influence and leading to an accumulation in the blood of toxic substances,” which could poison the nervous system; hence, his other appellation: “toxemic cerebropathy (cerebropathia psychica toxemica)” (85; 86). Despite his extensive clinical experience with this disorder, Korsakoff’s writings do not include a pathologic description of the disease because the patients he studied were in fact the chronic cases that had been selected for survival, whereas Wernicke encephalopathy was often fulminant, and therefore, Wernicke was able to describe the associated pathology.
Korsakoff was apparently unaware of the syndrome incorporating a confusional state, ophthalmoparesis and other oculomotor findings, ataxia, and neuropathic features, which had been described by German neuropsychiatrist Carl Wernicke (1848-1905) in 1881 and labeled as “Die acute, hämorrhagische Poliencephalitis superior” (acute hemorrhagic superior poliencephalitis) and is now generally called Wernicke encephalopathy (170; Koehler and 85; 86). This syndrome, as described by Wernicke, had an acute onset and a fulminant course, leading to death within a period of 10 to 14 days. Korsakoff did mention that “sometimes there are ophthalmoplegia externa, nystagmus, and like manifestations,” but he did not attach any particular significance to these manifestations. Wernicke similarly did not appreciate the close relationship between the disorders that he and Korsakoff had described. In 1896, German neuropsychiatrist Hans Gudden (1866-1940) described atrophy of the mammillary bodies and other pathological changes in the brains of alcoholics with Korsakoff syndrome (51), but it was not until the early years of the 20th century that German neuropsychiatrist Karl Bonhöffer (1868-1948) recognized the close relationship between Korsakoff psychosis, delirium tremens, and Wernicke encephalopathy (11; 12). By 1904, Bonhöffer concluded that neuritis (ie, neuropathy) and a memory disorder were present in all patients with Wernicke encephalopathy (12).
German neuropsychiatrist Carl Wernicke (1848-1905). Photograph by J.F. Lehmann in Munich. (Courtesy of the U.S. National Library of Medicine, a public domain.)
German neuropsychiatrist Karl Bonhöffer (1868-1948). (Courtesy of the U.S. National Library of Medicine and Wikipedia, public domains.)
The clinico-pathologic overlap between Wernicke encephalopathy and Korsakoff psychosis was ultimately recognized in the late 1920s and early 1930s (46; 69; 22). Some authors noted an amnestic disorder in all patients presenting with Wernicke encephalopathy and also found the characteristic brain stem pathology of Wernicke encephalopathy in all fatal cases of Korsakoff psychosis. In this same time period, careful pathological studies noted the selective distribution of symmetric lesions, including small dot-like hemorrhages, affecting the mamillary bodies, the grey matter immediately surrounding the third ventricle and involving the hypothalamus and the medial portion of the thalamus, the periaqueductal grey matter (including the oculomotor nuclei), the posterior colliculi, and less frequently the floor of the fourth ventricle. Specific histological changes in affected areas included hyperemia and small hemorrhages, proliferation of small blood vessels, relatively slight evidence of damage to nerve cells, and the absence of inflammatory infiltration.
In cases of alcoholic origin, the Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) designation for Korsakoff syndrome is alcohol-induced persisting amnestic disorder (04), and the new DSM-V designation is “alcohol-induced major neurocognitive disorder, amnestic confabulatory type” (05). Clinically, among alcoholics, the term Korsakoff syndrome is limited to patients with a disproportionate disorder of memory, whereas the term alcoholic dementia is used for patients with a more global cognitive impairment (133). However, the nosological distinction between Korsakoff syndrome and alcoholic dementia is somewhat controversial because the clinical differentiation is imprecise and because no distinct neuropathological basis has been established for alcoholic dementia (165). Indeed, some have concluded that alcohol-related cognitive disorders can more appropriately be seen as varying along a continuum of severity (15).
Korsakoff syndrome is marked by remote memory impairment together with characteristic profound anterograde memory deficits, out of proportion to dysfunction in other cognitive domains, in a person who is fully alert and responsive. Korsakoff syndrome typically results from a deficiency of thiamine (ie, a recognized etiologic agent), and then has a characteristic pathology, making this constellation a specific disease condition, Korsakoff disease. Clinically, similar disorders of memory can occur with other etiologies and pathologies (eg, head trauma, anterior communicating aneurysm rupture, herpes encephalitis), and these have been referred to with various terms (eg, Korsakowian syndrome, mental syndrome of Korsakoff, amnestic syndrome, etc.), but they could reasonably be included under the umbrella of Korsakoff syndrome (ie, as distinct from the specific disease entity, Korsakoff disease). However, a somewhat idiosyncratic use of the term “syndrome” has traditionally been applied with “Korsakoff syndrome,” and many authors continue to use this terminology for the specific disease condition in which the memory disorder results from thiamine deficiency with its consistent pathological alterations. The present chapter tries to maintain the distinction between a syndrome and a disease, where a syndrome is an aggregate of signs and symptoms associated with any morbid process, and a disease is a specific morbid process with an identifiable group of signs and symptoms, resulting from a recognizable etiologic agent, which produces consistent pathological alterations in tissues or organs.