Korsakoff’s Syndrome Research Paper

1. Origin Of The Name ‘Korsakoff’s Syndrome’

Although the syndrome is named after the Russian doctor Korsakoff, earlier authors had alluded to the disorder and it was Lawson in 1878 who first gave a formal description of a disorder in which there was a severe loss of recent memory that was frequently associated with chronic alcoholism. Lawson also distinguished between cases with relatively selective memory loss and those in whom alcohol consumption caused a progressive dementing condition, which is nowadays referred to as ‘alcoholic dementia.’ Between 1887 and 1891, Korsakoff then gave the classic description of a much larger series of amnesia cases, two-thirds of whom were chronic alcoholics. The other third of the cases comprised individuals with several etiologies including neoplasm, carbon-monoxide poisoning, and diabetes, as well as persistent vomiting. Korsakoff identified how the memory disorder varied in severity, and that it had a retrograde as well as an anterograde component. He also noted that patients often falsely recollected information, a disorder known as confabulation. Korsakoff further noted that the memory disorder was commonly preceded by a state of confusion, accompanied by eye movement disorders such as nystagmus, as well as gait disturbance (ataxia).

This triad of symptoms had first been described in 1881 by Wernicke, who also reported that the syndrome, which now bears his name, was associated with alcoholism. Although the syndrome is often incomplete, it is not diagnosed unless at least one of the complexes of motor symptoms is present. There has been controversy about the frequency with which the appearance of the usually chronic memory disorder is preceded by Wernicke’s encephalopathy. Although the issue is not fully resolved, it is clear that in many cases of alcoholic origin, perhaps over half, Wernicke’s encephalopathy is not detected prior to the onset of amnesia. Consistent with this, it is clear that many of these cases have a relatively insidious onset often lasting over a year, and that these cases are weakly associated with Wernicke’s encephalopathy. In contrast, more acute onset cases frequently show the Wernicke ocular signs. Emergence of the memory deficit may be preceded by acute coma, Wernicke’s encephalopathy (both of which are life threatening), or it may emerge gradually without either of these prodroma being detected. There even appear to be cases where the memory disorder is not identified in life, but is suspected retrospectively at postmortem on the basis of neuropathology and a history of alcoholism. No evidence indicates that the presence or absence of detectable Wernicke’s encephalopathy affects the memory disorder or its underlying neuropathology differently. It is, however, still possible to argue that the persistent memory disorder, caused by thiamine deficiency, is always preceded by one or more episodes of Wernicke’s encephalopathy, but that these episodes may often go undetected. If correct, the brain damage underlying Wernicke’s encephalopathy

 should be found in Korsakoff ’s syndrome regardless of whether or not it is preceded by a detectable Wernicke’s encephalopathy. This encephalopathy does not always lead to a persisting amnesia.

Although the term ‘Korsakoff ’s syndrome’ is some- times loosely used as a synonym for amnesia, it is more correctly reserved for those cases of relative persistent amnesia which are triggered by thiamine depletion, the most prominent cause of which is chronic alcoholism. Alcoholism is not the only cause of thiamine depletion, however, and the evidence about this cause as well as other causes of thiamine depletion has only emerged gradually over the last century. Diagnosis depends on identifying clinical and neuropsychological evidence of a disorder largely confined to memory and learning in which there is a history of alcoholism or nutritional problems.

2. Evidence For The Role Of Thiamine Depletion In Organic Amnesia

Both Wernicke’s encephalopathy and amnesia can result from a range of nutritional and other disorders related to malabsorption, which include self-starvation, intravenous feeding, particularly in the presence of glucose, persistent vomiting, surgical removal of parts of the gastrointestinal tract, and various carcinomas of the alimentary canal. De Wardener and Lennox (1947) notably observed Wernicke’s encephalopathy in 52 malnourished prisoners in Southeast Asia during World War II. Over 60 percent of the prisoners also developed memory loss within six to fourteen weeks of the start of captivity, often preceded by diarrhea and vomiting. This corresponds to the time it takes beriberi, which is caused by thiamine deficiency, to develop. Symptoms of other vitamin deficiencies take longer to develop. Also, as is now well known, the symptoms responded very well to thiamine treatment when this was available and could be instituted early before brain damage was irreversible. In recent years, cases of amnesia caused by malnutrition have been reported relatively rarely, although there may be under-reporting given the prevalence of anorexia. Nevertheless, Korsakoff ’s syndrome with a typical neuropathology has been reported to result from dieting, particularly when this is followed by high consumption of carbohydrates, which presumably overloads the already marginal thiamine stores.

A common feature of the alcoholic and nonalcoholic patients who develop the memory deficits and neuropathology typical of Korsakoff ’s syndrome is very probably thiamine deficiency. Not only is alcoholism often associated with poor nutrition, which causes thiamine deficiency, but alcohol directly impairs thiamine metabolism in many ways (e.g., by distruption of the gastrointestinal transport of the vitamin as well as its storage and use). Although thiamine treatment may be less effective with alcoholic than nonalcoholic cases, this could be related to incidental factors such as the patients’ ages and when the treatment was introduced. Nevertheless, it is often argued that some aspects of alcoholic Korsakoff ’s syndrome may be related to the direct neurotoxic effects of alcohol, and that nicotinic acid deficiency may also contribute to development of the disorder in some cases.

Korsakoff ’s syndrome is a rare complication of alcoholic abuse, although its frequency seems currently to show marked regional variations, as it is apparently much more frequent in Australia than in the USA and the UK. This variation could relate to differences in factors such as binge drinking or the amount of thiamine intake. However, the syndrome’s rarity has led to the suggestion that it is associated with a hereditary disorder affecting the enzyme transketolase, which needs thiamine pyrophosphate (TPP), the active form of thiamine, as a cofactor. The evidence about this is conflicting, although it is likely that some kind of transketolase abnormality is related to the development of Korsakoff ’s syndrome. Exactly how thiamine deficiency causes the brain damage that leads to amnesia is not known. However, TPP is involved in DNA synthesis, three enzymatic reactions vital for glucose metabolism, and the production of several neurotransmitters including acetylcholine, glutamate, gamma-aminobutyric acid (GABA), noradrenaline, and serotonin. All three of the thiamine-dependent enzymes have been found to be depressed in patients with Wernicke-Korsakoff syndrome, but not in other alcoholics. Some evidence suggests that thiamine deficiency depresses oxidative glucose metabolism more severely in brain regions implicated in the syndrome, although this does not exclude the possibility that the deficiency may also disrupt specific neurotransmitters as well.

2.1 Evidence Of Neurotransmitter Abnormalities In Korsakoff’s Syndrome

No work has related glutamate and GABA abnormalities to Korsakoff ’s syndrome. There is, however, evidence that reduced acetylcholine turnover occurs when thiamine activity is low, and that this may also cause reduced acetylcholine production. It has also been argued that Korsakoff patients suffer a nearly 50 percent reduction of neurons in their nucleus basalis, a basal forebrain structure which contains ascending projections that use acetylcholine as a neurotransmitter. However, other Korsakoff patients have shown minimal changes in basal forebrain structures at postmortem. This relates to an important feature of the syndrome, which is that the location of brain damage is very variable across patients so presumably only some will show marked abnormalities in cholinergic neurons. Furthermore, although studies using anticholinergic drugs have shown that the anterograde amnesia of patients who have cholinergic deficiencies may be partially caused by the transmitter deficit, their retrograde amnesia cannot be. This is because anticholinergic drugs do not disrupt premorbid memory.

Five patients with alcoholic Korsakoff ’s syndrome have been reported to show improved memory when given a serotonin reuptake inhibitor, and a similar effect has been reported in alcohol-treated volunteers. However, the patient study needs replicating and whether a serotonergic abnormality is linked to the syndrome remains unproved. The same can be said about the possible involvement in the syndrome of a noradrenergic disorder, as the relevant evidence is conflicting. Some work has found that levels of the noradrenergic metabolite, 3 methoxy 4-hydroxy phenyl glycol, were reduced in the cerebrospinal fluid of Korsakoff patients, that these levels correlated with memory test performance, and that treatment with adrenergic agonist drugs produced a small improvement in memory. However, other work has not replicated these findings and animal studies suggest that noradrenergic neurons are more concerned with the mediation of attentional and arousal processes. If the animal studies are correct, then any effects on memory must be secondary to attentional disturbances. As with cholinergic abnormalities, noradrenergic deficiencies are also a variable feature of Korsakoff ’s syndrome because the level of neuronal loss in the locus coeruleus is highly variable. This small brainstem nucleus is the major source of noradrenergic projections to the forebrain regions implicated in memory.

3. The Neuropathology Of The Syndrome

Postmortem examination of patients who have died during the acute stage of Wernicke’s encephalopathy, or following a relatively prolonged Korsakoff ’s syndrome, show a similar, although variable, pattern of lesions that is distributed in a bilaterally symmetrical fashion within the midline diencephalon, brain stem, and cerebellum. Pathology is most common in the mammillary bodies, midline thalamic nuclei such as the dorsomedial and anterior nuclei and medial pulvinar, the periventricular and periaqueductal grey, the walls of the third ventricle, the floor of the fourth ventricle, and the cerebellum. Cortical atrophy with associated neuronal loss and increased hydration, which may be particularly prominent in the frontal lobes, has also been reported in a minority of cases with the full syndrome. This atrophy is similar in alcoholic patients regardless of whether or not they have Korsakoff ’s syndrome. In the acute stages of the disease, gross lesions are usually small and circumscribed with nonhemorrhagic softening or, less commonly, hemorrhages, whereas in the chronic disease atrophy is prominent, but hemorrhages may not be present. Microscopic examination may be necessary to confirm the presence of Korsakoffian pathology because gross lesions are not identifiable in all patients.

The location of the pathology that underlies the triad of symptoms which Wernicke’s encephalopathy comprises is not fully resolved. The ocular symptoms perhaps involve damage to the tectal area as well as to several brain stem nuclei including the oculomotor, abducens, and vestibular nuclei, whereas the ataxia involves cerebellar damage. Identifying the location of the lesions underlying the memory deficits of Korsakoff ’s syndrome has proved particularly difficult because of the range and variability of the structures that may be compromised in this disorder. Also, many non-Korsakoff alcoholics have milder memory deficits. Victor and his colleagues (1989) have reported that all of their alcoholic Korsakoff cases in whom the dorsomedial thalamic nucleus was affected showed amnesia, whereas a few patients in whom this nucleus was intact, but in whom the mammillary bodies were affected, did not show clinically detectable amnesia. There is, however, good evidence from both animal and human lesion studies that damage to either the dorsomedial thalamic nucleus or the mammillary bodies is sufficient to cause some memory deficits, so, when present, damage to either of these structures is likely to be contributing to the amnesic deficit in Korsakoff ’s syndrome.

Korsakoff patients with an etiology of chronic alcoholism have nevertheless shown severe amnesia even when postmortem examination only found paratenial nucleus damage anterior and dorsal to the intact dorsomedial thalamic nucleus. These patients also had mammillary body damage as well as other cortical and subcortical lesions. Korsakoff patients show variable damage to structures of Papez circuit that includes demyelination of the fornix as well as atrophy of the mammillary bodies and anterior thalamus. However, damage in alcoholic Korsakoff patients compared to alcoholic Wernicke’s cases with milder memory problems has only been convincingly shown to be worse in one region: the anterior thalamus. Damage to Papez circuit structures is sufficient to cause a mild amnesia. It remains unknown how severe the amnesia produced by a combination of this damage with damage to other diencephalic nuclei, such as the dorsomedial nucleus and mammillary bodies, actually is. Most probably, extradiencephalic damage also contributes to the severe amnesia found in some patients with Korsakoff ’s syndrome.

3.1 Neuroimaging The Brains Of Korsakoff Patients In Life

Magnetic resonance imaging (MRI) has shown that, relative to healthy people, alcoholic Korsakoff patients show widening of the third ventricle, the Sylvian fissure, and frontal sulci, as well as reductions in thalamic density. The evidence is conflicting about whether these changes are greater in Korsakoff ’s syndrome than in non-Korsakoff alcoholic patients, although the postmortem data would suggest that it should not be. Similarly, there is conflict about whether measures of frontal and thalamic atrophy correlate with memory measures in the Korsakoff patients. This conflict may be resolved by improvement of MRI measurement techniques in the future. Resolving this issue is important because it has often been argued that frontal atrophy may contribute to the Korsakoffian memory impairment.

Functional imaging has tended to show a picture of reduced cortical activation in Korsakoff ’s syndrome, which, although prominent in frontal regions, extends into posterior neocortical regions, but minimally into the medial temporal regions where lesions are known to cause amnesia. One possibility is that the reduced neocortical activation does not disrupt basic processing ability, but impairs the ability of neocortical structures to store fact and event information. Further investigation needs to determine whether the extent of reduced neocortical activation correlates with memory.

4. Neuropsychology Of Korsakoff’s Syndrome

The degree of impairment of intelligence and other, noncognitive functions varies widely across Korsakoff patients. Patients often show impairments of visuoperceptive and visuospatial functions, which are also found in nonamnesic alcoholics and may be caused by neocortical atrophy. Korsakoff patients are also usually impaired on several tests of executive function, particularly when the ability to shift strategy is tapped. Such executive functions are believed to depend primarily on the integrity of the frontal lobes.

Immediate or working memory as tested by the ability to repeat a string of items is usually held to be intact in Korsakoff ’s syndrome. However, subtle span deficits have been claimed and performance on shortterm forgetting tasks has been highly variable across studies. Evidence suggests that this variability may relate to the degree of frontal lobe dysfunction. Unrelatedly, the apathy and lack of insight often reported in patients may also relate to frontal lobe dysfunction.

The anterograde amnesia of Korsakoff ’s syndrome comprises impaired recall and recognition of recently studied facts and events. Although recognition is lost at a normal rate even over short delays, there is evidence that free recall of complex associative information is lost pathologically fast over such short delays. There is also evidence that recall of semantically related words is more impaired than equivalent recognition after short delays, and that memory for temporal and other aspects of context is more impaired than item recognition. It remains controversial whether these disproportionate deficits, which are also found in amnesics with medial temporal lobe lesions, relate to frontal dysfunction, the severity of amnesia, or both.

Like other amnesics, Korsakoff patients also often show intact implicit or unaware memory. Thus, they show normal classical conditioning when the conditioned and unconditioned stimuli overlap in time, normal acquisition and retention of perceptual, motor, and cognitive skills, and normal priming. Priming is shown when subjects respond differently to previously shown verbal and visual stimuli, even when these are not consciously recognized. However, as with other amnesics, Korsakoff patients may show impaired priming for certain complex stimuli that were novel prior to study.

Although, like other amnesics, Korsakoff patients show normal semantic memory when this is defined as memory for factual information that was massively overlearnt premorbidly, they are impaired at learning new word definitions and public information even when given reasonable exposure over a long postmorbid time. Their retrograde amnesia is characterized by an impaired ability to recall and recognize personal and public incidents, and facts acquired as memories up to several decades prior to the clear onset of their memory disorder. Although there is typically a temporal gradient in which earlier acquired memories are less affected, amnesia usually extends back at least 25 to 30 years.

Confabulation is rare in Korsakoff ’s syndrome except at the initial confusional stage when spontaneous and florid confabulation may be found. Patients may make intrusional errors when retrieving autobiographical memories, but the rare, more florid confabulation that persists beyond the confusional stage probably reflects a disorganized and disinhibited retrieval of memories and their associations. This is believed to be caused by the frontal lobe dysfunction that may be severe in some Korsakoff patients. More typically, patients show a nonfluent pattern of retrieval that is characteristic of patients with frontal lobe pathology.

Retrograde and anterograde memory deficits share little variance in patients, and it has been argued that the functional deficits are relatively unrelated and that retrograde amnesia, at least for more remote premorbid memories, is mainly caused by frontal lobe dysfunction, which produces disorganization of retrieval processes. Although Korsakoff ’s syndrome may be associated with a more severe temporal order memory deficit than is typically found in amnesics with medial temporal lobe lesions, it is unclear whether this too may not result from Korsakoff patients’ frontal lobe dysfunction. It seems most likely that a failure to consolidate certain kinds of associations lies at the heart of the anterograde amnesia found in the syndrome, and that this is mainly caused by midline diencephalic lesions.

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