What is the Korsakoff syndrome? - a paper in tribute to Prof Alwyn Lishman.

INTRODUCTION: Alwyn Lishman was interested in how memory research could be applied to clinical psychiatry. After a brief review of his major contributions, this paper will focus on his research on the alcoholic Korsakoff syndrome. It will consider how his findings relate to contemporary debates, particularly on how the syndrome should be defined, and its relationship to broader alcohol-induced cognitive impairments. METHODS: A review of the contribution of Alwyn Lishman, Robin Jacobson and colleagues to our knowledge of Korsakoff's syndrome, together with a review of the pertinent recent literature. RESULTS: Lishman and colleagues followed earlier authors in defining the Korsakoff syndrome in terms of disproportionate memory impairment, but they also noted a variable degree of IQ, frontal-executive, and timed visuo-spatial impairment in their cases. More recent authors have included such features in their definitions of the syndrome. Lishman also argued for a specific "alcoholic dementia". The present paper argues that recent definitions of the Korsakoff syndrome confound its core and associated features, and also fail to recognise the multifactorial basis of alcohol-related brain damage. CONCLUSIONS: Korsakoff's syndrome is best defined in terms of disproportionate memory impairment, and more widespread cognitive impairment is best encompassed within "alcohol-related brain damage".

Into the future with little past: exploring mental time travel in a patient with damage to the mammillary bodies/fornix.

OBJECTIVE: Remembering the past and imaging the future are both manifestations of 'mental time travel'. These processes have been found to be impaired in patients with bilateral hippocampal lesions. Here, we examined the question of whether future thinking is affected by other Papez circuit lesions, namely: damage to the mammillary bodies/fornix. METHOD: Case (SL) was a 43-year-old woman who developed dense anterograde and retrograde amnesia suddenly, as a result of Wernicke-Korsakoff's syndrome. A region of interest volumetric Magnetic resonance imaging (MRI) analysis was performed. We assessed past and future thinking in SL and 11 control subjects of similar age and education with the adapted Autobiographical Interview (AI). Participants also completed a battery of neuropsychological tests. RESULTS: Volumetric MRI analyses revealed severely reduced fornix and mammillary body volumes, but intact hippocampi. SL showed substantial, albeit temporally graded retrograde memory deficits on the adapted AI. Strikingly, whilst SL could not provide any specific details of events from the past two weeks or past two years and had impaired recall of events from her late 30s, her descriptions of potential future events were normal in number of event details and plausibility. CONCLUSIONS: This dissociation of past and future events' performance after mammillary body and fornix damage is at odds with the findings of the majority of patients with adult onset hippocampal amnesia. It suggests that these non-hippocampal regions of the Papez circuit are only critical for past event retrieval and not for the generation of possible future events.

Rewriting the valuation and salience of alcohol-related stimuli via memory reconsolidation.

The transient period of memory instability that can be triggered when memories are retrieved under certain conditions offers an opportunity to modify the maladaptive memories at the heart of substance use disorders (SUDs). However, very well-learned memories (such as those in excessive drinking and alcohol use disorders) are resistant to destabilisation when retrieved or may not destabilise at all. Memory retrieval and intervention procedures that reliably destabilise and update maladaptive motivational memories may help to improve the long-term treatment of SUDs. In 59 hazardous drinkers, we tested a novel retrieval procedure for destabilising well-learned cue-drinking memory networks that maximises prediction error (PE) via guided expectancy violation during retrieval of these memories. This was compared with a retrieval procedure without PE and no-retrieval controls. We subsequently counterconditioned alcohol cues with disgusting tastes and images in all groups and assessed responding to alcohol stimuli 1 week later. Counterconditioning following PE retrieval produced generalised reductions in oculomotor attentional bias, explicit valuation and outcome expectancies in response to alcohol cues 1 week after intervention, evidence of updating of distributed motivational drinking memory networks. These findings demonstrate that well-learned cue-drinking memories can be destabilised and that learning history need not constrain memory destabilisation if PE is maximised at retrieval. Broad rewriting of diverse aspects of maladaptive memory by counterconditioning is achievable following this procedure. The procedure described may provide a platform for the development of novel memory-modifying interventions for SUDs.

Component processes of memory in alcoholism: pattern of compromise and neural substrates.

Initially, alcohol-related memory deficits were considered only through the prism of Korsakoff's syndrome (KS). It is now clear, however, that chronic alcohol consumption results in memory disorders in alcoholics without ostensible neurologic complications, such as Wernicke's encephalopathy and KS. Most of the principal memory components are affected, including working memory, episodic memory, semantic memory, perceptual memory, and procedural memory. The extent of those cognitive impairments depends on several factors, such as age, gender, nutritional status, and psychiatric comorbidity. While memory disorders, especially episodic memory deficits, are largely definitive in patients with KS, recovery of memory abilities has been described with abstinence in uncomplicated alcoholics. Neuropsychologic impairments, and especially memory disorders, must be evaluated at alcohol treatment entry because they could impede patients from benefiting fully from cognitive and behavioral treatment approaches for alcohol dependence. Screening of memory deficits could also enable clinicians to detect, among alcoholics without ostensible neurologic complications, those at risk of developing permanent and debilitating amnesia that features KS.

Pellagra encephalopathy in the context of alcoholism: review and case report.

AIMS: The aim of the study was to review and describe the Alcoholic Pellagra Encephalopathy, a severe neuropsychiatric condition caused by a combination of niacin (vitamin B3) deficiency and alcohol abuse. METHODS: PsychInfo, Medline and Embase databases were searched for peer-reviewed studies addressing this illness. RESULTS: A historical and conceptual review of the psychopathological aspects of this condition is offered, followed by the report of a patient with a history of chronic alcohol consumption showing signs of pellagra, delusions and visual hallucinations, which was treated successfully with niacin. CONCLUSION: Pellagra encephalopathy should still be considered in the differential diagnosis of acute psychotic disorders seen in the context of chronic alcoholism.

Executive functioning in chronic alcoholism and Korsakoff syndrome.

Korsakoff syndrome (KS) is characterized by dense anterograde and retrograde amnesia. There is often a temporal gradient to the retrograde amnesia, with earlier memories more readily recalled than recent memories. Executive functioning has also been found to be impaired in KS. However, research comparing executive functioning between chronic alcoholics (AL) and patients with KS has been relatively sparse to date. In a group comparison design, executive functioning in 15 KS patients and 16 chronic alcoholic patients was assessed using the Behavioural Assessment of the Dysexecutive Syndrome test (BADS) and other secondary measures. The KS group was found to be significantly more impaired than the AL group on overall performance on the BADS (p < .05). Korsakoff patients are significantly more impaired in executive functioning than non-Korsakoff chronic alcoholics. We thank the participants of the study and also acknowledge the support of the University of Nottingham, particularly Nadina Lincoln, and the North East London NHS Foundation Trust. We are also very grateful to the anonymous reviewers of earlier drafts of this manuscript for their invaluable comments.

Subjective ratings of prospective memory deficits in chronic alcohol users.

Previous research showing everyday memory is impaired by heavy alcohol use may have underestimated the cognitive impairment of heavy users because drinkers consuming over the recommended limits for safe drinking have often been treated as a homogeneous group, often with a low threshold for inclusion. The current study investigated whether the reported linear relationship applies to participants consuming alcohol significantly above recommended limits. The everyday memory of 80 participants (43 men; modal age, 31-35 years) was investigated using the Prospective Memory Questionnaire. Participants also detailed their average weekly intake of alcohol and other substances. Current heavy users of alcohol (who consumed on average over 25 units per week) reported more memory problems than low (1-9 units per week) or medium users (10-25 units per week). Participants undergoing counselling for alcohol use reported more deficits than low or medium drinkers, but fewer than current heavy drinkers. Possible reasons for this were discussed. Strengths and limitations of subjective approaches to memory assessment were discussed as well as suggestions for future research.

Categorization abilities for emotional and nonemotional stimuli in patients with alcohol-related Korsakoff syndrome.

OBJECTIVE: To investigate whether patients with alcohol-related Korsakoff syndrome (KR) have emotion-specific or general deficits in multicategoric classification performance. BACKGROUND: Earlier studies have shown reduced performance in classifying stimuli according to their emotional valence in patients with KS. However, it is unclear whether such classification deficits are of emotion-specific nature or whether they can also occur when nonemotional classifications are demanded. METHOD: In this study, we examined 35 patients with alcoholic KS and 35 healthy participants with the Emotional Picture Task (EPT) to assess valence classification performance, the Semantic Classification Task (SCT) to assess nonemotional categorizations, and an extensive neuropsychologic test battery. RESULTS: KS patients exhibited lower classification performance in both tasks compared with the healthy participants. EPT and SCT performance were related to each other. EPT and SCT performance correlated with general knowledge and EPT performance in addition with executive functions. CONCLUSIONS: Our results indicate a common underlying mechanism of the patients' reductions in emotional and nonemotional classification performance. These deficits are most probably based on problems in retrieving object and category knowledge and, partially, on executive functioning.

Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies.

The relationships between alcohol consumption and dementia and cognitive decline were investigated in a systematic review including meta-analyses of 15 prospective studies. Follow-ups ranged from 2 to 8 years. Meta-analyses were conducted on samples including 14,646 participants evaluated for Alzheimer disease (AD), 10,225 participants evaluated for vascular dementia (VaD), and 11,875 followed for any type of dementia (Any dementia). The pooled relative risks (RRs) of AD, VaD, and Any dementia for light to moderate drinkers compared with nondrinkers were 0.72 (95% CI = 0.61-0.86), 0.75 (95% CI = 0.57-0.98), and 0.74 (95% CI = 0.61-0.91), respectively. When the more generally classified "drinkers," were compared with "nondrinkers," they had a reduced risk of AD (RR = 0.66, 95% CI = 0.47-0.94) and Any dementia (RR = 0.53, 95% CI = 0.53-0.82) but not cognitive decline. There were not enough data to examine VaD risk among "drinkers." Those classified as heavy drinkers did not have an increased risk of Any dementia compared with nondrinkers, but this may reflect sampling bias. Our results suggest that alcohol drinkers in late life have reduced risk of dementia. It is unclear whether this reflects selection effects in cohort studies commencing in late life, a protective effect of alcohol consumption throughout adulthood, or a specific benefit of alcohol in late life.

Do amnesic patients with Korsakoff's syndrome use feedback when making decisions under risky conditions? An experimental investigation with the Game of Dice Task with and without feedback.

We investigated the role of feedback processing in decision making under risk conditions in 50 patients with amnesia in the course of alcoholic Korsakoff's syndrome (KS). Half of the patients were administered the Game of Dice Task (GDT) and the remaining 25 patients were examined with a modified version of the GDT in which no feedback was provided. Patients' results in the GDT and in the modified version were compared with that of 50 healthy subjects of whom 25 subjects performed the original GDT and 25 performed the modified version. While performance on the original GDT was superior to performance on the modified GDT in healthy subjects, KS patients performed similarly on both the GDT with and GDT without feedback. Performance on both task versions was correlated with categorization and set-shifting. The findings indicate that amnesic patients do not profit from receiving feedback for their decisions in explicit risk conditions.

Judgment and memory performance for emotional stimuli in patients with alcoholic Korsakoff syndrome.

In this study we investigated whether alcoholic Korsakoff patients are impaired in categorizing neutral and emotional stimuli according to their valence and whether memory performance for this material is reduced. In a group of Korsakoff patients and a comparison group two experimental tasks--one containing emotional and neutral pictures and the other containing words-were administered. Results showed that patients had difficulties in affective judgments due to problems in classifying neutral stimuli. Memory for emotional and neutral material was impaired to a similar degree. Thus, the facilitating effect of emotional valence on memory performance is absent in Korsakoff patients.

The effect of 12-week open-label memantine treatment on cognitive function improvement in patients with alcohol-related dementia.

There is compelling evidence that alcohol-induced neurotoxicity is related to glutamate excitotoxicity. It was hypothesized that the low-affinity NMDA receptor antagonist memantine would improve the cognitive function of patients with alcoholic dementia. The aim of this study was to test this hypothesis and to evaluate the effect of memantine on the cognitive improvement of patients with alcohol-related dementia (ARD). The study was designed as a 12-wk open-label study investigating the efficacy of 20 mg memantine, a low-affinity NMDA receptor antagonist, as a treatment for cognitive and behavioural problems in 19 patients with probable ARD according to the criteria for ARD proposed by Oslin and colleagues. The CERAD-K (Consortium to Establish a Registry for Alzheimer's Disease - Korean version) and several clinical assessment scales were completed before and after the 12-wk memantine treatment period. Significant improvements in the mean scores from baseline to final assessment were observed in the Global Deterioration Scale (p<0.05), Brief Psychiatric Rating Scale (p<0.01), Geriatric Quality of Life - Dementia scale (p<0.01) and Neuropsychiatric Inventory (p<0.01) at the end of week 12. The CERAD-K subscales of word list recall (p<0.05), word list recognition (p<0.05), time orientation (p<0.01), drawing an interlocking pentagon (p<0.05), and the total MMSE-K (Mini Mental State Examination - Korean version) scores (p<0.01) of the patients all showed significant improvement following the memantine trial. In this open-label study, patients with ARD treated with 20 mg/d memantine for 12 wk showed improvement on global cognition, quality of life and behavioural symptoms. The result of this study suggests the possible usefulness of memantine for the treatment of ARD. As this was an open-label study, the possibility that participants improved cognitively on their own due to protracted abstinence from alcohol cannot be discounted.

Elaborative processing in the Korsakoff syndrome: context versus habit.

Using a procedure of Hay and Jacoby [Hay, J. F., & Jacoby, L. L. (1999). Separating habit and recollection in young and older adults: Effects of elaborative processing and distinctiveness. Psychology and Aging, 14, 122-134], Korsakoff patients' capacity to encode and retrieve elaborative, semantic information was investigated. Habits were created during initial training, whereupon cued-recall memory performance was examined, with habit opposing as well as facilitating recollection of earlier studied words. A first group of patients was instructed and tested in the same way as healthy controls and showed poor test performance. Nevertheless, when given more processing and response time, additional explanation, and explicit encouragement, a second group of patients performed similarly to healthy controls. The results suggest that, when given adequate support, Korsakoff patients are able to encode and make use of semantic, contextual, and sequential information. Word distinctiveness, however, only influenced performance of controls.

Cognitive performance of detoxified alcoholic Korsakoff syndrome patients remains stable over two years.

Excessive alcohol consumption is assumed to promote cognitive decline, eventually increasing the risk of dementia. However, little is known about the time course of cognitive functions in patients with chronic alcoholic Korsakoff syndrome (KS). Therefore, we assessed neuropsychological performance in 20 detoxified chronic KS inpatients at time 1 (T1) with a follow-up after two years (T2). The neuropsychological tests assessed verbal and visual short- and long-term memory, working memory, basic executive functions, language, general knowledge, and visual-spatial abilities. Surveys with caregivers and medical records provided information about current and previous disease-related parameters, drinking history, additional pathologies, as well as psychosocial and cognitive therapy within the two-year period. At both sessions, the majority of the KS patients' results were inferior to those of normal subjects. Comparing T1 and T2 revealed no significant decline in any of the investigated functions. Instead, general knowledge, visual long-term memory, and verbal fluency improved slightly after two years, though they still remained within pathological range. Comparing most improved and most deteriorated patients, better outcome occurred more frequently in men than women and was associated with higher premorbid education and fewer detoxifications in the past. In this sample of detoxified KS patients there was no indication of accelerated cognitive decline or onset of dementia-like symptoms over two years.

Alcoholism and judgments of affective stimuli.

This study sought to differentiate alcoholism-related changes in judgments of emotional stimuli from those of other populations in which such changes have been documented. Two sets of visual stimuli, one containing words and the other containing drawings of faces (representing a range of emotional content), were presented to abstinent alcoholic adults with and without Korsakoff's syndrome, as well as to a healthy control group and four groups of patients with other neurobehavioral disorders: Parkinson's disease, schizophrenia, depression, and posttraumatic stress disorder. Participants rated the stimuli according to emotional valence and intensity of emotion. Results implicated bi-hemispheric frontal and subcortical involvement in the abnormalities of emotion identification associated with alcoholism, and they also support the notion of age-related vulnerabilities in conjunction with alcoholism.

[Quantitative electroencephalography features and cognitive impairment in alcoholic patients]. / Características del electroencefalograma cuantitativo y trastornos cognitivos en pacientes alcohólicos.

AIM: To determine the exact relation between the characteristics of quantitative electroencephalogram analyses and the estimators of the cognitive status in alcoholic patients undergoing withdrawal. SUBJECTS AND METHODS: The study examined 49 patients diagnosed with alcoholism (DSM-IV) after 10 days of withdrawal, as well as the correlation between the bandwidth measures from the quantitative electroencephalogram (qEEG) analysis and the characteristics of the visual and auditory cognitive evoked potentials (P300) and from the findings of the attention and memory tests. RESULTS: The patients were divided into two groups: group one, which displayed an overall increase in the delta and theta absolute powers with frontal predominance, and group two, with reduced delta and theta absolute powers. Latency of the P300 wave was delayed in patients, particularly in those in group one, but regional absence of the P300 wave was more frequent in group two. Results of attention and memory tests were abnormal in patients, especially those in group one. CONCLUSIONS: The findings in the two groups appear to reflect different stages in the progression of alcoholism: the first only involved cortical dysfunction due to metabolic causes and the second possibly had added cortical atrophy. They might also represent two types of biological response by their nervous systems to the same pathogenic agent. These findings suggest that it is advisable to conduct follow-up studies involving qEEG, cognitive tests and magnetic resonance imaging of the brain in this kind of patient.

Alcohol consumption and cognitive function in late life: a longitudinal community study.

OBJECTIVE: To examine the association between alcohol use and cognitive decline in a longitudinal study of a representative elderly community sample free of dementia at baseline. METHODS: Cognitive functions and self-reported drinking habits were assessed at 2-year intervals over an average of 7 years of follow-up. Cognitive measures, grouped into composites, were examined in association with alcohol consumption. Trajectory analyses identified latent homogeneous groups with respect to alcohol use frequency over time, and their association with average decline over the same period in each cognitive domain. Models controlled for age, sex, education, depression, smoking, general mental status (Mini-Mental State Examination [MMSE]), performance on the given test at baseline, and subsequent new-onset dementia during follow-up. RESULTS: The authors found three homogeneous trajectories that they characterized as no drinking, minimal drinking, and moderate drinking. Few heavy drinkers were identified in this elderly cohort. Compared to no drinking, both minimal and moderate drinking were associated with lesser decline on the MMSE and Trailmaking tests. Minimal drinking was also associated with lesser decline on tests of learning and naming. These associations were more pronounced when comparing current drinkers to former drinkers (quitters) than to lifelong abstainers. CONCLUSION: In a representative elderly cohort over an average of 7 years, a pattern of mild-to-moderate drinking, compared to not drinking, was associated with lesser average decline in cognitive domains over the same period.

Further evidence for a comparable memory advantage of self-performed tasks in Korsakoff's syndrome and nonamnesic control subjects.

Two experiments were carried out to examine memory in persons with amnesia using self-performed tasks. In Experiment 1, persons with Korsakoff's syndrome and nonamnesic participants with alcoholism learned action phrases not involving real objects by either self-performed tasks or verbal tasks. As indexed by free recall and recognition tests, a memory advantage favoring self-performed tasks was confirmed in both participant groups. In Experiment 2, persons with Korsakoff's syndrome, nonamnesic alcoholic participants, and young control participants learned object names under three different study conditions that differed from one another as to whether actions for each name were verbally generated and whether actions actually were performed. Verbal generation with or without performing the action facilitated recognition, whereas recall advantage was found only in the verbal generation-plus performance condition. These findings confirm a comparable memory advantage of self-performed tasks for a group with Korsakoff's syndrome and a group of nonamnesic comparison participants. Action memory therefore has potential therapeutic implications for memory rehabilitation.

Is there cognitive impairment in clinically 'healthy' abstinent alcohol dependence?

AIMS: The aim of this study was to determine neuropsychological performance in apparently cognitively, mentally, and physically healthy abstinent alcohol-dependent subjects compared with control subjects who were recruited for a number of different neuroimaging studies. METHODS: All subjects completed a battery of neuropsychological tests as part of the neuroimaging protocol. RESULTS: The group dependent on alcohol performed as well as controls on a non-verbal memory test and verbal fluency but performed worse in the verbal memory task, Trail A + B, and total IQ derived from Silverstein's short-form of the WAIS-R. However, the IQ performance of both groups was above average. In both groups, age was associated with slower performance on the Trail A + B task. In the alcohol-dependent group, severity of dependence and length of abstinence was not associated with performance of any task. CONCLUSIONS: In this apparently clinically healthy population of abstinent alcohol-dependent subjects, frontal lobe dysfunction was detectable using the Trail A + B and digit symbol tasks. This was despite above-average WAIS-R IQ scores. Consideration needs to be given to routine incorporation of cognitive testing in alcohol dependence since subtle deficits may not be easily apparent and may impact on treatment outcome.