The evolution and treatment of Korsakoff's syndrome: out of sight, out of mind?

Wernicke's Encephalopathy is an acute neuro-psychiatric condition caused by an insufficient supply of thiamine (Vitamin B1) to the brain. If undiagnosed or inadequately treated, it is likely to proceed to Korsakoff's Syndrome. Wernicke's Encephalopathy can result from dietary deficiency alone and this form is usually successfully treated, with little chance of Korsakoff's Syndrome supervening. On the other hand, thiamine deficiency associated with alcohol misuse/dependence may require up to 1 gram of thiamine IV in the first 24 hours to be treated successfully. The reasons for this difference in treatment will be discussed. Thiamine diphosphate acts as a co-factor for a number of thiamine-dependent enzymes. Thiamine deficiency leads to a reduction in the activity of these enzymes, and this leads to alterations in mitochondrial activity, impairment of oxidative metabolism, decreased energy status and eventually selective neuronal death. The damage caused by the combination of thiamine deficiency and alcohol metabolism probably interferes with adequate thiamine transport at a number of sites in the body, including the blood-brain barrier, as well as causing damage to the apoenzymes which then require higher concentrations of thiamine to work normally. The accumulated damage is likely to render the use of oral thiamine therapeutically inadequate since the body is unable to produce high enough concentrations of thiamine in the blood to traverse the blood-brain barrier. Some individuals are probably genetically predisposed to develop Wernicke's. Long before individuals with alcohol misuse or dependence develop Wernicke's Encephalopathy the neurons and other cells of the body are functioning sub-optimally because of the inadequate supply of thiamine and the neurotoxic effect of alcohol. This relative deficiency initiates a series of pathological changes which accumulate and further interfere with the supply of thiamine and its utilisation at a time when the requirements are increased. The best treatment for Korsakoff's Syndrome is timely recognition of Wernicke's Encephalopathy and appropriate intervention and prevention.

Genetic association study of GABRA2 single nucleotide polymorphisms and electroencephalography in alcohol dependence.

The gamma aminobutyric acid (GABA) system has been implicated in the susceptibility to develop alcohol dependence and in determining electroencephalogram (EEG) beta activity. The role of the GABA receptor alpha-2 gene (GABRA2) in human alcohol dependence was determined in a genetic and electrophysiological study. The study population comprised 586 white UK individuals with alcohol dependence but a very low prevalence of co-morbid drug dependence, and 603 ancestrally matched healthy controls. Genotyping for seven GABRA2 single nucleotide polymorphisms (SNPs), identified from the literature as positively associated with alcohol dependence, was performed with success rates of 90% or greater. EEGs were available in 32 selected patients who had been abstinent from alcohol for a minimum of 24 months and in 138 ancestrally matched healthy controls. None of the SNPs showed allelic or haplotypic association with alcohol dependence. All markers were in Hardy Weinberg equilibrium (HWE) in the controls. HWE for marker rs279841 in the alcohol dependent sample was p=0.0199 and combined p=0.0166. Linkage disequilibrium patterns appear to be very similar to that observed in the HapMap CEU data. A significantly higher prevalence of excess EEG fast activity was found in the patients (31 vs. 14%, p=0.018). A significant relationship was found between the presence of excess EEG fast activity and GABRA2 SNPs rs548583, rs279871 and rs279841. This allelic association study provides no evidence for an association between GABRA2 polymorphisms and alcohol dependence. However, a significant relationship was identified between GABRA2 and excess EEG fast activity. This dissociation of effect may reflect the fact that the EEG is a more direct marker of phenotypic GABRA2 expression than the more heterogeneous alcohol dependence phenotype.

Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of the Wernicke-Korsakoff syndrome.

The classic signs of vitamin deficiency only occur in states of extreme depletion and are unreliable indicators for early treatment or prophylaxis of alcoholic patients at risk. Post-mortem findings demonstrate that thiamine (vitamin B1) deficiency sufficient to cause irreversible brain damage is not diagnosed ante mortem in 80-90% of these patients. The causes of vitamin deficiency are reviewed with special attention to the inhibition of oral thiamine hydrochloride absorption in man caused by malnutrition present in alcoholic patients or by the direct effects of ethanol on intestinal transport. As the condition of the patient misusing alcohol progresses, damage to brain, liver, gastrointestinal tract, and pancreas continue (with other factors discussed) to further compromise the patient. Decreased intake, malabsorption, reduced storage, and impaired utilization further reduce the chances of unaided recovery. Failure of large oral doses of thiamine hydrochloride to provide an effective treatment for Wernicke's encephalopathy emphasizes the need for adequate and rapid replacement of depleted brain thiamine levels by repeated parenteral therapy in adequate doses.

A survey of the current clinical practice of psychiatrists and accident and emergency specialists in the United Kingdom concerning vitamin supplementation for chronic alcohol misusers.

Although it is well known that B-vitamin deficiencies directly affecting the brain are common in alcohol misuse, no concise guidelines on the use of vitamin supplements in alcohol misusers currently exist in the UK. The purpose of this study was to assess current practice and opinion among UK physicians. Questionnaires were completed by a total of 427 physicians comprising Accident and Emergency (A&E) specialists and psychiatrists, with a response rate of 25%. The main findings were that vitamin deficiency was perceived as being uncommon amongst alcohol misusers (<25%) and there was no consensus as to which B vitamins are beneficial in treatment or the best method of administration of B-vitamin supplementation. The majority of psychiatrists favoured oral administration for prophylaxis against the Wernicke-Korsakoff syndrome in chronic alcohol misusers and parenteral therapy in patients with signs of Wernicke-Korsakoff syndrome. Whilst only just over half the A&E specialists expressed a preference, most favoured parenteral therapy in both cases. Most respondents did not currently have a unit policy/protocol on the management of vitamin supplementation in chronic alcohol misusers. Overall, the findings suggest that there is wide variation in current practice and highlight the need for guidelines in this area.

B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse.

Alcohol misuse and alcohol withdrawal are associated with a variety of neuropsychiatric syndromes, some of which are associated with significant morbidity and mortality. B vitamin deficiency is known to contribute to the aetiology of a number of these syndromes, and B vitamin supplementation thus plays a significant part in prophylaxis and treatment. In particular, the Wernicke Korsakoff syndrome (WKS). due to thiamine deficiency, is a common condition in association with alcohol misuse, and is associated with high morbidity and mortality. Nicotinamide deficiency may result in a rarer condition, alcoholic pellagra encephalopathy, which often has a similar clinical presentation to WKS. This review considers the role of B vitamins in the aetiology and treatment of neuropsychiatric syndromes associated with alcohol misuse, with particular emphasis on WKS.

The detoxification experience of alcoholic in-patients and predictors of outcome.

This paper reports the detoxification experience and outcome at 6 months and 1 year following detoxification from alcohol in 160 patients admitted to a south-east London in-patient detoxification unit. Patients' socio-demographic characteristics are also described. The sample was predominantly middle-aged, mainly male, and highly dependent on alcohol. Subjects had been drinking heavily for many years and suffered physical and social complications in consequence. The rate of convulsions was 3.1% and of delirium tremens 1.25%. The details of the level of drug usage during detoxification and the assessment of severity of the withdrawal syndrome are also reported. The severity of the withdrawal syndrome and the incidence of significant complications of withdrawal were higher in those with a previous history of four or more episodes of detoxification, a previous history of withdrawal fits or evidence of high levels of tolerance and dependence assessed either by the Severity of Alcohol Dependence Questionnaire (SADQ) or by drinking on a typical heavy drinking day in excess of 24 U of alcohol. It is suggested that subjects with one or more of these attributes should be treated on an in-patient, rather than an out-patient, basis unless adequate support and monitoring systems are in place. Overall, patients made improvements on a wide range of social and psychological variables, but the 'abstinent' and 'controlled drinking' groups made significantly higher improvements on all variables in both follow-up periods. When patients improved their drinking status and reduced the levels of drink-related physical and social complications, in both time periods, their use of social and health resources decreased significantly. Living circumstances at intake were predictive of drinking status at both follow-up stages. The amount drunk on a heavy drinking day, at both follow-up stages, was predicted by severity of withdrawal, SADQ and living circumstances at intake in that order of importance.

Alcoholism: a long-term follow-up study of participants in an alcohol treatment programme.

This paper reports the results of a long-term follow-up study of 112 alcoholic patients admitted to an intensive 1-month residential programme. Outcomes at the 6-month and 1-year stages were reported in an earlier paper [G. K. Shaw et al. (1990) British Journal of Psychiatry 157, 190-196]. The length of the follow-up period in this study was an average of 9 years. Eighteen patients had died before the long-term follow-up stage, and of the remaining 94 a total of 60 patients were followed up. This study shows that major improvements on social, psychological and drinking behaviour measures, made at 6 months and 1 year follow-up, were, on the whole, maintained and there was a progressive improvement on most variables at each follow-up stage. Major improvements were achieved by those patients whose drinking was categorized as 'abstinent', 'controlled' and 'improved'. The proportion of patients categorized as 'unchanged' dropped from 43% at 6 months to 33% at 1 year and to 15% at 9 years. By the 1-year follow-up stage, the unchanged group showed deterioration on psychological variables such as neuroticism, self-esteem and satisfaction with life situations, continued to make use of health service resources, and the high level of alcohol-related physical and social complications remained unchanged. This group had similar results at long-term follow-up with the exception of neuroticism, which was significantly lower in all drinking categories.

B-complex vitamins in the prophylaxis and treatment of Wernicke-Korsakoff syndrome.

Wernicke-Korsakoff syndrome, which is associated with high morbidity and mortality, is a more common neuropsychiatric sequela of alcohol misuse than is widely realized. It is easily prevented and treated with parenteral B-complex vitamins, although this treatment is widely under-utilized.

Parenteral thiamine and Wernicke's encephalopathy: the balance of risks and perception of concern.

Wernicke's encephalopathy, a disorder with significant mortality and high morbidity, is common amongst alcohol-dependent patients. Thiamine deficiency appears to play a key role in its aetiology, and parenteral high-dose thiamine is effective in prophylaxis and treatment. Unfortunately, reports of rare anaphylactoid reactions have led to a dramatic reduction in the use of parenteral thiamine, and it is possible that this change in treatment has led, or will lead, to an increase in morbidity and mortality. There is a need for education of doctors who treat alcohol-dependent patients, in order to ensure appropriate use of parenteral thiamine in prophylaxis and treatment of this disorder.

Thiamine pyrophosphate effect and normalized erythrocyte transketolase activity ratio in Wernicke-Korsakoff patients and acute alcoholics undergoing detoxification.

Thiamine deficiency may be assessed clinically by an abnormally low specific erythrocyte transketolase activity and/or by abnormally large activation by thiamine diphosphate in vitro (or 'TPP effect'). In the present investigation, we report erythrocyte transketolase activation by TPP in acute alcoholics and Wernicke-Korsakoff patients undergoing detoxification. A new age-dependent parameter was used to improve the reliability of transketolase activity as an indicator of marginal thiamine deficiency. Thus normalized transketolase activity ratio (NTKZ), primary activation ratio (PAR) and further activation ratio (FAR) were measured in 29 acute alcoholics and 12 Wernicke-Korsakoff patients upon admission, and also on 47 control subjects. It was possible to follow up 14 of the 29 acute alcoholics after 7 days of treatment. Twenty-one per cent of the acute alcoholics and 33% of the Wernicke-Korsakoff patients, on admission to the detoxification Unit, had NTKZ values beyond the defined critical conditions for thiamine deficiency, whereas 7% of the former and 25% of the latter had PAR values beyond these critical conditions. Furthermore, all three parameters were significantly different in the Wernicke-Korsakoff patients compared to the other groups. The pattern of improvement of the different parameters on follow-up varied considerably and is difficult to explain, as only the NTKZ was statistically significant. Hence, only eight out of 14 acute alcoholics showed improvement in NTKZ, seven showed improvement of PAR and six showed improvement of FAR after treatment. Five patients showed improvement of both NTKZ and PAR and none of the patients showed improvement of all three parameters. We conclude that our findings confirm previous reports and that this modified transketolase activation test improves its reliability as an indicator of marginal thiamine deficiency.

Clubbing associated with oesophageal adenocarcinoma.

A patient with an oesophageal adenocarcinoma, recent onset of digital clubbing, and evidence of increased oestrogen synthesis is presented. In the discussion, some of the theories of the pathogenesis of clubbing are reviewed, together with previous reports of clubbing in gastro-oesophageal disorders. A possible unifying theory is proposed for our case which we believe is the first report of this triple association.

The genesis of alcoholic brain tissue injury.

1. Acetaldehyde has been implicated in the pathogenesis of alcohol-related liver damage by two mechanisms. Adduct formation with many tissue constituents, especially proteins, makes them immunologically foreign or reduces enzyme activity and formation of cytotoxic free radicals from acetaldehyde metabolism. Adduct formation damage to microtubule associated proteins and to hepatocyte membranes impedes protein movement into, out of and around the cell. 2. Evidence that these mechanisms also have a role in alcoholic brain damage includes raised blood acetaldehyde in alcoholics, especially in those chemically dependent, or in other abnormal states; effects of extra-hepatic free radical toxicity, including induction of superoxide dismutase activity and damaged, abnormal variants of the thiamin-dependent enzyme transketolase and extrahepatic acetaldehyde-adduct formation with haemoglobin. That acetaldehyde-mediated impairment of microtubule systems also damages the brain is suggested by its importance for the maintenance by protein transport of often greatly extended brain cell processes. 3. Oxygen-derived free radicals can damage brain tissue, the effects including cerebral oedema, neuronal loss and damage to the blood-brain barrier, all changes also reported in the brains from alcoholic patients. Alcohol-related pathology in the brain differing from that in the liver, shows sharper regional variations in vulnerability and adverse effects due to nutritional deficiencies, especially of B-group vitamins. Even though some such deficits are capable of causing encephalopathy in the non-alcoholic, the strong association between them and chronic alcoholism points to possible aggravation by metabolic interactions at various levels between acetaldehyde and thiamin or other B-vitamins. Selective regional vulnerability may reflect differences in ease of acetaldehyde access or to important metabolic differences. Alteration of animal behaviour by acetaldehyde points to a need to correlate clinical evidence of acetaldehyde central nervous cytotoxicity with the incidence of different types of cognitive defect.

The age dependence of the activity and activation of human red blood cell transketolase.

Erythrocyte transketolase has been measured in normal controls and non-alcoholic patients not at risk from nutritional deficiency and without signs of brain damage. The enzyme activity declines steadily with age over a range from 18 to 90 years with a statistically significant fall of 25% over this period. Since this decline is apparent whether or not thiamin diphosphate is added in vitro to activate the apoenzyme, the activation ratios are independent of the age effect. The decline is seen in both sexes in patients and normal subjects. It is concluded that the reliability of the specific transketolase activity as an indicator of marginal thiamin deficiency will be improved if the results are expressed as a percentage of the mean normal value corrected for age with values less than 60% of the age adjusted mean taken to indicate possible deficiency.

Superoxide dismutase in the erythrocytes of acute alcoholics during detoxification.

The activity of erythrocyte superoxide dismutase in acute alcoholic patients on admission does not form a single population but clusters in two groups either above or below the normal range. The values in both groups revert towards the normal after a week of treatment. The divergent activities of this free radical scavenging enzyme between the two groups could not be explained by differences in age, haematology or liver function tests but are likely to be acute responses, possibly to diverse drinking patterns in the period immediately preceding admission.

The effect of di-isopropyl 1,3 dithiol-2-ylidenemalonate (malotilate) on the hepatic changes induced by ethanol administration in the rat.

The sulphur-containing drug, di-isopropyl-1,3-dithiol-2-ylidenemalonate (Malotilate) protects against the increase in hepatic triglyceride concentration after acute ethanol administration (either 6 g/kg p.o. or 2 g/kg i.p.) in rats. The compound had no influence on the increased hepatic NADH:NAD ratio (measured as the lactate:pyruvate and 3-hydroxybutyrate:acetoacetate ratios) after acute ethanol dosing (2 g/kg i.p.), but was found to lower hepatic acetaldehyde concentrations and prevent some of the disturbances in lipid metabolism observed in liver slices from ethanol-treated animals (e.g. decreased oxidation of [1-14C]palmitate to 14CO2) after this ethanol dose. The drug did not inhibit ethanol metabolism in this acute experiment. Administration of Malotilate to Wistar rats (100 mg/kg/day orally) during chronic feeding of ethanol as 36% of the total calorie intake in a liquid diet, resulted in a lower intake of the alcohol-containing diet by ethanol-fed animals and reduced body weight gain in rats which received the drug, without blood ethanol levels or the ethanol intake (expressed in g/kg body weight/day) being affected. In ethanol-fed animals, Malotilate prevented the production of fatty liver and the adaptive increase in the ethanol elimination rate (EER) normally seen in ethanol-fed animals, although the drug actually caused a slight increase in EER in glucose pair-fed controls. Malotilate did not significantly decrease the degree of induction of microsomal cytochrome P-450 by ethanol, but the increase in aniline hydroxylation was much less marked in animals receiving ethanol and Malotilate, suggesting that the activity of the inducible microsomal ethanol oxidising system (MEOS) may be reduced by the compound. Determination of hepatic acetaldehyde concentrations during ethanol feeding, and during an acute ethanol challenge test following long-term ethanol treatment showed that the compound significantly lowered the level of this ethanol metabolite in the liver under both circumstances. This reduction of hepatic acetaldehyde concentrations, probably resulting in part from the reduced EER as well as increased low-Km aldehyde dehydrogenase activities and glutathione contents seen in the livers of Malotilate-treated rats, are possible mechanisms by which the drug protects against triglyceride accumulation after ethanol administration.