Wernicke's encephalopathy is an acute neuropsychiatric syndrome resulting from thiamine deficiency, which is associated with significant morbidity and mortality. According to autopsy-based studies, the disorder is still greatly underdiagnosed in both adults and children. In this review, we provide an update on the factors and clinical settings that predispose to Wernicke's encephalopathy, and discuss the most recent insights into epidemiology, pathophysiology, genetics, diagnosis, and treatment. To facilitate the diagnosis, we classify the common and rare symptoms at presentation and the late-stage symptoms. We emphasise the optimum dose of parenteral thiamine required for prophylaxis and treatment of Wernicke's encephalopathy and prevention of Korsakoff's syndrome associated with alcohol misuse. A systematic approach helps to ensure that patients receive a prompt diagnosis and adequate treatment.

http://unmhospitalist.pbworks.com/f/Wernickes+encephalopathy.pdf

Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management

The past decade has brought many advances in our understanding of GABAA receptor-mediated ethanol action in the central nervous system. We now know that specific GABAA receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABAA receptors promoting increases in GABA sensitivity. Ethanol’s effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABAA receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.

/pdf/the-role-of-gaba-a-receptors-in-the-acute-and-chronic-4zyeeaz5uz.pdf

The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress.

One of the sequelae of chronic alcohol abuse is malnutrition. Importantly, a deficiency in thiamine (vitamin B(1)) can result in the acute, potentially reversible neurological disorder Wernicke encephalopathy (WE). When WE is recognized, thiamine treatment can elicit a rapid clinical recovery. If WE is left untreated, however, patients can develop Korsakoff syndrome (KS), a severe neurological disorder characterized by anterograde amnesia. Alcohol-related brain damage (ARBD) describes the effects of chronic alcohol consumption on human brain structure and function in the absence of more discrete and well-characterized neurological concomitants of alcoholism such as WE and KS. Through knowledge of both the well-described changes in brain structure and function that are evident in alcohol-related disorders such as WE and KS and the clinical outcomes associated with these changes, researchers have begun to gain a better understanding of ARBD. This Review examines ARBD from the perspective of WE and KS, exploring the clinical presentations, postmortem brain pathology, in vivo MRI findings and potential molecular mechanisms associated with these conditions. An awareness of the consequences of chronic alcohol consumption on human behavior and brain structure can enable clinicians to improve detection and treatment of ARBD.

Clinical and pathological features of alcohol-related brain damage

F TWIN, AND adoption studies have convincingly demonstrated that genes play an important role in the development of alcohol dependence, accounting for approximately 50–60% of the population variance (McGue, 1999). Additionally, patterns of alcohol use seem to be under genetic influence. Twin studies have demonstrated that dimensions of alcohol use, such as quantity of alcohol consumed on a typical drinking occasion, frequency of use, and frequency of intoxication, and alcohol metabolism measures, such as time to peak blood alcohol concentration and rate of elimination, are under substantial genetic influence (Heath, 1995). Furthermore, there is evidence of genetic effects on patterns of alcohol use as early as adolescence, and these effects seem to increase over time (Rose et al., 2001). It is unclear to what extent the genes that influence patterns of alcohol use overlap with those that influence alcohol dependence. Despite strong evidence for genetic effects contributing to alcoholism susceptibility, detecting the specific genes that increase or decrease the risk for alcoholism has proven difficult. Many factors contribute to the slow progress in isolating the genes involved in drinking behavior. Many genes are thought to contribute to alcoholism susceptibility, and different genes are likely contributing to alcohol dependence in different individuals. Additionally, the environment plays a substantial role in drinking patterns, with nearly half of the variance in drinking patterns and alcohol dependence attributed to environmental factors. Furthermore, these genes and environments probably interact. Data from a Finnish twin study of alcohol use among adolescents demonstrated that the magnitude of genetic influences can vary dramatically between environments, with up to 5-fold differences demonstrated in different environments (Dick et al., 2001). This suggests that some environments may exacerbate the expression of genetic predispositions, whereas others may be protective. Finally, there is substantial phenotypic heterogeneity in the manifestation of alcohol dependence, with alcoholics differing on dimensions such as age of onset of problems, alcohol symptoms, drinking history, and comorbid disorders. Some evidence suggests that genes may be more important in certain subtypes of alcoholics (Cloninger et al., 1981). Other investigators have studied endophenotypes as a means to deal with the substantial heterogeneity involved in alcohol dependence. Endophenotypes are phenotypes that are thought to be intermediaries between a particular disorder and the biological processes that lead to the manifestation of this disorder. For example, brain wave activity, as measured by electroencephalogram (EEG) and eventrelated potential (ERP), has been studied as an endophenotype for both alcohol dependence and schizophrenia. It is possible that genes act more directly on an endophenotype, as compared with a diagnostic classification, and, therefore, the study of endophenotypes may more efficiently lead to the identification of genes. All of these factors considerably complicate efforts to identify the genes involved in alcohol dependence and to understand the contribution of any specific gene that is identified. A number of genetic strategies have been used in the study of alcohol dependence. These include both linkage and association studies. Linkage studies involve the ascertainment of families with multiple affected individuals; genotyping of segments of DNA that exhibit variation, called polymorphic markers, is often used to detect chromosomal regions in which affected individuals within a family demonstrate increased sharing of a particular marker allele, suggesting that there may be a gene nearby involved in the disorder. Association studies can use either families or unrelated controls; they test the association between a particular allele at a candidate gene and a specific outcome across families. Association methods typically can detect significant effects over much smaller physical distances as compared with linkage studies. For a more extensive review of the methods used in genetic studies, see Dick and Foroud (2003). Here we review the evidence for candidate genes that have been implicated in genetic studies of alcohol dependence and related phenotypes, such as quantitative indices of alcohol use, and endophenotypes, such as EEG. This review is not meant to be exhaustive in reporting all candidate genes, but, rather, covers in detail many of the candidate genes currently thought to be most promising. From the Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana. Received for publication September 30, 2002; accepted February 12, 2003. Supported by NIH Grants AA13358, AA00285, and AA07611. Reprint requests: Tatiana Foroud, PhD, Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 W. Walnut St., IB-130, Indianapolis, IN 46202-525; Fax: 317-274-2387; E-mail: tforoud@iupui.edu. Copyright © 2003 by the Research Society on Alcoholism.

Candidate Genes for Alcohol Dependence: A Review of Genetic Evidence From Human Studies

Alcoholism is a common, heritable, chronic relapsing disorder. GABAA receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABAA receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABAA receptors: tolerance is associated with generally decreased GABAA receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABAA receptors may be implicated in the switch from heavy drinking to dependence. GABAA receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABAA receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABAA receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

The Role of GABAA Receptors in the Development of Alcoholism

A role for the GABA/benzodiazepine receptor complex in alcohol dependence syndrome has been suggested by several lines of evidence To elucidate the role of GABAA subunits in human alcohol dependence syndrome, we identified polymorphisms in the GABAAbeta2 and GABAAalpha6 receptor subunit genes on 5q33 and assessed their potential contribution in an association study, together with a NciI RFLP at the GABAAgamma2 receptor subunit gene One hundred and eight alcohol-dependent subjects and 54 unrelated controls were recruited from Scotland Two novel genetic markers were identified at the GABAAbeta2 and GABAAalpha6 receptor subunit genes and examined for association with the alcohol dependence syndrome and subgroups of subjects with Korsakoff's psychosis and without Korsakoff's psychosis, together with a NciI RFLP at the GABAAgamma2 receptor subunit gene The chi2 tests demonstrated associations between all alcohol-dependent subjects (not stratified) and the BanI RFLP at the GABAAbeta2 receptor subunit gene (P = 0015), and the AlwNI RFLP at the GABAAalpha6 receptor gene (P = 0013) Significant associations were also found between the alcohol-dependent subjects with Korsakoff's psychosis and the BanI RFLP (P = 0039) and the AlwNI RFLP (P = 0003) Haplotype analysis also provided evidence of association when all alcohol-dependent subjects (P = 0013) and the subjects with Korsakoff's psychosis (P = 0007) were compared with controls Our findings provide evidence for a role for the GABAA receptor subunit cluster on chromosome 5q33 in susceptibility to the alcohol dependence syndrome and Korsakoff's psychosis

Association between variants at the GABAAbeta2, GABAAalpha6 and GABAAgamma2 gene cluster and alcohol dependence in a Scottish population.

Corrigendum: Association between variants at the GABA(A)β2, GABA(A)α6 and GABA(A)γ2 gene cluster and alcohol dependence in a Scottish population (Molecular Psychiatry (1999) 4 (539-544))

M. McLaughlin

Papers

Association between variants at the GABAAbeta2, GABAAalpha6 and GABAAgamma2 gene cluster and alcohol dependence in a Scottish population.

Corrigendum: Association between variants at the GABA(A)β2, GABA(A)α6 and GABA(A)γ2 gene cluster and alcohol dependence in a Scottish population (Molecular Psychiatry (1999) 4 (539-544))