5/31/98

Bibliography for W-K Syndrome

Blansjaar, B. A., G. J. Vielvoye, et al. (1992). “Similar brain lesions in alcoholics and Korsakoff patients: MRI, psychometric and clinical findings.” Clin Neurol Neurosurg 94(3): 197-203.
MRI examination revealed similar brain lesions in 5 alcoholic Korsakoff patients and 5 chronic alcoholics without cognitive impairment. Not only cerebral atrophy and demyelination, but also lesions thought to be specific for the Wernicke-Korsakoff syndrome were equally prominent in both groups. The morphological abnormalities thought to be typical of Wernicke-Korsakoff syndrome are probably common features of chronic alcoholism and malnutrition. Marked atrophy of the operculae was found in all Korsakoff patients and in 3 out of 5 chronic alcoholics. Alcohol amnestic disorder may not exclusively result from diencephalic lesions, but also from temporal lesions.

Butterworth, R. F., J. J. Kril, et al. (1993). “Thiamine-dependent enzyme changes in the brains of alcoholics: relationship to the Wernicke-Korsakoff syndrome.” Alcohol Clin Exp Res 17(5): 1084-8.
Chronic alcoholism results in thiamine deficiency as a consequence of poor nutrition, impaired absorption, and decreased phosphorylation to the enzyme cofactor form of the vitamin, thiamine pyrophosphate (TPP). Results of this study demonstrate significant reductions of TPP- dependent enzymes [pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase (alpha KGDH), and transketolase] in autopsied cerebellar vermis samples from alcoholic patients with the clinical and neuropathologically confirmed diagnosis of Wernicke-Korsakoff Syndrome (WKS). Enzyme activities in brain samples from alcoholics without WKS were within normal limits and activities of a nonthiamine-dependent enzyme, glutamate dehydrogenase, were not significantly different from control values in brain samples from alcoholics with or without WKS. These findings provide evidence, for the first time, of a direct implication of TPP-related metabolic processes in the pathogenesis of WKS. Decreased activities of alpha KGDH could be the trigger for a sequence of metabolic events resulting in energy compromise, and ultimately neuronal death in this syndrome.

Butterworth, R. F. (1995). “Pathophysiology of alcoholic brain damage: synergistic effects of ethanol, thiamine deficiency and alcoholic liver disease.” Metab Brain Dis 10(1): 1-8.
Chronic alcoholism results in brain damage and dysfunction leading to a constellation of neuropsychiatric symptoms including cognitive dysfunction, the Wernicke-Korsakoff Syndrome, alcoholic cerebellar degeneration and alcoholic dementia. That these clinically-defined entities result from independent pathophysiologic mechanisms is unlikely. Alcohol and its metabolite acetaldehyde are directly neurotoxic. Alcoholics are thiamine deficient as a result of poor diet, gastrointestinal disorders and liver disease. In addition, both alcohol and acetaldehyde have direct toxic effects on thiamine-related enzymes in liver and brain. Alcoholics frequently develop severe liver disease and liver disease per se results in altered thiamine homeostasis, in cognitive dysfunction and in neuropathologic damage to astrocytes. The latter may result in the loss of neuron-astrocytic trafficking of neuroactive amino acids and thiamine esters, essential to CNS function. The present review article proposes mechanisms whereby the effects of alcohol, thiamine deficiency and liver disease combine synergistically to contribute to the phenomena of cognitive dysfunction and "alcoholic brain damage".

Calingasan, N. Y., S. E. Gandy, et al. (1995). “Accumulation of amyloid precursor protein-like immunoreactivity in rat brain in response to thiamine deficiency.” Brain Res 677(1): 50-60.
Thiamine deficiency (TD) is a classical model of impaired cerebral oxidation. As in Alzheimer's disease (AD), TD is characterized by selective neuronal loss, decreased activities of thiamine pyrophosphate- dependent enzymes, cholinergic deficits and memory loss. Amyloid beta- protein (A beta), a approximately 4 kDa fragment of the beta-amyloid precursor protein (APP), accumulates in the brains of patients with AD or Down's syndrome. In the current study, we examined APP and A beta immunoreactivity in the brains of thiamine-deficient rats. Animals received thiamine-deficient diet ad libitum and daily injections of the thiamine antagonist, pyrithiamine. Immunocytochemical staining and immunoblotting utilized a rabbit polyclonal antiserum against human APP645-694 (numbering according to APP695 isoform). Three, 6 and 9 days of TD did not appear to damage any brain region nor change APP-like immunoreactivity. However, 13 days of TD led to pathological lesions mainly in the thalamus, mammillary body, inferior colliculus and some periventricular areas. While immunocytochemistry and thioflavine S histochemistry failed to show fibrillar beta-amyloid, APP-like immunoreactivity accumulated in aggregates of swollen, abnormal neurites and perikarya along the periphery of the infarct-like lesion in the thalamus and medial geniculate nucleus. Immunoblotting of the thalamic region around the lesion revealed increased APP-like holoprotein immunoreactivity. APP-like immunoreactive neurites were scattered in the mammillary body and medial vestibular nuclei where the lesion did not resemble infarcts. In the inferior colliculus, increased perikaryal APP-like immunostaining occurred in neurons surrounding necrotic areas. Regions without apparent pathological lesions showed no alteration in APP-like immunoreactivity. Thus, the oxidative insult associated with cell loss, hemorrhage and infarct-like lesions during TD leads to altered APP metabolism. This is the first report to show a relationship between changes in APP expression, oxidative metabolism and selective cell damage caused by nutritional/cofactor deficiency. This model appears useful in defining the role of APP in the reponse to central nervous system injury, and may also be relevant to the pathophysiology of Wernicke-Korsakoff syndrome and AD.

Charness, M. E. (1993). “Brain lesions in alcoholics.” Alcohol Clin Exp Res 17(1): 2-11.
Brain lesions in alcoholics are multifactorial in origin. Ethanol neurotoxicity, Wernicke's encephalopathy, hepatocerebral degeneration, head trauma, central pontine myelinolysis, Marchiafava-Bignami syndrome, pellagra, and premorbid pathological conditions, such as fetal alcohol syndrome, may all contribute to cognitive dysfunction in alcoholics. With the exception of ethanol neurotoxicity, all of these conditions are associated with specific neuropathological lesions. Wernicke's encephalopathy, the neurological syndrome of thiamine deficiency, is frequently overlooked during life and may cause global dementia as well as the more familiar Korsakoff's amnestic syndrome. Distinguishing ethanol neurotoxicity from nutritional deficiency can be facilitated by magnetic resonance imaging, which can visualize some of the specific macroscopic lesions of Wernicke's encephalopathy, central pontine myelinolysis, cerebellar degeneration, and Marchiafava-Bignami syndrome. Computerized morphometric studies of alcoholic brains have revealed ventricular enlargement, selective loss of subcortical white matter, and alterations in neuronal size, number, architecture, and synaptic complexity. These lesions tend to be more severe when there is coexisting nutritional deficiency or liver disease, suggesting that ethanol neurotoxicity may not be the sole cause. A search for similar lesions in nonalcoholic Wernicke's encephalopathy and nonalcoholic liver disease will help determine the specificity of these lesions.

Feuerlein, W., H. Kufner, et al. (1995). “[The mortality rate of alcoholic patients 4 years after inpatient treatment].” Versicherungsmedizin47(1): 10-4.
Data on mortality during a 48-month follow-up period in a group of 1410 alcoholics who had received inpatient treatment were evaluated. In 1266 patients known to be either living or deceased the death rate was 7.6%. The percentage of deceased subjects was highest in the group over 50 years of age. The mortality rate was higher for men (9.8%) than for women (4.8%); for those with more than one divorce (16.8%); for those who were not fit for work (18.1%) or were retired at the start of the treatment (43.3%); who were employed in the alcohol business (21.7%); who had reduced their alcohol consumption before treatment (13.4%); who were unemployed 6 months after discharge (12.4%). The mortality rate was higher for those with high scores on a scale assessing calmness in a personality inventory (7.9%) and low scores on a questionnaire assessing motivation (10.9%) and insight into the need of change (12.4%). Alcohol-related illness before the index treatment played an important role: the mortality rate was higher for those who had had Wernicke-Korsakoff-syndrome (40%), delirium tremens (15.3%), pancreatitis (13.9%) or cardiomyopathy (14.1%). The mortality rate was higher for treatment dropouts (12.9%) and for those who regularly or occasionally took sleeping pills (28.5%), psychoactive drugs (15.1%) or other drugs (11.5%) during treatment. In the follow-up periods substance use had a great effect on mortality. The mortality rate for those patients who still abstained from alcohol for after 6 months (4.4%) was only a third of that the patients who had relapsed (12.4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Martin, P. R., B. A. McCool, et al. (1995). “Molecular genetics of transketolase in the pathogenesis of the Wernicke- Korsakoff syndrome.” Metab Brain Dis 10(1): 45-55.
Thiamine deficiency, a frequent complication of alcoholism, plays an important role in the pathogenesis of the Wernicke-Korsakoff syndrome [WKS]. Previous work by a number of investigators has implicated the thiamine-utilizing enzyme transketolase [Tk] as being involved mechanistically in the genetic predisposition to WKS. In particular, Tk derived from fibroblasts has been found to have an increased Km app for its cofactor thiamine pyrophosphate [TPP] and/or exist in different isoelectric forms in alcoholic patients with WKS as compared with unaffected individuals. We have demonstrated that these differences are not due to different Tk alleles, tissue-specific Tk isozymes, or differential mRNA splicing. These findings point to other mechanisms to explain the biochemical Tk variants, such as differences in assembly of the functional holoenzyme or differences in modification of the primary translation product. Tk assembly or modification, once biochemically characterized, may be found to be subject to genetic variation.

Shear, P. K., T. L. Jernigan, et al. (1994). “Volumetric magnetic resonance imaging quantification of longitudinal brain changes in abstinent alcoholics [published erratum appears in Alcohol Clin Exp Res 1994 Jun;18(3):766].” Alcohol Clin Exp Res 18(1): 172-6.
Magnetic resonance imaging (MRI) of the brain was performed on a group of 24 recently detoxified, male alcoholics approximately 1 month after their date of last drink. The imaging was repeated 3 months later, at which point 9 subjects had resumed drinking and 15 had maintained abstinence. Contrasts between these two drinking groups revealed that, despite comparable baseline values, the Abstainers exhibited volumetric white matter increases and cerebrospinal fluid reductions over the follow-up interval, whereas the Drinkers did not show significant change on either of these MRI indices. These results provide the first evidence suggestive of significant volumetric white matter increase with abstinence.

Sullivan, E. V., L. Marsh, et al. (1995). “Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics.” Alcohol Clin Exp Res 19(1): 110-22.
Magnetic resonance imaging was used to quantify the volume of the hippocampus in 47 men with chronic alcoholism and 72 healthy male control subjects. The subjects ranged in age from 21 to 70 years, thus permitting a test of whether older alcoholics suffer greater brain tissue volume reduction than do younger ones. Comparison brain regions included temporal lobe gray matter, white matter, and cerebrospinal fluid, as well as measures of the lateral ventricles, third ventricle, and temporal horns. The results of this cross-sectional study showed that the anterior, but not the posterior, portions of the hippocampus in both hemispheres were significantly smaller in the alcoholic than the healthy control group. Furthermore, the bilateral anterior hippocampal volume loss was greater in older than younger alcoholics. Despite the hippocampal volume deficit, these alcoholics did not demonstrate an explicit memory impairment; furthermore, memory test scores did not correlate significantly with hippocampal volumes. In the alcoholics, the age-related volume loss, which was over and above that expected in normal aging, was also evident in the temporal cortex and white matter. Likewise, alcoholic ventricular enlargement was age- related. Analysis of covariance revealed that the anterior hippocampal deficit persisted after accounting for the temporal lobe gray matter volume deficit. Multiple regression analysis revealed that the age- related brain volume abnormalities observed in the alcoholics could not be attributed to duration of alcoholism or total lifetime consumption of alcohol.

Victor, M. (1994). “Alcoholic dementia.” Can J Neurol Sci 21(2): 88-99.
At least four distinct cerebral diseases--Wernicke-Korsakoff, Marchiafava-Bignami, pellagrous encephalopathy, and acquired hepatocerebral degeneration--have a close association with chronic alcoholism. Each is characterized by a distinctive pathologic change and a reasonably well-established pathogenesis; in each the role of alcohol in the causation is secondary. The question posed in this review is whether there is, in addition to the established types of dementia associated with alcoholism, a persistent dementia attributable to the direct toxic effects of alcohol on the brain--i.e., a primary alcoholic dementia. The clinical, psychologic, radiologic, and pathologic evidence bearing on this question is critically reviewed. None of the evidence permits the clear delineation of such an entity. The most serious flaw in the argument for a primary alcoholic dementia is that it lacks a distinctive, well-defined pathology, and it must remain ambiguous until such time as its morphologic basis is established.

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