1 Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of ErlangenNuremberg and 2 Department of Addiction Klinikum am Europakanal, Erlangen, Germany
* Author to whom correspondence should be addressed at: Friedrich-Alexander, University of ErlangenNuremberg, Department of Psychiatry and Psychotherapy, Schwabachanlage 6, D-91054 Erlangen, Germany. Tel.: +49 9131 8534597; Fax: +49 9131 8534105; E-mail: stefan.bleich{at}psych.imed.uni-erlangen.de
(Received 13 April 2004; first review notified 25 June 2004; in revised form 30 June 2004; accepted 9 August 2004)
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ABSTRACT |
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INTRODUCTION |
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There is growing evidence that chronic alcoholism, especially in non-abstinent patients, is associated with hyperhomocysteinaemia (Hultberg et al., 1993; Bleich et al. 2000a
; de la Vega et al., 2001
). The reasons for the increase of plasma homocysteine levels and its significant correlation with the blood alcohol concentration, regardless of whether beer, wine or spirits have been consumed (Bleich et al., 2000b
; 2001
), are most likely complex ones in alcohol-dependent patients. In the metabolism, homocysteine is either trans-sulfurated into cystathionine or it is remethylated to methionine by methionine synthase (MS). In actively drinking alcoholics, an impairment of remethylation of homocysteine is brought about on account of a dysfunction of MS, due to an alcohol-induced vitamin deficiency (folic acid, vitamin B12), as well as a direct inhibition of MS due to acetaldehyde, the product of oxidative degradation of alcohol (Kenyon et al., 1998
).
Most recently, it has been suggested that homocysteine levels on admission may be a useful screening method to identify patients with chronic alcoholism at risk of withdrawal seizures (Bleich et al., 2000c; Kurth et al., 2001
). The Lesch classification can be assessed at admission. A history of withdrawal seizures and withdrawal symptoms makes it possible to differentiate between type 1 and type 2. If it is not possible to determine an appropriate medical history, a period of five days should be allowed to pass before classification into type 1 or type 2. As this decision tree is to be classified in the order of type 4, type 3, type 1 and type 2, type 3 and type 4 patients can also have epileptic withdrawal seizures, while type 2 patients must not display withdrawal seizures (Lesch et al., 1990
; Poldrugo and Lesch, 1994
). Thus, from a clinical point of view, this is a limitation of Lesch's typology as a useful guide to identify alcoholic patients at risk of seizures in early alcohol withdrawal. Therefore, the aim of this study was to evaluate homocysteine levels in different types according to the typology of Lesch. The hypothesis was that alcoholics with a history of alcohol withdrawal seizures, who were classified as type 1 by Lesch, reveal higher homocysteine levels.
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SUBJECTS AND METHODS |
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Patients were initially divided into four groups (types 14) according to Lesch's typology (LT) (computerized allocation according to the decision tree; Lesch et al., 1990). Within the groups, patients with or without a history of alcohol withdrawal seizures were differentiated. As there were no significant differences in respect to variables at admission (i.e. plasma homocysteine, age, vitamins, blood alcohol concentration, %CDT) between the Lesch types 2, 3, and 4, these types were drawn together into one group (Lesch types 24 [LT 24]).
Fasting total homocysteine in plasma (reference value <15 µmol/l) was measured by an enzyme-linked immunosorbent assay (Axis Homocysteine EIA, IBL-No.: AX 513 01; Axis, Germany/Norway) according to Frantzen et al. (1998). Carbohydrate-deficient transferrin (CDT) at admission and after 10 days was assessed to identify chronic heavy alcohol consumption and monitoring abstinence. The %CDT turbidimetric immunoassay (reference value <2.6%, AxisShield, Norway) with assessment of the relative amount of CDT (primarily the asialo, monosialo and disialo transferrin isoforms) in proportion to total transferrin was performed (Helander et al., 2001
). Blood samples of vitamins (folate, vitamin B12) and blood alcohol concentrations (BAC) were also taken at admission. All fasting blood samples were promptly centrifuged following collection. Plasma was stored at 80°C. Vitamin B12 and serum folate concentrations were measured by chemiluminescence using Chiron kits (Chiron Diagnostics, Fernwald, Germany) on a Chiron ACS:180 automated analyser.
Statistical analyses
Comparisons were made using the KruskalWallis test and the MannWhitney test for independent samples. Logistic regression analysis was made using SCORE and STEPWISE options. The results are presented as central tendencies (CI ± SD). A P-value of <0.05 was considered significant.
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RESULTS |
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Logistic regression
All variables in Table 2 were fed into a logistic regression analysis. By using the SCORE and STEPWISE procedures, the best-fitting model was tested. No variables (such as age, sex, BAC, vitamins, LD, YD, %CDT) except the homocysteine levels met the 0.05 significance level for entry into the model. Thus, in this model, the criterion seizure was best predicted by a high homocysteine level in both LT 1 (Wald's 2 = 10.7; OR 1.24; 95%CI 1.031.51; P < 0.001) and LT 24 (Wald's
2 = 10.6; OR 1.06; 95%CI 1.031.14; P = 0.004), respectively.
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DISCUSSION |
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Unfortunately, little is known about how to predict the course of alcohol withdrawal and alcohol withdrawal seizures. Until recently, various risk factors and/or predictors, such as repeated alcohol withdrawals (kindling model) (Brown et al., 1988), alcohol level on admission (Vinson and Menezes, 1991
), hazardous alcohol drinking (Brathen et al., 1999
), genetic factors (Schaumann et al., 1994
), reduced white matter volume in the temporal lobes in alcohol-related seizures (Sullivan et al., 1996
), age, duration of disease or previous cerebral damage (to list a few), have been discussed. However, most of the known predictors have proven to be less useful.
Homocysteine is a simple sulfur-containing amino acid that has recently received a great deal of attention for neurodegenerative diseases such as Alzheimer's disease (Seshadri et al., 2002) and alcoholism associated brain atrophy (Bleich et al., 2003a
). There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Excitatory amino acids such as glutamate, aspartate and homocysteine have been shown to be increased in patients with chronic alcoholism (Tsai et al., 1998
; Bleich et al., 2004
). Furthermore, sustained hyperhomocysteinemia occurred in chronic alcoholics with an active drinking pattern. Taking into account that homocysteine levels are elevated but steadily decrease during early alcohol withdrawal (Bleich et al., 2000a
) this may possibly explain why alcoholism-associated disorders (e.g. brain atrophy) no longer progress during abstinence (O'Neill et al., 2001
).
Our results are consistent with the hypothesis that the up-regulation of NMDA receptor systems following chronic alcohol consumption may mediate the seizures associated with ethanol withdrawal (Grant et al., 1990; Hoffman et al., 1992
) and it is conceivable that excitotoxicity, possibly causing brain damage and withdrawal symptomatology (i.e. seizures), can be induced by rebound activation of NMDA receptor-mediated neurotransmission upon the removal of ethanol's inhibitory effect.
Both intra- and extracellular pathophysiological mechanisms that can basically be distinguished lead to homocysteine-induced neuronal excitotoxicty.
First, the mechanisms of excitotoxicity via overstimulation of NMDA receptors and the resulting apoptotic cell damage. Moreover, alcohol consumption leads to a disturbed permeability of the blood-brain barrier (Kornhuber et al., 1987). Thus, in hyperhomocysteinaemic patients, disruption of the bloodbrain barrier results in exposure of the brain to near plasma levels of homocysteine (Lipton et al., 1997
), leading to NMDA mediated excitotoxicity (Lipton et al., 1997
; Mattson and Shea, 2003
) with associated changes such as an impaired signal-to-noise ratio or long-term potentiation (Bleich et al., 2003b
). In accordance with the profile of action of homocysteine, generalized epileptic seizures can be triggered in animal experiments by systemic administration of both homocysteine and its breakdown products (i.e. homocysteic acid) (Kubová et al., 1995
; Folbergrová et al., 1997
, 2000
).
Second, various direct or indirect neurotoxic mechanisms that are not mediated by ionotropic NMDA receptors. These toxic effects are preceded by the ubiquitous intracellular accumulation of homocysteine, which is observed in chronic ethanol exposure (Barak et al., 2001) and then leads to extracellular overcharging of excitatory amino acids via anionic membrane transporters. Furthermore, homocysteine is rapidly taken up by neurons via a specific Na+-dependent membrane transporter (Grieve et al., 1992
), a further mechanism that results in accumulation of homocysteine within the cell.
Taking into account the relatively high potential of homocysteine to induce seizures we would like to recommend the possible usefulness of anticonvulsive strategies as an additional approach in alcohol withdrawal treatment. For example, benzodiazepines are accepted throughout the world in the therapy of alcohol withdrawal and, when administered at an adequate dose, have a sufficient antiepileptic potential. Furthermore, hyperhomocysteinemia is a treatable condition taking into account that folate therapy will reliably reduce plasma homocysteine levels. Thus, the administration of B vitamins might also be useful in patients undergoing alcohol withdrawal. Homocysteine levels on admission may be a useful screening method to identify actively drinking patients at risk of alcohol withdrawal seizures, especially in alcoholics with LT 1. The elevated excitability of the NMDA receptor mediated neurotransmission is also under intense discussion in relation to prophylaxis against recurrence. Acamprosate, as an NMDA antagonist, shows a marked improvement in relapse rates, whereby it has been shown that particularly type 1 patients benefit from the administration of acamprosate (Lesch and Walter, 1996; Lesch et al., 2001
).
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ACKNOWLEDGEMENTS |
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