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PubMedDate not supplied

Update on the neurobiology of alcohol withdrawal seizures.

Abrupt cessation of alcohol intake after prolonged heavy drinking may trigger alcohol withdrawal seizures. Generalized tonic-clonic seizures are the most characteristic and severe type of seizure that occur in this setting. Generalized seizures also occur in rodent models of alcohol withdrawal. In these models, the withdrawal seizures are triggered by neuronal networks in the brainstem, including the inferior colliculus; similar brainstem mechanisms may contribute to alcohol withdrawal seizures in humans. Alcohol causes intoxication through effects on diverse ion channels and neurotransmitter receptors, including GABA(A) receptors--particularly those containing delta subunits that are localized extrasynaptically and mediate tonic inhibition--and N-methyl-D-aspartate (NMDA) receptors. Alcohol dependence results from compensatory changes during prolonged alcohol exposure, including internalization of GABA(A) receptors, which allows adaptation to these effects. Withdrawal seizures are believed to reflect unmasking of these changes and may also involve specific withdrawal-induced cellular events, such as rapid increases in alpha4 subunit-containing GABA(A) receptors that confer reduced inhibitory function. Optimizing approaches to the prevention of alcohol withdrawal seizures requires an understanding of the distinct neurobiologic mechanisms that underlie these seizures.

Journal Article↗
PubMed2006

Methylenetetrahydrofolate reductase C677T-polymorphism and its association with alcohol withdrawal seizure.

BACKGROUND: Elevated homocysteine plasma levels are considered as a risk factor for the occurrence of seizures during alcohol withdrawal. Homocysteine plasma concentrations seem to be influenced by the methylenetetrahydrofolate reductase (MTHFR) C677T-polymorphism. It was investigated whether the T-allele of the MTHFR C677T-polymorphism is associated with alcohol dependence, alcohol withdrawal seizure (WS), or the daily amount of alcohol consumption. METHODS: A group of 102 healthy controls and 221 alcoholic patients, including 97 patients with a history of mild withdrawal symptoms (MWS) and 70 patients with a history of alcohol WS, were genotyped, and personal data were collected for statistical evaluation in a case-control design. RESULTS: The T-allele is significantly associated with WS by comparing alcoholic patients with a history of WS (T-allele frequency: 0.39) and healthy controls (T-allele frequency: 0.28) (p=0.03). Although there was no significant difference between alcoholic patients with only MWS and alcoholic patients with a history of WS, a trend for the T-allele frequency among the analyzed subgroups was noticed: T-allele frequency increased from f(T)=0.28 in healthy controls to f(T)=0.33 in alcoholic patients with MWS up to f(T)=0.40 in alcohol-dependent men having a WS. Differences between healthy male controls and male alcoholic patients concerning the T-allele frequency also turned out to be significant [f(T)=0.27 vs f(T)=0.37; p=0.03]. Daily alcohol intake was independent of T-allele carrier status in alcohol-dependent patients. CONCLUSION: The present study suggests an influence of the MTHFR C677T-polymorphism on the etiology of alcohol WS and alcohol dependence in men in a western European population. An influence of MTHFR C677T on the daily amount of alcohol intake before admission among alcohol-dependent patients could not be shown.

Adult↗
PubMed1979

Carbamazepine: prevention of alcohol withdrawal seizures.

Effects of carbamazepine on alcohol withdrawal seizures and symptoms were studied in rats. Carbamazepine was administered during alcohol feeding and continued during alcohol withdrawal. When carbamazepine serum levels were above 3 micrograms per milliliter, alcohol withdrawal seizures were not observed. Carbamazepine also alleviated alcohol withdrawal symptoms, especially heightened spontaneous activity, startle to noise, stereotyped chewing movements, and intermittent body stiffening.

Alcoholism↗
PubMed1989

Placebo-controlled trial of intravenous diphenylhydantoin for short-term treatment of alcohol withdrawal seizures.

PURPOSE: Despite conflicting experimental and clinical evidence, diphenylhydantoin continues to be used for the treatment of alcohol withdrawal seizures in emergency departments and alcohol detoxification centers. Our goal was to evaluate the effectiveness of intravenous diphenylhydantoin for prevention of alcohol withdrawal seizures in high-risk patients using a prospective, randomized, double-blind, placebo-controlled study design. PATIENTS AND METHODS: Ninety alcoholic patients, enrolled within six hours of the initial alcohol-related seizure in a withdrawal episode, were randomly assigned to treatment with intravenous diphenylhydantoin (1,000 mg) or placebo. Seventy-one patients had a history of seizures during prior alcohol withdrawal episodes. Patients with a history of seizures unrelated to alcohol withdrawal were excluded. Drugs known to affect the seizure threshold or demonstrating cross-tolerance with alcohol were withheld. For each patient, the study endpoint was either (1) seizure recurrence or (2) a minimum 12-hour seizure-free observation period after completion of the study drug infusion. RESULTS: During the postinfusion observation period, six of 45 diphenylhydantoin-treated patients and six of 45 placebo-treated patients experienced at least one recurrent seizure. Equivalent diphenylhydantoin serum levels were measured in patients with and without subsequent seizures. There was no statistically significant difference between the response rates for the two treatments (p greater than 0.05). The 95% confidence interval for the difference in response probabilities was -14.0%, 14%. CONCLUSION: When administered to non-epileptic patients within six hours of the onset of alcohol withdrawal seizures, intravenous diphenylhydantoin failed to show a significant benefit over placebo in the prevention of subsequent seizures. We suggest that the well-documented risks of intravenous diphenylhydantoin therapy outweigh the potential benefit in the short-term treatment of alcohol withdrawal seizures.

Adult↗
PubMed1975

Cerebrospinal fluid acid-base and lactate changes after seizures in unanesthetized man II. Alcohol withdrawal seizures.

Acid-base changes in arterial blood and lumbar cerebrospinal fluid were correlated with simultaneously determined lactate levels in patients admitted after alcohol withdrawal seizures. Arterial and cerebrospinal fluid lactate was elevated in association with a marked respiratory alkalosis in 13 patients studied 5 to 12 hours after the seizure. Similar elevations of arterial and cerebrospinal fluid lactate were found in five patients during delirium tremens without antecedent withdrawal seizure. The cerebrospinal fluid lactate determined on admission appeared to correlate best with the length and severity of the alcohol withdrawal syndrome that developed in patients after a withdrawal seizure.

Adult↗
PubMed1994

A prediction model for identifying alcohol withdrawal seizures.

A retrospective review of alcohol withdrawal seizures was performed at a private chemical-dependence treatment facility to help identify patients who were at high risk for having a seizure. Patients were identified by two means: controlled substance records were reviewed to determine patients having received intramuscular phenobarbital, and patient charts were reviewed for all patients with a discharge diagnosis of a seizure disorder. Two thousand and one patient records were reviewed; alcohol withdrawal seizure patients were identified. Twenty-eight randomly selected nonseizure patient records served as controls. The statistical test consisted of a discriminant function analysis. The data yielded a statistically significant predictive model for alcohol withdrawal seizures based on six interdependent patient variables which will be helpful in treating future patients undergoing alcohol withdrawal.

Adult↗
PubMed2006

ECG changes amongst patients with alcohol withdrawal seizures and delirium tremens.

INTRODUCTION: Alcohol withdrawal seizures and delirium tremens (DT) are serious complications of alcohol dependence. The prevalence of arrhythmias and other electrocardiographic (ECG) changes occurring in these clinical situations is not well studied. METHODS: We performed a retrospective analysis of clinical data and ECG's from patients discharged between 1995 and 2005 with the diagnosis of DT (ICD-Code F10.4) or alcohol withdrawal seizures (F10.3). Measurement of the ECG intervals was done in lead II. The corrected QT interval (QTc) was obtained using Bazett's formula. RESULTS: 49 patients (38 males; 11 females) with a mean age of 48 years were included in the study. 23 patients with DT and 16 with convulsions were admitted to the hospitals. Ten patients developed DT while being hospitalised for other reasons. The QTc interval was prolonged (>440 ms and >460 ms in males and females, respectively) in 31 patients (63%). Five patients (10%) developed tachyarrhythmias (two torsade de pointes, one sustained ventricular tachycardia, two supraventricular tachycardia, one atrial fibrillation). All returned to sinus rhythm after appropriate treatment. CONCLUSIONS: Tachyarrhythmias are common amongst patients with severe alcohol withdrawal syndromes. The majority of the patients had an acquired long QT syndrome which led to a torsade de pointes in two cases. No patient died in the hospital and all were discharged in sinus rhythm. Clinicians should possibly avoid QT prolonging drugs and carefully monitor the rhythm in patients with severe alcohol withdrawal syndromes.

Adult↗
PubMed2001

Risk assessment of alcohol withdrawal seizures with a Kohonen feature map.

Recently, it has been suggested that alcohol-induced hyperhomocysteinaemia in patients suffering from chronic alcoholism might be a risk factor for alcohol withdrawal seizures. In the present follow-up study 12 patients with chronic alcoholism who suffered from withdrawal seizures had significantly higher levels of homocysteine (Hcy) on admission (71.43 +/- 25.84 mol/l) than patients (n = 37) who did not develop seizures (32.60 +/- 24.87 mol/l; U = 37.50, p = 0.0003). Using a logistic regression analysis, withdrawal seizures were best predicted by a high Hcy level on admission (p < 0.01; odds ratio 2.07). Based on these findings we developed an artificial neural network system (Kohonen feature map, KFM) for an improved prediction of the risk of alcohol withdrawal seizures. Forty-nine patients with chronic alcoholism (12 with alcohol withdrawal seizures and 37 without seizures) were randomized into a training set and a test set. Best results for sensitivity of the KFM was 83.3% (five of six seizure patients were predicted correctly) with a specificity of 94.4% (one false positive prediction of 19 patients). We conclude that in patients with alcohol-induced hyperhomocysteinaemia the KFM is a useful tool to predict alcohol withdrawal seizures.

Adult↗
PubMed1991

Emergency department treatment of alcohol withdrawal seizures with phenytoin.

STUDY OBJECTIVE: Prevention of recurrent alcohol withdrawal seizures is a common emergency department problem. A prospective, randomized, placebo-controlled, double-blind study of adequate size was designed to assess the efficacy of phenytoin in preventing recurrence of alcohol withdrawal seizures. METHODS: Fifty-five patients who had seized from alcohol withdrawal were randomly assigned to treatment with IV phenytoin or placebo. Patients with known seizure disorders and those receiving any anticonvulsant were excluded. The study was terminated after seizure recurrence or passage of a six-hour, high-risk seizure interval. RESULTS: Six of 28 phenytoin-treated patients (21%) had recurrent seizures compared with five of 27 placebo-treated patients (19%). The 95% confidence interval for the difference in response probabilities was +16% to -20%. There was no statistically significant difference between the response rates for the two treatments (P greater than .05). CONCLUSION: Phenytoin does not show significant benefit over placebo in preventing recurrence of alcohol withdrawal seizures.

Double-Blind Method↗
PubMed1981

Prevention of alcohol withdrawal seizures with phenytoin in rats.

The efficacy of phenytoin in the prevention of alcohol withdrawal seizures was studied in rats. Phenytoin was administrated together with and again 12 hr after the last dose of chronic alcohol feeding. Protection against alcohol withdrawal seizures was not observed when phenytoin serum levels were below 8 micrograms/ml. However, with phenytoin serum levels between 8-25 micrograms/ml, only 1 out of 32 rats had alcohol withdrawal seizures.

Acoustic Stimulation↗
PubMed2006

An assessment of the potential value of elevated homocysteine in predicting alcohol-withdrawal seizures.

PURPOSE: Higher homocysteine levels were found in actively drinking patients with alcohol dependence. Recent studies have shown that high homocysteine levels are associated with alcohol-withdrawal seizures. The aim of the present study was to calculate the best predictive cutoff value of plasma homocysteine levels in actively drinking alcoholics (n = 88) with first-onset alcohol-withdrawal seizures. METHODS: The present study included 88 alcohol-dependent patients of whom 18 patients had a first-onset withdrawal seizure. All patients were active drinkers and had an established diagnosis of alcohol dependence, according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Sensitivity and specificity were calculated by using every homocysteine plasma level found in the study population as cut-off value. A Bayes theorem was used to calculate positive (PPV) and negative (NPV) predictive values for all cutoff values used. RESULTS: The highest combined sensitivity and specificity was reached at a homocysteine plasma cutoff value of 23.9 microM. Positive predictive values ranged from 0.23 to 0.745; the maximum was reached at a homocysteine plasma level of 41.7 microM. Negative predictive values ranged from 0.50 to 0.935, with a maximum at a homocysteine plasma level of 15.8 microM. CONCLUSIONS: Homocysteine levels above this cutoff value on admission are a useful screening tool to identify actively drinking patients at higher risk of alcohol-withdrawal seizures. This pilot study gives further hints that biologic markers may be helpful to predict patients at risk for first-onset alcohol-withdrawal seizures.

Adult↗
PubMed2006

Apolipoprotein E gene polymorphism and previous alcohol withdrawal seizures.

Aim of this study was to investigate the possible association of apolipoprotein E (ApoE) gene polymorphism with a history of alcohol withdrawal seizures. We included 194 patients with alcohol dependence who were divided into patients with (SZ+) and without (SZ-) previous alcohol withdrawal seizures. ApoE genotypes were determined using PCR. For statistical analysis we examined the number of ApoE alleles (ApoE2: n=36; ApoE3: n=311; ApoE4: n=41). A significant positive association with a positive history of withdrawal seizures (SZ+) was found in the ApoE3 allele group (Fisher's exact test: p=0.006) while a significant negative association was observed in the ApoE2 allele group (Fisher's exact test: p=0.029). For the ApoE4 allele group no significant differences were found regarding a history of withdrawal seizures. Our findings suggest an association between the apolipoprotein E3 gene variant and an elevated risk of alcohol withdrawal seizures. These preliminary results must be validated in further studies.

Adult↗
PubMed1984

Should alcohol withdrawal seizures be treated with anti-epileptic drugs?

Seizures and delirium tremens were recorded among 292 randomly selected patients admitted to an in-patient alcoholism program. Despite the almost routine prophylactic use of anticonvulsant and sedative drugs the incidence of seizures and delirium tremens during detoxification in hospital was 3%. However, as most alcohol withdrawal seizures occurred immediately before admission, the overall seizure incidence was higher (10%). Those patients who developed seizures during detoxification admitted previous abuse of benzodiazepines or erratic use of phenytoin. The results suggest that prescribing of anticonvulsants to alcoholics may increase their seizure problems, because they are prone to erratic drug taking, and because of drug-alcohol interactions, increased drug metabolism and abuse of the sedative anticonvulsants.

Adult↗
PubMed1978

Enhancement of alcohol withdrawal seizures with 6-hydroxydopamine.

The relationship between central catecholamine neurons and alcohol withdrawal seizures was studied in rats pretreated with 6-hydroxydopamine to selectively destroy the central catecholamine nerve terminals. The alteration of alcohol withdrawal seizures was manifested by (1) a higher percentage of the rats developing the seizures, (2) an earlier onset of seizures, and (3) a greater severity of seizure activity. Seizure status was exhibited in 25% of the 6-hydroxydopamine-treated rats.

Acoustic Stimulation↗
PubMed1997

Molecular pathogenesis of alcohol withdrawal seizures: the modified lipid-protein interaction mechanism.

The phrase alcohol withdrawal seizures (AWS) refers to seizures that result from the withdrawal of alcohol after a period of chronic alcohol administration. A mechanism of AWS is postulated, namely the modified lipid-protein interaction (MLPI) mechanism. This hypothesis is based upon an evaluation of the mechanisms of membrane fluidity, calcium channels, gamma-aminobutyric acid (GABA) and glutamate in the molecular pathogenesis of AWS. The mechanism hypothesizes that acute ethanol treatment alters the neuronal membrane lipids which then perturbs protein events, such as affecting the GABAA receptors, NMDA receptors and voltage-dependent Ca2+ channels synergistically or in combination. Subsequent adaptations in these systems occur after prolonged administration of ethanol. A sudden withdrawal of ethanol then leads to hyperexcitability which results in AWS.

Alcohol Withdrawal Delirium↗
PubMed1990

MK-801 potently inhibits alcohol withdrawal seizures in rats.

The ability of MK-801, an N-methyl-D-aspartate (NMDA)-channel antagonist, to suppress alcohol withdrawal seizures generated audio-genically was studied in adult male rats using a cross-over experimental design. MK-801 treatment reduced overall seizure score and proportion of rats seizing. In comparison to other seizure models, alcohol withdrawal seizures seem to be particularly sensitive to MK-801, suggesting that mechanisms which result in seizure susceptibility after withdrawal of chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes.

Acoustic Stimulation↗
PubMed2006

Biological markers to predict previous alcohol withdrawal seizures: a risk assessment.

Recent studies have shown that both, elevated homocysteine and prolactin plasma levels are associated with a higher risk of alcohol withdrawal seizures. The aim of this study was to evaluate the predictive qualities of a combined assessment of homocysteine and prolactin for previous alcohol withdrawal seizures. Therefore, 117 male patients suffering from alcohol dependency were included into the study. Homocysteine was measured directly at admission, prolactin the morning following admission for detoxification treatment. Pearson's chi(2)-test showed significant results for the combined assessment of both parameters (chi(2) = 14.71, p = 0.001). Multivariate logistic regression also revealed significant predictive qualities (p = 0.001, OR = 9.23, 95%CI = 2.36-36.05). A combination of both, homocysteine and prolactin, may help to assess the individual risk of alcohol withdrawal seizures in clinical practice.

Adult↗
PubMedDate not supplied

Lack of association between hippocampal volume reduction and first-onset alcohol withdrawal seizure. A volumetric MRI study.

AIMS AND METHODS: Magnetic resonance imaging (MRI) of the hippocampus has been extensively studied in both neurological and psychiatric disorders. Furthermore, hippocampal volume reductions on MRI have been reported in patients with chronic alcoholism. The present volumetric MRI study was undertaken to determine whether an association exists between hippocampal volume reduction and first-onset alcohol withdrawal seizure. Until recently, no data as to whether hippocampal volume reductions in alcoholics might serve as a predictor of withdrawal seizures were available. RESULTS: We found the average hippocampal volumes measured by high resolution MRI to be significantly reduced in 52 alcoholics compared with 30 healthy controls. Besides a decrease of hippocampal volume in patients with chronic alcoholism, we could not find any significant correlation between the occurrence of seizures during alcohol withdrawal and the amount of hippocampal volume reduction in these patients. CONCLUSIONS: Thus, the alcoholism-related atrophy within the hippocampal formation in patients suffering from chronic alcoholism does not seem to be the source of convulsive activity in these patients. Neither does the amount of atrophy allow the occurrence of first-onset withdrawal seizures to be predicted.

Adult↗