Alcohol withdrawal produces changes in excitability, population discharge probability, and seizure threshold

Alberto, Greg E.; Klorig, David C.; Goldstein, Allison T; Godwin, Dwayne W.

doi:10.1111/acer.15004

Cited by 3 publications

(8 citation statements)

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“…have demonstrated that one‐third of patients with a history and presence of ARS developed DT during withdrawal syndrome. Moreover, some reports have suggested that individuals diagnosed both with ARS and DT may be representing a genetically homogenous subgroup 24,30–35 . By demonstrating that the presence of DT has an explanatory role in developing ARS, our results support these observations.…”

Section: Discussionsupporting

confidence: 89%

“…Moreover, some reports have suggested that individuals diagnosed both with ARS and DT may be representing a genetically homogenous subgroup. 24,[30][31][32][33][34][35] By demonstrating that the presence of DT has an explanatory role in developing ARS, our results support these observations. Moreover, although several reports have evaluated that various factors such as older age, male sex, high blood level of homocysteine, low platelet count, low potassium level, and psychiatric and somatic co-morbidities can be risk factors for developing DT, 19,36,[43][44][45] the interplay of the occurrence of ARS and DT has not been evaluated in detail.…”

Section: Discussionsupporting

confidence: 84%

“…background of withdrawal seizures is different from that of other provoked seizures. [30][31][32][33][34][35] Additionally, it has been suggested that the severity of AWS may not be dependent on the presence of ARS. 10 Furthermore, it has been indicated that delayed climax of the severity of withdrawal, higher prevalence of cortical lesions, and history of DT and detoxification admissions could be determining factors to predict the presence of ARS.…”

Section: Key Pointmentioning

confidence: 99%

“…Moreover, it has been evaluated that since repeated seizures may render the central nervous system more excitable, a history of ARS can lead to the development of an epileptogenic state of the brain, which may be a potent risk factor for developing a future seizure during withdrawal syndrome 28,29 . Various reports have also revealed that the genetic and molecular background of withdrawal seizures is different from that of other provoked seizures 30–35 …”

Section: Introductionmentioning

confidence: 99%

“… 28 , 29 Various reports have also revealed that the genetic and molecular background of withdrawal seizures is different from that of other provoked seizures. 30 , 31 , 32 , 33 , 34 , 35 …”

Section: Introductionmentioning

confidence: 99%

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Characterization of alcohol‐related seizures in withdrawal syndrome

Kádár,

Gajdics,

Pribék

et al. 2024

Epilepsia Open

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ObjectiveAlcohol‐related seizures (ARS) are one of the most important consequences of alcohol withdrawal syndrome (AWS). However, demographic and clinical characteristics, and furthermore, the relationship of ARS with delirium tremens (DT), have not yet been evaluated in detail. Therefore, the aim of the present study was to reveal the correlates of ARS and examine the interaction of ARS with the occurrence of DT and with the severity of AWS.MethodsIn the retrospective study (Study 1) 2851 medical charts of inpatient admissions characterized by AWS and DT were listed. Demographic and clinical variables of ARS were assessed. In the follow‐up study (Study 2), patients admitted with AWS without (N = 28) and with (N = 18) ARS were enrolled. Study 1 was performed between 2008 and 2023, and Study 2 was performed in 2019 in Hungary. To determine the severity of AWS, the Clinical Institute Withdrawal Assessment Scale for Alcohol, Revised (CIWA‐Ar) was used. ARS is a provoked, occasional seizure; therefore, patients with epilepsy syndrome were excluded from the two studies. Statistical analyses were performed by the means of chi‐square tests, multinomial logistic regressions, mixed ANOVA, and derivation.ResultsThe occurrence of DT, the history of ARS, and somatic co‐morbidities were found to be risk factors for the appearance of ARS. ARS was proved to be a risk factor for the development of DT. In the follow‐up study, there was no difference in the decrease of CIWA‐Ar scores between the groups.SignificanceOur present findings support the likelihood of kindling, which is one of the most important mechanisms underlying the development of ARS, but do not directly prove its presence. Additionally, our results revealed that the severity of AWS is not influenced by the presence of ARS.Plain Language SummaryProvoked, occasional seizures during AWS are defined as ARS. In the present study, predictors and interactions of these seizures with DT—the most severe form of withdrawal—and with the severity of withdrawal were examined in retrospective and follow‐up studies. The present study shows that a history of withdrawal seizures, the occurrence of DT, and somatic comorbidities are predictors of the development of seizures. Furthermore, our findings suggest that the presence of seizures does not influence the severity of withdrawal.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 84%

Section: Key Pointmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of alcohol‐related seizures in withdrawal syndrome

Kádár,

Gajdics,

Pribék

et al. 2024

Epilepsia Open

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Cannabidiol regulates behavioral and brain alterations induced by spontaneous alcohol withdrawal

2023

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Protein kinase C epsilon‐mediated modulation of T‐type calcium channels underlies alcohol withdrawal hyperexcitability in the midline thalamus

Shan,

Smith,

Klorig

et al. 2024

Alcohol, Clinical and Experimental Research

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BackgroundMillions of people struggle with alcohol use disorder (AUD). Abrupt abstinence after a period of chronic alcohol use can precipitate the alcohol withdrawal syndrome (AWS), which includes hyperexcitability and, potentially, seizures. We have shown that T‐type Ca2+ channels are novel, sensitive targets of alcohol, an effect that is dependent upon protein kinase C (PKC). The purpose of this study was to (1) understand midline thalamic neuronal hyperexcitability during alcohol withdrawal and its dependence on PKC; (2) characterize T channel functional changes using both current clamp and voltage clamp methods; and (3) determine which PKC isoform may be responsible for alcohol withdrawal (WD) effects.MethodsWhole‐cell patch clamp recordings were performed in midline thalamic neurons in brain slices prepared from C57bl/6 mice that underwent chronic intermittent alcohol exposure in a standard vapor chamber model. The recordings were compared to those from air‐exposed controls. T‐channel inactivation curves and burst responses were acquired through voltage‐clamp and current‐clamp recordings, respectively.ResultsWhole‐cell voltage clamp recordings of native T‐type current exhibited a depolarizing shift in the voltage‐dependency of inactivation during alcohol withdrawal compared to air‐exposed controls. A PKCε translocation inhibitor peptide mitigated this change. Current clamp recordings demonstrated more spikes per burst during alcohol withdrawal. Consistent with voltage clamp findings, the PKCɛ translocation inhibitor peptide reduced the number of spikes per burst after WD.ConclusionWe found that alcohol WD produces T channel‐mediated hyperexcitability in the midline thalamus, produced in part by a shift in the inactivation curve consistent with greater availability of T current. WD effects on T current inactivation were reduced to control levels by blocking PKCε translocation. Our results demonstrate that PKCε translocation plays an important role in the regulation of alcohol withdrawal‐induced hyperexcitability in midline thalamic circuitry.

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Alcohol withdrawal produces changes in excitability, population discharge probability, and seizure threshold

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 3 publications

References 38 publications

Characterization of alcohol‐related seizures in withdrawal syndrome

Characterization of alcohol‐related seizures in withdrawal syndrome

Cannabidiol regulates behavioral and brain alterations induced by spontaneous alcohol withdrawal

Protein kinase C epsilon‐mediated modulation of T‐type calcium channels underlies alcohol withdrawal hyperexcitability in the midline thalamus

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