Abstract
Sansone G, Megevand P, Vulliémoz S, Corbetta M, Picard F, Seeck M. Eur J Neurol. 2024;31(1):e16075. doi:10.1111/ene.16075
Alcohol withdrawal seizures (AWS) are a well-known complication of chronic alcohol abuse, but there is currently little knowledge of their long-term relapse rate and prognosis. The aims of this study were to identify risk factors for AWS recurrence and to study the overall outcome of patients after AWS. In this retrospective single-center study, we included patients who were admitted to the Emergency Department after an AWS between January 1, 2013 and August 10, 2021 and for whom an electroencephalogram (EEG) was requested. AWS relapses up until April 29, 2022 were researched. We compared history, treatment with benzodiazepines or antiseizure medications (ASMs), laboratory, EEG and computed tomography findings between patients with AWS relapse (r-AWS) and patients with no AWS relapse (nr-AWS). A total of 199 patients were enrolled (mean age 53 ± 12 years; 78.9% men). AWS relapses occurred in 11% of patients, after a median time of 470.5 days. Brain computed tomography (n = 182) showed pathological findings in 35.7%. Risk factors for relapses were history of previous AWS (p = 0.013), skull fractures (p = 0.004) at the index AWS, and possibly epileptiform EEG abnormalities (p = 0.07). Benzodiazepines or other ASMs, taken before or after the index event, did not differ between the r-AWS and the nr-AWS group. The mortality rate was 2.9%/year of follow-up, which was 13 times higher compared to the general population. Risk factors for death were history of AWS (p < 0.001) and encephalopathic EEG (p = 0.043). Delayed AWS relapses occur in 11% of patients and are associated with risk factors (previous AWS >24 h apart, skull fractures, and pathological EEG findings) that also increase the epilepsy risk, that is, predisposition for seizures, if not treated. Future prospective studies are mandatory to determine appropriate long-term diagnostic and therapeutic strategies, in order to reduce the risk of relapse and mortality associated with AWS.Background and purpose:
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Commentary
Alcohol is ubiquitous in our society—sports bars, celebrity sponsored spirits, Super Bowl ads, to name a few. Alcohol, or more specifically alcohol withdrawal, is one of the most common causes of seizures presenting to the emergency department (ED). We are experts in epilepsy, but also in seizures, including acute symptomatic seizures such as alcohol withdrawal seizures (AWS). How big is the problem? More than 16 million people in the United States are classified as having an alcohol use disorder. 1 When a person with chronic heavy alcohol use presents to hospital, the incidence of AWS is 1.9% to 6.7%. 2 Alcohol withdrawal seizures are a preventable cause of seizures, so research and knowledge about AWS with related health care policy implementation should be a high priority.
Alcohol withdrawal seizures are defined as acute symptomatic seizures occurring within 6 to 48 hours after reduction or cessation of heavy alcohol use. During acute alcohol intoxication, excitatory NMDA receptors in the brain are depressed and inhibitory GABA-B receptors are stimulated. With chronic alcohol exposure, NMDA receptors are upregulated and GABA-B receptors downregulated. During alcohol withdrawal, in the absence of alcohol, excess NMDA hyperexcitability can lead to generalized convulsive or nonconvulsive seizures. 3
The authors conducted a retrospective, single centre study of 199 patients with convulsive AWS admitted to the regional medical center at the University Hospital of Geneva between 2013 and 2021, to examine their long-term follow-up and risk factors. 4 The hospital covers the region (or canton) around Geneva, serving a population of around 500,000.
The most common profile were males aged 40 to 60 years. In a median follow-up of 4.8 years, the authors found that 22 (11%) patients had AWS relapses with a median time to relapse of 470.5 days. Follow-up was confined to those representing to the ED with recurrent AWS. For purpose of analysis, patients were divided into those with and without relapses after the index seizure. Risk factors for relapse were at least 1 prior AWS—11 (50%) patients in the relapse group and 44 (24.8%) patients in the no relapse group.
Almost all patients had electroencephalogram (EEG) performed (given a year round EEG service) which were classified into “normal” (but which included beta or nonspecific focal slowing, 88.8% of patients), or encephalopathy with diffuse slowing (6.6% of patients), or epileptiform discharges (5.1% of patients). On analysis of computed tomography (CT) head results, 35.7% of patients had pathological CT findings, including 26.3% with brain atrophy, 10.4% with hemorrhage, 3.3% with trauma, and 2.2% with cranial fractures.
Epileptiform discharges on EEG and cranial fractures on CT head were more frequent in the relapse group and supports that CT head and EEG can provide important prognostic information. The authors highlight that these are similar to epilepsy risk factors although numbers were small, and not corrected for multiple comparisons. EEG may also inform as to the presence of an underlying genetic epilepsy in a younger patient, non-motor seizures, or focal abnormalities in the presence of an underlying lesion. 5
Twenty-five patients died (12.5%) in follow-up with a median of 811 days from the index AWS. The calculated yearly mortality rate was 2.9%, with no difference between the relapse and no relapse groups. Mortality was higher in patients with a history of prior AWS (up to 6.2% per year, relative risk of death 3.9) and/or encephalopathic EEG. The expected mortality in the same age-group in the region is 0.22% per year. The average age at death was 59.2 years, lower than expected. This is consistent with prior studies and supports a potential window of opportunity to prevent mortality in those presenting with AWS. 6
The authors looked at any prior use of benzodiazepines (BDZ) or anti-seizure medications (ASM). However, there was insufficient data to determine meaningful conclusions, although history of any use did not seem to affect relapse or mortality.
A history of BDZ use was seen in 46.7% of subjects, more prevalent in the non-relapse group, which could support a protective effect on the brain, rather than an additional relapse risk from BDZ withdrawal seizures. While the study focused on long-term outcomes, there was a protocol for early BDZ use in their ED for AWS and no early recurrent AWS occurred in any of the patients.
There are limits to the clinical significance of the findings, given the retrospective nature of the study with follow-up confined to those who represented to the same hospital. The study did not look at non-motor seizures, and while seizures on EEG are mentioned, more information is not provided. The results are linked with alcohol dependence prevalence in Switzerland so are not generalizable to countries where rates are much lower, such as Muslim-majority countries or higher, such as in Eastern Europe. National alcohol consumption rates are reported in liters of pure 100% alcohol per resident per year. Six liters of pure alcohol per year is equivalent to 50 bottles of wine a year (assuming 12% alcohol content). The national consumption rate in Switzerland is 11.5 liters per resident per year and 4.3% of Swiss adults are alcohol dependent, slightly higher than average. In comparison, the US national consumption rate is 9.87 liters of alcohol per resident per year. 7
How do we best serve this vulnerable but neglected patient group with AWS? Should patients with AWS be referred to a neurologist? The authors ask whether viewing AWS as purely acute symptomatic seizures should be reconsidered given a higher risk for recurrence. However, the rate of recurrence is well below the 60% recurrence risk over 10 years threshold suggested by the ILAE for epilepsy diagnosis and subsequent ASM use, and AWS are, in essence, provoked in nature. Previous trials of ASM after AWS did not show a consistent benefit. Benzodiazepines have the most evidence for reduction in acute recurrent AWS seizures and alcohol withdrawal symptoms, either as a set protocol for higher risk patients or in a symptom-triggered fashion. However, therapeutic studies are small and biased. 8 There is some evidence that chronic alcohol exposure and repeated detoxification can have a kindling effect on the brain. 9 Repeated heavy alcohol use can also have neurotoxic potential, and high rates of brain atrophy were noted in this study. 10
However, care should be taken not to erroneously diagnose epilepsy in patients with only AWS. Other provoking factors may coexist such as BDZ withdrawal, hyponatremia, and trauma. How can we differentiate an AWS from an epileptic seizure clinically? Alcohol withdrawal seizures typically occur with other alcohol withdrawal symptoms such as autonomic hyperactivity, hallucinations, insomnia, psychomotor agitation, tremor, or anxiety. Postictal symptoms such as restlessness, tremor, tachycardia, anxiety, sleeplessness, and sweating are more common after AWS than epileptic seizures. 11 Some authors suggest preventative treatment with ASM only after severe recurrent AWS or if recurrent unprovoked seizures emerge. 12
Public health measures aimed at educating the public about the dangers of alcohol dependency, as well as policies to reduce alcohol consumption such as limiting alcohol sale to minors and reducing advertising to vulnerable groups, are important. To remind ourselves, in the United States, the definition of safe alcohol consumption (“drinking in moderation”) is no more than 2 alcohol drinks in a day with no more than 14 in a week (men) or 1 in a day, or 7 a week (women or those aged >65 years). 13 Identification and intervention with closer follow-up, perhaps with combined neurology and addiction services input, of those presenting with an AWS should occur in our health programs and clinics.
