Introduction

It has been reported that various conditions can provoke seizures, including drug intake, cerebrovascular disease, traumatic brain injury, infection, inflammation, metabolic or toxic causes, and eclampsia [1,2,3]. While treatment is needed for patients’ comorbid conditions predisposing to seizures (e.g., liver failure, renal insufficiency), drug-induced seizures can easily be limited by the cessation of administration of the offending drugs. Therefore, during the initial evaluation, it is important to consider whether the new-onset seizure is caused by drugs. Furthermore, knowledge of drugs that can potentially induce seizures is crucial for making a timely differential diagnosis in a clinical setting.

Numerous drugs associated with seizures have been reported, including antidepressants, stimulants, antihistamines, antibiotics, and anticholinergics [4, 5]. However, few studies have compared the frequency of drug-induced seizures according to the type of drug used. Thus, which drugs more frequently induce seizures among potential offending drugs is still not established. Herein, we investigated the proportion of drug-induced acute symptomatic seizures in a large population of patients with new-onset seizures admitted to our unit.

Material and methods

This study is a retrospective review of an inpatient long-term video-electroencephalography (EEG) monitoring database of 2 consecutive years. From the entire database, we selected the medical records of 363 patients who were referred to a university-affiliated hospital and completed comprehensive tests for differential diagnosis of new-onset seizure of unknown cause. All patients underwent autonomic function tests, brain magnetic resonance imaging with angiography, electrocardiography, echocardiography, and long-term video-EEG monitoring. Cerebrospinal fluid tests were also performed when necessary. Patients were classified as having epilepsy, acute symptomatic seizures, syncope, and other seizure mimicking conditions.

The etiology of acute symptomatic seizure was further classified into drug, alcohol, encephalitis, stroke, hypoxic injury, metabolic, and unclassified. Only patients with seizures that had a close temporal relationship with the administration of a potentially provocative drug, had no recurrence after discontinuation of the drug, and who met the criteria for the “certain” and “probable” classifications of the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality categories [6] were classified into drug-induced seizures. Among the drugs frequently associated with seizures, newly taken drugs within 2 weeks prior to new-onset seizures were investigated as causative drugs. The elapsed time from drug use to seizures was investigated. Serologic laboratory findings (i.e., blood urea nitrogen [BUN], creatinine, aspartate transaminase [AST], alanine transaminase [ALT], and estimated glomerular filtration rate [eGFR]) were reviewed in patients with drug-induced seizures.

Results

Of the 668 patients enrolled in the database, 363 patients presenting with new-onset seizures (mean age = 50.2 ± 20.4 years, 183 women) were included in this study. The etiologies of new-onset seizures are presented in Fig. 1a. The most common cause of new-onset seizures was epilepsy, followed by syncope and acute symptomatic seizures. The provocation factors in the patients classified as having acute symptomatic seizures were drugs (n = 43), alcohol (n = 18), encephalitis (n = 7), stroke (n = 4), hypoxic injury (n = 5), metabolic derangement (n = 2), and unclassified causes (n = 7).

Fig. 1
figure 1

(A) The bar graph represents the etiologies of new-onset seizures. (B) The left circle graph represents the proportion of drugs associated with new-onset seizures. The right circle graph represents the details of antihistamine-based combinations of drugs associated with new-onset seizures

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The proportion of causative drugs of drug-induced seizures is presented in Fig. 1b. The most common drugs associated with new-onset seizures are antihistamines, followed by stimulants, antibiotics, and other drugs, including non-steroidal anti-inflammatory drugs and tramadol. Both first-generation and second-generation antihistamines were found to induce seizures. The clinical data of patients with antihistamine-induced new-onset seizures are detailed in Table 1. All 26 patients reportedly took antihistamine within the prescribed therapeutic dosage. In patients with antihistamine-induced seizures, the values of BUN, creatinine, eGFR, AST, and ALT were all unremarkable except for one patient who had an impairment in renal function. The mean interval between drug administration and the development of seizures was 4.2 days.

Table 1 Individual clinical data of 26 patients with antihistamine-induced seizures
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Discussion

We observed that antihistamine-induced seizures accounted for a large portion of drug-induced new-onset seizures in the selected sample of patients referred to our epilepsy monitoring unit. Most patients who experienced antihistamine-induced seizures had normal renal functions and had taken the drugs within the therapeutic dosage.

Antihistamines are widely used in the treatment of allergic rhinitis, dermatitis, urticaria, and the common cold [7]. These drugs exert their anti-allergic effects by blocking H1 receptors, which are known to facilitate vasodilation, increased blood vessel permeability, and pruritus. Sedation is a well-recognized and common adverse effect of these medications [8]. However, several studies have reported that, apart from sedation, antihistamines may also increase susceptibility to seizures [9, 10].

The mechanisms underlying antihistamine-induced seizures are largely unknown. An experimental study demonstrated that seizures were significantly longer and more severe in H1 receptor knock-out mice than in wild-type mice [10]. Moreover, the administration of H1 receptor antagonists increased seizure severity and ultimately resulted in increased neuronal damage [10]. These findings suggest that, by blocking H1 receptors, antihistamines may inhibit histaminergic neurons from decreasing seizure susceptibility [10]. In patients with febrile seizures, those treated with antihistamines experienced longer seizure durations and shorter time intervals between the onset of fever and seizures than those not treated with antihistamines [9]. These clinical observations further support the hypothesis that antihistamines may increase seizure susceptibility.

Epidemiologic data regarding the seizure-inducing effect of antihistamines in the general population are scarce. Our findings showed that antihistamine-induced seizures constitute a high proportion of new-onset seizures, and that antihistamine-induced seizures occurred even with an appropriate therapeutic dose and in patients with normal renal functions. These findings imply that the antihistamines themselves may have a more significant role in causing seizures than patients’ comorbidities.

This study has several limitations. First, because the study design was retrospective and cross-sectional, the causal relationships between seizures and antihistamines would be limited. Second, our study was based on a database of patients who were referred to a university-affiliated hospital; therefore, it may be difficult to apply our findings to the general population. Finally, there was a selection bias in our study. Some patients were not included in this study because the cause of seizure was clearly identified in the emergency room and then the patient admitted to the toxicology unit, stroke unit, or intensive care unit for the treatment of the causative conditions.

Conclusions

We observed that antihistamines accounted for as much as 60% of drug-induced new-onset seizures in our population. Given that more than 40 brands of antihistamines are currently used as over-the-counter drugs worldwide, physicians should consider the possible effects of these drugs on seizure susceptibility.