Category Archives: Seizure-inducing Drugs

Prescription drugs – potential for seizures

Psychotropic Medications, Seizure-inducing Drugs, , , ,

Assessment 5 – Prescription Drugs

Introduction

There is an extensive list of prescription drugs that induce seizures (Zacarra et al., 1990; Grosset and Grosset, 2004).  Most, but not all drugs on this list, act to influence the brain in one way or another.  For example, these drugs may reduce anxiety, depression, or psychotic behavior or alternatively, may stimulate activity of the brain.  However, some drugs such as antibiotics, surprisingly, do not fit in this category, yet are capable of inducing seizures (Sutter et al., 2015 Wanleenuwat et al., 2020). Previous blogs discussed potential seizure induction with caffeine and nicotine use (http://assessment 3 and http://assessment 4).

Basically, drugs with a history of seizure induction have the potential to remove normal inhibitory influences on the brain or enhance excitatory influences, both of which produce outcomes of inappropriate nerve activity termed seizures.  

Ways drugs induce seizures

In general, drug-dependent seizures occur following use of a) higher than therapeutic drug doses (overdose) (Chen et al., 2015), b) use of drugs for prolonged periods (years) (Hill et al., 2015) or c) an abrupt withdrawal of a drug (Robertson and Sellers, 1982).  Furthermore, according to Thundiyil et al, (2010) in a prospective observational study, there are many factors which can exacerbate drug-induced seizures such as “stimulant exposure, suicide attempt, initial hypotension, and admission acidosis or hyperglycemia”.  These conditions not only complicate drug-induced seizures but may also lead to death.

This blog will focus on the seizure-inducing potential of drugs categorized as psychotropic medications.  They include a) antidepressants, b) antipsychotics and c) anti-anxiety drugs. These are drugs with ” high epileptogenic potential”, that is ability to stimulate seizures (Lee et al., 2003).

Specific drugs: Antidepressant drugs

Hill et al., (2015) completed one of the most extensive evaluations of the effects of antidepressants on seizure induction.  In the UK, this group evaluated records from 200,000 depressed patients (20-65 years of age) over a 5 year period to determine the time of first diagnosis of epilepsy/seizures while taking anti-depressant medication.  Only individuals without a prior epilepsy/seizure diagnosis were included in this study. 

Hill et al.,(2015) reported a significant increase in seizure induction with” all antidepressant drug classes”.  Hill and his associates  determined that 8 of the 11 most commonly prescribed antidepressants (see Table 1 for a list of these drugs) are associated with a first diagnosis of epilepsy/seizures.  The top three antidepressants are trazodone (Desyrel), lofepramine (Gamanil, Lomont, Tymelyt) and venlafaxin (Effexor).  The exceptions, that is antidepressants with no relation to induction of seizures, are sertraline (Zoloft), escitalopram (Lexapro) and mirtazapine (Remeron).   Interestingly, the risk of seizure induction with antidepressant use is low if drugs are used for one year or less, the duration recommended by the FDA.  Long term use, as in this study, up to 5 years is associated with a significant risk of a first diagnosis of epilepsy or seizures.

Antidepressants and mortality

Josephson et al., 2017  (electronic health records of >2 million individuals; 0.6% with epilepsy and followed for 6 years) found that use of antidepressants termed serotonin receptor uptake inhibitors (SRI) which include drugs like Effexor and Prozac, in patients with epilepsy (PWE) is associated with increased mortality, not decreased mortality as expected.  Furthermore, use of 2 or more antidepressant prescriptions whether in PWE or otherwise, is statically associated with an ” elevated risk of all-cause mortality”.  The authors indicate that their data does not prove a cause and effect relationship.  Because of the limited number of PWE, the authors were unable to determine whether increased mortality was due to seizure-related deaths.  Clinical trials are needed to determine the adverse effects of long term use of antidepressants.

Antipsychotic drugs

Antipsychotic drugs are prescribed for the treatment of psychosis (mania, paranoid states, acute schizophrenia, bipolar disorder and dementia).  Hedges et al, (2003) concluded that antipsychotic drugs have the potential to lower seizure threshold and hence induce seizures.  This applies to the older original antipsychotic drugs such as chloropromazine as well as the later second generation drugs such as Clozapine (Clozaril).  Specific reports (Alper et al., 2007; Uvais and Sreeraj, 2018) indicate that Clozapine and Olanzpine (Zyprexa) induce seizures in a dose-related manner.  It is speculated that antipsychotics induce seizures by inhibition the neurotransmitter, gamma-amino-butyric-acid (GABA).

Case study reports provide much of the data on antipsychotics and seizures.  Whereas this is important information, it lacks the rigorousness of results obtained from randomized clinical trials.  To date, no clinical trial has examined the effect of antipsychotic drugs on seizure induction, other than that which is reported in phase 4 clinical trial for FDA drug approval (accordingly, less than 1% experience seizures).  Nevertheless, caution is advised since other factors such as ” history of seizure activity, concurrent use of other drugs that lower seizure threshold, rapid dose titration, slow drug metabolism, metabolic factors and drug-drug interactions” (Hedges et al., 2003), may play a role in facilitating seizure induction with antipsychotics.

Anti-anxiety drugs

Anti-anxiety drugs belong to a class of drugs termed benzodiazepines.  This class includes one of the most commonly prescribe drugs, alprazolam (Xanax) (Ait-Daoud et al., 2018)  (see Table 1 for similar drugs).  As a class, these drugs are widely prescribed and are used for the treatment of panic disorders, obsessive-compulsive disorders, sleep disorders, muscle spasms, pre-anesthetics preparation and are also used as a standard drug choice for the treatment of convulsive disorders such as epilepsy and seizures (Goodman and Gilman, 2005).  Benzodiazepines act by binding to and stimulating a select subset of GABA receptors to facilitate the anti-anxiety  and anti-convulsive effects.

Evidence of adverse effects appeared early on, since their advent some 60 years ago of the original anti-anxiety drugs,  Librium and Valium.  In particular, it was clear that potentially serious withdrawal symptoms occurred with drug stoppage.  Importantly, abrupt withdrawal of a drug from the benzodiazepine class leads to seizures (Robertson and Sellers, 1982).  Withdrawal symptoms may be mild (headache) to severe. Specifically, “seizures, mania and death from convulsions” (Calcaterra and Barrow, 2014; Brett and Murmion, 2015) may occur.  Generally, severe withdrawal symptoms are evident after prolonged use.  Therefore, short term use of benzodiazepines not exceeding 6 months, is recommended (Brett and Murmion, 2015).

Conclusions

Antidepressants, antipsychotics and anti-anxiety drugs have the potential to induce seizures.  This comes from several comprehensive medical record assessments and a wealth of case reports.  The available data suggests that seizures occur primarily during long term use of antidepressants and antipsychotic drugs and on abrupt withdrawal of anti-anxiety drugs.

There remain many unanswered questions:

1.  There is suggestive evidence that abrupt drug withdrawal even after short term use of an anti-anxiety drug may precipitate seizures.  Unanswered: What is the minimum duration of anti-anxiety drug use for which seizure induction will not occur following discontinuation?

2. The literature suggests that drug-induced seizures are different from epilepsy.  However, Hill et al., (2015) reported that a number of patients, with no prior history of epilepsy,  received  a first diagnosis of epilepsy while on antidepressants.  Unanswered question:  Is this observation important enough to warrant confirmation by additional studies?

3.  The literature suggests that long term use of psychotropic drugs is highly associated with seizure induction.  Unanswered:  If psychotropic drugs are generally prescribed for extended periods of time, would a clinical trial be appropriate to determine the adverse effects of long term use of psychotropic drugs?

4.  Unanswered questions:  Should individuals with a prior history of epilepsy and seizure free without medication for years be prescribed psychotropic medications in the future?    Can psychotropic drugs reactivate epilepsy?

Advice

Much of the seizure-inducing potential of psychotropic drugs can be reduced with short term (12 months or less) use and a prolonged (months) withdrawal when no longer needed.   Lack of knowledge or contrary actions clearly elevate the chance for seizures or epilepsy.

Biblio-Assess-5Download

Drugs That Induce Seizures

Nicotine, Seizure-inducing Drugs, ,

Assessment 4 – Does nicotine provoke seizures?

Background

Nicotine Use; Possible source of Seizures?

My previous blog discussed the effect of caffeine consumption on the possible induction of seizures (Assessment 3).  Another widely used substance is nicotine which reportedly has the potential to induce seizures under some conditions.  The main route of nicotine use is by inhalation in smoking  tobacco.  Alternative routes include absorption in the oral cavity with chewing tobacco, snuff, nicotine gum and lozenges, and as anti-smoking aids, vaping with E-cigarettes, and transdermal absorption with a nicotine patch.  How does nicotine use relate to seizures?

Seizures and Nicotine – Confounding Issues

The scientific literature on seizures and nicotine, comprehensively reviewed up to 2014 by Rong et al.,  emphasizes the following confounding issues: 

1.  Impossible to separate nicotine from toxins in smoke

It is incredibly difficult to determine whether nicotine in smoking tobacco can provoke seizures because in the act of smoking tobacco, the smoker not only absorbs nicotine, the addictive component of tobacco, but also absorbs over 7000 other compounds (Rong et al., 2014).  Among these, some cause seizures e.g. carbon monoxide; arsenic; cresol, some prevent seizures e.g. acetone and the remainder are unstudied.  So it is not only nicotine that might provoke a seizure but anyone of a number of inhaled compounds of smoke.  Hence, it is impossible at present to sort this out.

2.  Indirect effects of smoking on health may induce seizures

A second consideration is that long term smoking produces harmful changes in the heart, blood vessels and lungs, causes inflammation and blood clots and initiates cancers.  These changes secondarily may induce seizures, and are highly probable with a stroke.   Therefore, smoking (not necessarily nicotine alone) may indirectly elevate the risk of seizures.

3.  No convincing studies on seizures and just nicotine alone

Nicotine use, other than smoking, should provide insights into the direct effects of nicotine on seizures.  However, sadly, there are no large scale interventional studies that have investigated this.

Scientific literature (nicotine and seizures) – up to 2014

There have been two prospective studies with the objective of defining the risk of smoking to seizures (see review Rong et al., 2014).  The first of these by Dworetzky et al.,( 2010) using data from the Nurses’ Health Study II, assessed the effect of chronic cigarette smoking by women 25-42 (over 110,000 participants at start in 1989) on the risk of seizures or epilepsy.  Participants answered a questionnaire every two years and self-reported seizures over a 15 year period.  Only responses with seizure verification by medical records were included.  The researchers reported a “doubling in the risk of seizures and a modest non-significant increase in epilepsy in current smokers compared with never smokers that appeared to be independent of stroke”.  Whether this was strictly due to nicotine was not determined.  

The second study (de Carvalho et al., 2012) reported the relation of smoking to seizures in a specific systemic autoimmune disease, primary antiphospholipid syndrome.  Of the 88 individuals with primary antiphospholipid syndrome, approximately 10% experienced epileptic seizures.  Chronic smoking was the only factor statistically associated with their seizures.

In contrast, several case histories of individuals diagnosed with autosomal dominant nocturnal frontal lobe epilepsy are benefitted by use of nicotine patches (Rong et al., 2014).  In these few cases, nicotine patches were comparable to antiepileptic drugs and diminished seizure frequency.   

Results of animal studies tell a different story.  By different routes, (into the brain ventricles of cats),  (subcutaneously, intraperitoneally into rats and mice), nicotine induced seizures, reduced the efficacy of antiepileptic drugs or potentiated known proconvulsant compounds or electric shock.  Doses were considered high (generally 3mg/kg or higher). 

Interestingly, studies that chronically exposed rats to cigarette smoke or administered low doses of nicotine (0.8 -2 mg), observed a protective effect against chemically-induced seizures (kainic acid  or high dose nicotine).  In other words, in animal experiments, low doses of nicotine prevent seizures while high doses (greater than obtained with routine smoking) induce seizures.

Relation of nicotine use and seizures – up to present

A small pilot retrospective study of Chinese males (278) with various types of diagnosed epilepsy analyzed the effect of smoking on seizure frequency ( Gao et al., 2017) .  While the  data show a trend that smoking reduces the frequency of seizures, the type of study design and small size limit reliability of this report.  

In contrast, in a comparison of nonsmoking epileptic patients with smoking epileptic patients, Johnson et al.,(2019) showed that smokers had a higher risk of a seizure than non smokers in the past year.  Although the study validated smoking with a biochemical test, the cross-section study design, small number of participants and weak validation of seizures in the preceding year, limit reliability of this study.  Thus to date, there are no convincing data regarding the effect of smoking on seizures in man.

In animals, injection of cigarette smoke condensate (CSC) into the cerebral ventricle of the rat induced seizures comparable to those produced by intraventricular injection of kainic acid, a known proconvulsant.  Interestingly, the effect of the CSC could be block by pretreatment with atropine, a classic  inhibitor of the nicotinic acetylcholine receptor.  This is the receptor that nicotine activates to produce its  stress reducing effects (Xiao et al., 2020).  These findings strongly supporting a mechanistic role of nicotine in the induction of seizures (Laadraoui et al., 2018).  Iha et al.(2017) identified the seizure-sensitive brain regions affected by intraperitoneal injection of a high dose of nicotine (4mg/kg nicotine) in mice and rats.  Selectively removing these areas negated the seizure-inducing effects of nicotine.  These results strongly suggest that the nicotine in animal models is a potential cause of seizures.  Unfortunately, there is no corroborative data in man. 

Vaping and Seizures

Electronic nicotine delivery systems (ENDS) e.g. e-cigarettes are marketed as a means to quit smoking.  Seizures are associated with use of ENDS as summarized in 122 voluntary reports (Faulcon et al., 2020).  Sixty-two percent indicated seizures occurred within 30 minutes after last use; 85% indicated seizures occurred within 24 hours of last use.  According to Benowitz (2020) these reports lack  biological plausibility for the following reasons:  a) timing of seizures (30 minutes-24 hours) does not relate to the presence of nicotine (minutes), b) description of nicotine poisoning differs from voluntary reports, c)  impossibility of relating recurrent seizures to last use.  It is possible that other components, added drugs or e-cigarette components may be responsible for reported seizures.

Summary

Does nicotine consumption by any route induces seizures? 

Animal studies show low doses of nicotine protect against seizures while high doses induce them.  However, contradictory results also exist.  Generally, except with toxic overdosing, the high doses used in animals are never achieved in man with smoking or other routes. 

Thus, the bottom line is that in man there is no reliable data to indicate either way whether smoking presents a risk to seizure induction or is, in fact, protective.  Furthermore, these is no data at all on the effect of chewing tobacco, snuff, patches, lozenges or gum on seizure induction.

Unfortunately and regrettably, the available science is incomplete and inadequate to convincingly state whether nicotine use a) induces seizures, b) suppresses seizures or c) is without effect in man. 

Assessment-4-referencesDownload

Drugs That Induce Seizures

Caffeine, Seizure-inducing Drugs

Assessment 3: Drugs that promote seizures – focus on caffeine

Background – Evaluating Epilepsy

There is an extended list of drugs with potential to induce seizures, and hence, are referred to as  epileptogenic drugs (Grosset and Grosset, 2004).  Drugs on this list include analgesics, antibiotics, antidepressants, and antipsychotics to name a few.  What constitutes an epileptogenic drug is complicated because it depends on variables such as dose, duration of drug use, drug withdrawal, genetic sensitivity and prior history of seizures (Chen et al., 2015).

Working Hypothesis

Epileptogenic drugs do not cause epilepsy which is defined as a disease with re-occurring seizures (focal, generalized, unknown onset) and a complex etiology (Falco-Walter et al., 2017).  Although there is no cure for epilepsy, it is managed in the majority of persons with epilepsy (PWE) with antiepileptic drugs (AEDs).  The prevailing hypothesis is that epileptogenic drugs perturb normal brain activity in favor of heightened excitability (Chen et al., 2015).  Therefore, these drugs either enhance excitatory neurons, inhibit inhibitory neurons or do both to induce excitatory changes conducive to generating seizures (Chen et al., 2015).  Importantly, when the drugs are withdrawn, the seizures stop.

Assessment 3 will focus on one of the most widely used epileptogenic drugs and probably the most controversial:  caffeine and its relative, theophylline.  Subsequent evaluating epilepsy assessments will discuss other epileptogenic drugs:  nicotine, and  antidepressant, anxiolytic and antipsychotic drugs.

Caffeine – Most widely used epileptogenic drug

Caffeine is the” most common and widely used stimulant” (Chrosciñska-Krawczyk et al., 2011).  It is present in coffee, tea, energy drinks, cola drinks, chocolate and some drugs.  Caffeine belongs to the chemical group of methylxanthines with theophylline and theobromine as important additional group members. 

Caffeine affects the brain by influencing several different neurotransmitters that relay information from nerve to nerve.  The most significant action of caffeine at physiological doses is its ability to interfere with some of the actions of the neurotransmitter, adenosine (Monteiro et al., 2016).  Adensosine, an inhibitory neurotransmitter,  mediates effects on sedation and sleep.  As a result of blocking adenosine, caffeine use produces cognitive benefits such as motivation, focus and improved attention, reduced fatigue and improved muscle performance (Monteiro et al., 2016).  These benefits are the main reason for the consumption of caffeine-containing drinks.

Significantly, adenosine is considered “an endogenous anticonvulsant and neuroprotectant of the brain”; among its many defensive activities, adenosine controls seizures and influences the progression of epilepsy (Tescarollo et al., 2020).   Consequently, it is a neurotransmitter that should not be perturbed.

Epileptogenic effects of caffeine

The role that caffeine plays in the induction of seizures and interference with the efficacy of AEDs is controversial.  This is because there is an absence of quality studies in man such as a randomized control trials to provide definitive information. 

Caffeine effects in animal studies

Caffeine and its epileptogenic actions has been studied in some detail in experiments using animal models of epilepsy.  These studies contribute to our understanding of the mechanism of action of caffeine in the brain and its proconvulsant activities and are reviewed below:

Firstly, caffeine at modest to high doses (150 mg/kg and above) lowers the seizure threshold in rodent models of epilepsy (chemically induced) (Chu, 1981; Cutrufo et al., 1992;  Matovu and Alele, 2018; Esmalili and  Heydari, 2019) and in genetically epilepsy prone rats (De Sarro et al., 1997).  One study reported that whereas low doses of caffeine were proconvulsant, a high dose was not (Esmalili and   Heydari, 2019).

Secondly, caffeine administered to seizure models already protected with AEDs increases the dose of AED needed to prevent a seizure.  This effect varies with the specific AED.  In particular acute and chronic administration of caffeine to mice receiving maximal electroshocks reduced the efficacy of a previously protective dose of phenobarbital and valproate (Depakote) (Gasior et al., 1996).  In a chemically-induced seizure in rats, high doses of caffeine diminished  the efficacy of carbamazepine (Tegretol) (Kulkarni et al., 1989).  Overall, the AED most adversely affected by caffeine pretreatment was topiramate  (Topamax) (Van Koert et al., 2018).   Other AEDs such asoxcarbazepine (Trileptal), lamotrigine (Lamictal ) and tiagabine (Gabitril)  were unaffected by pretreatment with caffeine in electroshock seizure model (Chrosecinska-Krawczyk et al., 2009). In other words, a number of AEDs do not work well in the presence of caffeine.

Clinical reports on caffeine

There are no randomized control trials in adults exploring the role of caffeine in seizure susceptibility.  Evidence to date is derived from cases studies and survey studies.  The limited evidence is this:

Firstly, it has been known for nearly 40 years that caffeine improves the efficacy of electroconvulsive therapy used to treat depression (Coffey et al., 1987), confirming its pro-excitability nature.

Secondly, a review of numerous case studies show that consumption of generally high (but not always) quantities of caffeine-containing beverages induce seizures of many types in individuals of all ages (Chrosciñska-Krawczyk, 2011; Van Koert et al., 2018).  Seizures also occur following heavy consumption of energy drinks (Iyadurai  and Chung, 2007).  In one particular case study, a PWE with excellent seizure control experienced an increased frequency when drinking large quantities of Snapple tea. Substitution with decaffeinated tea returned seizure control to normal (Kaufman and Sachdeo, 2003)

Thirdly, as reviewed by Van Koert et al.(2018), one very early report (published in French in 1960) of caffeine administration to hospitalized epileptic patients on  AEDs (mephenytoin or combination of mephenytoin and phenytoin and/or barbiturates) found that a caffeine dose (1/2  that of the AED) increases the number of seizures and EEG activity in those with generalized seizures but not focal seizures.

Fourthly, in normal volunteers, caffeine (300 mg in 3 divided doses) altered the way the body handled the AED, carbamazepine (200 mg) but not sodium valproate (400 mg) (Vaz et al., 1998).    

Fifthly, in a prospective study (Nurses Health Study II) of over 100,000 “women at-risk for incident seizure or epilepsy”, and followed by questionnaire and medical records for 15 years, found no statistical increase in risk of seizures with long term consumption of caffeine (Dworetzky et al., 2010). 

Clinical reports on theophylline, relative of caffeine

Theophylline found in tea, coffee and chocolate (Monteiro et al., 2016) is best known as a bronchodilator used to treat asthma.  This therapy has a long history of inducing “largely focal onset generalized seizures” more common in children under 5. Theophylline-associated seizures are independent of epilepsy status and mostly but not always result from higher than therapeutic doses (Nakada et al., 1983; Bahls et al., 1991; Boison, 2011).   Theophylline-associated seizures are considered a medical emergency. As a result, theophylline is no longer used to treat asthma in PWE.

Application

Animal studies indicate that caffeine is a proconvulsant in seizure models and reduces the efficacy of a number of AEDs.  The problem is translating these results to humans in the absence of rigorous clinical trials that might confirm or refute this information.  However, if scientists believe animal seizure models are valid and data from them can be used to uncover mechanisms of seizures as well as to discover new AEDs, then the caffeine data from animals deserves similar respect.  It is a shame that considering the wide spread use of caffeine, there is no definitive answer available to guide PWE.  Thus it remains prudent for PWE to avoid caffeine-containing drinks and drugs.

Assessment-3-ReferencesDownload