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).

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  Importantly, when the drugs are withdrawn, the seizures stop.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.