Current Neurology and Neuroscience Reports (2019) 19: 32 https://doi.org/10.1007/s11910-019-0948-5

EPILEPSY (C. W. BAZIL, SECTION EDITOR)

The Use of by People with Epilepsy: the Myths and the Evidence

Prisca R. Bauer1 & Josemir W. Sander2,3,4

Published online: 14 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract Purpose of Review Caffeine is the most widely consumed central nervous . For people with epilepsy, it is often unclear whether drinking coffee carries a risk of triggering seizures. Recent Findings The relationship between caffeine, seizures, epilepsy, and anti-seizure drugs is not fully understood. Clinical studies are scarce. In animal models, caffeine can increase seizure susceptibility but can also protect from seizures. Effects seem dose-dependent and are influenced by the duration of intake and the developmental stage at which caffeine exposure started. Caffeine reduces the efficacy of several anti-seizure , especially . Summary It is unclear how these findings, mainly from animal studies, can be translated to the clinical condition. At present, there is no evidence to advise people with epilepsy against the use or overuse of caffeine. Until clinical studies suggest otherwise, caffeine intake should be considered as a factor in achieving and maintaining seizure control in epilepsy.

Keywords Seizures . Cortical excitability . Energy drinks . Anti-seizure drugs . Antiepileptic drugs

Introduction [5]. There are currently no guidelines that unequivocally an- swer this question. We review current evidence on the effect of Epilepsy is a complex paroxysmal neurological condition caffeine on seizures which was also covered in a recent sys- characterized by recurrent seizures. The condition is relatively tematic review [6]. We attempt to provide some practical ad- common with a prevalence of up to 0.7% in the general pop- vice on whether people with epilepsy should be advised to ulation [1–3]. Caffeine is the most consumed central nervous reduce their caffeine intake. system (CNS) stimulant worldwide [4]. Given its stimulative Caffeine (1,3,7-trimethylxanthine) has been found to offset effects, it is not surprising that people with epilepsy and health fatigue and enhance vigilance, reaction speed, information providers question whether caffeine is a trigger for seizures processing, arousal, and motor activity. The effects of caffeine are likely due to its interaction with various neurotransmitters, This article is part of the Topical Collection on Epilepsy most importantly adenosine [7]. Adenosine is produced as a by-product of neuronal firing. [8]Itpromotessleepandre- * Josemir W. Sander duces cortical excitability through binding to the adenosine [email protected] receptors [9]. As the molecular structure of caffeine is similar to adenosine, caffeine can also bind to the adenosine A1 and 1 INSERM U1028, CNRS UMR5292, UCBL Centre Hospitalier Le A2A receptors and in doing so prevents adenosine from bind- Vinatier (Bât. 462), Neurocampus, 95 Blvd. Pinel, 69675 Bron cédex, France ing, thus acting as an adenosine antagonist. Caffeine also in- teracts with another important inhibitory neurotransmitter, 2 Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands gamma-aminobutyric acid (GABA), by modulating GABA- A receptors [10–12]. The activation of the adenosine A1- 3 NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, London WC1N receptor inhibits dopamine, a neurotransmitter involved in fo- 3BG, UK cus and motivation, and release of glutamate, an important 4 Chalfont Centre for Epilepsy, Chalfont St Peter SL9 0RJ, UK excitatory neurotransmitter. Caffeine thus increases dopamine 32 Page 2 of 7 Curr Neurol Neurosci Rep (2019) 19: 32 and glutamate release and inhibits GABA, resulting in a stim- 35,000 women receiving antenatal care in Denmark [32]. ulating net effect [13, 14]. Maternal caffeine intake during pregnancy did not influence the risk of febrile seizures in the first 3 months of life. This study did not provide long-term follow-up or information on Clinical Studies seizures other than febrile seizures. In pre-term infants, caf- feine citrate can be used to improve the microstructural devel- Case Reports opment of white matter. In a randomized controlled trial, in- fants were given either the standard dose of 30 mg/kg or a high Several case reports have suggested that caffeine can trigger dose of 80 mg/kg of caffeine citrate [33]. In the group receiv- seizures in people with epilepsy. Seizures were either found to ing the high dose, there was a non-significant trend for more occur after the intake of unusually high (toxic) caffeine doses numerous and longer seizures compared to children that had [15–22] or after prolonged periods of caffeine intake [23–27]. received the standard dose. One case report describes a woman with several episodes of The anti-seizure drug enhanced caffeine clear- status epilepticus (SEs) occurring at weekends [27]. She reg- ance and the mean half-life of caffeine was reduced by almost ularly drank almost 2 l of coffee on Fridays to Sundays, and 50%. and valproic acid did not affect caffeine around half a liter of coffee on weekdays. When she stopped metabolism [34]. drinking coffee at the weekends, she had fewer seizures and no episodes of SEs [27]. In another case, a man with at least six focal pharmacoresistant seizures weekly became seizure- Animal Studies on the Effects of Caffeine free after stopping drinking more than 2 l of coffee per day on Seizures [25]. Conversely, there is a report of a man with generalized epilepsy who had been seizure-free on anti-seizure medica- Seizures after Caffeine Exposure tion, but his seizures recurred when he started drinking large quantities of caffeinated iced tea [23]. The seizures decreased In studies with rats, mice, rabbits, guinea pigs, cats, and dogs, again when he started to drink decaffeinated iced tea. There it has been found that extremely high doses of caffeine in- are also anecdotal reports of seizures after the intake of energy crease brain excitability and trigger seizures and encephalop- drinks [28]. Caffeine was also found to prolong seizures after athy. Caffeine is therefore used as an animal model of seizures electroconvulsive therapy, a treatment for severe depression [35]. When seizures are triggered by other agents such as [29]. (PTZ), another animal model for epilepsy, caffeine also lowers the seizure threshold [36–39]. Clinical Studies on the Effect of Caffeine on Seizures Seizures after Maternal Caffeine Exposure There are only a few clinical studies on the effect of caffeine on seizures. One was an observational study of people attend- The offspring of rat dams that received caffeine during preg- ing hospital after a seizure. They were asked about their usual nancy in doses that would be equivalent to about three to four caffeine intake [30]. On average, the coffee consumption on cups of coffee a day in humans was shown to be more sus- the day preceding the seizure was not higher than their average ceptible to seizures induced by hyperthermia or than consumption, or than their coffee consumption on a seizure- controls that received only water [40, 41•]. In the pups that had free day. About two-thirds of them were diagnosed with epi- been exposed to caffeine, there was a delayed migration of lepsy. In this subgroup, there was a trend towards less caffeine GABAergic neurons into the hippocampus which was not consumption prior to the seizure compared to the habitual found in controls. This delayed migration was associated with intake, which was statistically significant in those with gener- a general increase in neuronal network excitability [40]. alized epilepsy [30]. This may suggest that caffeine withdraw- Another study reported no difference in adenosine A1, A2A, al plays a role in triggering seizures in some forms of epilepsy. and GABA-A receptor mRNA expression in rat pups that had Two other studies were large questionnaire studies, exam- been exposed to caffeine in utero compared to a control group ining the effect of prolonged caffeine intake on seizures and that had not [42]. epilepsy. The first study assessed several health and lifestyle parameters in over 100,000 nurses, including epilepsy, sei- Protective Effects of Caffeine zures, and caffeine intake [31]. Those reporting seizures or epilepsy did not have a different caffeine intake than the total It may come as a surprise that there are studies in animals cohort. A second study assessed whether caffeine exposure in suggesting that caffeine may have protective effects against the womb influenced the development of febrile seizures, epilepsy and seizures. In young rodents, for example, using a questionnaire on lifestyle during pregnancy of over prolonged, low-dose caffeine exposure was shown to decrease Curr Neurol Neurosci Rep (2019) 19: 32 Page 3 of 7 32 seizure susceptibility. One study administered caffeine to rats intracranial EEG recordings were dose-dependently reduced in the first week after birth [43]. They were also infused with after a single medium dose of caffeine, compared to the base- one of five pro-: PTZ, , , line. This study found no effect of more chronic exposure to , or until the first myoclonic jerk ap- caffeine [52]. A more recent study also showed a decrease in peared. Compared to controls, rat pups that had been exposed SWD’s after the administration of caffeine, linked to an in- to caffeine had a 20–40% higher seizure threshold to PTZ at crease of cytokine levels (IL-6 and NFkB) in the thalamus 28 days after birth. There was a further increase in seizure [53]. In a rat model of severe traumatic brain injury, a single threshold (40–50% elevation) to PTZ and picrotoxin in rats dose of caffeine also reduced the duration of epileptic bursts of 42 days old that had been given caffeine compared to con- [54]. Interestingly, it was shown that a single dose of caffeine trols. In adulthood (70–90 days), the caffeine group showed a significantly reduced the incidence of seizure-induced respi- significant increase in seizure threshold for PTZ and kainic ratory arrest in mice, which may be involved in sudden death acid compared to controls. In another study, chronic low doses in epilepsy (SUDEP) [55•]. Overall, it appears that caffeine of caffeine 7–11 days after birth significantly elevated the has neuroprotective effects against seizures in animal models seizure threshold for generalized tonic-clonic seizures of absence epilepsy, after early life convulsions and traumatic (GCTS) but not for myoclonic jerks or minimal clonic sei- brain injury. The effect depends on age, pro-, sei- zures [44]. The seizure threshold in response to electrical stim- zure model, caffeine dose, and administration method. ulation was not altered in rats that received caffeine repeatedly for 7 to 11 days, or for 13 to 17 days after birth [45], nor when Interactions Between Caffeine and Anti-Seizure electrical seizures were induced at 67 days [46]. In a PTZ in Animal Models model of absence and myoclonic seizures, low-dose exposure to caffeine reduced the frequency of seizure-like episodes and Contrary to clinical studies, there is a relatively large number of shortened their duration in a dose-dependent fashion [47]. The studies on the interaction between caffeine and anti-seizure med- anti-seizure medication is commonly used to ication in animal models. In many, maximal electroshock (MES) treat neonatal seizures but carries the risk of inducing neuro- was used to induce seizures to assess the effects of caffeine degeneration [48•]. A study was carried out to assess the neu- administration on the properties of drugs roprotective properties of caffeine to counter the degeneration [56–61, 62•]. Rats were injected with caffeine as well as one of caused by phenobarbital. On day 4, after birth, the rat the following ASMs: carbamazepine, phenytoin, phenobarbital, pups received phenobarbital with or without caffeine for valproic acid, felbamate, oxcarbazepine, lamotrigine, tiagabine, three consecutive days. In the brains of rats that re- gabapentin, and topiramate. Single-dose caffeine injections re- ceived phenobarbital only, there was an increase of cell duced the seizure threshold and increased the amount of pheno- death, not seen in pups which had received caffeine co- barbital, carbamazepine, phenytoin, topiramate, gabapentin, treatment. Caffeine appeared to reduce inflammatory cy- valproic acid, and felbamate needed to protect 50% of the rats tokines and neurotoxicity and to counter the reduction against electroconvulsions, whereas no changes were seen for of A1- and A2A receptors induced by phenobarbital oxcarbazepine, lamotrigine, and tiagabine [56–58, 60, 61, 62•]. [48•]. In juvenile rats, caffeine combined with ethanol When caffeine was chronically administered, the amount of phe- increased the vulnerability to seizures triggered by PTZ, nobarbital, carbamazepine, phenytoin, topiramate, gabapentin, whereas caffeine alone had a protective effect [49]. and valproic acid needed to protect 50% of the rats against sei- zures was also increased, but again unaltered for oxcarbazepine, Caffeine Exposure in Adult Rodents lamotrigine, and tiagabine [57, 59–61, 62•]. The results of studies using other animal models of epilepsy such as PTZ or rhythmic Studies on the potential protective effects of caffeine against vestibular stimulation were also in line with these findings [63]. seizures and epilepsy in adult animals have shown conflicting Caffeine significantly decreased the amount of PTZ needed to results. One study found no effect of chronic low-dose expo- induce seizures compared to saline [38]. , however, sure to caffeine on seizures triggered by picrotoxin or kainic increased the threshold to PTZ-induced seizures. When diaze- acid compared to the control (water) [50]. Another study, pam and caffeine were given together, the anticonvulsant effect however, found that the duration of convulsions was signifi- of diazepam was decreased. When inducing seizures with PTZ in cantly decreased in animals receiving caffeine over several mice and rats treated with ethosuximide, carbamazepine, clonaz- days compared to injection with saline [51]. The differences epam, phenobarbital, or valproic acid [39, 64], the amount of between these two studies may be explained by methodolog- ethosuximide needed to protect 50% of the mice [39]andthe ical differences, including the different methods of caffeine amount of carbamazepine needed to protect all the rats against administration, and use of different pro-convulsive triggers. seizures [64] was significantly elevated compared to the control In a rat model of genetic absence epilepsy, the number and group/condition. In mice, there were no effects for clonazepam, duration of spike-and-wave discharges (SWDs) on phenobarbital, and valproic acid. 32 Page 4 of 7 Curr Neurol Neurosci Rep (2019) 19: 32

The interaction effects between caffeine and ASMs may Interestingly, adenosine has a role in seizure termination and occur on two different levels. First, as the concentrations of postictal depression [78, 79] potentially also through control phenobarbital, clonazepam, phenobarbital, valproic acid, car- of free radicals [80, 81] which were shown to play a role in bamazepine, gabapentin, topiramate, and ethosuximide were epileptogenesis [81, 82]. Long-term exposure to low doses of unaffected in the presence of caffeine, caffeine may act as an caffeine may have neuroprotective influences by changing antagonist of the anticonvulsant properties of these medica- A1- [83–85] and A2-receptor [54, 86, 87] density and sensi- tions [39, 58, 61, 62•]. Second, more simple explanation of the tivity to adenosine and caffeine [83]. These effects are area- pharmacodynamic interaction between caffeine and ASMs is [83] and age-dependent [83–85, 88]. Caffeine-exposure in that caffeine increases seizure susceptibility, indirectly in- early life may have more protective effects than in adulthood, creasing the need for drugs, which makes it analogous to the most likely because there are more changes in A-receptor interaction between any seizure precipitants. density at young ages [83–85, 88]. Our quantitative analysis of previously published studies has shown that the interaction of caffeine and ASMs varies greatly between AEDs. While all ASMs seem to be affected by caffeine to some extent, topiramate has the strongest inter- Discussion action with caffeine. Overall, there was no difference in the interaction with ASMs when comparing a single caffeine dose Evidence mainly from animal studies seems to show that caf- with repeated caffeine administration, except for carbamaze- feine can either increase seizure susceptibility or protect pine, in which the interaction with caffeine was stronger when against seizures. The effect depends on the dose, administra- caffeine was administered chronically [6]. tion type (a single dose or long-term exposure), and the de- velopmental stage at which exposure to caffeine started. In Pathophysiological Mechanisms Potentially animal studies, caffeine interacted with some ASMs, particu- Underlying the Effect of Caffeine on Seizures larly topiramate. Single-high doses of caffeine seem more likely to trigger seizures than repeated low doses of caffeine, What then may the pathophysiological mechanisms underly- suggesting the development of tolerance to A1- and A2A- ing these different effects of caffeine on seizures? First, seizure receptor blockade by caffeine [43, 46, 47, 52, 85, 89, 90]. susceptibility depends on brain excitability, which is influ- Some studies show conflicting results, which may have enced by genetics, structural anomalies, internal factors such been produced by the use of different models pertaining to as hormones and sleep, and external factors such as diet. different epilepsy types [40, 42, 52, 70, 90], different ways Genetics may influence (caffeine-related) seizure susceptibil- of inducing seizures [39, 58], different methods for caffeine ity in individuals, as suggested by a study in genetically mu- administration, and different doses of caffeine or chemical tated mice [65]. A more recent study suggests that caffeine can pro-convulsants [50–52, 70, 90]. Some sample sizes are small, induce epigenetic changes that affect neuronal excitability, limiting their reliability [38, 39]. which may underlie epileptogenesis [66]. Sleep deficiency is Translating findings of animal studies to humans is a major an independent seizure trigger, and epilepsy can disturb sleep challenge. There is a difference in caffeine metabolism be- [67–69], as caffeine counters fatigue [4] and the sleep- tween humans and animals. Caffeine doses used in many an- promoting effects of adenosine [9], the effects of caffeine on imal studies are much higher than the estimated equivalent seizure susceptibility may be related to its sleep-disrupting average human caffeine consumption. So far, the findings effects. Conversely, decreased or suboptimal sleep due to ep- from animal studies have not been replicated in clinical studies ilepsy and seizures may increase caffeine intake and increase and provocative or protective effects of caffeine on seizure seizure susceptibility. susceptibility have not been seen in humans [30–33]. Early studies show that caffeine interferes with the process- Like animal studies, there are some limitations to previous es that terminate the electrical seizure activity [70]. Results clinical studies. Caffeine intake, for example, was measured as from in vitro studies show that caffeine causes an increase in “units per day” [30–32, 67]. This method has limitations as the intracellular Ca2 release and Ca2 influx, which is linked to size of units (cups) and concentration of caffeine probably increased seizure activity through elevated neuronal excitabil- differed between studies and participants. These studies also ity and synchronous firing of neurons [71–73]. Similarly, caf- relied on self-reports, which are sensitive to recall and re- feine may facilitate seizures by changing potassium currents sponse biases. Selection bias may have been present in studies leading to a less negative membrane potential [74], and by in which only women were included [31, 32]. If it is true that binding with the inhibitory A1-receptor subtype for endoge- caffeine does not significantly affect seizure susceptibility in nous extracellular adenosine [75, 76]. Recent findings suggest humans, the lack of studies reporting such findings could be a the involvement of the A2a-receptor for adenosine, which result of publication bias, as negative results are notoriously may explain the dose-dependent effects of caffeine [77]. hard to publish. Curr Neurol Neurosci Rep (2019) 19: 32 Page 5 of 7 32

Future Research Neurology, and receives research support from the Marvin Weil Epilepsy Research Fund. We highlight the scarcity of clinical data on the effects of Human and Animal Rights and Informed Consent This article does not caffeine on seizures and epilepsy. Findings from animal stud- contain any studies with human or animal subjects performed by any of ies show that the relationship between seizures, AEDs, and the authors. caffeine is complex. Translating these results to a human sce- nario is challenging, which makes it impossible to develop clear clinical recommendations regarding the consumption of caffeine in people with, or at risk of, epilepsy. 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