What are the challenges with the pharmacological management of epilepsy in patients with Attention Deficit Hyperactivity Disorder (ADHD)?

KEYWORDS:

• ADHD
• antiepileptic drugs
• attention
• behavior
• cognition
• epilepsy
• management

1. Introduction

Epilepsy is one of the most common neurologic disorders in pediatric age, with a prevalence ranging from 3.2 to 5.5/1000, and an incidence from 40 to 180 per 100.000 [1]. Attention deficit hyperactivity disorder (ADHD) is a very frequent condition, as well. Psychiatric comorbidities are common in epilepsy patients, and among these comorbidities, ADHD is one of the most important. Epilepsy and ADHD have a complex relation, which can be confirmed by their relatively high comorbid occurrence and the possible existence of a bidirectional relation, whereby not only are people with epilepsy at greater risk of developing ADHD but also patients with ADHD are at higher risk of developing epilepsy. Indeed, ADHD can be present in about 12–40% of epileptic children, especially in those affected by peculiar types of epilepsy such as frontal lobe epilepsy, childhood absence epilepsy, and benign epilepsy with centro-temporal spikes [2].

The relationship between epilepsy and ADHD is more complex than expected: the presence of possible structural abnormalities of the central nervous system can be one of the causes of this association. There is a recent report about abnormal cortical structures (cortical thinning) found in children with benign epilepsy with centro-temporal spikes and ADHD: this cortical thinning is present also in epileptic children without ADHD, but patients with ADHD showed thinner cortical areas [3]. Apart from these data, in general, although the link between epilepsy and ADHD is still incompletely understood, epileptic children had a high level of parents’ reported behavioral difficulties and a high risk for ADHD, particularly in children with poor seizure control and higher seizure frequency [4]. Other possible causes of ADHD in epileptic patients are the adverse effects of antiepileptic drugs (AEDs). This point is important to remember because the choice of an appropriate AED depends on several factors: age, seizure types, epileptic syndrome, and possible adverse effects.

It is also essential to underline that diagnosis of ADHD in epileptic children is often underestimated because parents do not refer symptoms to the physicians and also because physicians suppose that ADHD symptoms are due to adverse effects of AEDs; moreover, often, the onset of ADHD can predate the symptoms of epilepsy.

The co-occurrence of ADHD and epilepsy may be based on several mechanisms, as underlying brain abnormalities, a genetic predisposition, a dysregulation of the neurotransmitters system [5], the chronic effects of ongoing seizures, the side effects of AEDs, and the presence of psychosocial factors [6].

2. Therapeutic implications for drugs for ADHD

It is well known that the treatment of children with chronic neurological diseases as ADHD and epilepsy must be based on a multimodal comprehensive therapeutic strategy, and in this strategy, drugs are only one of the components. The therapy of children suffering from both epilepsy and ADHD is a challenging problem for the physicians who must try to avoid AEDs that can worse attention and/or behavior.

Generally, drug treatment in children with ADHD begins with a stimulant drug (e.g. methylphenidate or amphetamine) or with atomoxetine [7,8]. Methylphenidate blocks dopamine and noradrenaline reuptake into neurons with consequent stimulation of the cerebral cortex. Among the studies that addressed the possible effect of methylphenidate on epilepsy, we must remember an open-label study carried out on 25 children with ADHD and epilepsy. This study showed that only 2 children had seizures during the study. Gucuyener K et al., also confirmed, in a group of 57 children with ADHD and active epilepsy that their seizure frequency did not modify during treatment with methylphenidate [9]. More recently, another open-label study that enrolled 30 epilepsy patients and ADHD showed that only one out of these 30 patients withdrew methylphenidate after seizure worsening [10]. Auvin A et al., in 2018 [11], reported in a systematic review the screening tools, diagnosis, and management of ADHD in children with epilepsy and underlined the risks and difficulties of pharmacological treatments of these patients: as the underdiagnosis of ADHD, possible attention and behavioral worsening due to AEDs and, on the other hand, the false myth that stimulants may lower the seizure threshold.

There are very few data about atomoxetine. Among the papers published on this topic, it is important to remember the study carried out by McAfee AT et al. [12], who studied a large cohort of patients treated with this drug: the risk of seizure was not significantly different between pediatric patients taking atomoxetine compared with those taking stimulants, suggesting that this drug is not associated with an increased risk of seizure.

In conclusion, treatment with psychotropic drugs can be carried out safely in the large majority of epileptic children with ADHD.

3. Therapeutic implications for AEDs

Despite decades of research on developing antiepileptic treatments, the currently available AEDs therapy is symptomatic in nature, and the mechanisms of action of the AEDs are partially unknown. Of course, in epileptic patients affected by ADHD, it is crucial to know the possible influence on behavior. Regarding the duration of treatment, ADHD in epilepsy is more likely to be a persistent problem and, for this reason, many epilepsy patients and ADHD tend to be on long-term treatment. The studies that evaluated cognition and behavior changes in children treated with first, second, and third-generation AEDs are sparse, mostly rely on small studies, and provide only imprecise results with low levels of evidence. Among the first generation AEDs, the most documented association of AEDs with behavioral disturbances and hyperactivity is about phenobarbital [PB] that can induce symptoms of ADHD, followed by valproic acid [VPA] and topiramate [TPM] [6,13]. A double-blind, randomized controlled trial that evaluated short term effects on attention skills of ethosuximide [ETS], VPA and lamotrigine [LTG], showed attention deficit in 49% of patients treated with VPA, 32% of those receiving ETS, and 24% of those receiving LTG [13]. About levetiracetam [LEV], there are conflicting results, while gabapentin [GBP] and vigabatrin [VGB] seem to have limited effects on behavior and attention. Lacosamide [LCM] may have some beneficial effects on behavior, as well as carbamazepine [CBZ]. Oxcarbazepine [OXC], eslicarbazepine [ESL], and rufinamide [RUF] do not seem to worsen or induce ADHD symptoms. Perampanel [PER] may aggravate or elicit irritability or aggressive behavior, mainly at higher dosages, and phenytoin [PHT] and zonisamide [ZNS] may worsen attention and elicit behavioral disturbances. Evidence about behavioral effects of tiagabine [TGB], pregabalin [PGB], and stiripentol [STR] are still scanty [11,14]

The behavioral effects (in terms of hyperactivity disturbances, irritability, and disinhibition) of the main AEDs are reported in Table 1.

Table 1. The behavioral effects of the main antiepileptic drugs (AEDs).

AESs	Behavioral effects
Carbamazepine [CBZ]	Positive
Eslicarbazepine [ELS]	Neutral, uncertain or conflicting data
Ethosuximide [ETS]	Negative
Gabapentin [GBP]	Neutral, uncertain or conflicting data
Lacosamide [LCM]	Neutral, uncertain or conflicting data
Lamotrigine [LTG]	Positive
Levetiracetam [LEV]	Neutral, uncertain or conflicting data
Oxcarbazepine [OXC]	Neutral, uncertain or conflicting data
Phenobarbital [PB]	Negative
Phenytoin [PHT]	Negative
Perampanel [PER]	Negative
Pregabalin [PGB]	No data
Rufinamide [RUF]	Neutral, uncertain or conflicting data
Stiripentol [STR]	No data
Tiagabine [TGB]	No data
Topiramate [TPM]	Negative
Valproate [VPA]	Negative
Vigabatrin [VGB]	Neutral, uncertain or conflicting data
Zonisamide [ZNS]	Negative

Moreover, it should be remembered that when AEDs are combined, pharmacokinetic interactions may also take place and affect the response. Traditional AEDs (PB, CBZ, and PHT), which are potent inducers of hepatic cytochrome P450 and other enzymes, may increase metabolism and reduce the efficacy of the associated drug. Likewise, TPM and OXC have mild inducing properties [15]. Conversely, VPA, felbamate [FBM], and stiripentol [STR], which are potent inhibitors of P450 enzymes, may increase levels of concomitant AEDs.

4. Conclusions

There are only a few data from clinical observations and clinical trials about the possible interference of drugs for ADHD on epilepsy and of AEDs on behavior and attention. However, it seems that stimulant drugs and atomoxetine do not affect the quality of seizure control in epileptic children, and on the other hand, AEDs do not severely influence behavioral outcomes in ADHD. Definitive evidence on the additive or super-additive effects of a drug combination in epilepsy patients can only be obtained from randomized controlled trials.

5. Expert opinion

One of the most challenging comorbidities in epileptic patients is ADHD. The relationship between these two conditions has been very well known for a long time, and it has attracted the interest of both neurologists and psychiatrists. In fact, not only this comorbidity can influence the quality of life of the patients negatively, but it also must be taken into consideration by the physicians in the choice of stimulant drugs. Treatment issues of these epilepsy patients and ADHD are very complex because of possible interactions with AEDs and the false myth of increased risk of seizures with stimulants drugs.

Given the lack of evidence-based options for the treatment of these patients, the first step in managing ADHD in epileptic patients is to try to clarify the clinical context where these symptoms occur, especially if they have a clear relationship with the quality of seizure control (seizure activity) and/or with the antiepileptic treatment, in particular, a long-term treatment. This last point is important because, nowadays, the available evidence about the safety profile of the newest AEDs in patients with ADHD are still limited.

Notably, although AEDs can be used safely in epileptic patients with ADHD, we must highlight that rapid titration, especially in pediatric patients, can increase the risk of the onset of ADHD symptoms, and high dosages also must be considered an important risk factor for attention deficits and behavioral disturbances. Moreover, combining drugs in an antiepileptic polytherapy in pharmacoresistant epilepsy can lead to more severe cognitive and behavioral side effects.

On the other side, the psychotropic drugs used to treat ADHD can be safely employed in children with seizures.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

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