**4. Cognitive side effects in children**

Most studies examining unwanted interference effects mainly focus on adults. For the treatment of children there are often no separate data available. Transferring the study results just to children and adolescents is not advisable. Naturally, a child's brain can, on the one hand, be restricted in its function by anticonvulsants, analogous to an adult brain. However, what is more is that unwanted interference effects can also adversely affect the further cognitive development. Disruptions in cognitive performances (e.g. working memory performance) can prevent or hinder the acquisition of new abilities and skills and may slow down the entire development. Especially child epilepsy syndromes can be associated with severe intellectual disabilities and developmental delays. Additional negative interference effects of the medication are detrimental, so that the child may not be able to exploit its entire and eventually already reduced development potential.

Not all available anticonvulsants are approved for the treatment of epilepsy in children Compared to adults, children are more sensitive to the undesirable effects of drugs. Lamotrigine, levetiracetam, rufinamide, and gabapentin appear to have a rather minor effect on cognitive performance - Lamotrigine is said to even improve concentration disorders in children [8, 15]. Topiramate and zonisamide, however, can also have a negative effect on cognitive performance in children. Both substances lead to the cognitive interference effects in children that have been observed in adults as well: word-finding disorders, cognitive slowdown, memory and working memory disorders [12]. In contrast to adults deteriorations in information processing speed, linguistic abilities, verbal learning and memory processes have also been described for valproic acid, oxcarbazepine and carbamazepine in children [16].

In contrast to adults, the drug-related cognitive deterioration is more serious in children, as further development and potential development in childhood and adolescence can be negatively influenced. Since school performance in particular plays an immense role in setting the course for later professional and social careers, the relevance of drug-related cognitive disruptive effects in childhood needs to be emphasized again, as the case study from the beginning illustrates very vividly.

As mentioned earlier, there is a connection between valproic acid during pregnancy and the intellectual abilities of the unborn child [17]. Compared to children who were exposed to carbamazepine during pregnancy, children after exposure to valproic acid (especially in higher doses) achieve an IQ value up to 10 points lower in the 6th year of life [18, 19]. Therefore this must be assessed as an irreversible, undesirable cognitive interference effect of valproic acid, even if this does not have a direct effect on the performance of the patient being treated, but rather on the unborn child who is been treated to. Since an association was also found between valproic acid during pregnancy and a later autism disorder in the child [20], therapy with valproic acid for women of childbearing age should be avoided.

## **5. Control of possible cognitive side effects**

As the case study shows, the patient - and also the clinicians - are not always aware of the cognitive interference effects of anticonvulsants. In order to control possible influences on cognitive performance, it is therefore advisable - at least for certain substances (topiramate, zonisamide), to record the performance in a standardized manner before starting therapy, after reaching the target dose and if the patient reports any of new subjective cognitive complaints that occur during adjustment respectively. In specialized centres, this is carried out by experienced neuropsychologists as part of neuropsychological follow-up examinations with change-sensitive test procedures. In the outpatient neurological setting, however, a neuropsychological examination accompanying the drug setting is often not possible. Therefore, it is important to monitor potential changes by a detailed and repeated questioning of the patients or their caregivers about tolerability, including specific questions about possible changes/failures in school or work since the medication changeover, as well as test instruments specially designed for this question, such as EpiTrack and EpiTrack Junior (only available in German [21, 22]). Many different neuropsychological tests are available to control cognitive functions. The following cognitive performances should always be recorded: Attention (especially information processing speed), executive functions, language functions (especially verbal fluidity) and working memory. When selecting tests, care should be taken to ensure that the tests can be used repeatedly (e.g. parallel versions). In addition, possible mood changes should always be recorded.

In summary, because of their low negative impact on cognitive performance, certain anticonvulsants (e.g. lamotrigine, levetiracetam) are superior to others (topiramate, zonisamide, valproic acid). A monotherapy is always preferable to a combination therapy and a low dose to a high one, since most of the undesirable interfering effects described are both dose-dependent (lower dose - fewer or less interfering effects) and can tend to accumulate in combination therapies. In some cases, negative interfering effects can be counteracted by slowly increasing the medication (start low – go slow). However, this does not apply to all substances (see topiramate). In the case of drugs known to have undesirable cognitive interferences, the start of therapy should, if possible, be accompanied by neuropsychological follow-up examinations.

The best possible seizure control or seizure reduction is necessary for both the quality of life and the general performance of a patient. Therefore, substances with cognitive interference effects may sometimes be preferable to others (e.g. when other substances are not effective). In these cases, an individual assessment of the cost–benefit profile is necessary.
