Background

Epilepsy surgery is the first-line treatment for patients with pharmacoresistant epilepsy. If resection of the epileptogenic area is not possible or not successful, the only approved treatment options currently available in Germany include vagus nerve stimulation, anterior thalamic stimulation, and, more recently, focal cortex stimulation. These are invasive, have limited efficacy, and are associated with some risk of side effects. Preliminary data give hope that transcranial direct current stimulation (tDCS) may provide a noninvasive, customizable treatment alternative with only few side effects.

Mechanism of action of cathodal direct current stimulation

Transcranial DCS represents a long-established method for modifying dysfunctional brain activity. It is based on the transcranial application of a continuous low-amplitude current (1–2 mA), which causes a change in the membrane potential of cortical neurons [26]. For this purpose, the current is usually delivered via two rubberized plate electrodes, which are placed on the scalp in 0.9% NaCl-soaked sponges and fixed in position by means of rubber bands. The applied current is of such low amplitude that it can, though, penetrate the scull and reach the cortical neurons, but once there can only generate a membrane potential shift and not an action potential.

The nature of the effect of tDCS depends primarily on the direction of stimulation: Anodal stimulation (a-tDCS) causes a net focal increase at the network level, whereas cathodal stimulation (c-tDCS) causes a net reduction in cortical excitability [34]. The measurable network effects reflect the sum of the stimulation effects at the cellular level, with tDCS causing neuronal depolarization or hyperpolarization mainly depending on the distance and orientation of the somatodendritic axes relative to the stimulation electrode [6, 18]. The role played by endothelial cells, lymphocytes, and glial cells currently remains unclear [42].

Depending on the stimulation intensity, application duration, and stimulation regimen, the tDCS-induced aftereffects can sometimes be amplified and prolonged in duration, outlasting the stimulation interval [17, 32, 38]. These medium- to longer-term effects are thought to be due to plasticity in the connection strength of glutamatergic synapses [7, 28, 34, 35], which is referred to as “long-term potentiation” (LTP) and “long-term depression” (LTD). Repeating tDCS during the aftereffects of the preceding stimulation has been described as increasing effectiveness in a systematic study of healthy individuals [32, 33]. Specifically, 9‑min stimulation with repetition after a break interval of 20 min has been shown to be highly effective [32, 33]. However, an unfavorable choice of the interstimulation interval of, e.g., several hours, may also negatively influence or even reverse the tDCS-induced effects [32, 33].

Principle of use and safety aspects of tDCS in epilepsy

Unifocal epilepsy is based on regionally limited cortical hyperexcitability. Thus, as in virtually no other disease, the application of cathodal stimulation over the epileptogenic focus seems to be an obvious approach to take, since regional hyperpolarization or a reduction of cortical excitability can be achieved [34]. Surprisingly, however, there have been only few studies to date on the use of tDCS in epilepsy. This could be due to the historical fear of triggering seizures in the context of applying current to the brain.

Safety data result mainly from years of use of tDCS in, e.g., tinnitus, stroke or aphasia, depression, migraine, and chronic pain syndromes (e.g., [8, 9, 12, 21,22,23, 47]) as well as healthy individuals (e.g., [37, 38, 40]). In this context, tDCS has proven over the years to be extremely safe and well tolerated. To date, no serious complications have occurred in the over 33,200 tDCS applications using conventional tDCS protocols (≤ 4 mA, ≤ 7.2 coulombs, ≤ 40 min), with over 1000 individuals receiving repetitive tDCS application and individual participants receiving over 1000 applications [5]. Mild side effects have been observed, such as temporary reddening of the skin (2%), headache (12%), fatigue (35%), mild unpleasant tingling (70%), and itching (30–40%), especially at the beginning of the stimulation [5, 31, 40], with few publications including systematic and quantitative reports of adverse events [10]. It is worth mentioning here that comparable side effects of similar intensity and frequency have also been described with placebo stimulation [10]. Only very rarely, especially in the case of daily stimulation with high current density, long duration, and use of dry electrodes, skin lesions similar to small burns may occur in individual cases [31]. The risk of side effects can be significantly reduced by following the guideline recommendation for tDCS [27]. The application of tDCS according to the standard protocol has been evaluated as safe not only in healthy and in diseased adult patients but also in children and older patients [5, 25]. This was further supported by the investigation of biomarkers such as neuron-specific enolase (NSE; [37, 38]), MRI [36], and EEG [49], which showed no negative effect of tDCS. A European guideline detailing the evidence base and safety of the use of tDCS in various neurological and psychiatric conditions was formulated by leading experts in 2017 [27].

Up to now, only a few studies exist on tDCS in epilepsy, although those that do exist demonstrate its safe and effective use. The spectrum of side effects corresponds to that of tDCS application in other diseases [24, 45]. A systematic study using the comfort rating questionnaire (CRQ), an established questionnaire to assess tDCS-associated side effects [39], described mild sensory sensations such as tingling, burning, or slight pain in the area of the stimulation electrodes in 40–85% of patients during cathodal tDCS (2 × 9 min) with a 2-mA stimulation amplitude [24]. Only individual patients reported a feeling of fatigue (n = 6/15, 40%), nervousness (n = 3/15, 20%), or difficulty concentrating (n = 3/15, 20%). The side effects were all of low intensity and transient with symptom relapse at or shortly after the end of stimulation [24]. Only one case report described a possible association between tDCS and seizure recurrence [13]. However, it should be mentioned that in this case, anodal stimulation was applied and the anticonvulsant medication was reduced beforehand. Furthermore, the seizure occurred 4 h after stimulation treatment, meaning that no clear causal relationship can be established [13]. Under cathodal tDCS, a total of eight patients have been described in whom an epileptic seizure occurred under active or sham tDCS treatment [44, 46, 52]. These were habitual seizures that most likely occurred incidentally during stimulation in known pharmacoresistant epilepsy and were not a negative predictor of clinical response.

Efficacy of tDCS in epilepsy

The increasing number of PubMed-listed publications on the keywords “epilepsy” and “tDCS” reflects the growing clinical/scientific interest in this noninvasive stimulation method (Fig. 1).

Fig. 1
figure 1

Trend in the number of publications on the topic of transcranial direct current stimulation in epilepsy

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Currently, in addition to case series and individual case reports, there are essentially 12 randomized, sham-controlled studies on tDCS in pharmacoresistant epilepsy, two of which are of pediatric patients. Their key points, in particular study design, stimulation, and effect size, are summarized in Table 1.

Table 1 Overview of placebo/sham-controlled tDCS trials in pharmacoresistant epilepsy
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The available data clearly demonstrate that cathodal direct current stimulation can lead to an effective reduction of epileptic activity in patients with pharmacoresistant epilepsy in contrast to sham stimulation. In this regard, even one-off 20-min tDCS can produce a significant reduction in seizure frequency of > 40% in the 4 weeks after intervention [2, 3, 15]. Serial stimulation several days in a row leads to an enhancement of effect, with significant seizure frequency reduction rates of up to 79% after 1 month [4, 20, 29, 30, 44, 50, 52]. The duration of the effect seems to be prolonged by using an interstimulation interval [52, 53]. Thus, in a comparative study conducted 1 month after 14 days of tDCS treatment, identical seizure frequency reduction rates of 50% were detectable when using daily 1 × 20- or 2 × 20-min stimulation (with a 20-min break interval), whereas at 2 months, only a 25% reduction (p = 0.086) vs. 45% in group 2 (p = 0.382) was observed [52]. Contrary to expectations, cathodal tDCS treatment seems to be effective not only in cortical, clearly unifocal epilepsy, but also in deeper or more diffuse epileptogenic foci such as mesial temporal lobe epilepsy [44, 50], Lennox–Gastaut syndrome [4], and Rasmussen encephalitis [43, 51]. The partially negative results regarding seizure frequency reduction after cathodal tDCS can be most likely be explained by small intervention groups [16], low baseline seizure frequencies [30], inclusion of patients with more than one seizure focus [30], or possible suboptimal positioning of the stimulation electrode far from the epileptogenic focus [30]. In addition, different statistical methods were applied, i.e., intra- as well as intergroup comparisons (active vs. sham), the latter being of higher quality but reducing the probability of statistically significant results.

Regarding the effect on the frequency of interictal epileptiform potentials (IEP), there are contradictory data. In the vast majority of studies, a significant reduction in IEP frequency was observed in the weeks following cathodal tDCS [3, 4, 15, 30, 41]. Failure to reduce IEP, as reported in a few studies [1, 29], is most likely due to low baseline IEP frequency and early EEG examination time points following tDCS [24]. Inconsistent study results are also explained by the varying case numbers and collectives, which clearly limit comparability.

A comparison of different stimulation regimens is also virtually impossible at present, since in the studies available so far on tDCS in epilepsy, very different stimulation protocols and electrode positions, especially for the anode, have been used. Accordingly, no recommendations on patient selection, choice of stimulation parameters, and repetition frequency of tDCS treatment can be derived at present. Furthermore, there is a lack of long-term observations for the evaluation of the long-term effects and safety of tDCS therapy.

Effects of tDCS on comorbidities

In other disorders such as depression, anodal stimulation over the dorsolateral prefrontal cortex has already gained acceptance and, as such, has received an evidence-level B rating from leading tDCS experts [9, 11, 14, 27]. Given the frequent comorbidity of epilepsy and depression, initial studies have attempted to combine the two therapeutic approaches. Cathodal stimulation over the epileptogenic focus with placement of the anode over the contralateral dorsolateral prefrontal region resulted in an improvement of depressive symptoms in the first two studies [19, 29]. Cognitive function was not or only transiently impaired [19, 29]. However, longitudinal studies with more than 4 weeks of tDCS treatment and systematic evaluation of psychiatric and neuropsychological function are still lacking.

Outlook and application scenarios

Further systematic studies are needed to define the optimal stimulation parameters, identify predictors of good response, and assess the safety and efficacy of tDCS therapy in the long term. Furthermore, in addition to the effects on epileptic activity, further studies on changes in quality of life, mood, and cognition are needed.

Further developments of tDCS such as multichannel tDCS, together with digital applications, already enable more precise and individualized stimulation, which is likely to contribute to an increase in the efficacy of tDCS treatment. In addition, an increasing number of home-use tDCS systems are becoming commercially available, which could also offer the perspective of continuous tDCS treatment for epilepsy. Unfortunately, no CE-marked tDCS devices are currently approved for epilepsy. However, a multicenter, double-blind intervention study is currently underway with the goal of obtaining FDA approval of tDCS for the treatment of adult patients with pharmacoresistant epilepsy (clinical trials identification number: NCT04770337), after which CE approval may also be expected. Thus, tDCS would expand the treatment spectrum for patients with pharmacoresistant epilepsy by a noninvasive method of fully reversible neurostimulation with a low side-effects profile. In this context, tDCS would be of interest not only for patients with cortical, non-resectable epileptogenic foci, but also as a bridge to surgical treatment. The application of tDCS could possibly also pare down the use of seizure-suppressing drugs and thus reduce the side-effect burden. Furthermore, the application of tDCS could possibly test or potentially predict response to implantable stimulation systems such as responsive neurostimulation or epicranial stimulation. Epicranial stimulation (see [48]) integrates the treatment principle of cathodal tDCS, meaning that in the future, the optimal stimulation site and the respective clinical response could possibly be tested by cathodal tDCS before implantation of such a system.

Practical conclusion

  • Cathodal direct current stimulation has been shown to be safe, have few side effects, and to be effective for patients with pharmacoresistant epilepsy.

  • Further studies are needed to optimize therapy parameters and to exploit the therapeutic potential of transcranial direct current stimulation (tDCS).

  • At present, however, there is no CE-marked device approved for epilepsy, which continues to limit use of the method to scientific studies and individual curative trials.