Attention and Executive Functions in Patients with Drug-Resistant Epilepsy: Focus on vagus nerve stimulation

Cognitive impairment is a common comorbidity in drug-resistant epilepsy (DRE), and it can have a significant impact on patients' daily functioning and quality of life. Vagus nerve stimulation (VNS), an adjunct treatment option for patients with DRE, has established its efficacy for seizure control in randomized controlled trials, long- term extension studies and real-world follow-up studies. Recently, interest in investigating the effects of VNS on cognition has increased. However, most of the research on VNS and cognition has focused on memory, with limited coverage given to other cognitive domains, including attention and executive functions (AEFs). Furthermore, clinical studies investigating the long-term effects of VNS on cognition in patients with DRE are scarce.

The purpose of this thesis was to assess AEF performance in patients with DRE and to investigate the long-term effects of VNS on this specific cognitive domain. Additionally, we aimed to identify essential clinical factors influencing AEF performance in DRE patients and to explore the associations between these clinical factors and changes in AEF performance during VNS therapy.

In the first part of the study (Study I), we included 95 consecutive DRE patients who underwent EpiTrack evaluation as a part of a planned treatment modification. EpiTrack is a screening tool for the assessment of AEFs and includes six cognitive tests (an interference test, the trail-making test Parts A and B, a maze test, the digit span backwards task and a written verbal fluency test). Patients were classified into cognitively unimpaired, mildly impaired, or severely impaired performance categories based on the EpiTrack total score. We observed that EpiTrack performance was severely impaired in 51%, mildly impaired in 23%, and normal in 26% of the patients. A significant difference in the EpiTrack performance categories was observed when the patient had a psychiatric comorbidity. Furthermore, a trend towards better performance in EpiTrack was observed among patients taking 2 antiseizure medications (ASMs) than among those taking 3–4 ASMs.

The second part of the study (Studies II-IV) involved cohorts of 46 and 33 DRE patients who were implanted with VNS and evaluated cognitively prior to implantation and after implantation with repeated EpiTrack tests according to our standard VNS protocol. All patients with a minimum follow-up of 12 months and at least two postimplantation EpiTrack assessments were included. The main finding was that the EpiTrack total score improved significantly at the group-level, along with the performance category changing on average from severely impaired to almost normal during the five-year follow-up. Additionally, significant improvements in group-level performance were observed in the trail making test (Parts A and B), the digit span backwards task and the maze test, with the most robust enhancements detected in the trail-making test Part B and in the maze test. In contrast, performance in the interference and verbal fluency tests did not show notable changes during follow-up. Patients with psychiatric comorbidities exhibited a 3.5-fold improvement in the EpiTrack total score compared with those without psychiatric comorbidities, while patients taking 1–2 ASMs improved almost quadruple in comparison to those taking 3–4 ASMs. Moreover, patients with frontal lobe epilepsy experienced an almost twofold improvement compared with patients with temporal lobe epilepsy. According to our individual analyses, 83% of the patients who experienced clinically meaningful improvement in AEF performance during follow-up had received VNS therapy for at least 2 years.

To conclude, deficits in AEFs were common in our study population, with the presence of psychiatric comorbidities and the use of more than 2 ASMs correlating with more pronounced deficits. A gradual improvement representing a clinically meaningful change in AEFs among DRE patients after the initiation of VNS therapy was observed. The enhancement of AEFs associated with VNS seems to specifically involve cognitive flexibility, planning and visual anticipation. The majority of the cognitive responders had received VNS therapy for at least 2 years, suggesting a potential timeframe for the expected cognitive benefits from VNS. Patients with psychiatric comorbidities appear to achieve the best cognitive outcome from VNS therapy, which should be taken into consideration in treatment choices. In addition, patients taking fewer than three ASMs and those with frontal lobe epilepsy can be expected to gain good cognitive benefits from VNS. By identifying the patient groups with the potential to achieve the greatest cognitive improvement during VNS therapy, we can optimize the treatment of DRE patients and improve their quality of life.