Rick Van Lanen

Epilepsie is een veelvoorkomende aandoening. De behandeling van eerste keuze voor patiënten met epilepsie is medicatie, echter 30-40% van de patiënten met epilepsie is medicatieresistent, met hogere percentages bij kinderen. Ongeveer 60% van deze patiënten heeft focale aanvallen, die in een gedeelte van de hersenen beginnen. Medicatieresistente focale epilepsie is een belangrijk volksgezondheidsprobleem, leidend tot beperkingen op verschillende gebieden zoals cognitieve functies, ontwikkeling, deelname aan het sociale leven en een verminderde kwaliteit van leven. Naast deze problemen is de kans op sterfte 2-3 keer hoger bij mensen met epilepsie vergeleken met de algemene bevolking.

De pathofysiologie van epilepsie is nog steeds niet volledig opgehelderd. De ontwikkeling van alternatieve behandelingen is noodzakelijk en kan gericht zijn op nog onontdekte mechanismen in de pathofysiologie van epilepsie. Eén van de mechanismen waarop dit proefschrift zich richt is de cerebrale microvascularisatie die onderzocht is in patiënten die een temporaal kwab verwijdering zouden ondergaan. Resectieve epilepsiechirurgie wordt in geselecteerde gevallen van medicatieresistente focale epilepsie aangeboden als een evidence-based, curatieve behandeloptie. Het resultaat van de operatie hangt sterk af van een grondige preoperatieve evaluatie om een aanvalsfocus of laesie af te bakenen. Een van de belangrijkste voorspellende factoren voor een succesvol resultaat is de aanwezigheid van een structurele afwijking op MRI.

In het eerste deel van het proefschrift wordt uiteengezet dat de cerebrovasculaire microcirculatie door middel van vasculaire endotheliale groeifactor een sleutelrol speelt bij angio- en barrière-genese. Deze processen zijn kritisch voor de ontwikkeling van een gezond cerebrovasculair netwerk. Verstoringen in het evenwicht tussen angio- en barrière-genese kunnen leiden tot abnormale microvascularisatie, veranderingen in microvasculaire dichtheid en disfunctie van de bloed-hersenbarrière (BBB). De integriteit van de BBB, mede gereguleerd door de glycocalyx, is cruciaal voor het handhaven van cerebrale homeostase. Disfunctie van de glycocalyx kan leiden tot een toename in BBB doorlaatbaarheid met lekkage, wat resulteert in neuro-inflammatoire processen, verhoogde neuronale excitabiliteit, leidend tot epilepsie.

Om de rol van cerebrovasculaire microcirculatie bij epilepsie te onderzoeken, werd sidestream dark field-imaging gebruikt om microcirculatoire processen en eigenschappen van de glycocalyx te beoordelen bij patiënten met temporaal-kwab-epilepsie (TLE) die epilepsiechirurgie ondergingen. De bevindingen toonden veranderde eigenschappen van de cerebrale microcirculatie bij patiënten met medicatieresistente TLE, waaronder verminderde integriteit van het glycocalyx, gestoorde bloedstroomregulatie en capillaire rekruteringscapaciteit. Deze microcirculatie afwijkingen dragen bij aan verstoord parenchymaal evenwicht, leidend tot epilepsie.

In het tweede deel van de scriptie verschoof de focus naar het verbeteren van de detectie van epileptogene afwijkingen met behulp van UHF MRI. Er werd een systematische review uitgevoerd naar de klinische toepassing van UHF MRI bij volwassenen en kinderen met epilepsie. De review toonde aan dat 7 Tesla (T) MRI een diagnostisch voordeel biedt ten opzichte van conventionele MRI, met verbeterde detectie van epileptogene afwijkingen zoals focale corticale dysplasie en hippocampale sclerose. Bepaalde sequenties, zoals T2*- en susceptibiliteits-gewogen beelden, bleken bijzonder nuttig voor deze detectie. Er was echter onvoldoende bewijs in de literatuur om het effect van UHF MRI op chirurgische besluitvorming en postoperatieve aanvalsuitkomsten te bepalen.

Om deze kennishiaten te onderzoeken en detectie van epileptogenen afwijkingen verder te verbeteren, werd de EpiUltraStudy geïntroduceerd. Dit onderzoek heeft als doel de detectieratio van structurele en functionele hersenafwijkingen te onderzoeken in patiënten met medicatieresistente focale epilepsie met behulp van zowel 7T als 9.4T MRI. Hoewel de resultaten van deze studie nog niet bekend zijn, worden de technische ontwikkelingen op dit gebied gedemonstreerd in de eerste klinische 9.4T MRI bij een patiënt met epilepsie. Het uiteindelijke doel is om chirurgische procedures en uitkomsten voor patiënten met medicatie-resistente focale epilepsie te verbeteren.

Concluderend heeft dit proefschrift nieuwe inzichten opgeleverd in de rol van afwijkingen in de cerebrovasculaire microcirculatie bij epilepsie en is het potentieel van UHF MRI onderzocht bij het verbeteren van de detectie van epileptogene afwijkingen. De bevindingen benadrukken het belang van het herstel van microvasculaire afwijkingen, zoals glycocalyxdisfunctie en verminderde bloedstroomregulatie, als potentiële therapeutische doelen voor epilepsie. Bovendien biedt de toepassing van UHF MRI, samen met geavanceerde beeldvormingssequenties en post-processing technieken, mogelijkheden om de detectieratio van epileptogene afwijkingen te verbeteren en de chirurgische uitkomsten te optimaliseren voor patiënten met medicatieresistente focale epilepsie. Uiteindelijk biedt de combinatie van in vivo microcirculatiemetingen, in vivo beoordeling met MRI-technieken en ex vivo visualisatie en kwantificering, de mogelijkheid voor de ontwikkeling van nieuwe behandelingsstrategieën in de poging om epilepsie te genezen, terwijl ook nieuwe therapeutische mogelijkheden worden geopend voor andere neurologische aandoeningen.

Valorisation

Relevance

Epilepsy is a prevalent chronic neurological disorder; it is estimated that about 200,000 epilepsy patients reside in The Netherlands. 7,18 Despite continuous development of novel antiseizure medication (ASM), epilepsy continues to pose significant health care challenges. Especially drug-resistant epilepsy (DRE) poses a major challenge, as consequently the continuation of ASM usage and disease burden, leads to neurocognitive and psychological decline, disturbances in social life, premature morbidity and mortality, and ultimately inferior health-related quality of life. 1,13,19 Approximately 30% of patients with epilepsy continue to have frequent seizures despite ASM therapy. 6,14 In children, the effects of epilepsy are even more profound, leading to impairment in different domains like cognitive function and development. The societal and healthcare impact is significant, as evidenced by the expenditure of 192 million euros on healthcare costs related to epilepsy in The Netherlands. Chronic DRE, which accounts for approximately 80% of total epilepsy-related expenses, imposes an immense burden on society.

The epilepsy-related costs are high due to the treatment intensity. Chronic DRE often necessitates ongoing medical management, including the long-term use of ASM and associated frequent outpatient clinic visits. These expenses can accumulate over time and place a significant financial burden on healthcare systems. 3,17 In addition, health care costs due to seizures and associated injuries, emergency care visits following a seizure and consequent work absenteeism are not to be underestimated. Moreover, patients with epilepsy often undergo extensive and costly additional examinations, such as video-EEG examinations and brain imaging. Epilepsy surgery is an excellent curative treatment option for drug-resistant pediatric and adult patients after thorough diagnostic workup. Even though epilepsy surgery is effective, only a subset of patients is eligible. Therefore, curation of epilepsy is currently only a reality in this group of patients.

Despite many years of basic and clinical research, the pathophysiology of epilepsy has not been fully elucidated. Besides expansion of the cohort of eligible patients for epilepsy surgery, the armamentarium of surgical treatment options may also be a way to improve curation rate of epilepsy. The development of treatment alternatives is desperately needed and may be aimed at yet unraveled mechanisms in the pathophysiology of epilepsy. The value of this thesis firstly lies in the potential to enable novel targets in the treatment of DRE through the exploration of the cerebrovascular glycocalyx and microcirculation in relation to epilepsy. Secondly, the expansion of eligible patients, including children, for resective epilepsy surgery by using ultra-high field (UHF) MRI, while improving surgical treatment and postoperative seizure outcome.

Impact

Targeted anti-seizure treatment

Neurovascular interactions play a critical role in the pathophysiology of epilepsy by influencing processes such as blood-brain barrier (BBB) dysfunction, neuroinflammation, angiogenesis, vascular remodeling, and metabolic changes, but research like e.g., the development of intra- and extraoperative neuroimaging techniques. Understanding these interactions is vital for unraveling the complex mechanisms underlying epilepsy and developing new therapeutic interventions to improve patient outcome. The scientific community's focus on neurovascular interactions in epilepsy research stems from the discovery of neurovascular and BBB dysfunction in various neurological disorders like stroke, Alzheimer's disease, cerebral small vessel disease, and traumatic brain injury. Consequently, the findings and future prospects discussed in this thesis can potentially enhance our comprehension of these neurological conditions as well.

Based on the findings and insights presented in this thesis, there is an opportunity for drug development experts and pharmaceutical companies to explore new avenues in the creation of ASM. Specifically, focusing on addressing the underlying cerebrovascular changes identified in the study could lead to the development of targeted ASM. One potential approach is to design medications that aim to restore the glycocalyx. By targeting the glycocalyx and microcirculatory dysfunction, these medications may help to stabilize the blood-brain barrier and improve overall cerebrovascular function, potentially reducing seizure occurrence or severity. Therefore, ASM designed to enhance microcirculatory function and optimize blood flow within the brain could hold significant therapeutic potential for epilepsy patients.

Taking a broader perspective, there is a compelling case to consider epilepsy patients as individuals with cerebrovascular conditions. Understanding the close interplay between cerebrovascular health and epilepsy may lead to novel therapeutic approaches. By acknowledging the importance of healthy vascularity in managing and treating epilepsy, medical professionals can adopt a more comprehensive approach to patient care. This could involve implementing lifestyle interventions and medical strategies to promote cerebrovascular well-being alongside traditional antiseizure treatments.

Underutilization of epilepsy surgery

Looking at the treatment option of epilepsy surgery, we notice that studies have consistently shown that epilepsy surgery is more effective than medical management for treating DRE in both children and adults. 6,9,14 Not only does surgery increase the likelihood of achieving seizure freedom, but it also improves quality of life and reduces the risk of early mortality. 6,9,14 Despite these benefits, epilepsy surgery remains highly underutilized, even among the estimated 10 million individuals worldwide who would be suitable candidates for the procedure. 13,14,20 While research, such as the use of UHF MRI as described in this thesis, aim to increase numbers of suitable candidates for epilepsy surgery and improve postoperative seizure outcome, this underutilization is surprisingly not limited to low- and middle-income countries but also affects high-income developed nations with state-of-the-art medical facilities. 16,

Despite the growing body of clinical evidence supporting epilepsy surgery, its utilization rate is 14 stagnating or even declining. To address this issue, several interventions are needed. First, there is a need for educational programs targeting patients, their families, caregivers and the wider community to increase awareness and understanding of the benefits of epilepsy surgery, along 22 with referring health care professionals like general practitioners and neurologists. Second, it is essential to increase awareness of this disease among politicians and health care policy makers and planners. An already good example is the adoption of a global action plan on Epilepsy 2022-2031 by the 75th World Health Assembly of the WHO. 21 In addition to continuous medical education, advancements in technology should be harnessed to improve access to epilepsy surgery. This could involve leveraging telemedicine and other remote healthcare solutions to reach patients in underserved areas. Creating a standardized system within comprehensive epilepsy centers can also help streamline the process and ensure consistent and high-quality care. Expanding the number of epilepsy centers and promoting collaboration among centers with different resources, including technology and expertise, is another potential solution. By pooling resources and sharing knowledge, epilepsy centers can enhance their capabilities and reach a larger number of patients. Lastly, to increase research funding for epilepsy is crucial for advancing the field and developing innovative treatment options. By investing in research, we can further improve the effectiveness and safety of epilepsy surgery and explore alternative therapies. Thus, addressing the underutilization of epilepsy surgery requires a multi-faceted approach involving education, technological advancements, standardized systems, increased collaboration, and research funding. By implementing these strategies, we can ensure that more individuals with 15 DRE have access to this evidence-based treatment option.

Cost-effectiveness

In addition to considering the clinical aspects of diseases and their treatments, understanding the economic implications of healthcare is crucial. Resective epilepsy surgery, while effective, can be a costly intervention. Furthermore, the diagnostic work-up leading to surgery often involves extensive and potentially expensive evaluations. Therefore, it is vital to assess the cost-effectiveness of these approaches. Recent studies have investigated the economic aspects of resective epilepsy surgery and invasive EEG monitoring, such as stereo-EEG, in cases of drug-resistant focal epilepsy. 5,8,17 These studies have concluded that epilepsy surgery, compared to medical management, is a cost-effective option for eligible surgical candidates, as it proves to be more effective in the long term and leads to cost savings. 8,17 In children, surgery was found to be even more effective, but also more expensive. However, when considering broader impacts, such as improved educational and employment opportunities for patients, as well as better outcomes 5 for caregivers and reduced caregiver costs, a stronger argument for cost-effectiveness emerges. Additionally, there may be hesitancy in referring patients for evaluation due to the substantial upfront costs associated with presurgical testing and uncertainty regarding surgical eligibility. However, a recent study demonstrated that surgical evaluation is cost-effective even when the probability of being deemed a surgical candidate is as low as 5% for patients with drug-resistant temporal lobe epilepsy. From a societal perspective, surgery becomes cost-effective between 3 17 to 10 years. 10,14,17

Additionally, epilepsy treatment has implications for research and innovation by encouraging ongoing scientific exploration and technological advancements. These developments not only benefit epilepsy patients but also have broader implications for neurology and neuroscience as a whole. 22 The knowledge gained from epilepsy surgery procedures can contribute to a deeper understanding of the brain and potentially pave the way for innovative treatment approaches for other neurological conditions. In conclusion, better treatment of epilepsy offers significant valorization in terms of improving patient outcomes, reducing healthcare costs, increasing economic productivity, and driving advancements in medical research. By investing in treatment alternatives for epilepsy and expanding upon its surgery and ensuring its accessibility, we can enhance the well-being of individuals living with DRE while simultaneously benefiting society at large.