Rick Van Lanen

Epilepsy is a common neurological disease. The first-choice treatment for patients with epilepsy is medication; however, 30-40% of patients with epilepsy are medication-resistant, with higher percentages among children. Approximately 60% of these patients experience focal seizures, which begin in a specific part of the brain. Medication-resistant focal epilepsy is a significant public health issue, leading to limitations in various areas such as cognitive functions, development, social life participation, and a reduced quality of life. In addition to these problems, the mortality rate is 2-3 times higher in people with epilepsy compared to the general population.

The pathophysiology of epilepsy is still not fully understood. The development of alternative treatments is necessary and can target as-yet undiscovered mechanisms in the pathophysiology of epilepsy. One of the mechanisms that this dissertation focuses on is cerebral microvascularization, which has been investigated in patients undergoing temporal lobe resection. Resective epilepsy surgery is offered in selected cases of medication-resistant focal epilepsy as an evidence-based, curative treatment option. The outcome of the surgery strongly depends on thorough preoperative evaluation to delineate a seizure focus or lesion. One of the most important predictive factors for a successful outcome is the presence of a structural abnormality on MRI.

The first part of this thesis explains that cerebrovascular microcirculation, mediated by vascular endothelial growth factor, plays a key role in angiogenesis and barrier genesis. These processes are critical for the development of a healthy cerebrovascular network. Disturbances in the balance between angiogenesis and barriergenesis can lead to abnormal microvascular morphology, microvascular density changes, and blood-brain barrier (BBB) dysfunction. The integrity of the BBB, regulated by the glycocalyx, is crucial for maintaining cerebral homeostasis. Dysfunction in the glycocalyx can result in BBB permeability and leakage, leading to neuroinflammatory processes, increased neuronal excitability, and epileptogenesis.

To investigate the role of cerebrovascular microcirculation in epilepsy, sidestream dark field imaging was employed to assess microcirculatory processes and glycocalyx properties in patients with temporal lobe epilepsy (TLE) undergoing epilepsy surgery. The findings revealed altered cerebral microcirculatory properties in patients with drug-resistant TLE, including reduced glycocalyx integrity, impaired blood flow control, and capillary recruitment capacity. These microcirculatory abnormalities contribute to disturbed parenchymal homeostasis, facilitating epileptogenesis and seizures.

In the second part of the thesis, the focus shifted to improving epileptogenic lesion detection using UHF MRI. A systematic review on the clinical application of UHF MRI in adult and pediatric epilepsy was conducted. This review demonstrated that MRI at 7 Tesla (T), provides a diagnostic gain over conventional MRI, with increased detection rates of focal cortical dysplasia and hippocampal sclerosis. Certain sequences, such as T2* and susceptibility-weighted images, proved useful for lesion detection. However, the literature lacked sufficient evidence to determine the impact of UHF MRI on surgical decision-making and postoperative seizure outcomes.

To address the limitations and improve detection rates, the EpiUltraStudy was introduced. This study aims to estimate the detection rate of structural and functional brain lesions in patients with drug-resistant focal epilepsy using both 7T and 9.4T MRI. While we await the results of this study, the technical advances in this field are showcased in the first clinical 9.4T MRI in a patient with epilepsy. The ultimate goal is to tailor personalized surgical procedures for patients with drug-resistant focal epilepsy and improve their postoperative seizure outcomes.

In conclusion, this thesis provided novel insights into the role of cerebrovascular microcirculation abnormalities in epilepsy and explored the potential of UHF MRI in improving epileptogenic lesion detection. The findings highlight the importance of restoring microvascular abnormalities, such as glycocalyx dysfunction and impaired blood flow control, as potential therapeutic targets for epilepsy. Additionally, the application of UHF MRI, along with advanced imaging sequences and post-processing techniques, holds promise for enhancing lesion detection rates and optimizing surgical outcomes for patients with drug-resistant focal epilepsy. Ultimately, the combination of in vivo microcirculation measurements, in vivo assessment with MRI techniques, and ex vivo visualization and quantification, provides the opportunity for the development of novel treatment strategies in the effort to cure current epilepsies, while also opening therapeutic targets for other neurological disorders.