Ursachen und Diagnostik pharmakoresistenter fokaler Epilepsien

In den Originalarbeiten der vorliegenden Habilitationsschrift wurden die Mechanismen und Ursachen von Pharmakoresistenz bei Patient*innen mit fokalen strukturellen und autoimmunassoziierten Epilepsien untersucht. Dabei wurden Biomarker der Pharmakoresistenz von strukturellen Epilepsien und die Beteiligung des Multidrug-Efflux-Transporterproteins P-gp mit Hilfe von (R)-[11C]Verapamil-PET. Bei Patient*innen mit fokalen strukturellen Epilepsien aufgrund einer Hippocampussklerose oder zerebraler Entwicklungsstörungen konnte eine on P-gp im Vergleich zu anfallsfreien Patient*innen und gesunden Kontrollpersonen nachgewiesen werden. In Zukunft könnten Patient*innen hinsichtlich einer Überfunktion von P-gp mit (R)-[11C]Verapamil-PET untersucht und ihre ASM individuell angepasst werden, um die Pharmakoresistenz zu überwinden – beispielsweise mittles neu entwickelter Substanzen, die P-gp hemmen oder die dieses Multidrug-Efflux-Transporterprotein umgehen. In unserer Studie bei Patient*innen mit Autoimmunenzephalitiden konnten wir zeigen, dass sich bei Nachweis von GAD-Antikörpern häufig eine autoimmunassoziierte Epilepsie entwickelt. Oft wird eine Autoimmunenzephalitis aufgrund von GAD-Antikörpern jedoch zu spät erkannt und eine Therapie verzögert begonnen. Zusätzlich sprechen diese Antikörper generell schlecht auf Immunsuppressiva an. Im Vergleich dazu ist die Entstehung autoimmunassoziierter Epilepsien bei Autoimmunenzephalitiden aufgrund von neuronalen Oberflächenantikörpern nur sehr selten. Vielmehr treten hier die Anfälle nur in der Akutphase auf. Bei früher Diagnosestellung und rechtzeitiger Einleitung der immunsuppressiven Therapie kann ein Auftreten von wiederkehrenden, unprovozierten Anfällen vermieden werden. Eine langfristige Gabe von ASM ist daher nicht nötig. In der prächirurgischen Diagnostik findet die [18F]FDG-PET insbesondere bei unauffälligem cMRT ihre Anwendung. Mit unserer multizentrischen Studie an fast 1.000 Epilepsie-Patient*innen konnten wir die hohe Sensitivität von [18F]FDG-PET zur Lokalisation der Anfallsursprungszone gerade bei Patienten mit negativem MRT bestätigen. Andere Radiotracer wie der Perfusionstracer [15O]H2O-PET haben diesbezüglich auch vielversprechende Ergebnisse gezeigt

Utility of 18F-fluorodeoxyglucose positron emission tomography in presurgical evaluation of patients with epilepsy: A multicenter study

OBJECTIVE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used in presurgical assessment in patients with drug-resistant focal epilepsy (DRE) if magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) do not localize the seizure onset zone or are discordant. METHODS: In this multicenter, retrospective observational cohort study, we included consecutive patients with DRE who had undergone FDG-PET as part of their presurgical workup. We assessed the utility of FDG-PET, which was defined as contributing to the decision-making process to refer for resection or intracranial EEG (iEEG) or to conclude surgery was not feasible. RESULTS: We included 951 patients in this study; 479 had temporal lobe epilepsy (TLE), 219 extratemporal epilepsy (ETLE), and 253 epilepsy of uncertain lobar origin. FDG-PET showed a distinct hypometabolism in 62% and was concordant with ictal EEG in 74% in TLE and in 56% in ETLE (p < .001). FDG-PET was useful in presurgical decision-making in 396 patients (47%) and most beneficial in TLE compared to ETLE (58% vs. 44%, p = .001). Overall, FDG-PET contributed to recommending resection in 78 cases (20%) and iEEG in 187 cases (47%); in 131 patients (33%), FDG-PET resulted in a conclusion that resection was not feasible. In TLE, seizure-freedom 1 year after surgery did not differ significantly (p = .48) between patients with negative MRI and EEG-PET concordance (n = 30, 65%) and those with positive MRI and concordant EEG (n = 46, 68%). In ETLE, half of patients with negative MRI and EEG-PET concordance and three quarters with positive MRI and concordant EEG were seizure-free postsurgery (n = 5 vs. n = 6, p = .28). SIGNIFICANCE: This is the largest reported cohort of patients with DRE who received presurgical FDG-PET, showing that FDG-PET is a useful diagnostic tool. MRI-negative and MRI-positive cases with concordant FDG-PET results (with either EEG or MRI) had a comparable outcome after surgery. These findings confirm the significance of FDG-PET in presurgical epilepsy diagnostics

Bildgebung in der prächirurgischen Epilepsiediagnostik

While two thirds of patients with epilepsy become seizure-free with antiseizure medications, 30% remain drug-resistant. In drug-resistant focal epilepsy, epilepsy surgery offers an approximately 65% chance of becoming seizure-free; however, for a successful outcome of surgery a seizure focus must be precisely located, for which imaging techniques are essential. In recent years, the proportion of patients with apparently inconspicuous findings in magnetic resonance imaging (MRI) in the presurgical evaluation has increased. The sensitivity of MRI can be increased using special MRI sequences and MRI postprocessing techniques. Ictal and interictal source localization based on electroencephalography (EEG) and magnetencephalography (MEG) aim at determining the onset of interictal discharges and seizures. Nuclear medicine imaging techniques such as interictal positron emission tomography (PET) and ictal single photon emission computed tomography (SPECT) can detect chronic or acute seizure-related changes in brain metabolism and can indicate an epileptogenic focus even if MRI is inconspicuous. The results of these techniques are used to plan invasive EEG recordings and subsequently surgery. Concordant findings are associated with better surgical outcomes and show significantly higher rates of seizure freedomin the long-term seizure outcome

Automatic and manual segmentation of the piriform cortex: Method development and validation in patients with temporal lobe epilepsy and Alzheimer's disease.

The piriform cortex (PC) is located at the junction of the temporal and frontal lobes. It is involved physiologically in olfaction as well as memory and plays an important role in epilepsy. Its study at scale is held back by the absence of automatic segmentation methods on MRI. We devised a manual segmentation protocol for PC volumes, integrated those manually derived images into the Hammers Atlas Database (n = 30) and used an extensively validated method (multi-atlas propagation with enhanced registration, MAPER) for automatic PC segmentation. We applied automated PC volumetry to patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE; n = 174 including n = 58 controls) and to the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 151, of whom with mild cognitive impairment (MCI), n = 71; Alzheimer's disease (AD), n = 33; controls, n = 47). In controls, mean PC volume was 485 mm3 on the right and 461 mm3 on the left. Automatic and manual segmentations overlapped with a Jaccard coefficient (intersection/union) of ~0.5 and a mean absolute volume difference of ~22 mm3 in healthy controls, ~0.40/ ~28 mm3 in patients with TLE, and ~ 0.34/~29 mm3 in patients with AD. In patients with TLE, PC atrophy lateralised to the side of hippocampal sclerosis (p < .001). In patients with MCI and AD, PC volumes were lower than those of controls bilaterally (p < .001). Overall, we have validated automatic PC volumetry in healthy controls and two types of pathology. The novel finding of early atrophy of PC at the stage of MCI possibly adds a novel biomarker. PC volumetry can now be applied at scale

Risk of Seizure Recurrence Due to Autoimmune Encephalitis With NMDAR, LGI1, CASPR2, and GABABR Antibodies: Implications for Return to Driving

Rada A, Hagemann A, Aaberg Poulsen C, et al. Risk of Seizure Recurrence Due to Autoimmune Encephalitis With NMDAR, LGI1, CASPR2, and GABABR Antibodies: Implications for Return to Driving. Neurology: Neuroimmunology &amp; Neuroinflammation . 2024;11(4): e200225.BACKGROUND AND OBJECTIVES: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries.; METHODS: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models.; RESULTS: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR.; DISCUSSION: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months