High-precision stereotactic irradiation for focal drug-resistant epilepsy versus standard treatment: a randomized waitlist-controlled trial (the PRECISION trial).

INTRODUCTION: The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). METHODS: In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. DISCUSSION: This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

Value of ultra-high field MRI in patients with suspected focal epilepsy and negative 3 T MRI (EpiUltraStudy): protocol for a prospective, longitudinal therapeutic study.

PURPOSE: Resective epilepsy surgery is a well-established, evidence-based treatment option in patients with drug-resistant focal epilepsy. A major predictive factor of good surgical outcome is visualization and delineation of a potential epileptogenic lesion by MRI. However, frequently, these lesions are subtle and may escape detection by conventional MRI (≤ 3 T). METHODS: We present the EpiUltraStudy protocol to address the hypothesis that application of ultra-high field (UHF) MRI increases the rate of detection of structural lesions and functional brain aberrances in patients with drug-resistant focal epilepsy who are candidates for resective epilepsy surgery. Additionally, therapeutic gain will be addressed, testing whether increased lesion detection and tailored resections result in higher rates of seizure freedom 1 year after epilepsy surgery. Sixty patients enroll the study according to the following inclusion criteria: aged ≥ 12 years, diagnosed with drug-resistant focal epilepsy with a suspected epileptogenic focus, negative conventional 3 T MRI during pre-surgical work-up. RESULTS: All patients will be evaluated by 7 T MRI; ten patients will undergo an additional 9.4 T MRI exam. Images will be evaluated independently by two neuroradiologists and a neurologist or neurosurgeon. Clinical and UHF MRI will be discussed in the multidisciplinary epilepsy surgery conference. Demographic and epilepsy characteristics, along with postoperative seizure outcome and histopathological evaluation, will be recorded. CONCLUSION: This protocol was reviewed and approved by the local Institutional Review Board and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Results will be submitted to international peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: www.trialregister.nl : NTR7536.

Ultra-high field magnetic resonance imaging in human epilepsy: A systematic review.

RATIONALE: Resective epilepsy surgery is an evidence-based curative treatment option for patients with drug-resistant focal epilepsy. The major preoperative predictor of a good surgical outcome is detection of an epileptogenic lesion by magnetic resonance imaging (MRI). Application of ultra-high field (UHF) MRI, i.e. field strengths ≥ 7 Tesla (T), may increase the sensitivity to detect such a lesion. METHODS: A keyword search strategy was submitted to Pubmed, EMBASE, Cochrane Database and clinicaltrials.gov to select studies on UHF MRI in patients with epilepsy. Follow-up study selection and data extraction were performed following PRISMA guidelines. We focused on I) diagnostic gain of UHF- over conventional MRI, II) concordance of MRI-detected lesion, seizure onset zone and surgical decision-making, and III) postoperative histopathological diagnosis and seizure outcome. RESULTS: Sixteen observational cohort studies, all using 7T MRI were included. Diagnostic gain of 7T over conventional MRI ranged from 8% to 67%, with a pooled gain of 31%. Novel techniques to visualize pathological processes in epilepsy and lesion detection are discussed. Seizure freedom was achieved in 73% of operated patients; no seizure outcome comparison was made between 7T MRI positive, 7T negative and 3T positive patients. 7T could influence surgical decision-making, with high concordance of lesion and seizure onset zone. Focal cortical dysplasia (54%), hippocampal sclerosis (12%) and gliosis (8.1%) were the most frequently diagnosed histopathological entities. SIGNIFICANCE: UHF MRI increases, yet variably, the sensitivity to detect an epileptogenic lesion, showing potential for use in clinical practice. It remains to be established whether this results in improved seizure outcome after surgical treatment. Prospective studies with larger cohorts of epilepsy patients, uniform scan and sequence protocols, and innovative post-processing technology are equally important as further increasing field strengths. Besides technical ameliorations, improved correlation of imaging features with clinical semiology, histopathology and clinical outcome has to be established.

MEG-guided analysis of 7T-MRI in patients with epilepsy.

PURPOSE: To study possible detection of structural abnormalities on 7T MRI that were not detected on 3T MRI and estimate the added value of MEG-guidance. For abnormalities found, analysis of convergence between clinical, MEG and 7T MRI localization of suspected epileptogenic foci. METHODS: In adult patients with well-documented localization-related epilepsy in whom a previous 3T MRI did not demonstrate an epileptogenic lesion but MEG indicated a plausible epileptogenic focus, 7T MRI was performed. Based on semiologic data, visual analysis of the 7T images was performed as well as based on prior MEG results. Correlation with other data from the patient charts, for as far as these were available, was analysed. To establish the level of concordance between the three observers the generalized or Fleiss kappa was calculated. RESULTS: In 3/19 patients abnormalities that, based on semiology, could plausibly represent an epileptogenic lesion were detected using 7T MRI. In an additional 3/19 an abnormality was detected after MEG-guidance. However, in these later cases there was no concordance among the three observers with regard to the presence of a structural abnormality. In one of these three cases intracranial recording was performed, proving the possible abnormality on 7T MRI to be the epileptogenic focus. CONCLUSIONS: In 32% of patients 7T MRI showed abnormalities that could indicate an epileptogenic lesion whereas previous 3T MRI did not, especially when visual inspection was guided by the presence of focal interictal MEG abnormalities.

Evaluation of MEG vs EEG after sleep deprivation in epilepsy.

OBJECTIVE: MEG and EEG after sleep deprivation (EEG-SD) are applied as diagnostic tools in the evaluation of patients with possible epilepsy. There is no gold standard to check whether the diagnosis based on these two modalities is correct. The best standard available is the long-term follow-up of patients. As follow-up of an earlier study in which the additional value of MEG vs EEG-SD diagnosis was evaluated, we investigated the long-term validity of MEG-based and EEG-SD-based diagnosis. MATERIALS AND METHODS: Data collected from 46 patients were used in a comparative study of the last known diagnosis against the original one of 8 years ago. RESULTS: Long-term (3-8 years) sensitivity of sharp phenomena (combining spikes and sharp waves) in routine MEG and in EEG-SD for the diagnosis epilepsy is 71% and 62%, respectively. When compared to the original study, this hardly changed. Over time, uncertainty on diagnosis diminishes. CONCLUSION: MEG as well as EEG-SD are robust long-term predictors for epilepsy.

Detection superiority of 7 T MRI protocol in patients with epilepsy and suspected focal cortical dysplasia.

In 11 adult patients with suspicion of Focal cortical dysplasia (FCD) on 1.5 T (n = 1) or 3 T (n = 10) magnetic resonance imaging (MRI), 7 T MRI was performed. Visibility, extent, morphological features and delineation were independently rated and subsequently discussed by three observers. Additionally, head-to-head comparisons with corresponding 3 T images were made in the eight patients with a previous 3 T MRI and sustained suspicion of FCD. Comparison with histopathology was done in the five patients that underwent surgery. All lesions, seen at 1.5 and 3 T, were also recognized on 7 T. At 7 T FLAIR highlighted the FCD-like lesions best, whereas T2 and T2* were deemed better suited to review structure and extent of the lesion. Image quality with the used 7 T MRI setup was higher than the quality with the used 3 T MRI setup. In 2 out of 11 patients diagnosis changed, in one after re-evaluation of the images, and in the other based on histopathology. With the used 7 T MRI setup, FCD-like lesions can be detected with more confidence and detail as compared to lower field strength. However, concordance between radiologic diagnosis and final diagnosis seems to be lower than expected.

Prospective multi-center study of an automatic online seizure detection system for epilepsy monitoring units.

OBJECTIVE: A method for automatic detection of epileptic seizures in long-term scalp-EEG recordings called EpiScan will be presented. EpiScan is used as alarm device to notify medical staff of epilepsy monitoring units (EMUs) in case of a seizure. METHODS: A prospective multi-center study was performed in three EMUs including 205 patients. A comparison between EpiScan and the Persyst seizure detector on the prospective data will be presented. In addition, the detection results of EpiScan on retrospective EEG data of 310 patients and the public available CHB-MIT dataset will be shown. RESULTS: A detection sensitivity of 81% was reached for unequivocal electrographic seizures with false alarm rate of only 7 per day. No statistical significant differences in the detection sensitivities could be found between the centers. The comparison to the Persyst seizure detector showed a lower false alarm rate of EpiScan but the difference was not of statistical significance. CONCLUSIONS: The automatic seizure detection method EpiScan showed high sensitivity and low false alarm rate in a prospective multi-center study on a large number of patients. SIGNIFICANCE: The application as seizure alarm device in EMUs becomes feasible and will raise the efficiency of video-EEG monitoring and the safety levels of patients.

Eliciting patients' preferences for epilepsy diagnostics: a discrete choice experiment.

BACKGROUND: Diagnosing epilepsy is a lengthy and burdensome process for patients and their family. Although the need for a more patient-centered approach in clinical practice is widely acknowledged, empirical evidence regarding patient preferences for diagnostic modalities in epilepsy is missing. The objectives of this study were 1) to identify to what extent important attributes of diagnostic procedures in epilepsy affect preferences for a procedure, 2) to determine the relative importance of these attributes, and 3) to calculate overall utility scores for routine electroencephalography (EEG) and magnetoencephalography (MEG) recordings. METHODS: A discrete choice experiment was performed to determine patients' preferences, which involved presentation of pairwise choice tasks regarding hypothetical scenarios. Scenarios varied along six attributes: "way of measuring brain activity", "duration", "freedom of movement", "travel time", "type of additional examination", and "chance of additional examination". Choice tasks were constructed using a statistically efficient design, and the questionnaire contained 15 unique unlabeled choice tasks. Mixed multinomial logistic regression was used to estimate patients' preferences. RESULTS: A total of 289 questionnaires were included in the analysis. McFadden's pseudo R(2) showed a model fit of 0.28, and all attributes were statistically significant. Heterogeneity in preferences was present for all attributes. "Freedom of movement" and "Chance of additional examination" were perceived as the most important attributes. Overall utility scores did not substantially differ between routine EEG and MEG. CONCLUSION: This study suggests that the identified attributes are important in determining patients' preference for epilepsy diagnostics. It can be concluded that MEG is not necessarily more patient-friendly than a routine EEG in primary diagnostics and, regarding additional diagnostics, patients have a strong preference for long-term 24-h EEG over EEG after sleep deprivation. Furthermore, barring substantial heterogeneity within the parameters in mind, our study suggests that it is important to take individual preferences into account in medical decision-making.

A framework to integrate EEG-correlated fMRI and intracerebral recordings.

EEG-correlated functional MRI (EEG-fMRI) has been used to indicate brain regions associated with interictal epileptiform discharges (IEDs). This technique enables the delineation of the complete epileptiform network, including multifocal and deeply situated cortical areas. Before EEG-fMRI can be used as an additional diagnostic tool in the preoperative work-up, its added value should be assessed in relation to intracranial EEG recorded from depth electrodes (SEEG) or from the cortex (ECoG), currently the clinical standard. In this study, we propose a framework for the analysis of the SEEG data to investigate in a quantitative way whether EEG-fMRI reflects the same cortical areas as identified by the IEDs present in SEEG recordings. For that purpose, the data of both modalities were analyzed with a general linear model at the same time scale and within the same spatial domain. The IEDs were used as predictors in the model, yielding for EEG-fMRI the brain voxels that were related to the IEDs and, similarly for SEEG, the electrodes that were involved. Finally, the results of the regression analysis were projected on the anatomical MRI of the patients. To explore the usefulness of this quantitative approach, a sample of five patients was studied who both underwent EEG-fMRI and SEEG recordings. For clinical validation, the results of the SEEG analysis were compared to the standard visual review of IEDs in SEEG and to the identified seizure onset zone, the resected area, and outcome of surgery. SEEG analysis revealed a spatial pattern for the most frequent and dominant IEDs present in the data of all patients. The electrodes with the highest correlation values were in good concordance with the electrodes that showed maximal amplitude during those events in the SEEG recordings. These results indicate that the analysis of SEEG data at the time scale of EEG-fMRI, using the same type of regression model, is a promising way to validate EEG-fMRI data. In fact, the BOLD areas with a positive hemodynamic response function were closely related to the spatial pattern of IEDs in the SEEG recordings in four of the five patients. The areas of significant BOLD that were not located in the vicinity of depth electrodes, were mainly characterized by negative hemodynamic responses. Furthermore, the area with a positive hemodynamic response function overlapped with the resected area in three patients, while it was located at the edge of the resection area for one. To conclude, the results of this study encourage the application of EEG-fMRI to guide the implantation of depth electrodes as prerequisite for successful epilepsy surgery.

MRS-lateralisation index in patients with epilepsy and focal cortical dysplasia or a MEG-focus using bilateral single voxels.

PURPOSE: To evaluate if single voxel proton magnetic resonance spectroscopy (SV-MRS) can help in lateralising and sometimes in localizing an epileptogenic focus. The assumption is that in MRI negative patients the underlying pathology most often is focal cortical dysplasia (FCD). Several studies have shown that in the presence of FCD there are also (1)H-MRS abnormalities on the contralateral side. However, in most cases the studied group was not homogeneous and included different forms of dysplasias, including band heterotopias and polymicrogyria, and the studies used different spectroscopy protocols. In the present study, using bilateral SV-MRS we investigated the presence of a lateralisation index in two groups of patients with localisation related epilepsy: patients with focal cortical dysplasia on MRI and patients without MRI abnormalities with a focus identified by MEG. Aim of the study was to show that in both groups the expected epileptogenic side shows more pronounced metabolic alterations, making MRS a possible screening tool for clarifying lateralisation questions in patients with cryptogenic localisation related epilepsy. METHODS: In ten patients a single voxel was placed over the FCD and in nine patients over the region of interest (ROI) as indicated by MEG. In all patients a voxel was also placed in the contralateral homologus location. We used metabolite concentrations as peak ratios relative to the creatine (Cr) peak to calculate a lateralisation index. RESULTS: In both groups NAA/Cr was significantly lower on the affected side whereas the results for Cho/Cr were more diverse. There were no significant differences between the two groups. The limitations of the used methods and the implications of the findings are discussed.

Motor evoked potentials after transcranial magnetic stimulation support hypothesis of coexisting central mechanism in obstetric brachial palsy.

Six infants with obstetric brachial palsy, ranging from 4 to 7 months of age, were investigated. One was suspected of having extensive brachial plexus lesions and five were suspected of having a unilateral lesion of both roots C5 and C6. All were referred to our center to investigate the possibility for reconstructive surgery. In all infants, even at this age, transcranial magnetic stimulation resulted in motor evoked potentials (MEP) in the biceps (in one, in the brachioradial) muscles. Averaging could not be done because of the intraindividual variation in latency. The MEP was easier to recognize if evoked when the infant had the arm bent. In all five infants suspected of upper brachial plexus lesion with avulsion of both roots C5 and C6 and/or complete rupture of the upper trunk, proven in four, an MEP on the lesioned side could be evoked. Combined with earlier investigations showing (almost) normal EMG and somatosensory evoked potentials in infants with upper plexus lesion, this leads us to the conclusion that the paralysis of these infants cannot only be attributed to the peripheral axonal damage alone but that central plasticity must also play an important role. As this is a slow process, some infants might not yet be able to use the paralytic muscles. Some theoretic issues are discussed.

Extensive somatosensory innervation in infants with obstetric brachial palsy.

In the pre-operative screening of infants with obstetric brachial palsy (OBP), the results of routine electromyography are often overly optimistic when compared to the peri-operative findings. This prompted us to include investigation of the sensory innervation of these infants using the N20 (the first cortical response to a peripheral stimulation) of the somatosensory evoked potentials (SSEP). Three to seven months after birth, SSEP were recorded at the skull after stimulation of the thumb and middle finger in infants with obstetric rupture of the upper trunk or avulsion of roots C5, C6, or C7, and in whom no clinical improvement of motor function was observed in the biceps brachii and deltoid muscles. In most infants, a normal N20 could be evoked, indicating the existence of peripheral sensory pathways. From the thumb, these sensory pathways would necessarily bypass the upper trunk and dorsal roots of spinal nerves C5 and C6, and from the middle finger bypass the middle trunk and dorsal root C7, before extending into the dorsal column and projecting toward the thalamus and cerebral cortex. These data suggest that in infancy the segmental sensory innervation of the hand is more diverse than is described in most textbooks.

The significance of routine chest X-ray in acute stroke.

We retrospectively evaluated the significance of making a chest X-ray in the acute stage of a stroke. Forty percent of the chest X-rays were of suboptimal quality. Abnormal chest X-rays were, in part, the reason for consultation of chest specialists in 5%. A chest X-ray in patients with acute stroke should only be performed if there is clinical suspicion of pulmonary or cardiac pathology, not as a routine.

[Thoughts on hypertensive encephalopathy after an atypical case]. / Considérations sur l'encéphalopathie hypertensive d'après un cas atypique.

Nowadays hypertensive encephalopathy is rare. A patient of 49 with neurological symptoms that are not classical for this syndrome is presented. While treating the hypertension the neurological symptoms disappeared. The necessary condition for the development of this syndrome is a fast rise of arterial pressure that is followed by intra-cranial edema. The edema is incited by vasodilatation that appears at tensions above the limits of cerebral autoregulation. It is recommended to treat the patients in an intensive care unit. Without treatment the patient will die.