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.

Risk factors for behavioral and psychotic dysregulation at the epilepsy monitoring unit in patients with intracranial electrodes.

OBJECTIVE: Aberrant behavior in patients with epilepsy (PWE) admitted to an epilepsy monitoring unit (EMU) can endanger their safety. We sought to identify predictive factors for post-ictal behavioral dysregulation and psychosis in patients with refractory epilepsy being monitored at an EMU. METHODS: Retrospective data were gathered from electronic patient files of all patients with refractory epilepsy who underwent intracranial registration at our EMU. We assessed behavioral and psychotic dysregulations by reviewing clinical notes, administered emergency medication, and reports of injuries or casualties in patients and nurses. In addition, we compared patient demographic characteristics, clinical characteristics, and antiepileptic drug (AED) profiles between patients with and without behavioral and/or psychotic dysregulation. RESULTS: Out of 73 admissions, 23 patients (32%) experienced behavioral dysregulation, and five patients experienced psychosis (7%). Behavioral dysregulation was only significantly associated with a previous history of interictal or postictal psychosis. Psychotic dysregulation is significantly associated with a psychiatric history, including a history of agitation or psychosis, whether or not epilepsy-related. For both types of dysregulations, there was no relation with a pre-admission frequency of seizures, clustering of seizures during monitoring, or a temporal focus of seizures. We could not report a relationship between AED use, tapering, and the occurrence of dysregulation. CONCLUSION: We conclude that a psychiatric history, including a history of agitation and psychosis, is related to an increased risk of behavioral and psychotic dysregulation in patients undergoing invasive seizure monitoring at the EMU.

Phenytoin as seizure prophylaxis in hematopoietic stem cell transplantation with busulfan conditioning.

Background: Phenytoin is widely used as primary seizure prophylaxis in hematopoietic stem cell transplantation in patients undergoing myeloablative conditioning with busulfan. Because of the negative side effects of phenytoin, we abandoned phenytoin use in these patients. To assess the effect of this change, we performed a retrospective cohort study on all patients receiving busulfan. Methods: We included 139 patients who underwent conditioning with busulfan for hematopoietic stem cell therapy. We registered the use of phenytoin, as well as the occurrence of seizures, until 7 days after busulfan administration. We compared seizure incidence between patients who received phenytoin and those who did not. Results: Of the 43 patients who received phenytoin prophylaxis, four patients (9.3%) had a seizure during the conditioning regimen, of which two patients had cerebral non-Hodgkin lymphoma. Furthermore, all these 4 patients had very high levels of phenytoin (intoxication). Of the 96 patients that did not receive phenytoin prophylaxis, three patients (3.1%) had a seizure, and one of these patients had an undefined cerebral lesion. Phenytoin did not relate to seizure prevention in a logistic regression analysis. Conclusion: We conclude that phenytoin prophylaxis in patients treated with busulfan is obsolete and possibly harmful, as phenytoin intoxication can occur. We recommend discontinuing the use of phenytoin as primary seizure prophylaxis in these patients.

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.

[Frontal lobe epilepsy or a psychogenic disorder? The importance of taking a good patient history]. / Frontale epilepsie of een psychogene aandoening?

BACKGROUND: Frontal lobe epilepsy (FE) is a diagnosis which can be easily missed due to the variety in symptoms. The symptoms depend on the location of the epileptical activity in the frontal lobe. CASE DESCRIPTION: A 48-year-old man of Moroccan descent is diagnosed with frontal epilepsy, but this diagnosis is rejected based on the 24-hours EEG. Instead he is diagnosed with psychogenic non-epileptic seizures (PNES). Upon this diagnosis, he develops reactive depressive symptoms and he is referred to the psychiatrist. However, based on the clinical presentation the diagnosis PNES is overruled and replaced with frontal lobe epilepsy. The patient recovers when he is treated with valproic acid. CONCLUSION: The article describes the symptoms of FE and those of PNES. This case description demonstrates the difficulties and illustrates the importance of a good history when diagnosing FE.

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.

Medication use in poststroke epilepsy: A descriptive study on switching of antiepileptic drug treatment.

OBJECTIVE: Currently, as evidence-based guidelines are lacking, in patients with poststroke epilepsy (PSE), the choice of the first antiepileptic drug (AED) is left over to shared decision by the treating physician and patient. Although, it is not uncommon that patients with PSE subsequently switch their first prescribed AED to another AED, reasons for those switches are not reported yet. In the present study, we therefore assessed the reasons for switching the first prescribed AED in patients with PSE. METHOD: We gathered a hospital-based case series of 53 adult patients with poststroke epilepsy and assessed the use of AEDs, comedication, and the reasons for switches between AEDs during treatment. We also determined the daily drug dose (DDD) at the switching moment. RESULTS: During a median follow-up of 62 months (Interquartile range [IQR] 69 months), 21 patients (40%) switched their first prescribed AED. Seven patients switched AED at least once because of ineffectivity only or a combination of ineffectivity and side effects, whereas 14 patients switched AED at least once because of side effects only. The DDD was significantly (p < 0.001) higher in case of medication switches due to ineffectivity (median 1.20, IQR 0.33) compared to switching due to side effects (median 0.67, IQR 0.07). There was no difference in the use of comedication between the group that switched because of ineffectivity compared to the group that switched because of side effects. CONCLUSION: In our case series, up to 40% of patients with epilepsy after stroke needed to switch their first prescribed AED, mostly because of side effects in lower dosage ranges.

Cognition and quality of life in patients with poststroke epilepsy: A case-control study.

INTRODUCTION: Though seizures are a common complication after stroke, only little scientific evidence is available about the impact of epilepsy on cognitive functioning and quality of life in patients who have had a stroke. Therefore, we assessed these items in a case-control study. METHODS: We studied 36 patients with poststroke epilepsy (PSE) and 36 matched patients who have had a stroke without epilepsy using parts of the FePsy (the computerized visual searching task (CVST) for central information processing speed and a reaction time test), the mini-mental-state examination (MMSE), the EuroQol, the stroke-adapted Sickness Impact Profile questionnaire (SA-SIP-30), the Barthel index, the modified Rankin scale, and the National Institutes of Health stroke scale (NIHSS). RESULTS: Patients with PSE had significantly lower scores on the CVST and MMSE. Generic quality of life was the same in patients with poststroke epilepsy and patients with stroke only, however, the SA-SIP-30 showed a lower disease-specific quality of life in patients with poststroke epilepsy. The Barthel index showed no difference between both groups, but both the modified Rankin scale and the NIHSS were significantly higher in patients with poststroke epilepsy, indicating more disability and neurological impairment in patients with PSE. CONCLUSIONS: We found that PSE relates to impaired cognitive functioning, a lower disease-specific quality of life and more disability and neurological impairment. This underlines the importance of further clinical research in this field. This article is part of the Special Issue "Seizures & Stroke".

Correction to: The occurrence of seizures after ischemic stroke does not influence long-term mortality; a 26-year follow-up study.

The original article can be found online at.

The occurrence of seizures after ischemic stroke does not influence long-term mortality; a 26-year follow-up study.

OBJECTIVE: Epileptic seizures are a common complication after stroke. The relation between occurrence of seizures after stroke and long-term mortality remains elusive. We aimed to assess whether seizures in an early or late phase after ischemic stroke are an independent determinant of long-term mortality. METHODS: We prospectively included and followed 444 ischemic stroke patients with a first-ever supratentorial brain infarct for at least 2 years after their stroke regarding the occurrence of seizures. The final follow-up for mortality is from April 2015 (follow-up duration 24.5-27.8 years, mean 26.0 years, SD 0.9 years). We compared patients with early-onset seizures with all seizure-free patients, whereas the patients with late-onset seizures were compared with the 1-week survivors without any seizures. We used Cox-regression analyses to correct for possible confounding factors. RESULTS: Kaplan-Meier analysis showed significantly higher mortality for the patients with early-onset seizures (p = 0.002) but after correction for known risk factors for (long term) mortality early-onset seizures had no independent influence on long-term mortality (HR 1.09; 95% CI 0.64-1.85). In patients with late-onset seizures, no significant influence from late-onset seizures on long-term mortality was found (univariate p = 0.717; multivariate HR 0.81; 95% CI 0.54-1.20). CONCLUSION: Both early-onset and late-onset seizures do not influence long-term mortality after ischemic stroke.

Inter- and intraobserver agreement of seizure behavior scoring in the amygdala kindled rat.

INTRODUCTION: The Racine scale is a 5-point seizure behavior scoring paradigm used in the amygdala kindled rat. Though this scale has been applied widely in experimental epilepsy research, studies of reproducibility are rare. The aim of the current study was, therefore, to assess its interobserver variability and intraobserver variability. MATERIAL AND METHODS: A video database set was acquired in the course of amygdala kindling of 67 Wistar rats. Six blinded observers received scoring instructions and then viewed a set of 15 random videos (session #1). Next, each observer scored 379 to 1048 additional videos (session #2) and finally scored the same set of 15 videos again (session #3). Scores included the occurrence of seizures (yes or no), the total seizure time (start of stimulus until the absence of seizure behavior), and the highest Racine stage. Interobserver variability and intraobserver variability were assessed in and between sessions #1 and #3 using a 2-way mixed intraclass correlation or Cohen's kappa depending on the variable. RESULTS: Interobserver agreement in session #1 was 0.664 for seizure occurrence, 0.861 for total seizure time, and 0.797 for the highest Racine stage. In session #3, interobserver agreement on seizure occurrence declined to 0.492, total seizure time declined to 0.625, and agreement for the highest Racine stage was 0.725. Interobserver agreement was scored insufficiently on focal R2 seizures in both sessions (0.287 and 0.182). Intraobserver agreement reached >0.80 agreement for seizure occurrence, highest seizure score, and total seizure time in 3 out of 4 observers. Racine's scale stage 2 seizure scores were only 0.135 in one observer but 0.650, 0.810, and 0.635 in the other observers. DISCUSSION AND CONCLUSION: Overall, interobserver agreement and intraobserver agreement in scoring with Racine's scale were adequate. However, because interobserver agreement declined after a period of individually scoring videos, we suggest periodic repetition of the standardized instruction in the course of evaluating videos in order to ensure reproducible results.

Levels of heparin-releasable TFPI are increased in first-ever lacunar stroke patients.

OBJECTIVES: New insights in the pathophysiology of lacunar stroke (LS) suggest that it is caused by increased permeability of the blood-brain barrier due to endothelial activation. Because endothelial cells are the major production and storage site of tissue factor pathway inhibitor (TFPI), this protein can be used as marker of endothelial activation. In this observational study we measured the different pools of TFPI, as a marker of endothelial function, in first-ever lacunar stroke patients. METHODS: We determined antigen levels of total and free full-length (FL) TFPI using ELISA in 149 patients and 42 controls. Heparin-releasable free FL TFPI was determined in a random subset of 17 patients and 15 controls. By brain MRI, we classified LS patients as having isolated lacunar infarct (ILA) or silent ischemic lesions (SILs). RESULTS: Plasma levels of total TFPI were highest in patients with SILs compared with those with ILA, but this association disappeared after correction for age and levels of low-density lipoprotein cholesterol. However, levels of heparin-releasable free FL TFPI were higher in patients than in controls. CONCLUSIONS: Although ambient plasma levels of total TFPI were not different in subtypes of LS, the increased levels of heparin-releasable TFPI in patients suggest a role of endothelial activation in the pathogenesis of LS.

Metabolic syndrome relates to lacunar stroke without white matter lesions: a study in first-ever lacunar stroke patients.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of three or more of the following risk factors: obesity, elevated blood pressure, elevated triglyceride level, elevated glucose level, and low high-density lipoprotein level. Lacunar infarcts (LS) account for 25% of all ischemic strokes and are small, deeply located brain infarcts. Two different subtypes exist, which are distinguished by the presence of concomitant white matter lesions (WML) on brain imaging. We determined the prevalence of MetS in LS and the association between MetS with LS subtypes in a series of first-ever LS patients. METHODS: We included 92 patients with a first-ever LS, and 92 patients with a first-ever atheroslerotic cortical stroke (CS) matched for age and sex. LS subtypes were defined according to presence of concomitant WML. We defined MetS retrospectively according to previously defined standards. RESULTS: 35.9% of LS patients and 45.7% of CS patients had MetS (OR 0.67; 95% CI 0.37-1.20). MetS was more prevalent in LS without WML than in LS with WML (44.4 and 23.7%, respectively; OR 2.98; 95% CI 1.04-8.47). Similarly, MetS related more to CS compared to LS with WML (OR 2.56; 95% CI 1.03-6.37). CONCLUSION: MetS relates more strongly to LS without WML and to CS, than to LS with WML. Our results suggest a different underlying mechanism between LS without WML and CS, and lacunar stroke with WML.

Haptoglobin phenotype may alter endothelial progenitor cell cluster formation in cerebral small vessel disease.

Cerebral small vessel disease results in silent ischemic lesions (SIL) among which is leukoaraiosis. In this process, endothelial damage is probably involved. Endothelial progenitor cells (EPC), are involved in endothelial repair. By restoring the damaged endothelium, EPC could mitigate SIL and cerebral small vessel disease. Haptoglobin 1-1, one of three phenotypes of haptoglobin, relates to SIL and may therefore attenuate the endothelial repair by EPC. Our aim was to quantify EPC number and function and to assess haptoglobin phenotype and its effect on EPC function in patients with a high prevalence of SIL: lacunar stroke patients. We assessed EPC In 42 lacunar stroke patients and 18 controls by flow cytometry and culture with fetal calf serum, patient and control serum. We determined haptoglobin phenotype and cultured EPC with the three different haptoglobin phenotypes. We found that EPC cluster counts were lower in patients (96.9 clusters/well +/- 83.4 (mean +/- SD)), especially in those with SIL (85.0 +/- 64.3), than in controls (174.4 +/- 112.2). Cluster formation was inhibited by patient serum, especially by SIL patient serum, but not by control serum. Patients with haptoglobin 1-1 had less clusters in culture, and when haptoglobin 1-1 was added to EPC cultures, cluster numbers were lower than with the other haptoglobin phenotypes. We conclude that lacunar stroke patients, especially those with SIL, have impaired EPC cluster formation, which may point at decreased endothelial repair potential. The haptoglobin 1-1 phenotype is likely a causative factor in this impairment.

ESPRIT: is aspirin plus dipyridamole superior to aspirin alone in TIA or minor stroke patients?

Transient ischemic attack (TIA) or a (minor) ischemic stroke increases the risk of a recurrent stroke or death. Antiplatelet therapy with aspirin or clopidogrel is, in the absence of a potential cardiac embolic source, common practice to lower this risk. Until recently, adjuvant dipyridamole or low intensity oral anticoagulation were not generally prescribed in secondary prevention. In this article, we will summarize and discuss the published results of the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT). In this trial, treatments with anticoagulants, aspirin alone and the combination of aspirin plus dipyridamole were compared, in a multicenter, three-armed, randomized, open-label study in patients with TIA or minor stroke.

Virchow-Robin spaces relate to cerebral small vessel disease severity.

BACKGROUND AND PURPOSE: Virchow-Robin spaces (VRs) are perivascular spaces surrounding the deep perforating brain arteries. VRs dilatation is pathologic, and it could be a manifestation of cerebral small vessel disease. In the present study we assessed the relation between VRs and silent ischemic lesions in a cohort of patients with cerebral small vessel disease. METHODS: We divided dilated VRs on MRI (1.5 Tesla) into three semi-quantitative categories in 165 first ever lacunar stroke patients. We counted asymptomatic lacunar infarcts and graded white matter lesions, and compared the prevalence of vascular risk factors in different categories of VRs. We also determined independent predictors of silent ischemic lesions. RESULTS: VRs at basal ganglia level related to age, hypertension, asymptomatic lacunar infarcts, and white matter lesions. VRs at basal ganglia level predicted silent ischemic lesions (odds ratio 10.58 per higher VRs category; 95 %- confidence interval 3.40 - 32.92). CONCLUSION: Dilated VRs in the basal ganglia relate to the severity of cerebral small vessel disease and might be a manifestation of the same small vessel abnormality that causes silent ischemic lesions. This adds a role for VRs as a potential marker for small vessel disease.