Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy.

OBJECTIVE: Adult drug-resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well-controlled epilepsy (WCE). METHODS: Peripheral blood mononuclear cells and serum from >120 age- and sex-matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array. RESULTS: Using a data-driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)-17A, IL-22, tumor necrosis factor, interferon-γ, and granulocyte-macrophage colony-stimulating factor, but not anti-inflammatory cytokines IL-10 and IL-4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17-related circulating proinflammatory cytokines are elevated, but Th2-related cytokine IL-4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals. SIGNIFICANCE: Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.

Utility of magnetic source imaging in nonlesional focal epilepsy: a prospective study.

OBJECTIVE: For patients with nonlesional refractory focal epilepsy (NLRFE), localization of the epileptogenic zone may be more arduous than for other types of epilepsy and frequently requires information from multiple noninvasive presurgical modalities and intracranial EEG (icEEG). In this prospective, blinded study, the authors assessed the clinical added value of magnetic source imaging (MSI) in the presurgical evaluation of patients with NLRFE. METHODS: This study prospectively included 57 consecutive patients with NLRFE who were considered for epilepsy surgery. All patients underwent noninvasive presurgical evaluation and then MSI. To determine the surgical plan, discussion of the results of the presurgical evaluation was first undertaken while discussion participants were blinded to the MSI results. MSI results were then presented. MSI influence on the initial management plan was assessed. RESULTS: MSI results influenced patient management in 32 patients. MSI results led to the following changes in surgical strategy in 14 patients (25%): allowing direct surgery in 6 patients through facilitating the detection of subtle cortical dysplasia in 4 patients and providing additional concordant diagnostic information to other presurgical workup in another 2 patients; rejection of surgery in 3 patients originally deemed surgical candidates; change of plan from direct surgery to icEEG in 2 patients; and allowing icEEG in 3 patients deemed not surgical candidates. MSI results led to changed electrode locations and contact numbers in another 18 patients. Epilepsy surgery was performed in 26 patients influenced by MSI results and good surgical outcome was achieved in 21 patients. CONCLUSIONS: This prospective, blinded study showed that information provided by MSI allows more informed icEEG planning and surgical outcome in a significant percentage of patients with NLRFE and should be included in the presurgical workup in those patients.

The clinical impact of integration of magnetoencephalography in the presurgical workup for refractory nonlesional epilepsy.

OBJECTIVE: For patients with nonlesional refractory focal epilepsy (NLRFE), localization of the epileptogenic zone is more arduous, and intracranial electroencephalography (EEG) (icEEG) is frequently required. Planning for icEEG is dependent on combined data from multiple noninvasive modalities. We report the negative impact of lack of integration of magnetoencephalography (MEG) in the presurgical workup in NLRFE. METHODS: Observational MEG case series involving 31 consecutive patients with NLRFE in an academic epilepsy center. For various reasons, MEG data were not analyzed in a timely manner to be included in the decision-making process. The presumed impact of MEG was assessed retrospectively. RESULTS: Magnetoencephalography would have changed the initial management in 21/31 (68%) had MEG results been available by reducing the number of intracranial electrodes, modifying their position, allowing for direct surgery, canceling the intracranial study, or providing enough evidence to justify one. Good surgical outcome was achieved in 11 out of 17 patients who proceeded to epilepsy surgery. Nine out of eleven had MEG clusters corresponding to the resection area, and MEG findings would have allowed for direct surgery (avoiding icEEG) in 2/11. Six patients had poor outcome including three patients where MEG would have significantly changed the outcome by modifying the resection margin. Magnetoencephalography provided superior information in 3 patients where inadequate coverage precluded accurate mapping of the epileptogenic zone. CONCLUSION: In this single center retrospective study, MEG would have changed patient management, icEEG planning, and surgical outcome in a significant percentage of patients with NLRFE and should be considered in the presurgical workup in those patients.

Outcome of psychogenic non-epileptic seizures following diagnosis in the epilepsy monitoring unit.

Objective: To study the outcome of patients with psychogenic non-epileptic seizures (PNES) after their diagnosis in the epilepsy monitoring unit (EMU). Methods: Patients diagnosed in our EMU with definite PNES between January 2009 and May 2023 were contacted by phone, and those who agreed to participate were asked a set of predetermined questions. Comparative analyses were carried out on several variables before and after diagnosis: number of participants with daily PNES, number of visits to the emergency department, number of participants who consulted their general practitioner or a neurologist outside of a scheduled follow-up, number of participants who took antiseizure medications (ASMs) or psychotropic drugs, and employment status. Results: Out of the 103 patients with a definite diagnosis of PNES, 61 patients (79% female) accepted to participate in our study. The median age at PNES onset was 35 years, and the median delay to diagnosis was 3 years. Almost two-thirds (62%) were receiving ASMs and 40% psychotropic drugs. The mean stay at the EMU was 5 days. PNES diagnosis was explained to almost all patients (97%) by the end of their EMU stay and was well-accepted by most (89%). When contacted, 46% of participants no longer had PNES; 32% mentioned that their PNES had ceased immediately upon communication of the diagnosis. The median follow-up duration was 51 months. Fewer patients had daily seizures after the diagnosis (18 vs. 38%; p < 0.0455). Similarly, the median number of emergency department visits was significantly lower (0 vs. 2; p < 0.001). Only 17 patients consulted their general practitioner (vs. 40, p < 0.001) and 20 a neurologist (vs. 55, p < 0.001) after a PNES attack outside of a scheduled follow-up. The use of ASMs was also significantly reduced from 70 to 33% (p < 0.01), with only one still taking an ASM for its antiseizure properties. Significantly more participants were working at last follow-up than at PNES diagnosis (49 vs. 25%; p < 0.001). Conclusion: Our study revealed a relatively favorable long-term outcome of definite PNES diagnosed in the EMU that translated in significant reductions in PNES frequency, health care utilization and ASM use, as well as a significant increase in employment rate.

Unexpected cardiorespiratory findings postictally and at rest weeks prior to SUDEP.

Introduction: Mechanisms underlying sudden unexpected death in epilepsy (SUDEP) are unclear, but autonomic disorders are thought to play a critical role. However, those dysfunctions have mainly been reported in the peri-ictal context of generalized tonic-clonic seizures. Here, we explored whether heart rate variability (HRV), heart rate (HR), and breathing rate (BR) changes could be observed perictally during focal seizures with or without impaired awareness as well as interictally to assess the risk of SUDEP. We report the case of a 33-year-old patient with drug-resistant bilateral temporal lobe epilepsy who died at home probably from an unwitnessed nocturnal seizure ("probable SUDEP"). Methods: Ictal and interictal HRV as well as postictal cardiorespiratory analyses were conducted to assess autonomic functions and overall SUDEP risk. The SUDEP patient was compared to two living male patients from our local database matched for age, sex, and location of the epileptic focus. Results: Interictal HRV analysis showed that all sleep HRV parameters and most awake HRV parameters of the SUDEP patient were significantly lower than those of our two control subjects with bitemporal lobe epilepsy without SUDEP (p < 0.01). In two focal with impaired awareness seizures (FIAS) of the SUDEP patient, increased postictal mean HR and reduced preictal mean high frequency signals (HF), known markers of increased seizure severity in convulsive seizures, were seen postictally. Furthermore, important autonomic instability and hypersensitivity were seen through fluctuations in LF/HF ratio following two seizures of the SUDEP patient, with a rapid transition between sympathetic and parasympathetic activity. In addition, a combination of severe hypopnea (202 s) and bradycardia (10 s), illustrating autonomic dysfunction, was found after one of the SUDEP patient's FIAS. Discussion: The unusual cardiorespiratory and HRV patterns found in this case indicated autonomic abnormalities that were possibly predictive of an increased risk of SUDEP. It will be interesting to perform similar analyses in other SUDEP cases to see whether our findings are anecdotal or instead suggestive of reliable biomarkers of high SUDEP risk in focal epilepsy, in particular focal with or without impaired awareness seizures.

Association of Hyperuricemia With Acute Kidney Injury: Case Series Report Among Patients Hospitalized With General Tonic-Clonic Seizures.

BACKGROUND: Urate nephropathy is a rare cause of acute kidney injury. Although most risk factors are associated with chemotherapy, tumor lysis syndrome or rhabdomyolysis, occurrence following severe seizure has also been reported. Uric acid measurement following convulsion is rarely performed and, therefore, the incidence of hyperuricemia in this context is unknown. OBJECTIVE: The objective is to present a case of urate nephropathy following generalized tonic-clonic seizure (GTCS) and to investigate the kinetics of serum uric acid and creatinine levels in a series of patients admitted for severe seizures. DESIGN: Retrospective case report and prospective case series. SETTING: Emergency room department and neurology unit of a tertiary care hospital. PATIENTS: The study included 13 hospitalized patients for severe GTCS. MEASUREMENTS: Type, timing, and duration of seizure episodes were documented. Demographic data, weight, hypouricemic therapy, and baseline serum creatinine were recorded. Blood samples (uric acid, creatinine, blood gas, lactate, and creatinine kinase) and urine samples (uric acid, creatinine, and dipstick) were prospectively collected at Day 0, 1, 2, and 3 following the GTCS episode. METHODS: We identified and described one rare case of urate nephropathy following GTCS. Then, we presented the kinetic of uric acid and creatinine levels and the acute kidney injury incidence over the follow-up period. All analyses were using descriptive statistics. RESULTS: During the study period, 13 patients with a median tonic-clonic seizure duration of 5.0 minutes (interquartile range [IQR], 2.0-12.5) were included. From day 0 to day 3, the median serum uric acid level decreased from 346.0 µmol/L (IQR, 155.0-377.5) to 178.0 µmol/L (IQR, 140.0-297.5) and median serum creatinine from 73.0 µmol/L (IQR, 51.0-80.0) to 57.0 µmol/L (IQR, 44.0-70.0). Acute kidney injury occurred in four patients. LIMITATIONS: This is a single-center observational study with small sample size, which does not allow us to demonstrate causality between the increase of uric acid levels observed and the occurrence of acute kidney injury. A delay between the first sampling and seizure episodes was observed and could explain the limited increase of uric acid levels captured. CONCLUSIONS: There is a signal for an acute increase of uric acid levels following a severe seizure before returning to baseline within 3 days. During that period, there might be an increased risk of acute kidney injury, although these changes seem to be usually mild and reversible. Our findings suggest that routine serum uric acid measurement in patients presenting with GTCS could help to identify those patients at risk of developing acute kidney injury as a result of acute hyperuricemia. Further larger studies are required to confirm the effectiveness of such screening in acute kidney injury prevention. TRIAL REGISTRATION: As an observational noninterventional study, no registration was required.

CONTEXTE: La Néphropathie à l'acide urique est une cause rare d'insuffisance rénale aiguë (IRA). Bien que la plupart des facteurs de risque soient associés à la chimiothérapie, au syndrome de lyse tumorale ou à la rhabdomyolyse, des occurrences ont également été rapportées à la suite d'une grave crise d'épilepsie. Le taux d'acide urique est rarement mesuré après les convulsions et, ainsi, l'incidence de l'hyperuricémie demeure inconnue dans ce contexte. OBJECTIFS: Cette étude a pour objectif de présenter un cas de Néphropathie à l'acide urique à la suite d'une crise généralisée de type tonico-clonique (CGTC) et d'étudier la cinétique des taux sériques d'acide urique et de créatinine chez des patients admis pour une crise d'épilepsie grave. TYPE D'ÉTUDE: Un rapport de cas rétrospectif et une série de cas prospective. CADRE: L'urgence et le service de neurologie d'un hôpital de soins tertiaires. SUJETS: L'étude a inclus treize patients hospitalisés pour une CGTC grave. MESURES: Le type, le moment et la durée des épisodes de crise ont été documentés. Les données démographiques, le poids, le traitement hypo-uricémique et le taux sérique initial de créatinine ont également été colligés. De plus, des échantillons de sang (acide urique, créatinine, gaz sanguin, lactate, créatinine kinase) et d'urine (acide urique, créatinine, bandelette réactive) ont été recueillis de façon prospective aux jours 0, 1, 2 et 3 suivant l'épisode de CGTC. MÉTHODOLOGIE: Nous avons répertorié et décrit un cas rare de Néphropathie à l'acide urique suivant une CGTC, puis nous avons présenté la cinétique des taux d'acide urique et de créatinine ainsi que l'incidence de l'IRA au cours de la période de suivi. Toutes les analyses ont été faites à l'aide de statistiques descriptives. RÉSULTATS: Au cours de la période de suivi, treize patients dont l'épisode de CGTC avait une durée médiane de 5,0 minutes (ÉIQ: 2,0-12,5) ont été inclus. Du jour 0 au jour 3, l'uricémie médiane est passée de 346,0 µmol/L (ÉIQ: 155,0-377,5) à 178,0 µmol/L (ÉIQ: 140,0-297,5) et le taux médian de créatinine sérique de 73,0 µmol/L (ÉIQ: 51,0-80,0) à 57,0 µmol/L (ÉIQ: 44,0-70,0). Quatre patients ont eu un épisode d'IRA. LIMITES: Il s'agit d'une étude observationnelle monocentrique portant sur un faible échantillon, ce qui nous empêche de démontrer une causalité entre l'observation d'une augmentation du taux d'acide urique et l'apparition de l'IRA. Un délai a été observé entre le moment où est survenue la crise et le moment du premier prélèvement, ce qui pourrait expliquer les hausses limitées observées pour les taux d'acide urique. CONCLUSION: Certains signes indiquent une accentuation des taux d'acide urique à la suite d'une crise d'épilepsie grave, avec un retour aux taux initiaux dans les trois jours. Au cours de cette période, le risque d'IRA pourrait s'accroître, bien que ces changements semblent généralement légers et réversibles. Nos résultats donnent à penser que la mesure systématique de l'acide urique dans le sérum des patients admis pour une CGTC pourrait contribuer à identifier les patients susceptibles de développer une IRA découlant d'une hyperuricémie aiguë. Des études supplémentaires de plus grande envergure sont nécessaires pour confirmer l'efficacité de ce dépistage pour prévenir l'IRA.