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

Ouédraogo, Oumarou; Rébillard, Rose-Marie; Jamann, Hélène; Mamane, Victoria Hannah; Clénet, Marie-Laure; Daigneault, Audrey; Lahav, Boaz; Uphaus, Timo; Steffen, Falk; Bittner, Stefan; Zipp, Frauke; Bérubé, Arline; Lapalme-Remis, Samuel; Cossette, Patrick; Nguyen, Dang Khoa; Arbour, Nathalie; Keezer, Mark R; Larochelle, Catherine

doi:10.1111/epi.16742

Cited by 32 publications

(24 citation statements)

References 49 publications

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“…Brain injury markers have attracted some interest in epilepsy. NfL levels can increase after prolonged febrile seizures in children and in older individuals with drug-resistant epilepsy [15,16]. Children with new-onset epilepsy have higher levels of S100B than controls [17].…”

Section: Introductionmentioning

confidence: 99%

Brain injury markers in new-onset seizures in adults: A pilot study

Eriksson

Banote

Larsson

et al. 2021

Seizure

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Background: Biochemical markers of brain pathology could potentially contribute to diagnosis and prediction in epilepsy. We describe levels of five brain injury markers in adults with new-onset seizures, and assess group differences in patients with a single seizure, epilepsy, and poststroke epilepsy. Methods: In this prospective observational study, adults with new-onset seizures were recruited at Sahlgrenska University Hospital, Sweden, and concentrations of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), microtubule-associated protein tau (tau), S100 calcium-binding protein (S100B), and neuron-specific enolase (NSE) were measured. Participants were categorized as epilepsy, poststroke epilepsy (PSE), or single seizure (no additional seizures). Patients were followed until a diagnosis of epilepsy or PSE, or for at least two years in single seizure cases. Results: The cohort included 23 (37%) individuals with a single seizure, 24 (39%) with epilepsy, and 15 (24%) with PSE. The concentrations of S100B were higher in patients with epilepsy and PSE than in single seizures (p = 0.0023 and p = 0.0162, respectively). The concentrations of NfL were higher in patients with PSE than in single seizures (p=0.0027). After age-normalization, levels of S100B were higher in patients with epilepsy and levels of NfL were higher in patients with PSE (p = 0.0021 and p = 0.0180). Conclusion: Levels of S100B and NfL were higher in patients with epilepsy or PSE than patients with single seizures. Further studies are needed to investigate the biomarker potential of brain injury markers as predictors of epilepsy course or indicators of epileptogenesis.

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Section: Introductionmentioning

confidence: 99%

Brain injury markers in new-onset seizures in adults: A pilot study

Eriksson

Banote

Larsson

et al. 2021

Seizure

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“…Recently, Ouédraogo et al observed that compared to healthy controls, CD4 T-cell populations were more abundant in the peripheral blood of focal onset epilepsy subjects, in line with our results. 33 Author data support that epilepsy is linked to an expansion of the CD4 T cell subset, which is skewed toward a proinflammatory Th17/Th1 phenotype. Additionally, Xu et al for the first time demonstrate that proinflammatory IL-17-producing T cells gamma delta are concentrated in the epileptogenic zone, and their populations positively related to seizure severity, 34 which are corroborated by animal experiments in the brains of a mouse model of SE induced by the kainic acid displaying similar activation of adaptive and innate immune responses, in accordance with our analysis data.…”

Section: Discussionmentioning

confidence: 86%

Characterization of Immune-Related Genes and Immune Infiltration Features in Epilepsy by Multi-Transcriptome Data

Hou¹,

Chen²,

Wang³

et al. 2022

JIR

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Background Epilepsy encompasses a group of heterogeneous brain diseases that afflict about 1% of the world’s population. Accumulating evidence shows that the immune system plays a key role in epileptogenesis. Nevertheless, the immune-related mechanisms remain not been precisely understood. Methods Three epilepsy datasets (GSE16969, GSE32534 and GSE143272) were screened to obtain differentially expressed immune-related genes (DEIRGs). Random forest (RF) and protein–protein interaction (PPI) network were constructed to identify core genes. Another dataset (GSE31718) and 60 clinical samples via quantitative real-time polymerase chain reaction (qRT-PCR) were utilized to validate core genes. Immune cell infiltration score was performed with CIBERSORTx tools and single-sample gene set enrichment analysis (ssGSEA). Gene set variation analysis (GSVA) and ssGSEA were conducted to determine the pathways that are significantly enriched during normal and epilepsy. The correlation between hub genes, immune cells, and enriched molecular pathways was evaluated by Pearson correlation analysis. Results Based on RF and PPI, 4 DEIRGs (CSF1R, IL6R, TLR2, and TNFRSF1A) were identified as hub genes. Results of qRT-PCR validated that higher expression levels of CSF1R, IL6R, TLR2, and TNFRSF1A in epilepsy samples compared to control sample. Immune infiltration analysis by CIBERSORTx displayed immune signatures that are significantly richer in epilepsy, T cell subsets in particular. Notably, ssGSEA found that Th1 signatures were more abundant in normal tissues; yet Th2 signatures were more abundant in epilepsy tissues. Cytokine cytokine receptor interaction (CCR) was significantly enriched in epilepsy based on multi-transcriptome data. Additionally, hub genes were significantly correlated with score of Th1/Th2 signatures and enrichment score of CCR in multi-transcriptome data. Conclusion Four IRGs (CSF1R, IL6R, TLR2, and TNFRSF1A) were closely correlated pathogenesis of epilepsy, which may be by impacting CCR and the balance of Th1/Th2 signatures involved in the occurrence of epilepsy. Our data offer compelling insights into the pathogenesis and promising therapeutic targets for epilepsy.

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“…While their absolute levels were similar to our study, the age-dependent slope of NFL levels was steeper in DRE than in WCE and HC. The authors linked this finding to the expanded inflammatory CD4-T cells and proinflammatory cytokine levels, which may, in the long run, drive neurodegeneration in people with DRE (14). We recently published data on the impact of acute, tonic clonic seizures (TCS) in patients with DRE on the biomarkers described here.…”

Section: Discussionmentioning

confidence: 91%

“…The authors did not find significant associations between the levels of NFL or other biomarkers and classical markers of neuroinflammations such as CSF cell count or MRI alterations (10)(11)(12)(13). Ouédrago et al (14) very recently showed elevated NFL levels in drugresistant epilepsy (DRE) when compared to well-controlled epilepsy (WCE) or healthy controls (HC). While their absolute levels were similar to our study, the age-dependent slope of NFL levels was steeper in DRE than in WCE and HC.…”

Section: Discussionmentioning

confidence: 97%

CSF and Serum Biomarkers of Cerebral Damage in Autoimmune Epilepsy

et al. 2021

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Introduction: Our goal was to investigate whether biomarkers of cerebral damage are found in autoimmune-mediated epilepsy (AIE) and whether these can differentiate AIE from other seizure disorders.Methods: We retrospectively searched our cerebrospinal fluid (CSF) database for patients with definite AIE, hippocampal sclerosis due to other causes (HS), genetic generalized epilepsy (GGE), and psychogenic, non-epileptic seizures (PNES). We measured serum and CSF tau, neurofilament 1 (NFL), glial fibrillary acid protein (GFAP), and ubiquitin-carboxy-terminal hydrolase L1 with a single-molecule array.Results: We identified suitable samples from patients with AIE (n = 13) with different antibodies and compared them to HS (n = 13), GGE (n = 7), and PNES (n = 8). The NFL levels were significantly elevated in the serum (p = 0.0009) and CSF (p < 0.0019) of AIE patients. The AIE group was significantly older, while the disease duration was significantly shorter than in the control groups. NFL correlated significantly with age in all groups, and the NFL levels of AIE patients were hardly higher than those of healthy elderly people published elsewhere.Conclusions: Our data indicate that the elevated NFL levels in AIE patients are most likely due to the higher age in this group and not due to the underlying inflammation. Unless larger prospective studies with intra-individual, longitudinal analyses and treatment responses would contradict our findings, NFL in serum might yet become a biomarker for disease activity and differential diagnosis.

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

Cited by 32 publications

References 49 publications

Brain injury markers in new-onset seizures in adults: A pilot study

Brain injury markers in new-onset seizures in adults: A pilot study

Characterization of Immune-Related Genes and Immune Infiltration Features in Epilepsy by Multi-Transcriptome Data

CSF and Serum Biomarkers of Cerebral Damage in Autoimmune Epilepsy

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