<scp>CSF</scp> neopterin and quinolinic acid are biomarkers of neuroinflammation and neurotoxicity in <scp>FIRES</scp> and other infection‐triggered encephalopathy syndromes

Dale, Russell C.; Thomas, Terrence; Patel, Shrujna; Han, Velda X.; Kothur, Kavitha; Troedson, Christopher; Gupta, Sachin; Gill, Deepak; Malone, Stephen M.; Waak, Michaela; Calvert, Sophie; Subramanian, Gopinath; Andrews, P Ian; Menezes, Manoj P.; Ardern‐Holmes, Simone; Mohammad, Shekeeb S.; Bandodkar, Sushil; Yan, Jingya

doi:10.1002/acn3.51832

Cited by 7 publications

(2 citation statements)

References 40 publications

(106 reference statements)

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“…Recent studies have suggested that acid and the kynurenine-tryptophan pathway serve as neuroinflammation biomarkers. [40][41][42] A previous study has shown elevated levels of CSF quinolinic acid and kynurenine in patients with infectiontriggered encephalopathy syndrome, including febrile infection-related epilepsy syndrome (FIRES), which is a subgroup of refractory SE. This elevation could be linked to the excessive conversion of tryptophan into kynurenine by the IDO enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…44 Exploring interventions such as tryptophan supplementation and kynurenic acid (an NMDA receptor antagonist) may prove beneficial in preventing SE-related consequences. 41,42 A recent study even demonstrated the usefulness of an IDO inhibitor in reducing the frequency of infantile spasms. 28 Although alterations in glutamate levels have been observed frequently in the serum of patients with epilepsy, 12,13,16 and in animal models, our study did not find significant differences in glutamate levels in either plasma or CSF samples.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomic changes in adults with status epilepticus: A human case–control study

Hanin,

Chollet,

Demeret

et al. 2024

Epilepsia

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ObjectiveStatus epilepticus (SE) is a life‐threatening prolonged epileptic seizure that affects ~40 per 100 000 people yearly worldwide. The persistence of seizures may lead to excitotoxic processes, neuronal loss, and neuroinflammation, resulting in long‐term neurocognitive and functional disabilities. A better understanding of the pathophysiological mechanisms underlying SE consequences is crucial for improving SE management and preventing secondary neuronal injury.MethodsWe conducted a comprehensive untargeted metabolomic analysis, using liquid chromatography coupled with high‐resolution mass spectrometry (LC‐HRMS), on plasma and cerebrospinal fluid (CSF) samples from 78 adult patients with SE and 107 control patients without SE, including 29 with CSF for both groups. The metabolomic fingerprints were compared between patients with SE and controls. Metabolites with differences in relative abundances that could not be attributed to treatment or nutrition provided in the intensive care unit were isolated. Enrichment analysis was performed on these metabolites to identify the most affected pathways.ResultsWe identified 76 metabolites in the plasma and 37 in the CSF that exhibited differential expression in patients with SE compared to controls. The enrichment analysis revealed that metabolic dysregulations in patients with SE affected primarily amino acid metabolism (including glutamate, alanine, tryptophan, glycine, and serine metabolism), pyrimidine metabolism, and lipid homeostasis. Specifically, patients with SE had elevated levels of pyruvate, quinolinic acid, and keto butyric acid levels, along with lower levels of arginine, N‐acetylaspartylglutamate (NAAG), tryptophan, uracil, and uridine. The tryptophan kynurenine pathway was identified as the most significantly altered in SE, resulting in the overproduction of quinolinic acid, an N‐methyl‐d‐aspartate (NMDA) receptor agonist with pro‐inflammatory properties.SignificanceThis study has identified several pathways that may play pivotal roles in SE consequences, such as the tryptophan kynurenine pathway. These findings offer novel perspectives for the development of neuroprotective therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metabolomic changes in adults with status epilepticus: A human case–control study

Hanin,

Chollet,

Demeret

et al. 2024

Epilepsia

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RANBP2 evolution and human disease

Desgraupes,

Etienne,

Arhel

2023

FEBS Letters

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RANBP2/Nup358 (Ran Binding Protein 2) is a nucleoporin and a key component of the nuclear pore complex. Through its multiple functions (e.g. SUMOylation, regulation of nucleocytoplasmic transport) and subcellular localizations (e.g. at the nuclear envelope, kinetochores, annulate lamellae), it is involved in many cellular processes. RANBP2 dysregulation or mutation leads to the development of human pathologies, such as Acute Necrotizing Encephalopathy 1 (ANE1), cancer, neurodegenerative diseases and it is also involved in viral infections. The chromosomal region containing the RANBP2 gene is highly dynamic, with high structural variation and recombination events that led to the appearance of a gene family called RGPD (RANBP2 and GCC2 Protein Domains), with multiple gene loss/duplication events during ape evolution. Although RGPD homoplasy and maintenance during evolution suggest they might confer an advantage to their hosts, their functions are still unknown and understudied. In this review, we discuss the appearance and importance of RANBP2 in metazoans and its function‐related pathologies, caused by an alteration of its expression levels (through promotor activity, post‐transcriptional or post‐translational modifications), its localization or genetic mutations.

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Autoimmune‐associated seizure disorders

Smith,

Budhram,

Geis

et al. 2024

Epileptic Disorders

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With the discovery of an expanding number of neural autoantibodies, autoimmune etiologies of seizures have been increasingly recognized. Clinical phenotypes have been identified in association with specific underlying antibodies, allowing an earlier diagnosis. These phenotypes include faciobrachial dystonic seizures with LGI1 encephalitis, neuropsychiatric presentations associated with movement disorders and seizures in NMDA‐receptor encephalitis, and chronic temporal lobe epilepsy in GAD65 neurologic autoimmunity. Prompt recognition of these disorders is important, as some of them are highly responsive to immunotherapy. The response to immunotherapy is highest in patients with encephalitis secondary to antibodies targeting cell surface synaptic antigens. However, the response is less effective in conditions involving antibodies binding intracellular antigens or in Rasmussen syndrome, which are predominantly mediated by cytotoxic T‐cell processes that are associated with irreversible cellular destruction. Autoimmune encephalitides also may have a paraneoplastic etiology, further emphasizing the importance of recognizing these disorders. Finally, autoimmune processes and responses to novel immunotherapies have been reported in new‐onset refractory status epilepticus (NORSE) and febrile infection‐related epilepsy syndrome (FIRES), warranting their inclusion in any current review of autoimmune‐associated seizure disorders.

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CSF neopterin and quinolinic acid are biomarkers of neuroinflammation and neurotoxicity in FIRES and other infection‐triggered encephalopathy syndromes

Cited by 7 publications

References 40 publications

Metabolomic changes in adults with status epilepticus: A human case–control study

Metabolomic changes in adults with status epilepticus: A human case–control study

RANBP2 evolution and human disease

Autoimmune‐associated seizure disorders

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