Decreased cerebrospinal fluid kynurenic acid in epileptic spasms: A biomarker of response to corticosteroids

Jingya Yan; Kavitha Kothur; Emily A Innes; Velda X Han; Hannah F Jones; Shrujna Patel; Erica Tsang; Richard Webster; Sachin Gupta; Christopher Troedson; Manoj P Menezes; Jayne Antony; Simone Ardern-Holmes; Esther Tantsis; Shekeeb Mohammad; Louise Wienholt; Ananda S Pires; Benjamin Heng; Gilles J Guillemin; Anna Guller; Deepak Gill; Sushil Bandodkar; Russell C Dale

doi:10.1016/j.ebiom.2022.104280

Decreased cerebrospinal fluid kynurenic acid in epileptic spasms: A biomarker of response to corticosteroids

EBioMedicine. 2022 Oct:84:104280. doi: 10.1016/j.ebiom.2022.104280. Epub 2022 Sep 26.

Authors

Jingya Yan¹, Kavitha Kothur², Emily A Innes³, Velda X Han⁴, Hannah F Jones⁵, Shrujna Patel⁶, Erica Tsang⁷, Richard Webster³, Sachin Gupta³, Christopher Troedson⁸, Manoj P Menezes⁸, Jayne Antony³, Simone Ardern-Holmes³, Esther Tantsis⁶, Shekeeb Mohammad⁹, Louise Wienholt¹⁰, Ananda S Pires¹¹, Benjamin Heng¹¹, Gilles J Guillemin¹¹, Anna Guller¹², Deepak Gill³, Sushil Bandodkar¹³, Russell C Dale¹⁴

Affiliations

¹ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Department of Biochemistry, The Children's Hospital at Westmead, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
² Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.
³ TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.
⁴ Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore.
⁵ Starship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
⁶ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁷ Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁸ TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁹ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
¹⁰ Department of Clinical Immunology and Allergy, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
¹¹ Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia.
¹² Computational NeuroSurgery Lab, Macquarie University, Sydney, NSW, Australia.
¹³ Department of Biochemistry, The Children's Hospital at Westmead, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
¹⁴ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia. Electronic address: russell.dale@health.nsw.gov.au.

Abstract

Background: Epileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations.

Methods: A panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3-3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3-3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1-2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8-2.5 yrs).

Findings: There was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p<0.0001). In addition, the kynurenic acid/kynurenine (KYNA/KYN) ratio was lower in the epileptic spasms subgroup compared to OND (p<0.0001). Epileptic spasms patients who were steroid responders or partial steroid responders had lower KYNA/KYN ratio compared to patients who were refractory to steroids (p<0.005, p<0.05 respectively).

Interpretation: This study demonstrates decreased CSF kynurenic acid and KYNA/KYN in epileptic spasms, which may also represent a biomarker for steroid responsiveness. Given the anti-inflammatory and neuroprotective properties of kynurenic acid, further therapeutics able to increase kynurenic acid should be explored.

Funding: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP1176660 and Macquarie University.

Keywords: Cerebrospinal fluid; Epileptic spasms; Infantile spasms; Ketogenic diet; Metabolomics; Tryptophan-kynurenine pathway.

MeSH terms

3-Hydroxyanthranilic Acid
Adrenal Cortex Hormones
Animals
Biomarkers
Chromatography, Liquid
Epilepsy* / drug therapy
Kynurenic Acid* / cerebrospinal fluid
Kynurenine / cerebrospinal fluid
Male
Quinolinic Acid / cerebrospinal fluid
Spasm
Tandem Mass Spectrometry
Tryptophan / metabolism

Substances

Adrenal Cortex Hormones
Biomarkers
3-Hydroxyanthranilic Acid
Kynurenine
Tryptophan
Quinolinic Acid
Kynurenic Acid