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

EBioMedicine (Oct 2022)

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

Affiliations

Jingya Yan: 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
Kavitha Kothur: 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
Emily A. Innes: TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
Velda X. Han: Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore
Hannah F. Jones: Starship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
Shrujna Patel: 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
Erica Tsang: Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia
Richard Webster: TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
Sachin Gupta: TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
Christopher Troedson: 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
Manoj P. Menezes: 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
Jayne Antony: TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
Simone Ardern-Holmes: TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
Esther Tantsis: 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
Shekeeb Mohammad: 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
Louise Wienholt: Department of Clinical Immunology and Allergy, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
Ananda S. Pires: Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia
Benjamin Heng: Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia
Gilles J. Guillemin: Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia
Anna Guller: Computational NeuroSurgery Lab, Macquarie University, Sydney, NSW, Australia
Deepak Gill: TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia
Sushil Bandodkar: 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
Russell C. Dale: 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; Corresponding author at : Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Journal volume & issue: Vol. 84
p. 104280

Abstract

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Summary: 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.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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