Quantitative MRI susceptibility mapping reveals cortical signatures of changes in iron, calcium and zinc in malformations of cortical development in children with drug-resistant epilepsy
Sara Lorio,
Jan Sedlacik,
Po-Wah So,
Harold G. Parkes,
Roxana Gunny,
Ulrike Löbel,
Yao-Feng Li,
Olumide Ogunbiyi,
Talisa Mistry,
Emma Dixon,
Sophie Adler,
J. Helen Cross,
Torsten Baldeweg,
Thomas S. Jacques,
Karin Shmueli,
David W Carmichael
Affiliations
Sara Lorio
Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, UK; Wellcome EPSRC Centre for Medical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, St Thomas’ Hospital, London SE1 7EH, UK
Jan Sedlacik
Biomedical Engineering Department, School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK; Center for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK
Po-Wah So
Department of Neuroimaging, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
Harold G. Parkes
Department of Neuroimaging, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
Roxana Gunny
Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Ulrike Löbel
Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Yao-Feng Li
Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London and Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; Pathology Department, Tri-Service General Hospital and National Defence Medical Centre, Taipei, Taiwan, ROC
Olumide Ogunbiyi
Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London and Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Talisa Mistry
Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London and Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Emma Dixon
MRI Group, Department of Medical Physics and Biomedical Engineering, University College London, London, UK
Sophie Adler
Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, UK
J. Helen Cross
Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, UK
Torsten Baldeweg
Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, UK
Thomas S. Jacques
Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London and Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Karin Shmueli
MRI Group, Department of Medical Physics and Biomedical Engineering, University College London, London, UK
David W Carmichael
Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, UK; Wellcome EPSRC Centre for Medical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, St Thomas’ Hospital, London SE1 7EH, UK; Corresponding author at: Wellcome EPSRC Centre for Medical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, St Thomas’ Hospital, London SE1 7EH, UK.
Objective: Malformations of cortical development (MCD), including focal cortical dysplasia (FCD), are the most common cause of drug-resistant focal epilepsy in children. Histopathological lesion characterisation demonstrates abnormal cell types and lamination, alterations in myelin (typically co-localised with iron), and sometimes calcification. Quantitative susceptibility mapping (QSM) is an emerging MRI technique that measures tissue magnetic susceptibility (χ) reflecting it's mineral composition.We used QSM to investigate abnormal tissue composition in a group of children with focal epilepsy with comparison to effective transverse relaxation rate (R2*) and Synchrotron radiation X-ray fluorescence (SRXRF) elemental maps. Our primary hypothesis was that reductions in χ would be found in FCD lesions, resulting from alterations in their iron and calcium content. We also evaluated deep grey matter nuclei for changes in χ with age. Methods: QSM and R2* maps were calculated for 40 paediatric patients with suspected MCD (18 histologically confirmed) and 17 age-matched controls.Patients’ sub-groups were defined based on concordant electro-clinical or histopathology data. Quantitative investigation of QSM and R2* was performed within lesions, using a surface-based approach with comparison to homologous regions, and within deep brain regions using a voxel-based approach with regional values modelled with age and epilepsy as covariates.Synchrotron radiation X-ray fluorescence (SRXRF) was performed on brain tissue resected from 4 patients to map changes in iron, calcium and zinc and relate them to MRI parameters. Results: Compared to fluid‐attenuated inversion recovery (FLAIR) or T1‐weighted imaging, QSM improved lesion conspicuity in 5% of patients.In patients with well-localised lesions, quantitative profiling demonstrated decreased χ, but not R2*, across cortical depth with respect to the homologous regions. Contra-lateral homologous regions additionally exhibited increased χ at 2–3 mm cortical depth that was absent in lesions. The iron decrease measured by the SRXRF in FCDIIb lesions was in agreement with myelin reduction observed by Luxol Fast Blue histochemical staining.SRXRF analysis in two FCDIIb tissue samples showed increased zinc and calcium in one patient, and decreased iron in the brain region exhibiting low χ and high R2* in both patients. QSM revealed expected age-related changes in the striatum nuclei, substantia nigra, sub-thalamic and red nucleus. Conclusion: QSM non-invasively revealed cortical/sub-cortical tissue alterations in MCD lesions and in particular that χ changes in FCDIIb lesions were consistent with reduced iron, co-localised with low myelin and increased calcium and zinc content. These findings suggest that measurements of cortical χ could be used to characterise tissue properties non-invasively in epilepsy lesions.
