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Journal of Pediatric Neurology 2021; 19(05): 321-329
DOI: 10.1055/s-0041-1728687
Original Article

Perilesional Gliosis Is Associated with Outcome after Perinatal Stroke

Sabrina Yu
1   Department of Pediatrics, University of Calgary, Calgary, Canada
,
Charissa Lam
1   Department of Pediatrics, University of Calgary, Calgary, Canada
,
Siddharth Shinde
1   Department of Pediatrics, University of Calgary, Calgary, Canada
,
Andrea M. Kuczynski
1   Department of Pediatrics, University of Calgary, Calgary, Canada
,
Helen L. Carlson
1   Department of Pediatrics, University of Calgary, Calgary, Canada
2   Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
3   Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada
,
Sean P. Dukelow
2   Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
6   Department of Radiology, University of Calgary, Calgary, Canada
,
Brian L. Brooks
1   Department of Pediatrics, University of Calgary, Calgary, Canada
2   Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
3   Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada
4   Department of Psychology, University of Calgary, Calgary, Canada
,
Adam Kirton
1   Department of Pediatrics, University of Calgary, Calgary, Canada
2   Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
3   Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada
5   Department of Clinical Neuroscience, University of Calgary, Calgary, Canada
6   Department of Radiology, University of Calgary, Calgary, Canada
› Author Affiliations Funding This work was funded by The Canadian Institutes of Health Research and The Heart and Stroke Foundation of Canada.
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Abstract

Perinatal ischemic stroke results in focal brain injury and life-long disability. Hemiplegic cerebral palsy and additional sequelae are common. With no prevention strategies, improving outcomes depends on understanding brain development. Reactive astrogliosis is a hallmark of brain injury that has been associated with outcomes but is unstudied in perinatal stroke. In this article, we hypothesized that gliosis was quantifiable and its extent would inversely correlate with clinical motor function. This was a population-based, retrospective, and cross-sectional study. Children with perinatal arterial ischemic stroke (AIS) or periventricular venous infarction (PVI) with magnetic resonance (MR) imaging were included. An image thresholding technique based on image intensity was utilized to quantify the degree of chronic gliosis on T2-weighted sequences. Gliosis scores were corrected for infarct volume and compared with the Assisting Hand and Melbourne Assessments (AHA and MA), neuropsychological profiles, and robotic measures. In total, 42 children were included: 25 with AIS and 17 with PVI (median = 14.0 years, range: 6.3–19 years, 63% males). Gliosis was quantifiable in all scans and scores were highly reliable. Gliosis scores as percentage of brain volume ranged from 0.3 to 3.2% and were comparable between stroke types. Higher gliosis scores were associated with better motor function for all three outcomes in the AIS group, but no association was observed for PVI. Gliosis can be objectively quantified in children with perinatal stroke. Associations with motor outcome in arterial but not venous strokes suggest differing glial responses may play a role in tissue remodeling and developmental plasticity following early focal brain injury.

Keywords

perinatal stroke - gliosis - neuroimaging - cerebral palsy - cognition


Publication History

Received: 04 January 2021

Accepted: 26 February 2021

Article published online:
25 June 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Raju TN, Nelson KB, Ferriero D, Lynch JK. NICHD-NINDS Perinatal Stroke Workshop Participants. Ischemic perinatal stroke: summary of a workshop sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics 2007; 120 (03) 609-616
    CrossrefPubMedGoogle Scholar
  • 2 Kirton A, Deveber G. Life after perinatal stroke. Stroke 2013; 44 (11) 3265-3271
    CrossrefPubMedGoogle Scholar
  • 3 Dunbar M, Kirton A. Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury. Lancet Child Adolesc Health 2018; 2 (09) 666-676
    CrossrefPubMedGoogle Scholar
  • 4 Mineyko A, Kirton A. The black box of perinatal ischemic stroke pathogenesis. J Child Neurol 2011; 26 (09) 1154-1162
    CrossrefPubMedGoogle Scholar
  • 5 Kirton A, Deveber G, Pontigon AM, Macgregor D, Shroff M. Presumed perinatal ischemic stroke: vascular classification predicts outcomes. Ann Neurol 2008; 63 (04) 436-443
    CrossrefPubMedGoogle Scholar
  • 6 Craig BT, Hilderley A, Kirton A, Carlson HL. Imaging developmental and interventional plasticity following perinatal stroke. Can J Neurol Sci J DOI: 10.1017/cjn.2020.166.
    CrossrefPubMedGoogle Scholar
  • 7 Baker K, Carlson HL, Zewdie E, Kirton A. Developmental remodelling of the motor cortex in hemiparetic children with perinatal stroke. Pediatr Neurol 2020; 112: 34-43
    CrossrefPubMedGoogle Scholar
  • 8 Bandera E, Botteri M, Minelli C, Sutton A, Abrams KR, Latronico N. Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke: a systematic review. Stroke 2006; 37 (05) 1334-1339
    CrossrefPubMedGoogle Scholar
  • 9 Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. J Neuroimmunol 2007; 184 (1-2): 53-68
    CrossrefPubMedGoogle Scholar
  • 10 Ferriero DM. Neonatal brain injury. N Engl J Med 2004; 351 (19) 1985-1995
    CrossrefPubMedGoogle Scholar
  • 11 Huang L, Wu Z-B, Zhuge Q. et al. Glial scar formation occurs in the human brain after ischemic stroke. Int J Med Sci 2014; 11 (04) 344-348
    CrossrefPubMedGoogle Scholar
  • 12 Tachibana M, Ago T, Wakisaka Y. et al. Early reperfusion after brain ischemia has beneficial effects beyond rescuing neurons. Stroke 2017; 48 (08) 2222-2230
    CrossrefPubMedGoogle Scholar
  • 13 Hu R, Zhou J, Luo C. et al. Glial scar and neuroregeneration: histological, functional, and magnetic resonance imaging analysis in chronic spinal cord injury. J Neurosurg Spine 2010; 13 (02) 169-180
    CrossrefPubMedGoogle Scholar
  • 14 Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302 (5651): 1760-1765
    CrossrefPubMedGoogle Scholar
  • 15 Faustino JV, Wang X, Johnson CE. et al. Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. J Neurosci 2011; 31 (36) 12992-13001
    CrossrefPubMedGoogle Scholar
  • 16 Anderson MA, Burda JE, Ren Y. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 2016; 532 (7598): 195-200
    CrossrefPubMedGoogle Scholar
  • 17 Willmore LJ. Post-traumatic seizures. Neurol Clin 1993; 11 (04) 823-834
    CrossrefPubMedGoogle Scholar
  • 18 Yun C-H, Lee SK, Lee SY, Kim KK, Jeong SW, Chung C-K. Prognostic factors in neocortical epilepsy surgery: multivariate analysis. Epilepsia 2006; 47 (03) 574-579
    CrossrefPubMedGoogle Scholar
  • 19 Fernández-López D, Faustino J, Klibanov AL. et al. Microglial cells prevent hemorrhage in neonatal focal arterial stroke. J Neurosci 2016; 36 (10) 2881-2893
    CrossrefPubMedGoogle Scholar
  • 20 Salmaso N, Jablonska B, Scafidi J, Vaccarino FM, Gallo V. Neurobiology of premature brain injury. Nat Neurosci 2014; 17 (03) 341-346
    CrossrefPubMedGoogle Scholar
  • 21 Janz P, Schwaderlapp N, Heining K. et al. Early tissue damage and microstructural reorganization predict disease severity in experimental epilepsy. eLife 2017; 6: e25742
    CrossrefPubMedGoogle Scholar
  • 22 Wagenaar N, de Theije CGM, de Vries LS, Groenendaal F, Benders MJNL, Nijboer CHA. Promoting neuroregeneration after perinatal arterial ischemic stroke: neurotrophic factors and mesenchymal stem cells. Pediatr Res 2018; 83 (1-2): 372-384
    CrossrefPubMedGoogle Scholar
  • 23 Singhal S, Lawrence JM, Bhatia B. et al. Chondroitin sulfate proteoglycans and microglia prevent migration and integration of grafted Müller stem cells into degenerating retina. Stem Cells 2008; 26 (04) 1074-1082
    CrossrefPubMedGoogle Scholar
  • 24 Suhonen JO, Peterson DA, Ray J, Gage FH. Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature 1996; 383 (6601): 624-627
    CrossrefPubMedGoogle Scholar
  • 25 Kirton A, Shroff M, Visvanathan T, deVeber G. Quantified corticospinal tract diffusion restriction predicts neonatal stroke outcome. Stroke 2007; 38 (03) 974-980
    CrossrefPubMedGoogle Scholar
  • 26 Kitchen L, Westmacott R, Friefeld S. et al. The pediatric stroke outcome measure: a validation and reliability study. Stroke 2012; 43 (06) 1602-1608
    CrossrefPubMedGoogle Scholar
  • 27 Krumlinde-Sundholm L, Holmefur M, Kottorp A, Eliasson A-C. The Assisting Hand Assessment: current evidence of validity, reliability, and responsiveness to change. Dev Med Child Neurol 2007; 49 (04) 259-264
    CrossrefPubMedGoogle Scholar
  • 28 Bourke-Taylor H. Melbourne assessment of unilateral upper limb function: construct validity and correlation with the pediatric evaluation of disability inventory. Dev Med Child Neurol 2003; 45 (02) 92-96
    CrossrefPubMedGoogle Scholar
  • 29 Kuczynski AM, Semrau JA, Kirton A, Dukelow SP. Kinesthetic deficits after perinatal stroke: robotic measurement in hemiparetic children. J Neuroeng Rehabil 2017; 14 (01) 13
    CrossrefPubMedGoogle Scholar
  • 30 Kuczynski AM, Dukelow SP, Semrau JA, Kirton A. Robotic quantification of position sense in children with perinatal stroke. Neurorehabil Neural Repair 2016; 30 (08) 762-772
    CrossrefPubMedGoogle Scholar
  • 31 Dukelow SP, Herter TM, Moore KD. et al. Quantitative assessment of limb position sense following stroke. Neurorehabil Neural Repair 2010; 24 (02) 178-187
    CrossrefPubMedGoogle Scholar
  • 32 Semrau JA, Herter TM, Scott SH, Dukelow SP. Robotic identification of kinesthetic deficits after stroke. Stroke 2013; 44 (12) 3414-3421
    CrossrefPubMedGoogle Scholar
  • 33 Coderre AM, Zeid AA, Dukelow SP. et al. Assessment of upper-limb sensorimotor function of subacute stroke patients using visually guided reaching. Neurorehabil Neural Repair 2010; 24 (06) 528-541
    CrossrefPubMedGoogle Scholar
  • 34 Essig M, Wenz F, Schoenberg SO, Debus J, Knopp MV, Van Kaick G. Arteriovenous malformations: assessment of gliotic and ischemic changes with fluid-attenuated inversion-recovery MRI. Invest Radiol 2000; 35 (11) 689-694
    CrossrefPubMedGoogle Scholar
  • 35 Hao X-Z, Yin L-K, Zhang X-X. et al. Combining systemic and stereotactic MEMRI to detect the correlation between gliosis and neuronal connective pathway at the chronic stage after stroke. J Neuroinflammation 2016; 13 (01) 156
    CrossrefPubMedGoogle Scholar
  • 36 Weber RA, Chan CH, Nie X. et al. Sensitivity of diffusion MRI to perilesional reactive astrogliosis in focal ischemia. NMR Biomed 2017;30(07):
    PubMedGoogle Scholar
  • 37 Riddle A, Dean J, Buser JR. et al. Histopathological correlates of MRI-Defined chronic perinatal white matter injury. Ann Neurol 2011; 70 (03) 493-507
    CrossrefPubMedGoogle Scholar
  • 38 Weidenheim KM, Epshteyn I, Rashbaum WK, Lyman WD. Patterns of glial development in the human foetal spinal cord during the late first and second trimester. J Neurocytol 1994; 23 (06) 343-353
    CrossrefPubMedGoogle Scholar
  • 39 Sizonenko SV, Camm EJ, Dayer A, Kiss JZ. Glial responses to neonatal hypoxic-ischemic injury in the rat cerebral cortex. Int J Dev Neurosci 2008; 26 (01) 37-45
    CrossrefPubMedGoogle Scholar
  • 40 Yu S, Carlson HL, Mineyko A. et al. Bihemispheric alterations in myelination in children following unilateral perinatal stroke. Neuroimage Clin 2018; 20: 7-15
    CrossrefPubMedGoogle Scholar
  • 41 Back SA. White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol 2017; 134 (03) 331-349
    CrossrefPubMedGoogle Scholar
  • 42 Kriz J. Inflammation in ischemic brain injury: timing is important. Crit Rev Neurobiol 2006; 18 (1-2): 145-157
    CrossrefPubMedGoogle Scholar
  • 43 Kuczynski AM, Dukelow SP, Hodge JA. et al. Corticospinal tract diffusion properties and robotic visually guided reaching in children with hemiparetic cerebral palsy. Hum Brain Mapp 2018; 39 (03) 1130-1144
    CrossrefPubMedGoogle Scholar