Mechanisms and timing of brain injury among persons with cerebral palsy

Cerebral palsy (CP) is the most prevalent chronic motor impairment among children and is associated with physical, psychological, and economic burdens for affected individuals, families, and community education and health care systems. A better understanding of the mechanisms and timing of the brain injury that contribute to the development of CP is critical to efforts to prevent this disorder and improve function of affected individuals. In addition to this population-based perspective, patients and parents can be understandably determined in their efforts to understand the cause(s) of their specific case of CP.

Toward the goal of increased understanding of causal mechanisms and timing, Reid et al., in a large study of a geographically based cohort, evaluated the potential value of brain magnetic resonance imaging (MRI) as a source of information about CP causation among individuals born either late preterm or at term.¹ Strengths of the study include the population-based sample, the availability of data to classify study participants with respect to neonatal well-being, and brain MRI for 93% of study participants.

Since normal brain development involves sequential structural changes across gestation, patterns of MRI abnormalities can be associated, to some degree, with the timing of brain injury. MRI-based estimates of timing are probably most precise for individuals with CP and an MRI-identified brain malformation; in such individuals the timing of CP causation can be classified as prenatal with a high level of confidence. However, the large majority of individuals with CP do not have brain malformation. In such cases, neuroinflammation is likely involved in etiopathogenesis, and the complexity of the pathological processes could limit the precision of attempts to define timing.²

The complexity of CP causation also gives rise to challenges when attributing causes based on brain MRI findings. Specific causes, such as hypoxia-ischemia or neuroinflammation can underlie different patterns depending on the timing of disrupted brain development.³ Conceptually, hypoxia-ischemia and infection can both be present in the same patient and share molecular and physiological biomarkers that have been used to infer a mechanistic role for infection and hypoxia-ischemia.⁴ Given these complexities, it is reasonable to ask whether ‘global hypoxic-ischemia’ is the only, or even the predominant, mechanism of injury for individuals whose MRI contained predominant grey matter injury within the basal ganglia-thalamic and cortico-subcortical regions (the neuroimaging pattern referred to by the authors as ‘C’). As Korzeniewski et al.⁵ note in a systematic review of neuroimaging in CP: ‘… the use of etiologic terms to describe image findings distorts their importance and inhibits our understanding of CP.’ Thus, while MRI patterns are likely to provide information about timing of injury, it is less clear whether these patterns can inform specific conclusions about mechanisms in individual patients.

Despite the limited specificity of MRI patterns as indicator of mechanism of injury in patients, such patterns might nonetheless provide insights into mechanisms of brain injury at a population level. The finding by Reid et al. that the relative proportion with perinatal timing decreased over time suggests the possibility that interventions implemented during the perinatal interval, such antenatal antibiotics and neonatal therapeutic hypothermia for presumed hypoxic-ischemic encephalopathy, might have reduced the risk of brain injury manifesting later as CP.

Hopefully, other researchers will attempt to replicate the findings reported by Reid et al, employing both rigorous methods to maximize the reliability of MRI interpretations as well as data on clinical complications and treatments and more specific markers of exposures and mechanisms, such as assays of toxic chemicals in water and commercial products, and omics-based biomarkers of molecular processes.