**3. Neuropathological substrates of some significant risk factors for CP**

An awareness of the neuropathology of CP will facilitate comprehension of the clinico-pathological correlates of CP—the phenotypes, clinical features and the accompanying physical, mental or physiological impairments.

### **3.1 Prematurity and CP**

Prematurity plays a relatively greater role in CP causation in HICs (increased survival of preterm babies due to advanced healthcare systems) than in resource-poor countries where the mortality rate of preterm/low birth weight babies remains high [19]. Studies have shown that the prevalence of CP is inversely proportional to gestational age and indeed a meta-analysis reports rates of 111.80 per 1000 live births in infants born <28 weeks and 1.35 per 1000 for children born after 36 weeks [30]. Some factors postulated to contribute to this increased prevalence of CP among children born preterm include: infection/inflammation, organ immaturity, hormone and growth factor deficiency, metabolic factors, environmental factors and pregnancyrelated complications [19]. In a word, prematurity increases susceptibility of the foetus to multiple insults or accumulation of risk factors ("multiple hit phenomena") by increased predisposition to infection/inflammation, periventricular leukomalacia (PVL), periventricular-intraventricular haemorrhage, Persistent pulmonary hypertension of the newborn (PPHN), Respiratory Distress Syndrome (RDS), perinatal asphyxia, Patent Ductus Arteriosus (PDA), encephalopathy of prematurity, mechanical ventilation, unconjugated hyperbilirubinaemia and so on (see **Figure 1** above). This may explain why prematurity is a major risk factor for CP.

In prematurity, the neuropathological substrate for CP is a hypoxia-ischaemiainfection-inflammation-glutamate excitotoxic-free radical-cytokine-mediated cerebral white matter injury termed periventricular leukomalacia (PVL) [31]. The selective vulnerability of the periventricular white matter to injury during this

gestational period (24–34 weeks GA) relates to factors such as vascular immaturity/ arterial end zones in the periventricular region, significantly lower basal blood flow to cerebral white matter, pressure-passive cerebral blood flow, high angiogenesis and high proliferation, maturation and migration of glial cells and premyelinating oligodendrocytes (pre-OLs) [31]. PVL manifests a spectrum of severity with the most severe injury resulting in focal necrotic cysts (cystic PVL) and focal necrotic but non-cystic gliotic scars (appears as punctuate white matter lesions on MRI) while mild injuries result in diffuse white matter gliosis that is non-necrotic and non-cystic termed chronic white matter injury (CWMI) [32]. The latter appears on MRI as diffuse excessive high signal intensity (DEHSI) [32]. Obviously, the more severe lesions of cystic PVL (focal cysts) are correlated more frequently with bilateral spastic CP (spastic diplegia) and also with more severe motor deficits than the less striking diffuse CWMI [32, 33]. Fortunately, owing to mitigation of preterm cerebral injury through improved neonatal intensive care in HICs, cystic PVL is currently rare (<5%) in very preterm infants [31]. This has contributed to some reports of dwindling prevalence of CP associated with prematurity and significantly the occurrence of less severe motor deficits [28, 32]. However, the currently predominant diffuse CWMI in infants born prematurely translates to prominent cognitive disturbance, albeit with minor motor deficits [32].

Ultimately, the result of PVL is delayed/impaired myelination caused by loss or damage to the oligodendrocyte precursors (pre-OLs) in the periventricular region [32]. The higher prevalence of preterm/LBW babies in HICs may partly explain why white matter lesions are the commonest MRI findings in children with CP [28, 32]. It also contributes to spasticity being the most prevalent CP type since more medial PVL damages descending corticospinal (pyramidal) tracts for lower limb control resulting in spastic diplegia (spastic bilateral CP) and with more severe lesions (lateral extension to the centrum semiovale and internal capsule) affect upper limbs and intellectual functions in addition—spastic quadriplegia (spastic bilateral CP) [28, 31, 32]. Thus, in spastic CP, the severity of motor deficit/functional impairment and frequency of accompanying impairments correlate with the severity and extent of brain injury [31, 32].
