**3.8 Perinatal stroke and CP**

In children, the perinatal period is associated with the highest risk of stroke and its long-term correlate of spastic unilateral CP (spastic hemiplegia) [54]. Both perinatal arterial ischaemic stroke (foetal/intrauterine and neonatal arterial ischaemic stroke) (PAIS) and cerebral venous sinus thrombosis (CSVT) increase the likelihood of later development of CP [54]. Perinatal ischaemic stroke (PIS) is defined as "a group of heterogeneous conditions in which there is a focal disruption of CBF secondary to arterial or cerebral venous thrombosis or embolization, between 20 weeks of foetal life through twenty-eighth postnatal day confirmed by neuroimaging or neuropathological studies" [55]. Thus, PIS can be of arterial or venous origin (arterial more common), focal or multifocal and occur during intrauterine/prenatal (foetal), intrapartum or postnatal (neonatal) period. In the causation of PAIS, multiple risk factors usually interact [19, 54]. This implies that the pathogenesis of PAIS is multifactorial. The risk factors involved could be maternal, placental or neonatal factors. Some maternal factors include smoking, preeclampsia, thrombophilia, maternal infections and intrapartum complications while neonatal factors are male sex, APGAR score of <7 (5 minutes), prolonged resuscitation, congenital heart disease, thrombophilia, early-onset sepsis/meningitis and vascular abnormality [19, 54]. The placental factors include chorioamnionitis, chronic villitis with obliterative foetal vasculopathy, thrombotic vasculopathy and small placenta (see **Figure 4**) [19, 54].

The neuropathological lesions of PAIS are localized areas of infarction (necrosis of all cellular elements) within the distribution of single (or multiple) major cerebral vessel(s) (specific vascular distribution) and commonly with cavity formation depending on the time of occurrence. Focal and multifocal necroses of brain in the prenatal and early postnatal periods are associated with dissolution of tissue and cavity formation variously termed porencephaly, hydranencephaly and multicystic encephalomalacia which have all been reported by MRI studies on CP [4, 54].

#### **3.9 Unconjugated hyperbilirubinaemia and CP**

Severe unconjugated hyperbilirubinaemia remains a significant perinatal/postnatal aetiological factor for CP in LMICs of sub-Saharan Africa and south Asia due to suboptimal management of neonatal jaundice [56, 57]. However, in HICs, kernicterus spectrum disorder (KSD) also occurs especially in preterm/low birth weight babies where brain damage may be present at levels of total serum bilirubin (TSB) below the "safe level" or without signs of acute bilirubin encephalopathy (ABE) (the so-called "low bilirubin kernicterus") [56]. Some causes of unconjugated hyperbilirubinaemia that manifest as ABE and KSD include Rhesus and ABO incompatibilities, G6PD deficiency, prematurity/low birth weight and Crigler-Najjar syndrome type 1 while the risk factors for KSD are: asphyxia, prematurity, low birth weight, acidosis, sepsis, hypoalbuminaemia, hyperthermia and respiratory distress [56–58]. The latter are factors that facilitate bilirubin neurotoxicity (BNTx) by making it easier for the hydrophobic, lipid soluble free or unconjugated bilirubin to cross the blood brain barrier (BBB) to damage specific regions of the brain (selective bilirubin neurotoxicity) [56, 57].

The neuropathology of ABE and KSD comprises bilirubin (yellow) staining of brainstem nuclei ("kernicterus") and neuronal necrosis, loss and gliosis in the basal ganglia/nuclei (Globus pallidus & subthalamic nucleus) and hippocampus [56–58]. Thus, the major areas of neuronal damage (selective bilirubin neurotoxicity) are basal nuclei/ganglia (globus pallidus), subthalamic nucleus of thalamus, oculomotor and cochlear (auditory) brainstem nuclei and the cerebellar dentate and Purkinje cells of the cerebellum in preterm infants [8, 56–58]. On MRI, the main findings in ABE are bilateral and symmetrical abnormalities (hyperintensities) of Globus pallidus and subthalamic nucleus (rarely hippocampus) on T1 and T2-weighted images [4]. These neuropathological substrates underlie the clinical manifestations of dyskinetic CP (basal ganglia injury) and the accompanying impairments of sensorineural deafness (cochlear/auditory nuclear damage), gaze palsies (brainstem CN III, IV, VI nuclear damage) in kernicterus [56–58].

#### **3.10 Meningitis/meningoencephalitis, cerebral malaria and CP**

Preventable postnatal risk factors for CP are more prevalent in LMICs than HICs and include bacterial meningitis, meningoencephalitis and cerebral malaria [3, 59–61]. In a population-based study in Uganda, cerebral injury resulting in CP was attributed to cerebral malaria/cerebral infections in 25% of cases [60]. Over 90% of cases of cerebral malaria occur in sub-Saharan Africa and in children under 5 years of age [59–61].

In brief, the neuropathology of meningitis/meningoencephalitis comprises diffuse neuronal injury (necroses) and cerebral white matter injury (PVL similar to that of prematurity) through a complex cascade of inflammatory cytokine-mediated damage that leads to cerebral oedema, increased intracranial pressure, decreased CBF, vasculitis and thromboses, ischaemia and infarction [62]. On the contrary, the precise *Aetiology and Pathophysiology of Cerebral Palsy DOI: http://dx.doi.org/10.5772/intechopen.106685*

neuropathogenesis of cerebral malaria has not been fully elucidated but a number of theories have been put forward including the "mechanical (sequestration) hypothesis" and the "cytokine storm hypothesis" [63]. In a word, regardless of either vascular obstruction from sequestration of parasitized red blood cells in brain capillaries and venules or cytokine-mediated inflammatory injury, ultimately, cerebral malaria causes grey and white matter damage. Severe spastic bilateral CP specifically spastic quadriplegia is the expected long-term correlate of these postnatal CNS infections since they are diffuse processes with extensive brain damage [64]. Indeed, Iloeje and Ogoke [64] in their study on severity of CP in children found a strong correlation between postnatal CNS infections and severe/non-ambulatory CP. Thus the greater contribution of postnatal CNS infections to CP causation in LMICs may in part be the reason for the relatively poorer gross motor function in children with CP from LMICs compared to their counterparts from HICs [64].
