**3.7 Birth/perinatal asphyxia, hypoxic-ischaemic encephalopathy (HIE) or neonatal encephalopathy and CP**

Earlier in the discussion, very important facts concerning birth/perinatal asphyxia, HIE and birth complications have been mentioned owing to their

#### *Aetiology and Pathophysiology of Cerebral Palsy DOI: http://dx.doi.org/10.5772/intechopen.106685*

significance and the abundance of studies and discussions on them in the literature. Here, a highlight of the definitions/subtle differences between these terms and the neuropathology of neonatal encephalopathy (NE) are emphasized.

Hypoxaemia means a diminished amount of oxygen in the blood supply and at the cellular level while ischaemia is insufficient perfusion; in this context, insufficient cerebral blood flow (CBF) [48]. Ischaemia is usually but not necessarily preceded or accompanied by hypoxia at the cellular level and so the combined term hypoxicischaemic injury is applied to describe the combined effect of ischaemia and hypoxia in causing cerebral damage (HIE) [48]. Asphyxia ("suffocation") implies an impairment of respiratory gas exchange accompanied by increased PCO2, decreased PO2 (hypoxia) and acidosis. In the early stages of asphyxia, the increased PCO2 increases CBF through vasodilatory effects on cerebral arteries while later impaired CBF occurs. The ultimate result of ischaemia, hypoxia and or asphyxia is cell death/neuronal necrosis (cerebral damage) through deprivation of O2 and glucose and energy depletion [48]. When asphyxial events occur in the first or second stage of labour, it is strictly referred to as "birth asphyxia" but "perinatal" or "peripartum asphyxia" is a preferred term since it encompasses foetal or maternal prepartum conditions that predispose to intrapartum hypoxic injury, intrapartum hypoxic injury (birth asphyxia) and the postpartum period of resuscitation for compromised babies with low APGAR scores [49]. Indeed, a failure to initiate and or sustain breathing at birth (birth asphyxia) may originate in the peripartum period (shortly before, during and immediately after birth) with antecedents further upstream in the antenatal period. The latter concept gave birth to the term "Neonatal Encephalopathy" (NE) which is broader than the other terms and has better correlation with CP and long-term neurodevelopmental outcome than birth or perinatal asphyxia that is usually not confirmed in most studies [49].

According to the 2014 report of the American College of Obstetricians and Gynaecologists' (ACOG) Task Force on Neonatal Encephalopathy, Neonatal encephalopathy is a clinically defined syndrome of disturbed neurologic function in the earliest days of life in an infant born at or beyond 35 weeks of gestation, manifested by a subnormal level of consciousness or seizures, and often accompanied by difficulty with initiating and maintaining respiration and depression of tone and reflexes [50]. Thus hypoxic-ischaemic injury (HIE) is only one cause of NE though a significant one. Indeed, a wide range of metabolic, dysgenetic and infectious disorders in the antepartum and postpartum periods also result in NE or are risk factors for NE [49, 50]. Most risk factors for NE are ante-partum risk factors [49, 50].

In the literature, one clearly identified challenge is determining with certainty that an intrapartum hypoxic ischaemic injury is responsible for NE or HIE except in few cases when there is a clinically recognized sentinel event like abruptio placentae, umbilical cord prolapse, ruptured uterus, maternal cardiac arrest or amniotic fluid embolus [49, 50]. In view of this, in 2014 the ACOG published criteria for confirming NE due to an acute peripartum or intrapartum event. The neonatal signs reported to be consistent with acute peripartum or intrapartum event are: [50].

a.APGAR scores of <5 at 5 and 10 minutes


d.Presence of multisystem organ failure (cardiac dysfunction, metabolic & haematologic abnormalities, hepatic, renal & gastrointestinal injuries) consistent with HIE.

However, the presence of other significant risk factors such as maternal infection, IUGR/FGR, foetomaternal haemorrhage, chronic placental lesions and neonatal sepsis makes it unlikely that an acute intrapartum event is the sole underlying pathogenesis of NE [50].

In the earlier report in 2003, the criteria required to define an acute intrapartum hypoxic event as sufficient to cause CP were: [51].


Obviously, the pivotal role of neuroimaging in delineating brain lesions from diverse aetiologies in CP is recognized by its inclusion in the more recent criteria by ACOG. The neuropathology of NE, though variable depending on gestational age, nature of insult and type of intervention, includes the following predominant patterns of injury in term infants identified by MRI: [49, 52].

• Selective neuronal necrosis: This is the most common injury pattern and involves widespread neuronal necrosis/loss in a characteristic distribution depending on severity and temporal characteristics of the insult. With very severe and very prolonged insults, there is global or diffuse neuronal injury; that is, all levels of the neuraxis (cerebral cortex, basal ganglia, thalamus, brain stem and anterior horn cells of the spinal cord) are affected and the usual long-term sequelae are severe spastic bilateral CP (spastic quadriplegia) with many accompanying impairments due to widespread neuronal injury. The anterior horn cell injury ("hypoxic-ischaemic myelopathy") may explain the characteristic persistence of hypotonia into the first months of life and when severe the unusual persistence into childhood of hypotonia and weakness—the so-called "atonic CP" with atonic quadriparesis. With moderately severe and prolonged insults, cerebral cortex-deep nuclear (cerebral neocortex, hippocampus, basal ganglia [putamen] and thalamus) injury occurs while severe but abrupt insults cause deep nuclearbrainstem (basal ganglia [putamen]-thalamus and brainstem nuclei) injury. The cerebral cortical injury is most prominent in the perirolandic cortex and depths of sulci while the deep nuclear grey matter injury is most prominent in the thalamus and putamen with the intervening posterior limb of the internal capsule (PLIC) affected in moderate or severe thalamo-putaminal injury. In basal nucleithalamic injury, neuronal loss, gliosis and hypermyelination in the putamen and thalamus may evolve into status marmoratus (marbled appearance). The basal ganglia-thalamic lesions (BGTL) explain the occurrence of dyskinetic (dystonic/ choreoathetoid) CP in NE/HIE (severe perinatal asphyxia) with manifestations

of abnormal involuntary movements, tone variability and relatively spared intellectual functions due to the cortical sparing.

• Parasagittal cerebral injury ("watershed infarcts"): This refers to bilateral cerebral cortical and subcortical white matter ischaemic lesions in the parasagittal and superomedial aspects of the cerebral convexities (in the arterial end/border zones or "watershed areas").

• PVL (CWMI): apparently similar to "non-cystic" PVL of very premature infants.

In encephalopathy of prematurity, the main neuropathological feature remains PVL with additional intraventricular haemorrhage with or without periventricular haemorrhagic infarction [31]. The ultimate consequence of PVL is delayed/impaired myelination of cerebral white matter and secondary dysmaturation of grey matter structures such as cortex, thalamus and cerebellum [31].

It is important to note that although MRI best defines the nature and extent of cerebral injury in NE, it is severely limited in determining the aetiology of hypoxicischaemic injury and the exact timing of the insult [49, 52]. This may partly explain the apparent contradiction of findings of MRI studies with earlier reports of epidemiological studies [49]. Epidemiologic studies suggest that 70% of CP causation are related to chronic antenatal factors while MRI studies suggest that 75% of cerebral injury in CP occur in the perinatal/intrapartum period owing the preponderance of acute injury patterns (acute peripartum lesions) [49]. In the study by Cowan et al. [53], of 245 infants who had an MRI scan after neurological signs and evidence of intrapartum/perinatal asphyxia (("neonatal encephalopathy"), 80% had MRI evidence of acute peripartum lesions consistent with hypoxic-ischaemic injury, only 4% had MRI evidence of antenatal injury, 16% had normal MRI scans and 4% had other disorders like neuromuscular or metabolic disease [53].
