Aetiology and Pathophysiology of Cerebral Palsy

Abstract

The accurate identification of the actual causes (aetiology) of cerebral palsy (CP) and understanding the causal pathways and the neuropathological correlations are critical to the development of both prevention strategies and a holistic classification of CP. The aetiology of CP is multifactorial with diverse and complex causal mechanisms. It has remained a challenge to identify all the non-progressive disturbances and causal pathways in CP despite pivotal contributions from recent advances in neuroimaging. The objectives of this chapter are to discuss the risk factors for CP, elucidate the causal pathways based on current perspectives and explain the pathophysiology of the clinical manifestations of an abnormally developing or damaged motor system. It is expected that at the end of this chapter, the reader should be able to comprehend the challenge in accurately identifying the actual causes of CP and understanding the complex causal pathways and explain the protean clinical features of CP.

1. Introduction

The accurate identification and understanding of the actual causes (aetiology) of cerebral palsy (CP), timing of insults, the causal pathways, mechanisms and “hows” and “whys” (pathophysiology/neuropathological correlations) are critical to the development of both prevention strategies and a holistic or standardized classification of CP [1, 2]. However, it has remained a challenge to identify the non-progressive disturbances or events and causal pathways/processes that led to the damage to the developing motor system in the foetal/infant brain since most of these factors are antenatal in timing [1, 3]. Though there are significant contributions from recent advances in neuroimaging to our understanding of the aetiology and pathology of CP and timing of insults, there are still limitations and these have debarred the emergence of a comprehensive neuropathologic classification of CP [1, 2, 4].

It is obvious that CP is not a single disorder/disease but a group of aetiologically heterogeneous disorders. This implies the aetiology is multifactorial and the causal mechanisms multiple and complex [1, 5]. Thus, various aetiological/risk factors act through multiple pathways to damage the developing motor system resulting in variable phenotypes (clinical subtypes of CP) that have common denominators: abnormal pattern of posture and/or movement and presence of accompanying impairments. Therefore, in simplistic terms, a plethora of factors acting at different times and more commonly in combination interfere with brain development or specifically increase the risk of damage to the developing motor system in the brain (CP).

2. Aetiology/risk factors for cerebral palsy

2.1 Aetiology or risk factors?

The most recent definition of cerebral palsy stipulates that the disorders collectively termed cerebral palsy are attributed to non-progressive disturbances that occurred in the developing foetal or infant brain [6]. The non-progressive disturbances refer to events or processes that within a limited period/duration (static in nature) permanently damage the brain (specifically motor development) or influence the expected patterns of brain maturation [1, 6]. Many different processes or events can result in this damage and so CP is understandably said to be aetiologically heterogeneous (due to multiple aetiologies) and compatible with many aetiologic diagnoses [1, 4]. Indeed, CP on its own is not an aetiologic diagnosis [1]. Furthermore, CP is pathologically heterogeneous since different aetiological factors acting at different stages of development result in different neuropathological substrates even if they lead to the same clinical subtype [4]. For instance, both severe neonatal encephalopathy from perinatal asphyxia and kernicterus from severe unconjugated hyperbilirubinaemia are different aetiological factors for dyskinetic (choreoathetoid/dystonic) CP but they damage different parts of the brain (the ventrolateral nucleus of the thalamus and putamen versus globus pallidus and subthalamic nucleus, respectively) [7, 8].

Direct causal links or relationships are difficult to establish with certainty and explains why the phrase “attributed to” is used in the most recent definition with respect to the causes of CP instead of “are due to” or “caused by” [1, 6]. Therefore, risk factors (correlational) that increase the probability or chances of occurrence of CP are epidemiologically more appropriate than causes. The significance of identification/knowledge of actual causes/risk factors of CP is its implication for prevention. That is, it will help devise prevention strategies for CP.

2.2 Identification of the actual causes of CP: the challenge

The accurate identification of the specific disturbance or specific timing of the event or process that damaged the developing motor system has remained difficult since most (about 75%) of the events occur in the antenatal (prenatal) period [1, 6]. There is also a challenge in designing prospective studies to identify risk factors across populations since only 2–3 per 1000 pregnancies will result in a child with CP [3]. However, neuroimaging has made significant contribution to the understanding of the aetiology and pathology of CP and timing of insults [4  5]. Neuroimaging can be used to identify the neuropathological substrates of the various aetiologic or risk factors of CP, possibly provide information about timing of insults and detect cerebral dysgenesis [2, 4]. Nevertheless, there exists some limitations presently as neuropathologic—aetiological correlations are not yet fully clear and comprehensive [4].

2.3 Causal pathways/mechanisms

Certainly a large number of risk factors are associated with CP and have been identified in numerous earlier studies [9, 10, 11, 12, 13, 14, 15] in different parts of the world. These studies have shown that in many cases it is not a single factor but a combination of risk factors (multifactorial) or a cascade of events or disturbances that result in CP [3, 16, 17]. This gave birth to the concept of causal pathways or mechanisms in CP causation and in disorders without a single definitive cause.

According to Stanley et al. [18], a causal pathway refers to a sequence of interdependent events that culminate in disease. This implies that one risk factor leads to another, to another and so on ultimately resulting to the disorder or disease. For instance, prematurity is an important risk factor for CP and can lead to periventricular leukomalacia (white matter injury), poor lung development or respiratory distress at birth, birth asphyxia, increased risk of chronic bilirubin encephalopathy (kernicterus) and so on, ultimately resulting in CP. Nevertheless, prematurity alone is not a sufficient cause for CP since not all children born prematurely have CP. Another example is breech presentation at birth leads to increased risk of cranial trauma or injury and increased risk of CP in places where breech delivery per vaginam is rife.

From the foregoing, it is obvious that the risk factors in a pathway are interconnected and in most cases additively increase the risk of CP. This explains the “two-hit” and “multi-hit” models that consider accumulation of risk factors/insults and a synergistic increase in risk in causation of CP [16, 19]. That is, the brain of a neonate with in-utero exposure to placental inflammation (chorioamnionitis/funisitis/chronic vasculitis) or who had foetal growth restriction (“first-hit”) is more vulnerable or conditioned to another injury like sepsis in the neonatal period (“second-hit”) (“two-hit” model) while exposure to three or more adverse events/risk factors underlies the “multiple-hit model” of CP causation [16, 19]. Another example of interaction of risk factors is the increased cumulative risk of CP in a child with co-occurrence of early-onset pre-eclampsia, foetal infection/foetal inflammatory response syndrome (FIRS), perinatal asphyxia and neonatal sepsis [19].

One identifiable challenge is that there are so many possible and complex pathways since the risk factors are numerous and each pregnancy presents new possibilities [19]. Some examples of known CP causal pathways are shown in Figures 1–4 below. The significance of identifying and understanding all these complex causal pathways is in formulating preventive strategies as earlier mentioned. Thus, more research is needed to elucidate the combined effect and specific sequence of multiple risk factors on the occurrence of CP.

Figure 1.

Casual pathway from prematurity to CP.

Figure 2.

Causal pathway from maternal genitourinary tract infection to CP.

Figure 3.

Casual pathway from twinning to CP.

Figure 4.

Casual pathway from placental pathology to CP.

2.4 Aetiology of cerebral palsy: historical vs. current perspectives and well-resourced/high income countries (HICs) vs. low & Medium Income countries (LMICs)

Historically, William J. Little and Sigmund Freud made significant contributions to the understanding of the aetiology of CP [20]. In brief, Little first described spastic diplegia (Little’s disease) and causally related it to difficult delivery, preterm birth and birth asphyxia—a conception that has survived centuries [5, 20]. However, Freud was the first to state that CP could result solely from antenatal or intrauterine factors (in utero abnormalities of brain development) or combined with birth complications [5, 20]. This assertion which was at variance with that of Little derived from his observations that children with CP had many other neurological disorders and children with birth asphyxia could be completely normal [5, 20]. Nevertheless, the contribution of the perinatal period to CP causation (Little’s view) has also been supported by subsequent research [16]. But this is indeed much less frequent than previously thought.

Current understanding of the aetiology of CP support more of Freud’s views since epidemiological studies [9, 10] notably the National Collaborative Perinatal Project [9] brought to the fore that less than 10 percent of CP were causally related to birth asphyxia but rather most predictors of CP were antenatal factors [10]. Thus, the debate on causation and timing has moved from intrapartum events (birth asphyxia, birth trauma/complications, Little’s view) to antenatal factors or antecedents (cerebral dysgenesis, genetics, maternal infection, Freud’s view) [4, 9, 10]. Further support for the significant role of antenatal factors or “antecedents” in CP causation is the fact that the reduction in perinatal asphyxia by improved perinatal and obstetric care in well-resourced countries (HICs) of Europe and America did not lower the prevalence of CP [21]. Recent studies involving neuroimaging and inflammatory markers [22, 23, 24, 25] which continue to debunk Little’s view of birth asphyxia as a major cause of CP abound in literature from developed countries of Europe and America. However, studies from low and middle income countries (LMICs) of Africa continue to implicate preventable perinatal and postnatal aetiological factors in CP (perinatal asphyxia, kernicterus, meningitis, cerebral malaria) [26]. Majority of these studies are of low-quality with simple cross-sectional design and lacking appropriate control groups for proper assessment of risk factors [26]. The studies involving neuroimaging and inflammatory markers are rare in LMICs due to financial constraints, unavailability of equipment and lack of expertise. Therefore, the type and quality of studies on aetiological factors in CP seen in well-resourced countries are needed in developing countries (LMICs) to harmonize the spectrum of aetiological factors and timing of insults in CP worldwide.

As regards the relative contribution of individual risk factors to CP causation, variations also exist between HICs and LMICs. It is well known that in HICs, improved preventive measures, use of guidelines and better management of neonatal jaundice have resulted in a significant reduction of cases of CP attributed to kernicterus [27]. Moreso, prolonged obstructed labour and breech delivery with its attendant increased risk of intracranial haemorrhage/injury are currently rare in HICs owing to the high rates of planned caesarean deliveries [19]. Furthermore, congenital rubella infection and meningitis caused by Haemophilus influenzae Type B (HIB) and Neisseria meningitidis have been significantly reduced through effective immunization programmes in HICs while the recent introduction of the malaria vaccine is expected to reduce the relative contribution of cerebral malaria to brain damage in malaria-endemic regions [27]. The reducing incidence and severity of CP associated with prematurity has been reported in some HICs [28]. Further reduction in the prevalence of CP among children with low birth weight is expected with the implementation in many HICs of guidelines recommending administration of magnesium sulphate (MgSO₄) for neuroprotection in imminent preterm delivery at <32–34 weeks of gestation (pre-eclampsia and preterm labour) [19, 28].

2.5 Comprehensive list of risk factors for CP

A comprehensive list of risk factors for CP does not exist and a number of cases may be devoid of known risk factors. A plethora of epidemiological studies [3, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25] worldwide have been done to ascertain risk factors for CP and have reported countless risk factors for CP categorized as antenatal (prenatal), perinatal (natal) or postnatal (postneonatal) in timing. A meta-analysis [29] of 18 studies in China identified six major risk factors for CP during pregnancy namely: advanced maternal age (≥ 35 years), multiple pregnancy, medicine use in early pregnancy, harmful environment, recurrent vaginal bleeding during pregnancy and pregnancy-induced hypertension (pre-eclampsia). A systematic review [26] of 25 articles identified 10 consistent risk factors (statistically significant in each study) for CP in children born at term in well-resourced countries/HICs namely: placental abnormalities, major and minor birth defects, low birth weight, meconium aspiration, instrumental/emergency caesarean delivery, birth asphyxia, neonatal seizure, respiratory distress syndrome, hypoglycaemia and neonatal infections. Another systematic review of paediatric cerebral palsy in Africa [26] reported that the most common risk factors identified in African cohorts were birth asphyxia, kernicterus and neonatal infections. From the foregoing, it is already clear that there are numerous risk factors for CP with variations in the spectrum of risk factors for preterm and term babies (different gestation ages), HICs and LMICs and strength of associations (some strongly correlated and others weakly associated).

Table 1 shows a list of risk factors for CP but the list is inexhaustive since many cases of CP have unidentifiable aetiological factors. Subsequently, a discussion of some of the risk factors with emphasis on their neuropathological substrates will follow.

Pre-pregnancy/maternal factors: low socioeconomic status, maternal medical conditions (server maternal iodine deficiency/thyroid disorder, intellectual disability, epilepsy)

Antenatal: prematurity, genetic factors/mutations, congenital malformations/cerebral dysgenesis, placental pathology, infections (TORCH, maternal genitourinary infections), Intrauterine growth restriction (IUGR/FGR/SGA), multiple births, antepartum haemorrhage

Perinatal: perinatal asphyxia/birth complications, neonatal encephalopathy, perinatal stroke, kernicterus

Postnatal (postneonatal): meningitis/encephalitis (including cerebral malaria), kernicterus, traumatic head injuries, shaken baby syndrome, cardiopulmonary arrest (near drowning)

Table 1.

Risk factors for cerebral palsy.

TORCH syndrome refers to transplacental &/parturitional infections with Toxoplasmosis, Others (syphilis, HIV, EBV, Zika, varicella, enterovirus), Rubella, Cytomegalovirus, Herpes simplex. FGR = Foetal Growth restriction. SGA = Small for Gestational Age.

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 pregnancy-related 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-ischaemia-infection-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].

3.2 Infection, inflammation and CP

There is a consensus in the literature that infections/inflammation via cytokine-mediated injury to the immature brain are causally associated with CP (see Figure 2). Infection, inflammation and cytokines play a fundamental role in CP causation through their link with preterm labour (prematurity), placental pathology (chorioamnionitis, funisitis), congenital malformation, FGR, cerebral white matter injury (WMI) and perinatal asphyxia [29, 33, 34, 35, 36, 37]. Studies including recent meta-analyses have shown compelling evidence that maternal infections in pregnancy, intra-amniotic infection (chorioamnionitis), evidence of FIRS and neonatal infections are causally associated with CP [25, 29, 35, 36, 37]. Both transplacental TORCH infections (Toxoplasmosis, Others [syphilis, Epstein Barr virus, HIV, Zika virus], Rubella, Cytomegalovirus [CMV], Herpes virus), genitourinary infections (bacterial vaginosis, chlamydia, trichomonas, UTI) and neonatal infections (GBS-early onset sepsis, neonatal pneumonia, meningitis) have all been implicated in CP [37]. Many studies [22, 23, 24, 25] in the twentieth and twenty-first centuries have suggested that inflammatory phenomena/infections play a more critical role in the aetiology of brain lesions common in CP. Additionally, placental histology should be requested for in babies compromised at birth since chorioamnionitis, funisitis (umbilical cord inflammation) (placental pathology) are evidence of infection predating labour [17].

In the setting of infection/inflammation, one neuropathological substrate for CP is a cytokine-mediated cerebral white matter injury (PVL) in the preterm infant, though minimal evidence exists for such a process in term newborns [37]. Other mechanisms include: brain damage/cerebral dysgenesis by TORCH infections especially CMV, direct cytokine toxicity to premyelinating oligodendrocytes (pre-OLs), hypoxic brain damage by neonatal pneumonia with PPHN, ischaemic cerebral damage from microvascular thrombosis and hypoperfusion in neonatal meningitis et cetera [31, 33, 37].

3.3 Cerebral dysgenesis and CP

Disruption of the development of motor pathways that control movement and posture is the underlying pathogenesis of CP attributed to cerebral malformations. Cerebral dysgenesis has a firm causal link with CP and both cerebral and non-cerebral malformations increase the likelihood of CP [17, 19]. Some brain malformations have genetic causes like LIS1 and doublecortin (DCX), TUBA1A mutations in lissencephaly while acquired intrauterine infections such as CMV and Zika virus also cause cerebral malformations. A wide range of cerebral malformations especially cortical migration defects are seen in children with CP and include: lissencephaly, polymicrogyria, schizencephaly, cortical dysplasia, agenesis of the corpus callosum, holoprosencephaly, and posterior fossa malformations such as Dandy-Walker malformation and Joubert syndrome [19, 38].

Neuroimaging reliably detects cerebral malformations which mainly occur in early gestation thereby implicating antenatal aetiological factors [4]. The detection of cerebral malformation is useful in establishing that the aetiology of CP is unrelated to perinatal events and this may protect the attending Obstetrician from “maternity negligence” claims that are rife in HICs [4, 17].

3.4 Genetic mutations and CP

Genetic aetiology for CP is predictable since CP occurs more frequently in some families/consanguineous families (familial clustering), monozygotic twins and congenital malformations and should be suspected even in those without traditional risk factors [39]. Rare genetic mutations (inherited or de novo) or CP-associated genes are implicated in CP [40, 41]. Indeed, current studies employing new genetic testing techniques called Next Generation Sequencing (NGS) such as whole exome sequencing (WES), whole genome sequencing (WGS) and copy number variant analysis continue to identify pathogenetic variants (copy number variants and single nucleotide variants) and likely pathogenic variants in some cases of CP [40]. For instance, some implicated gene mutations (pathogenic variants) involve KANK1, AP4MI, GAD1, ZC4H2 genes [17, 41]. CP genomics is currently evolving and the discovery of more CP-associated genes or genetic mutations underlying CP is expected to add to the presently known panel of pathogenic variants [41].

The neuropathology of genetic mutations in CP stems directly from disrupting early brain development (specifically motor development) (cerebral malformation) and indirectly through genetic susceptibility to different pathways that cause different neuropathologies [41]. These different pathways include infection/inflammatory cytokine responses, foetal growth restriction/IUGR, prematurity or perinatal stroke since genetic susceptibility has been reported to underlie these other risk factors [41].

3.5 Foetal growth restriction (FGR) and CP

Birth weights below the tenth percentile (10th centile) for gestational age (GA) (small-for-gestational age; SGA) remains a major aetiological/risk factor for CP in both term and preterm babies as shown by multiple studies [42, 43, 44]. The risk of CP has been reported to increase with increasing severity of foetal growth restriction (FGR) with babies below the 3rd centile having the greatest risk [44]. However, it has been shown that the large for gestational age (LGA) baby also has increased risk of CP [44]. Recall that macrosomic babies have higher risks related to maternal diabetes and obstructed labour [27] FGR acts indirectly to damage the developing brain through chronic hypoxia-ischaemia resulting from impaired placental function (utero-placental insufficiency) and increased occurrence of perinatal asphyxia and hypoglycaemia [27, 32, 33] (see Figures 3 and 4). Thus the neuropathology includes grey matter and WMI (PVL).

3.6 Multiple pregnancy/births and CP

Twinning and higher-order births (triplets, quadruplets, quintuplets, sextuplets, septuplets) from natural or spontaneous conception and Assisted Reproductive Technology (ART) are well-known risks factors for both cerebral dysgenesis and CP [45, 46]. Indeed, the risk of CP increases with increasing number of infants [46]. Peterson et al. [46] in a study of multiple births in Western Australia reported prevalence of CP of 1.6, 7.3 and 28 per 1000 live births in singletons, twins and triplets respectively. The increased risk of CP in multiple births is a consequence of the increased odds of congenital malformations, placental vascular anomalies, FGR, low birth weight (LBW), preterm birth, co-twin death and birth complications/asphyxia (see Figure 3) [19, 27, 46]. More so, the increased risk of CP among co-twins has been attributed partly to monochorionic placentation and in-utero death of the co-twin. The “dissolving” or “disappearing twin” is said to release thromboplastin and emboli that can damage the brain of the surviving twin (disappearing twin syndrome) [19, 27, 46]. But a more common setting for brain injury in monochorionic twins by ischaemia and infarctions is the twin-twin transfusion syndrome (TTTS) that results from abnormal placental vascular anastomoses (A-V connections) in which placental tissue supplied by an artery from a donor twin is drained by a vein from the recipient twin [19, 27, 46].

The increasing rate of multiple births reported in HICs suggests an increasing contribution of multiple births to CP pathogenesis [46]. However, a recent large population-cohort study based on Surveillance for Cerebral Palsy in Europe (SCPE) registers found a decreasing risk of CP among the multiples despite the increased prevalence since the 1990s [47]. This study [47] further reported that multiples displayed similar severity of motor impairment as singletons and concluded that advances in obstetric care accounted for these changes in CP risk among preterm low birth weight multiples.

Patently, the neuropathologies of multiple births are the indirect effects on the brain of prematurity, FGR, congenital malformations and hypoxic-ischaemic injury and cerebral infarctions (intrauterine stroke) to which multiples are predisposed (see Figure 3).

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 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 hypoxic-ischaemic 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].

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

2. Foetal umbilical artery academia (pH < 7.0 &/or base deficit ≥12 mmol/L

3. Neuroimaging (MRI or magnetic resonance spectroscopy [MRS]) evidence of acute brain injury consistent with hypoxic-ischaemic injury,

4. 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].

1. Evidence of a metabolic acidosis in foetal umbilical cord arterial blood obtained at delivery (pH < 7.0 & base deficit ≥12 mmol/L)

2. Early onset of severe or moderate NE in infants of 34 or more weeks of gestation

3. CP of the spastic quadriplegic (spastic bilateral) or dyskinetic type

4. Exclusion of other identifiable aetiologies such as trauma, coagulation disorders, infectious conditions or genetic disorders.

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 nuclear-brainstem (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 nuclei-thalamic 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 hypoxic-ischaemic 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].

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 sub-optimal 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, 57, 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, 57, 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, 57, 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, 57, 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, 60, 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, 60, 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 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].

4. Clinico-neuropathological correlations in CP: the “hows and “whys”

The clinical features, clinical subtypes of CP and the accompanying physical, mental and physiological impairments are described here in relation to the aforementioned neuropathological substrates of CP.

4.1 Overview of brain areas and pathways involved in control of posture and movement

The normal control of movement (voluntary and involuntary, gross and fine), maintenance of a stable posture and balance, muscle tone and coordination of motor activity involve intricate interactions between the cerebral motor cortex, basal nuclei/subcortical grey mater (putamen, globus pallidus, subthalamic nucleus, substantial nigra, thalamus), brainstem nuclei (vestibular nucleus, superior colliculus, red nucleus) and cerebellum with the cells of the ventral or anterior horn of the spinal cord (alpha and gamma motor neurons) [65]. On emerging from the anterior horn cells, the motor neurons in peripheral nerves (lower motor neurons [LMN]) innervate the muscles of the body to effect movement/muscle contraction [65]. Each alpha motor neuron and all muscle fibres that it innervates constitute a motor unit—the functional unit of the motor system [65]. Functionally, the descending motor pathways from the brain to spinal cord (upper motor neurons [UMN]) are subdivided into pyramidal and extrapyramidal pathways [65]. The pyramidal pathway arise from the cerebral cortex and send motor signals to the spinal cord (corticospinal tract) and to brainstem nuclei (corticobulbar tract) for voluntary control of muscles of the body and face respectively [65]. The extrapyramidal tracts (vestibulospinal, reticulospinal, rubrospinal, tectospinal tracts) take their origin from different brainstem nuclei and project to the spinal cord for control of involuntary/automatic muscle activity like control of muscle tone through the stretch reflex, posture and movement [65]. The stretch reflex arc for maintenance of muscle tone is controlled by the inhibitory influence of corticospinal and dorsal reticulospinal tracts and facilitatory influence by medial reticulospinal and vestibulospinal tracts [65, 66]. The basal nuclei function to facilitate or fine tune voluntary movement while inhibiting undesired movements and they receive projections from the motor cortex and project back to the motor cortex through the thalamus [65]. Thus, the occurrence of unwanted involuntary movements in basal ganglia injury. The cerebellum is also deeply involved in maintenance of balance, posture and coordination of movement and damage to it produces ataxia [65, 66]. The pyramidal/corticospinal tract is increasingly vulnerable to damage at different points along their long course to the spinal cord and commonly include their site of origin at the cerebral cortex, corona radiata and the white matter (internal capsule) between the thalamus and basal nuclei [65]. This may contribute to the high prevalence of spastic CP and its combination with other forms of CP in the so-called “mixed CP” subtypes such as spastic dystonic CP and combinations of spasticity and choreoathetosis.

4.2 Neuromotor impairments and musculoskeletal deficits in CP

In spastic CP, the brain lesions in the various predominant locations disrupt the descending pyramidal pathways resulting in an UMN syndrome whose primary manifestations are categorized into positive and negative features that act in concert to cause secondary progressive musculoskeletal pathology/impairments [66, 67, 68]. The positive features of UMN syndrome are spasticity, hyperreflexia, clonus, co-contraction while the negative features include weakness, loss of selective motor control (SMC), poor balance, fatigability and sensory deficits [66, 67, 68]. The positive features result from brain lesions disrupting the facilitatory corticobulbar fibres (from the premotor cortex), thus leading to inhibition of the dorsal reticulospinal tract (from the brainstem ventromedial reticular formation) which exerts inhibitory control over the stretch reflex [66, 67, 68]. Spasticity refers to a velocity-dependent increase in muscle tone with exaggerated tendon jerks due to hyperexcitable or increased tonic spinal stretch reflex [65, 66, 67, 68]. This implies that the loss of inhibition of the spinal stretch reflex by descending pathways result in overactivity of the spinal stretch reflex and underlies the findings of spasticity, hyperreflexia and clonus in pyramidal CP [66, 67, 68]. The voluntary output from the motor cortex activates motor neurons targeting the agonist muscles while simultaneously inhibiting the antagonist muscles through the Ia interneurons (reciprocal inhibition) [66]. It is the loss of this reciprocal inhibition of antagonist muscles during voluntary command that underlies co-contraction and it makes generation of force or movement difficult [66].

In spastic CP, there is significant weakness that contributes to abnormal posture and movement. The weakness is consequent on a number of factors such as reduced muscle size/volume, reduced muscle activation, lower frequency motor unit firing rates and increased Type 1 muscle fibres due to an altered neural input to muscle (reduced neuromuscular activation) caused by the damage to the descending corticospinal tracts [68]. This is also accompanied by decreased muscle endurance and loss of selective motor control (SMC) [67, 68]. Loss of selective motor control is the impaired ability to single out the activation of specific muscles in response to demands of a voluntary posture or movement [67, 68]. For example, the co-activation of quadriceps femoris (knee extension) and gastrocnemius (ankle planter flexion) in a child with severe spastic CP [68]. The weakness, impaired SMC and poor balance (negative features) are pivotal in determining when or if a child with CP will walk [67, 68]. It is also important to note that some surgical interventions for spasticity such as muscle lengthening, tendon transfer, selective dorsal rhizotomy and intrathecal baclofen all reduce muscle strength while orthoses and serial casting may worsen weakness through immobilization [67, 68]. The reduced descending excitatory signals on muscle growth results in impaired muscle growth (smaller muscles) and a short muscle-tendon unit which contributes to muscle weakness in spastic CP(“short muscle disease”) [67, 68]. The failure of muscle growth to progress at same speed with bone growth (muscle-to-bone growth rate discrepancy) which is more prominent in bi-articular muscles like rectus femoris, hamstrings and gastrocnemius underlies the joint contractures and gait abnormalities such as toe-walking and flexed-knee gait in spastic CP [67, 68].

In non-spastic or extrapyramidal CP with damage to the basal nuclei, the clinical manifestations are abnormal, involuntary, uncontrolled, recurrent and occasionally stereotyped movements with fluctuating tone and persistence of primitive reflexes [68]. In dystonia, there are involuntary sustained or intermittent muscle contractions of both agonist and antagonist muscles causing twisting and repetitive movements and or abnormal postures with increased tone [65, 66, 67, 68]. Choreoathetosis is characterized by a combination of random-appearing sequence of one or more discrete, excessive and rapid movements or fragment of movement of proximal body parts/trunk (chorea) with slow, continuous, writhing movements of distal body parts that impedes maintenance of a stable posture (athetosis) [65, 66, 67, 68]. Both dystonic and choreoathetoid movements impair function [68].

However, the terms spastic (pyramidal) and extrapyramidal CP are strictly incorrect [5, 65]. It is more accurate to refer to these as “predominantly spastic” and “predominantly non-spastic” [65] . Due to the complex interactions of the upper motor neuron system (the pyramidal, extrapyramidal and cerebellar pathways) with anterior horn cells to control posture and movement, lesions causing CP in real life usually involve both pyramidal and extrapyramidal pathways [65]. This explains the clinical combination of motor/movement abnormalities such as spasticity with dystonia, and spasticity with choreoathetosis (“mixed CP”). Thus, the mixed CP subtype should actually be very common but spastic CP remains the commonest type thereby exposing the subjectivity and imprecision in assessment of patients based on the physiologic classification of CP [2, 69].

In the rare ataxic CP with damage to the cerebellum, clinical features are hypotonia, limb incoordination, and poor balance and these result in instability and a compensatory wide base of support with elevated, outstretched arm postures to improve balance during gait (ataxia) [65, 68].

Therefore, the primary neurologic correlates of early brain injury in CP include: [2, 66, 67, 68].

• Delayed developmental milestones; invariably and most severely affecting the motor domain

• Abnormalities of movement or motor patterns, muscle tone and reflex patterns including persistence of primitive reflexes

• Abnormalities of gait and posture ranging from toe-walking to crouched gait

• Muscle weakness, poor balance, impaired selective motor control

• Incoordination and ataxia

4.3 Secondary impairments and accompanying disorders in CP

The accompanying physical, mental or physiological impairments identified in the current definition of CP include epilepsy, cognitive impairment (intellectual disability), speech, visual and hearing impairments and secondary musculoskeletal pathology [1]. These secondary or accompanying impairments are significant since they may cause more functional limitation than the primary motor dysfunction (the core feature of CP) [1, 2].

4.3.1 Epilepsy

Epilepsy is a chronic brain disease characterized by two or more unprovoked or reflex seizures more than 24 hours apart or presence of an epilepsy syndrome [70]. Epilepsy remains a common accompanying disorder in CP occurring in 30–60% of children diagnosed with CP [71, 72]. Both CP and epilepsy in most cases arise from the same underlying neuropathological substrate [71]. Cerebral dysgenesis (disorders of cortical malformation like lissencephaly, cortical dysplasia, heterotopias, corpus callosal agenesis), cortical infarctions (perinatal stroke and meningoencephalitis) and diffuse cortical neuronal necrosis (severe neonatal encephalopathy/HIE) are neuropathological substrates for both CP and epilepsy [71]. Thus the aetiology of epilepsy in CP could be structural (cerebral dysgenesis, infarctions, postnatal head trauma), postinfectious (CMV, Toxoplasmosis, post meningoencephalitis) or genetic [70]. The latter occurs in cases of CP who on newer genetic testing techniques (WES, WGS) also show genetic or copy number variants pathogenic for epilepsy with or without a family history of epilepsy [70]. Epilepsies in CP are more common in spastic quadriplegia and hemiplegia owing to the cerebral cortical involvement in spastic quadriplegia and hemiplegia and are relatively uncommon in spastic diplegia due to the relative sparing of the cortex in PVL of prematurity [71, 72, 73].

It has been reported that epilepsy is more prevalent in severe CP/GMFCS levels IV-V and in the presence of co-morbid intellectual disability (ID) [72]. These findings most likely relate to the degree/topography of cortical injury since diffuse cortical neuronal necrosis (SNN) from severe neonatal encephalopathy/HIE or cortical malformations result in spastic quadriplegia that is usually associated with severe gross motor dysfunction (non-ambulatory status) [2, 49].

4.3.2 Cognitive deficits/intellectual disability (ID), behavioural, attentional and socialization defects

The ID that occurs in severe CP is a consequence of mainly the cerebral cortical injury with injury to the basal nuclei, thalamus and cerebellum playing an additional role [49]. Intellectual retardation almost invariably accompanies the diffuse variety of selective neuronal necrosis (SNN) in severe NE/HIE in term infants [49]. In preterm infants, intellectual function is more severely affected (significantly lower intelligence quotients [IQ]) in those with spastic quadriplegia than spastic diplegia [32]. In the PVL of encephalopathy of prematurity, more severe lesions with lateral extension into the centrum semiovale and corona radiata would be expected to affect upper extremities in addition (spastic quadriplegia) and intellectual functions as well [32]. The primary white matter injury in encephalopathy of prematurity leads to secondary dysmaturation of grey matter structures with widespread reduction in cerebral volumes (cerebral cortex, deep nuclear grey matter, hippocampus, total cerebral tissue and cerebellum) [32]. White matter injury also underlies the deficits in executive function, behavioural disturbances and socialization deficits and partly explains why language delay, Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) may accompany CP especially in children born prematurely [32]. Hyperactivity and inattention may in part be due to involvement of neurons of the reticular activating system (RAS), the basal nuclei or the cerebellum [32].

4.3.3 Visual abnormalities/squints and cortical visual impairments

Ptosis, oculomotor and gaze abnormalities result primarily from disturbance or injury to brainstem cranial nerve (CN) nuclei (CN III, IV, VI, VII). in the deep nuclear-brainstem variety of SNN associated with severe and abrupt hypoxic-ischaemic insults in term infants. Severe diffuse cortical necrosis (SNN) involving the visual or occipital cortex underlies impairment of cortical visual functions in children with CP since many of them have cerebral cortical atrophy [49]. Nevertheless, in prematurity, visual impairment could be a consequence of retinopathy of prematurity or injury to white matter visual pathways (PVL) (cerebral visual impairment [CVI]) [32]. PVL is strongly associated with visual impairment since the principal area of injury includes the optic radiations (geniculocalcarine tracts) and visual association areas [32]. This implies that more severe PVL with more extensive lesions involving the peritrigonal white matter, optic radiations and occipital cortex correlates with poorer future vision [32].

4.3.4 Hearing and speech deficits, feeding difficulties and undernutrition

Brainstem CN nuclear involvement in severe NE/HIE underlies the accompanying feeding difficulties due to poor coordination and impairments of sucking (CN V), swallowing (CN IX & X) and tongue movements (CN XII) [49]. It is also possible that in addition to the nuclear injury (bulbar palsy), corticobulbar disturbance (pseudobulbar palsy) contributes to these deficits [49]. The ultimate consequences of the feeding difficulties in young children with CP are undernutrition and stunting unless alternative means of feeding like gastrostomy are employed. However, some well-fed non-ambulatory children with CP may become overweight due to the imbalance between energy intake and utilization.

Oral-motor-dysfunction (from bulbar and or pseudobulbar palsy) causes speech deficits due to weakness and poor coordination of the muscles innervated by CN V, VII, IX, X and XII that are involved in speech and phonation. Injury to the dorsal cochlear nuclei and or cochlea, superior olivary nucleus and inferior colliculus result in hearing deficits in CP [49]. Free or unconjugated bilirubin damages the brainstem auditory nuclei and auditory nerve (bilirubin neurotoxicity) in auditory neuropathy spectrum disorders with or without sensorineural hearing loss (ANSD). This explains the common co-morbid sensorineural deafness in dyskinetic CP secondary to chronic bilirubin encephalopathy (Kernicterus spectrum disorders) [56, 57].

4.3.5 Musculoskeletal problems, gait abnormalities and pain

The musculoskeletal pathology such as muscle shortening/contracture, bony torsion, joint instability, premature degenerative arthritis in weight-bearing joints are secondary to the integrated effects of the positive and negative features of the UMN syndrome in CP [67, 68]. These musculoskeletal problems and the resultant gait abnormalities and pain are progressive as they worsen over time without early intervention [67, 68]. As children with CP grow, the growth of bone outpaces that of the skeletal muscle resulting in contractures such as gastrocnemius contracture and planter flexed or equinus gait [67, 68]. Thus juveniles develop scoliosis, hip dislocation/subluxation, and fixed contractures as growth spurts occur [67, 68]. Immobility contributes to the pathogenesis of the musculoskeletal abnormalities and explains in part the increased frequency of orthopaedic complications in children with severe gross motor dysfunction or non-ambulatory CP (spastic quadriplegia/Gross Motor Function Classification [GMFCS] levels IV/V) [67, 68].

5. Conclusions

The aetiology of CP is attributed to the interaction of multiple risk factors which through complex causal pathways within a limited duration disrupt brain development or augment the risk of damage to the motor system in the foetal/infant brain. It has remained a challenge to identify with certainty the timing of these non-progressive disturbances. Nevertheless, the increasing role of genetic susceptibility in CP causation is evolving.

A link between neuropathology and the clinical-neurological features of CP (neuromuscular deficits, accompanying impairments, severity/functional level, clinical types) exists. However, limitations currently remain in devising a comprehensive neuropathologic classification of CP due to inconsistent structure-function correlations and difficulties in estimating timing of insults. Overall, a gap currently exists in our understanding of the aetiology and pathogenesis of CP despite the pivotal roles of advanced neuroimaging and evolving genomics.

Acknowledgments

I express my deep appreciation to my supervisor Dr. Abdul Hawas Manshour for his assistance and Dr. Ahmed Shamakhi and the staff of Department of Paediatrics at the King Fahd Central Hospital, Jazan, for their support by providing me a platform to deepen my knowledge and practice of Paediatric Neurology. I am indebted too to my beautiful “Finebaby”—Mrs. Linda Chigozie Ogoke whose sweet love and support sustained me during the period of writing up of this book chapter.

Conflict of interest

None.