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Year : 2007  |  Volume : 10  |  Issue : 5  |  Page : 33-43

Cerebral palsy: A neonatal perspective

National Centre for Young People with Epilepsy, Lingfield RH7 6PW, United Kingdom

Correspondence Address:
Lyvia Dabydeen
National Centre for Young People with Epilepsy, Lingfield RH7 6PW
United Kingdom
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Source of Support: None, Conflict of Interest: None

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Cerebral palsy is the commonest form of motor disability in developed countries. Its prevalence has remained essentially unchanged, affecting two per 1000 live births, despite the advances in obstetric and neonatal care over the last three decades. This article reviews preterm and term infants most at risk of developing cerebral palsy and examines recent developments in the understanding of corticospinal tract development and plasticity.

Keywords: Cerebral palsy

How to cite this article:
Dabydeen L. Cerebral palsy: A neonatal perspective. Ann Indian Acad Neurol 2007;10, Suppl S1:33-43

How to cite this URL:
Dabydeen L. Cerebral palsy: A neonatal perspective. Ann Indian Acad Neurol [serial online] 2007 [cited 2022 Jan 28];10, Suppl S1:33-43. Available from:

   Introduction Top

Cerebral palsy (CP), which results from damage to the developing corticospinal tract, is the commonest form of motor disability in developed countries occurring with a frequency of two per 1000 live births.[1] The term describes a group of conditions which are characterized by chronic disorders of movement and posture, often accompanied by disturbances in sensation, cognition and seizures.[1],[2] It was recognized as heterogeneous in both pathology and etiology as early as 1958 by the Little Club and although the definition of CP has been refined over the years the most recent classification continues to emphasize both the motor component and that it arises from lesions, malformations or injury to the developing brain.[2]

CP is widely used as one outcome measure of both obstetric and neonatal care; and particularly as an indicator of the hazards of preterm birth. The fall in neonatal mortality in the last four decades has disappointingly not been accompanied by a concomitant decrease in CP. Longitudinal studies in most developed countries have shown a rise in cerebral palsy rates in the 1970s and 1980s and overall rates have fluctuated since then.[3],[4],[5] However the gestational age specific prevalence has changed with babies less than 32 weeks gestation now accounting for 25% of the total population with cerebral palsy; as compared to 10% in 1980s.[6] The commonest type of CP seen in this group is spastic diplegia. Whilst there are some reports of decreasing CP prevalence in preterm infants, rates in term infants, who account for 50% of cases, are essentially unchanged.[7],[8],[9] Hemiplegic and quadriplegic CP occur most commonly in this group although in one recent series there was a rise in dyskinetic CP.[5] In addition, the severity of the disorder may be increasing at all gestational ages. One quarter of children are unable to walk, feed or dress themselves independently and severe learning disability (IQ less than 50) is seen in one third.[3],[4]

It is therefore unlikely, when faced with these figures, that there will be a significant decrease in the numbers of children with cerebral palsy in the foreseeable future.[10] As well as understanding the causal pathways that lead to the development of cerebral palsy there is a need to develop strategies which may ameliorate the effects of early brain insults.

This review focuses on preterm and term infants at risk of developing cerebral palsy and examines current concepts surrounding corticospinal system development and plasticity.

   Preterm Infants at Risk of Developing Cerebral Palsy Top

Advances in modern neonatal and obstetric care mean that 85% of infants less than 32 weeks gestation or 1500 g now survive.[11],[12] Around 10% of this population will develop later spastic motor deficits and cognitive or behavioral problems are seen in up to 50%.[11],[12],[13] Whilst these babies account for only 2% of all births they contribute to 25% of all cases of cerebral palsy.[5]

The brain lesions seen in preterm infants include germinal matrix/ intraventricular hemorrhage and white matter damage.[12] Injury to the periventricular white matter underlies most of the neurological damage seen in these babies. The predominant location of damage is within the corticospinal tracts, centrum semiovale and corona radiate.[12],[14],[15] The dominance of the motor projection fiber bundles may account for the clinical manifestation of impaired motor functioning.

The two major lesions accounting for white matter damage are periventricular leucomalacia (PVL) and intraventricular hemorrhage with associated periventricular hemorrhagic infarction (PVHI), also know as grade IV hemorrhage. These lesions are seen in infants up to 32 weeks gestation and rarely occur after this age. The incidence of intraventricular hemorrhage (IVH) has declined from 50% in the early 1980s to

10-20% in the mid 1990s making PVL the major form of brain injury.[11] More recently low pressure ventricular enlargement has been recognized as a further significant risk factor for neurodisability and is now thought to be part of the spectrum of white matter disease.[16] In contrast, IVH with no parenchymal involvement is not associated with adverse neurodevelopmental sequelae.[12]

   Periventricular Leucomalacia Top

PVL is the most important brain lesion in determining the neurodevelopmental outcome of the premature infant and consists of focal and diffuse components.


The term "periventricular leukomalacia" was first used by Banker and Larroche to describe the lesion which was found in postmortem examinations of infants dying before one month.[17] They described changes involving both cell necrosis and activation of inflammatory cells. Coagulation necrosis was the earliest change affecting all cellular elements and was responsible for the visual appearance of 'white softening' or leukomalacia. An associated finding was 'retraction balls and clubs' interpreted as interrupted axons. This was followed by astrocytic degeneration and ependymal loss with cavitation as the end result. Microglial activation was prominent in the early stages; this was followed by astrocytic and subsequent macrophage activation. Vascular proliferation was the last stage, prominent after one week, with new vessels outlining the necrotic zones.

Subsequent neuropathological studies have agreed with this description of PVL. Kuban and Gilles[18] noted that one group of acutely damaged glia were seen only in white matter regions undergoing active myelination at the time of the insult and not in areas that were already myelinated or unmyelinated. These are likely to be oligodendrocyte (OL) precursors.[19],[20] It was Leviton and Gilles who recognized that PVL occurred in focal and diffuse forms.[16] Focal lesions originally described by Banker and Larroche are typical for cystic PVL. Diffuse white matter injury, likely to result from damage to OL precursors is associated with the later development of ventriculomegaly and delayed myelination.

Pathogenesis of PVL

The pathogenesis of PVL is complex and involves a number of converging developmental factors that influence the vulnerability of preterm white matter. These include the propensity for occurrence of ischemia in the white matter due to the arrangement of blood vessels in the preterm infant, the vulnerability of oligodendrocyte (OL) precursors and cytotoxic cytokines.[12],[14],[21],[22]

Vascular factors

Deep periventricular white matter is supplied by long penetrators from the main cerebral arteries which end in border zones.[23] Short penetrators supply subcortical white matter. From 24 to 30 weeks gestation there are few anastomoses between long and short penetrators. After this time there is an increase in both vessel length and anastamoses. This may explain some of the increased vulnerability of the deep periventricular white matter early in gestation to hypoperfusion. A recent post-mortem study of preterm infants confirmed that regionalized white matter injury had characteristics consistent with the presence of vascular end zones and furthermore, there was evidence of lipid peroxidation consistent with ischemia/reperfusion in these areas.[19]

Maturation dependent vulnerability of Oligodendrocyte precursors

During the time window for the development of PVL cerebral white matter is populated exclusively by oligodendrocyte (OL) precursors.[21] OL precursors undergoing the myelination process are vulnerable to ischemic injury to which mature cells appear to be resistant. Diffuse white matter injury is associated with the prominence of activated microglia and the preferential death of OL precursor cells has been demonstrated using specific immunocytochemical markers.[20] Studies with antibodies specific for sequential expressed OL cell surface antigens have defined five stages in the OL cell lineage, from multipotential progenitor to OL cell capable of myelin basic protein production.[16] In normal development there is an overproduction of glia with cell numbers regulated by apoptosis. Disturbance of the maturation of OL precursors may result in a decreased pool of cells and those that survive may go on to produce faulty or deficient myelin.

In vitro studies have confirmed an enhanced susceptibility of OL precursors to death from oxidative stress. Experimental models and human post mortem work have confirmed that OL precursors accumulate free radicals whereas mature OL cells do not. This may be related to delay in maturation of antioxidant defense systems. Catalase, which converts the hydrogen peroxide formed from superoxide to water and oxygen is not present until 31 weeks gestation. Ferrous iron needed to generate the hydroxyl radical is present in substantial quantities in the immature OL cell as it is essential for differentiation of the OL precursors and myelination. This does not apply to mature cells.[12],[18] In addition, OL precursors seem to be particularly sensitive to glutamate triggered apoptosis.[12] Glutamate release is triggered both by hypoxia/ischemia and from leakage during coagulation necrosis by damaged and disrupted axons. These factors all contribute to the maturation dependent window of vulnerability of white matter.[12]

Infection and cytokines

Gilles[22] first suggested a relationship between sepsis and white matter damage. Intraperitoneal injections of lipopolysaccharide (LPS) from E. coli caused white matter damage in kittens but not in cats. Subsequent animal work included administration of LPS to pregnant rabbits which resulted in white matter lesions to their offspring.[24] There have been conflicting reports of the association between intrauterine infection and development of white matter lesions and cerebral palsy in premature infants.[14],[25],[26] One of the difficulties in comparing studies is the lack of a gold standard to define intrauterine infection. This has been the subject of a recent systematic review by Wu[27] which concluded that there was there was an association between CP and intrauterine infection in all gestational age groups.

LPS is a potent stimulator of the pro inflammatory cytokines interleukin 1 (IL1) interleukin 6 (IL6) and tumor necrosis factor a (TNFa). IL1 and TNF a are known to alter the permeability of the blood brain barrier in animal models. Cytokines can then enter brain parenchyma and affect white matter directly by inducing thrombosis or vasoconstriction. Perturbations in cerebral blood flow can then result in hypoxia and ischemia.[24],[28]

Microglia play an important role in the immune response of the central nervous system and are the first line of defense against microorganism invasion. Microglial activation is responsible for LPS toxicity to OL precursors through the activation of a specific microglial signal transduction pathway which is not expressed by astrocytes, OLs or cortical neurons.[29] Peroxynitrite, a highly reactive oxidant, is generated by LPS activated microglia that is toxic to OL precursors.[30]

Clinical features

The focal component, termed cystic PVL, consists of multiple often, symmetrical areas of necrosis in the deep periventricular white matter, adjacent to the lateral ventricles. Cystic PVL is seen in 2-5% in babies between 24 to 32 weeks gestation or with a birth weight of less than 1500g.[25] The commonest type of CP seen in this group is spastic diplegia.

Cystic PVL can be detected by serial cranial ultrasound examinations. The sonographic evolution of PVL starts with increased echogenicity in the periventricular white matter, which may resolve after seven days or progress to the development of cysts 10-40 days later [Figure - 1],[Figure - 2].[31],[32] The risk of developing CP varies with the site and size of lesions. Cysts that are large and located in the parietal and occipital regions are more likely to be result in CP and extensive cystic PVL is almost invariably associated with the development CP.[25],[31],[32],[33] Clinical risk factors for cystic PVL include hypocarbia, hypotension, apnoea and bradycardia, sepsis, patent ductus arteriosus and maternal chorioamnionitis.[12],[14],[25]

In contrast, diffuse PVL is often invisible on ultrasound and may only be detected on magnetic resonance imaging (MRI). Diffuse PVL can be seen in up to 70% of infants less than 32 weeks.[12],[34] The clinical correlates of diffuse PVL are still unknown and may be responsible for the some of the cognitive sequelae seen in these children. These effects cannot be explained by white matter disease alone. They may however be mediated through damage to the subplate zone. This transient layer contains neurons that provide a link for ascending and descending axons guiding them to ultimate neuronal targets and so has an important role in cerebral cortical organization and later neuronal connectivity.[12]

   Periventricular Haemorrhagic Infarction Top

Periventricular hemorrhagic infarction (PVHI), otherwise known as Grade IV IVH, accounts of 10-15% of all IVH.[35] Preterm babies are susceptible to developing IVH because of the presence of the germinal matrix which is the highly vascular, transient embryonic structure where postmitotic neuroblasts and glioblasts originate. It extends throughout the ventricular system and is at its maximal volume at 26 weeks after which it decreases in size to involute by 32 weeks.[36] Its vessels are fragile with no muscular coat[12],[19] and bleeding comes from rupture of this fragile capillary network.[37] Bleeding is restricted to the area over the head of the caudate nucleus where it is separated from the cerebrospinal fluid of the lateral ventricles by only a single layer of ependyma allowing for the extension of bleeding into the ventricles. IVH was originally graded using CT scans.[35] Grades I-III described germinal matrix hemorrhage, IVH and IVH with ventricular dilatation respectively. Grade IV was described as IVH with 'parenchymal extension'.


Postmortem examinations have demonstrated that the parenchymal hemorrhage is composed of a confluence of multiple perivascular hemorrhages radiating outwards from the angles of the lateral ventricles.[38] The fan-shaped distribution was found to correspond with the location and distribution of medullary veins and is consistent with hemorrhagic venous infarction. The proximity of the vein of Galen and terminal veins to the subependymal layer and the sharp 'U' turn taken by the internal cerebral veins may predispose the venous system to increased pressure when there is IVH.[39]


The pathogenesis of PVHI, like that PVL is complex and fluctuations in cerebral blood flow are thought to play a central role.[14] Increases in cerebral blood flow can be caused by rapid volume expansion and pneumothorax and decreases may be secondary to hypotensive episodes. Vessels may rupture on reperfusion, especially if cerebral autoregulation is impaired, as occurs in small sick infants.[12]

Clinical features

Although the incidence IVH has declined in the last decade, this has been less marked in severe IVH.[25] The most consistent risk factor for development of this lesion is low gestational age with one third occurring in babies less than 750 g.[40]

Cranial ultrasound appearances consist of asymmetric large IVH in 80% of cases [Figure - 3].[35],[40] The associated parenchymal hemorrhage is visible as a fan- shaped echodensity which is unilateral in two thirds of cases appearing on the same side as the larger bleed. These appearances can be seen acutely, within hours of the insult and, after a few weeks, characteristically evolve to a single large porencephalic cyst.[26] The outcome of PVHI depends on the size and site of lesion.[14],[40] Large lesions are associated with a mortality rate of 40-80% and two thirds of survivors with lesions posterior to the trigone greater than 1cm develop a contralateral hemiplegia.

Preventative strategies for white matter damage

The complex pathogenesis of white matter damage has made prevention difficult. The increased survival of low gestational age babies and decline in frequency of IVH has been largely credited to the use of antenatal steroids and postnatal surfactant. Their effect has been less marked on the frequency of IVH associated with PVHI. Trials using Vitamin E, Indomethacin and Ethamsylate have been disappointing in that they have not been shown to have a major impact on the frequency of PVHI.[12],[14],[25]

Changes in ventilatory practice and avoidance of hypocarbia have been associated with a decrease in rates cystic PVL in some centers.[25] Inhaled nitric oxide has attracted attention recently because of its potential to improve neurodevelopmental outcome in babies with respiratory distress syndrome.[41] Increasing insights into the mechanisms involved in OL precursor vulnerability may lead to the development of novel neuroprotective strategies.

Term infants at risk of developing cerebral palsy

Term or near term babies make up the majority of those with CP and account for half of all cases.[4],[5],[42] Little first attributed CP to difficulties in labor and this belief persisted for over 150 years.[43] More recently the role of hypoxia ischemia in CP has been questioned with a shift in focus away from events occurring in labor to antenatal factors. The widespread use of electronic fetal monitoring and the five- fold rise in cesarean section rates has not had a significant impact on the prevalence of CP in term infants. This has remained essentially stable suggesting that intrapartum hypoxia is unlikely to be responsible for the majority of cases in this group.[44]

Neonatal Encephalopathy

Neonatal encephalopathy (NE) refers to a constellation of neurological signs seen in the first seven days of life that involve abnormalities of conscious level, tone, neonatal reflexes, autonomic function, respiration and seizures.[45] In the past, NE has been almost synonymous with hypoxic ischemic encephalopathy. Population-based studies have proposed alternative pathways for NE that include malformations, maternal thyroid disease, maternal fever in labor and cytokines.[46],[47],[48]

The National Collaborative Perinatal Project, a study of nearly 40,000 children born in California between 1959 and 1966 with birth weights of more than 2.5 kg, found that less than 5% of those with Apgar scores between 0-3 at five minutes developed CP.[49],[50] The vast majority of those with CP were born following uneventful pregnancies with no evidence of fetal distress or NE. A tiny high-risk subgroup (less than 0.1%) with a combination of seizures, abnormal neurological signs and low Apgar score at five minutes had an overall risk of death or disability of 70%. Of those with problems at birth, CP only resulted if there was an associated neonatal neurological syndrome and the authors concluded that NE was a necessary link between birth complications and increased risk of CP.[51] Risk factors identified in this study were maternal fever which was associated with a nine-fold increase in the risk of CP, maternal thyroid disease and maternal IQ. A Norwegian group has recently reported a similar association between low Apgar scores and CP with 6.8% of those with Apgar scores of 0-3 at five minutes developing later CP.[52]

A population-based study of NE in Western Australia[47],[48] confirmed that the majority of cases resulted from antenatal factors including maternal pyrexia in labor and thyroid disease. In addition, it identified further risk factors, namely family history of seizures, increasing maternal age and treatment for infertility. This study found that 70% of NE was accounted for by antenatal and intrapartum factors and that perinatal asphyxia alone was not the primary cause of NE in the majority of cases. The same group reported that three quarters of term infants who developed CP had an uneventful neonatal period with no NE; and those that developed CP after NE were more likely to be severely disabled and had a four-fold increase in mortality before the age of six years.[53]

Maternal fever in labor is associated with an increased risk of cerebral palsy even if gas exchange is unaffected and bacterial cultures in the infant are negative.[54],[55] Cytokines may act to prime the immune system and down regulate compensatory responses rendering the fetus more vulnerable to additional insults.[56] Retrospective comparisons of cord blood in children with CP with that of healthy controls have shown higher levels of cytokines in affected children.[57] The same study found elevated thrombophilic factors in cord blood of those with CP who had comparable cytokine levels to control group. A large Australian study did not find elevated thrombophilic factors in association with term CP.[58] It is likely thrombophilic factors form a part of the causal sequence in cerebral palsy rather than acting in isolation.

In contrast to the above population-based retrospective studies which have shown a preponderance of antenatal factors, Cowan et al[59] found evidence for perinatally acquired lesions in 80% of a cohort presenting with NE and 'signs of perinatal asphyxia'. This was a prospective imaging study using early MRI examinations. There were methodological differences with respect to inclusion criteria and the possibility of selection bias arose, as this was a hospital-based study. However the rate of antenatal lesions such as cysts, atrophy, developmental abnormalities and established infarcts and hemorrhage was still very small and maternal thyroid disease was rare. It is likely that CP in many term infants has a complex and multifactorial etiology. Intrapartum events probably do not occur in isolation and in a substantial proportion of babies antenatal factors are likely to initiate a causal pathway leading to increased vulnerability and diminished reserves to deal with the stresses of normal labor.

   Hypoxic Ischemic Encephalopathy Top

Although not responsible for the majority of CP in term infants, hypoxic ischemic encephalopathy (HIE) still forms the largest single subgroup of NE accounting for around 20% of all cases of cerebral palsy in term infants.[5] HIE occurs in 3-5/1000 live births.[1],[12] Asphyxia refers to impaired gas exchange from hypoxia or ischemia resulting in hypercapnia and significant metabolic acidosis.[60] During a hypoxic insult, cerebral oxygenation is initially preserved by redistribution of blood flow. However this mechanism fails when the insult is severe or sustained and brain damage


There are no direct ways to measure fetal brain oxygenation and blood flow. Instead, its presence is inferred from proxy measures such as the Apgar score, fetal heart rate patterns and acid base status. Many factors including antenatal brain damage, sepsis and maternal analgesia can influence the Apgar score. Animal work suggests that base deficit reflects perinatal asphyxia most clearly and a values less than minus 12 mmol/L is the threshold after which NE increases.[60] However acid-base status only provides a 'snapshot' and does not necessarily indicate the severity or duration of an insult.

The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics[63] have listed the four essential criteria to define an acute intrapartum event sufficient to cause CP as:

  1. Metabolic acidosis in umbilical cord blood at delivery (pH less than 7 or base deficit less than minus 12 mmol /L).
  2. Early onset of moderate or severe NE.
  3. Development of spastic quadriplegic or dyskinetic CP.
  4. Exclusion of other identifiable causes.

Excitotoxic cascade

Severe hypoxia ischemia sets into motion a series of biochemical alterations, the excitotoxic cascade.[61] The precise mechanisms are not yet understood but its components include excitatory amino acids, calcium, free radicals and nitric oxide.


Adenosine tri phosphate (ATP) is the primary energy modulator of neurons and glia and is generated in the mitochondria by oxidative phosphorylation.[62] It promotes energy consuming reactions and drives ion pumping to maintain neuronal gradients. If hypoxia continues ATP production is curtailed and there is a switch to anaerobic metabolism. This is inefficient and ultimately there is cellular energy failure and tissue death. Magnetic resonance spectroscopy (MRS) studies have shown a consistent biphasic pattern of energy derangement during perinatal asphyxia. High energy phosphate reserves are partially restored by resuscitation and energy production is able to meet metabolic demands.[64],[65] This is then followed by a secondary energy failure 12-24h later seen on MRS as a decline in ATP and the Phosphocreatine to inorganic phosphate ratio. Persistent mitochondrial dysfunction is likely to underlie the delayed energy failure.[64] ATP dependent sodium extrusion cannot continue and cytotoxic edema and cell death result.

Excitatory amino acids

Glutamate is one of the main excitatory neurotransmitters in the brain. The NMDA ( N -methyl-D aspartate) receptor plays an important role in excitotoxicity.[66] Expression of these receptors is up-regulated in the immature brain and reflects their part in neuronal development, particularly in plasticity and pruning of excess synaptic connections.[67] Enriched glutamate synapses are seen in the thalamus and putamen, corresponding to the topography of hypoxic ischemic damage. Glutamate acts directly on ion channels whose opening is dependent on depolarisation and influenced by energy state. Hypoxia enhances channel opening through depolarisation and glutamate can then exert its effects through ion fluxes.[68] Channel opening allows calcium influx which causes permanent damage.


Calcium concentrations are normally highly regulated with low intracellular concentrations of the free ion. Most intracellular calcium is tightly bound and there is active calcium extrusion regulated by fluxes across the cell membrane. As a consequence there is an enormous gradient across the membrane. Cell injury from calcium influx is mediated through activation of lipases and proteases which attack its structural integrity.[69],[70] Furthermore, energy generated in the recovery phase is used to reverse the calcium gradient at the expense of cell repair. Calcium is also involved in free radical formation.

Free radicals

Free radicals are normal by-products of metabolism from electron leaks in the respiratory chain and are scavenged before they can produce damage.[71] Hypoxia ischemia increases this leak and during reperfusion free fatty acid and prostaglandin metabolism generate hydrogen peroxide, superoxide and hydroxyl radicals. Nitric oxide is a free radical gas stimulated by calcium release from NMDA receptor activation. It has the potential to transform these mildly reactive species to more damaging species.[72] Combination with superoxide forms the highly toxic peroxynitrite radical which is cytotoxic and damages DNA. The brain is especially vulnerable to free radical attack as it has a high concentration of phospholipids. Free radicals cause cell injury by lipid peroxidation, proteolysis and DNA degradation.

   Hypothermia and Hypoxic Ischemic Encephalopathy Top

Hypothermia may intervene at several stages in the sequence between energy failure and neuronal death in HIE. Its mechanisms of action include decreased metabolic rate and ATP consumption, increased inhibitory neurotransmitter activity and reduced glutamate release.[65] The results from two randomized studies of whole body hypothermia or selective head cooling in neonates with moderate or severe NE have now been published.[73],[74] Recruitment was within six hours of birth and entry criteria were based on abnormal amplitude integrated EEG and/or clinical examination. Selective head cooling was associated with a decrease in death and severe disability at 18 months in those with less severe EEG changes. Whole body cooling was associated with a significant reduction in death and severe disability but not cerebral palsy at 18 to 22 months. These two studies suggest that brain cooling may be a useful therapy in HIE although more data are required from long term follow up of these infants before it can be considered beneficial therapy.

   Outcome in Neonatal Encephalopathy Top

The presence of NE is the major predictor of neurodevelopmental disability in term infants and occurs with a frequency of 1-6 per 1000 live births.[53],[75] Overall 20% of those with NE die and 25% survive with permanent deficits.[76] The severity of NE is graded as mild, moderate or severe. Those with mild disease do well and the majority survives without sequelae. At the other end of the spectrum almost all those with severe NE (absence of suck, Moro and oculovestibular reflexes; stuporose and the presence of decerebrate posturing) die or are severely disabled. The severity of NE has been shown to be the best predictor of outcome.[45],[76]

MRI studies performed in the neonatal period may provide additional prognostic information in infants with HIE. Basal ganglia and thalamic changes and loss of the normal signal in the posterior third of the internal capsule are associated with the development of motor deficits. Severe damage to basal ganglia is seen in severe HIE and results in death or disability in all survivors who develop extrapyramidal CP and cognitive impairment.[77] The increased vulnerability of deep grey matter is likely to relate to its transient dense glutaminergic innervation.[78]

The corticospinal system

The corticospinal system in humans is the principle motor system for voluntary limb control. The corticospinal tract is the longest and the last of the descending fiber systems to enter the spinal cord. It is not well-developed at birth but with maturity it confers the capacity for skilled movements especially reaching and grasping of the forelimb.[79] The performance of skilled movements of the extremities relies on direct monosynaptic input from the motor cortex to the spinal α motor neurons.

In most young mammals the corticospinal projection neurons have an initially widespread distribution that is not found in the adult. The macaque monkey has six topographically separate subpopulations of corticospinal neurons at birth that include the frontal, cingulate, parietal and insular cortex. Retrograde labeling studies using tracers injected into the spinal cord to identify cortical origins of projections have shown that in the first eight months of life, the area from which contralateral projections originate has halved and there is a 3-fold reduction in labeled corticospinal neurons that project to the spinal cord.[80] This is consistent with the presence of initially exuberant axonal projections followed by significant axonal withdrawal. This excess of projections may confer plastic potential to the developing system should brain injury occur before this time through the retention of neuronal processes and synapses that would normally be eliminated. At present there is no corresponding human data on the origins and subsequent shaping of corticospinal projections.

Corticospinal projections in many mammalian species develop transient ipsilateral projections early in development that are withdrawn when maturity is reached.[81] In both sub primates and subhuman primates the elimination of supernumerary synapses and axonal withdrawal occurs in conjunction with proliferation and strengthening of connections from projections that are maintained.[82],[83]

In humans, information about corticospinal termination development has come from post mortem examinations and indirectly from studies using transcranial magnetic stimulation (TMS). Postmortem work has shown that corticospinal axons in both the contralateral and ipsilateral corticospinal tracts are actively growing and innervating the spinal cord. They express GAP43, a marker for axonal growth and plasticity, from 26 weeks PCA until the postnatal period.[84],[85]

Focal TMS studies of babies from 26 weeks gestational age onwards have confirmed that these connections are functional.[85] Stimulation of the motor cortex evoked responses in both ipsilateral and contralateral arm muscles suggesting that connections are functionally active and, in addition there is significant bilateral innervation of the motoneuronal pool at birth. Longitudinal and cross-sectional study data of healthy babies and children were consistent with the withdrawal of corticospinal projections over the first 24 postnatal months.[86] Differential development of the ipsilateral and contralateral projections occurred so that at two years of age ipsilateral responses were less frequent, significantly smaller and had higher thresholds than responses in contralateral muscles. This pattern is seen in older children and adults. The small and late ipsilateral response seen in older children was consistent with the persistence of a small ipsilateral projection. This has been confirmed by anatomical studies in humans and monkeys that have demonstrated that the mature corticospinal tract consists of 8-15% uncrossed axons.[80]

Activity dependent competition

The developing corticospinal system uses neural activity to refine the initial widespread and bilateral pattern of terminations to achieve the topographic specificity of connections seen in the mature system.[87] The cat develops a mature, predominantly contralateral pattern of terminations over several weeks from the initial pattern of exuberant bilateral projections. Silencing the sensorimotor cortex in kittens with a 30-day infusion of the GABA A agonist muscimol between the ages of three and seven weeks had a profound effect on the development of corticospinal terminations from both the active and silenced cortex. The silenced cortex failed to maintain the normal complement of terminations in most regions of spinal gray matter with sparse contralateral and absent ipsilateral projections.[88],[89] In contrast the active cortex had a normal contralateral projection and maintained its ipsilateral terminations. The reduction of termination space of the silenced side was balanced on that side by the ipsilateral terminations from the active side and these changes persisted into maturity.

Bilateral cortical inactivation however, resulted in a normal distribution although the density of terminations was slightly less than expected. This suggested that activity during early development confers a competitive advantage in forming spinal connections.[88]

Increasing activity enhances competitive advantage. Electrical stimulation of pyramidal tract corticospinal axons in kittens during a similar time frame resulted in changes in both sides. Dense terminations bilaterally were seen in the stimulated side in contrast to the unstimulated side, which had fewer terminations. This raises the possibility that activity can be harnessed to bias corticospinal terminal development.[90]

Motor experience during the refinement period is also essential for the normal maturation of the corticospinal system.[87] Botulinum Toxin A administered to kittens to prevent forelimb use was associated with failure to maintain terminations in spinal gray matter with permanent reductions in axonal branching. However this did not result in the retention of ipsilateral terminations from the active limb. These changes were accompanied by permanent impairments in skilled forelimb movements during prehension.

Early cortical inactivation and limb disuse resulted in a loss of corticospinal termination space with no recovery when normal activity resumed. Other motor and afferent pathways may already be well-formed prior cortical or limb inactivation. These pathways would be expected to would normal activity after the period of cortical silencing or limb disuse rendering the corticospinal system at a competitive disadvantage at each subsequent stage of development relative to these pathways. This may explain the long-term consequences of such an early transient manipulation.[87]

Plasticity of corticospinal development

The corticospinal system is capable of substantial reorganisation in response to injury. In adults this is mediated through the formation of new circuits by collateral sprouting of both injured and intact fibers.[91] This process is limited and may span over several years. In contrast, the developing nervous system has a greater potential for plasticity that may involve reorganisation of both the damaged and intact motor cortex.[86],[92],[93],[94] The developing nervous system does, however, have a protracted period of vulnerability due to the prolonged period of activity and use dependence. The correlation between late motor development and the late development of the corticospinal system has significance in relation to damage of the system. As the corticospinal system matures, adaptive motor behaviors are expressed and an insult to this system will impair this adaptive control.[87] Although early brain damage produces patterns of impairment which are different from adults they are often both severe and complex.

Unilateral brain damage in the pre and perinatal period may arise from a number of pathologies including infarction, dysplasia, neoplasms and arteriovenous malformations.[92],[93],[94] In these children significant bilateral corticospinal innervation persists from the unaffected hemisphere. TMS studies have demonstrated fast onset ipsilateral responses from the undamaged hemisphere coupled in association with absent responses from the affected one in children with hemiplegic cerebral palsy.[86],[93] Fast onset ipsilateral responses do not occur in healthy subjects after the perinatal period or where cortical lesions are acquired in adulthood.[86],[95] Studies of quadriplegic children have shown fast onset contralateral responses bilaterally within the normal range[86],[96] suggesting that projections from both hemispheres were qualitatively normal. These results are consistent with animal work using unilateral and bilateral activity blockade.

The persistence of fast conducting ipsilateral pathway is not associated with preservation of limb function unless the lesion/malformation has arisen before the second trimester. When reorganisation occurs early in gestation, the projection is probably able to form the links required for effective movement control. Functional outcome in perinatal unilateral lesions is dependent on the presence of responses in the affected hemisphere, in common with stroke in adulthood.[97],[98]

The ipsilateral projections may be maintained at the expense of the contralateral projections from the infarcted hemisphere. Post mortem measurements in human subjects have shown significant increases in the numbers of corticospinal axons projecting from the intact hemisphere in adult subjects with hemiplegic cerebral palsy when compared to normal subjects and those with lesions acquired in adulthood.[98] MRI studies of those with early unilateral lesions have demonstrated an increased size of the corticospinal projection.[99]

   Treatment Strategies Top

The period of activity dependent development of the corticospinal system may provide a window of opportunity for therapeutic intervention. There has been recent interest in constraint-induced therapy originally developed to promote recovery in adult stroke. A modification of this involved the use of a restraint glove on the non-paretic limb for two hours a day together with training of the paretic limb. This was associated with improved paretic hand function after two months of treatment which persisted for at least six months.[100] More information on the duration, timing and long-term effects of treatment is needed before making definite recommendations.

Other future treatment options may involve harnessing activity dependent mechanisms to enhance the competitive advantage of the damaged corticospinal tract and repetitive TMS to alter excitability of both the damaged and intact hemispheres.[98]

   Conclusion Top

It is now recognized that cerebral palsy has a complex and multifactorial etiology. The increased survival in preterm infants coupled with constant rates in term infants means that cerebral palsy is likely to continue to contribute a large burden of disability in the population. New insights into factors responsible for vulnerability of preterm cerebral white matter and the mechanisms underlying the excitotoxic cascade in hypoxic ischemic injury; in conjunction with a deeper understanding of corticospinal system development and plastic potential may lead to novel treatment strategies for the future.

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