Cerebral palsy H .

| Cerebral palsy is the most common cause of childhood-onset, lifelong physical disability in most countries, affecting about 1 in 500 neonates with an estimated prevalence of 17 million people worldwide. Cerebral palsy is not a disease entity in the traditional sense but a clinical description of children who share features of a non-progressive brain injury or lesion acquired during the antenatal, perinatal or early postnatal period. The clinical manifestations of cerebral palsy vary greatly in the type of movement disorder, the degree of functional ability and limitation and the affected parts of the body. There is currently no cure, but progress is being made in both the prevention and the amelioration of the brain injury. For example, administration of magnesium sulfate during premature labour and cooling of high-risk infants can reduce the rate and severity of cerebral palsy. Although the disorder affects individuals throughout their lifetime, most cerebral palsy research efforts and management strategies currently focus on the needs of children. Clinical management of children with cerebral palsy is directed towards maximizing function and participation in activities and minimizing the effects of the factors that can make the condition worse, such as epilepsy, feeding challenges, hip dislocation and scoliosis. These management strategies include enhancing neurological function during early development; managing medical co-morbidities, weakness and hypertonia; using rehabilitation technologies to enhance motor function; and preventing secondary musculoskeletal problems. Meeting the needs of people with cerebral palsy in resource-poor settings is particularly challenging. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 1 PRIMER © 2016 Macmillan Publishers Limited. All rights reserved this Primer, and discussed in detail elsewhere6, many unanswered questions remain. Among the most com­ pelling challenges for the twenty­first century is the need to chart and understand the life course of adults who have grown up with a ‘children’s condition’ and whose adult lives remain affected by the condition7. Hopefully this Primer on cerebral palsy will begin a new and fruit­ ful dialogue, and stimulate a new generation of young practitioners and scientists to work towards answers to these basic clinical and scientific issues. Epidemiology Cerebral palsy is the most common motor disability of childhood. Population­based registries of cerebral palsy, largely in Australia and Europe, have historically found cerebral palsy prevalence ranging from 1.5 to 2.5 per 1,000 live births8. However, recent studies in the United States9, Taiwan10 and Egypt11 have found prevalence rates above 3 per 1,000 live births in people 4–48 years of age. The increased survival of very premature infants has contributed to a modest increase in the prevalence of cerebral palsy in developed countries over the final quarter of the twentieth century that now appears to be levelling off 12. The earliest clinical description of children with cere­ bral palsy recognized that most patients had two factors in common: premature birth and difficult labour with neonatal asphyxia (or oxygen deprivation)5. Both fac­ tors were considered direct causes of cerebral palsy, but are now considered reflective of factors operating earlier in development13. Infants who experience fetal inflam­ mation, for example, are more likely to be born prema­ turely and to develop cerebral palsy; fetal inflammation probably contributes independently to both outcomes14. Indeed, although newborns with Down syndrome are five­times more likely to experience birth depression, as indicated by a low (<6 out of 10 points) Apgar score (which evaluates the baby’s condition based on skin colour, heart rate, reflexes, muscle tone and breathing rate and effort) 5 minutes after birth, we do not ascribe Down syndrome to birth asphyxia15. Preterm birth is the most important risk factor for cere bral palsy. Risk increases steadily with declining gestational age at birth, with a modest increase in risk already detectable as early as 38 weeks of gestation16. The risk in infants born before 28 weeks of gestation is approximately 50­times that of full­term births17 (FIG. 3). Among premature births, the most important risk factor is evidence of white matter damage on cranial ultrasono­ graphy or other brain­imaging modalities. Infants with evidence of persistent damage, such as single or multi­ ple brain lesions (cystic or cavitary) or ventriculomegaly (dilatation of the lateral brain ventricles), have a roughly 50% risk of develop ing cerebral palsy18. Perinatal factors that have been associated with the development of cere­ bral palsy in premature infants include: chorioamnionitis (intra­amniotic infection) or other evidence of perinatal inflammation, especially when sustained postnatally19; transient hypothyroxinaemia (low maternal thyroid hor­ mone levels)20; and hypocapnoea (reduced carbon diox­ ide levels, which can induce cerebral vasoconstriction) in association with mechanical ventilation21. Some of these factors are also associated with the risk of develop­ ing white matter damage, but whether all of these associ­ ations are directly causal is unclear. The finding that intra­uterine growth retardation and postnatal inflam­ mation have additive effects on the risk of cerebral palsy development in premature infants indicates that combi­ nations of biological processes could also be involved in acquiring this condition22. Several recent trials have demonstrated that cerebral palsy is reduced by approxi­ mately 30% in premature infants whose mothers received magnesium sulfate during labour (see below)23–26. In full­term infants, who account for the majority of cases of cerebral palsy (FIG. 3), signs of birth depres­ sion, such as low Apgar score, also correlate with an increased risk of developing cerebral palsy27. However, in the absence of birth depression, many other complica­ tions of labour probably do not raise the risk of cerebral palsy28. Imprecision regarding the proportion of cere­ bral palsy that is causally attributable to birth asphyxia in part reflects the difficulty of rigorously defining birth asphyxia29, but only ≤10% of children who develop cere bral palsy clearly experienced major birth asphyxia. Various perinatal abnormalities often attributed to birth asphyxia — such as meconium passage, need for caesar­ ean section, neonatal seizures and respiratory difficul­ ties after birth — are correlated with cerebral palsy30, but may reflect other underlying biological processes that occur earlier in development. Birth defects outside of the brain, such as cardiac and skeletal abnormalities31, are found with much greater frequency in cerebral palsy. A most important recent advance in cerebral palsy pre­ vention is the discovery that 72 hours of brain or body cooling in full­term infants with birth asphyxia will reduce the prevalence of cerebral palsy32. Other factors that are associated with a higher risk of cerebral palsy at term include placental abnor­ malities and fetal growth retardation33. Neonatal Author addresses Orthopaedic Department, The Royal Children’s Hospital, 50 Flemington Road, Parkville, Victoria 3052, Australia. Murdoch Childrens Research Institute, The Royal Children’s Hospital, Victoria, Australia. Department of Paediatrics, University of Melbourne, The Royal Children’s Hospital, Victoria, Australia. CanChild Centre, McMaster University, Hamilton, Ontario, Canada. Departments of Epidemiology, Biostatistics and Pediatrics, and Human Development, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA. Department of Neurology, Université Libre de Bruxelles (ULB), Brussels, Belgium. Complex Motor Disorders Service, Evelina Children’s Hospital, London, UK. Rehabilitation Medicine Department, National Institutes of Health, Bethesda, Maryland, USA. Department of Rehabilitation Medicine, VU University Medical Center, Amsterdam, The Netherlands. Department of Physical Medicine and Rehabilitation and Pediatrics, Feinberg Northwestern School of Medicine, Rehabilitation Institute of Chicago, Chicago, Illinois, USA. Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK. Developmental Disability and Rehabilitation Research, Murdoch Childrens Research Institute, The Royal Children’s Hospital, Victoria, Australia. Rehabilitation Institute of Chicago, Chicago, Illinois, USA. P R I M E R 2 | 2016 | VOLUME 2 www.nature.com/nrdp © 2016 Macmillan Publishers Limited. All rights reserved hyperbilirubinaemia (excessive levels of bilirubin in the blood owing to red blood cell breakdown) can cause dyskinetic cerebral palsy at any gestational age, but is now fortunately very rare in developed countries as a result of preventive interventions, including exchange blood transfusion, phototherapy and, most importantly, Rho(D) immune globulin therapy (that is, maternal anti­ RhD immunoglobulin treatment to prevent Rhesus disease in the fetus or newborn)34. Approximately 10–15% of children with cerebral palsy have a brain malformation other than a brain lesion, which usually requires neuroimaging to detect35. A small percentage of cerebral palsy (<5%) in full­term infants is a consequence of perinatal ischaemic stroke; this is mainly associated with hemiplegic cerebral palsy in which only one side of the body is affected36. Given that socioeconomic status is strongly associ­ ated with preterm birth and low birth weight, one might Nature Reviews | Disease Primers GMFCS expanded and revised between 6th and 12th birthday: descriptors and illustrations GMFCS level II Children walk in most settings and climb stairs holding onto a railing. They may experience difficulty walking long distances and balancing on uneven terrain, inclines, in crowded areas or confined spaces. Children may walk with physical assistance, a hand-held mobility device or use wheeled mobility over long distances. Children have only minimal ability to perform gross motor skills such as running and jumping. GMFCS level III Children walk using a hand-held mobility device in most indoor settings. They may climb stairs holding onto a railing with supervision or assistance. Children use wheeled mobility when travelling long distances and may self-propel for shorter distances. GMFCS level IV Children use methods of mobility that require physical assistance or powered mobility in most settings. They may walk for short distances at home with physical assistance or use powered mobility or a body support walker when positioned. At school, outdoors and in the community children are transported in a manual wheelchair or use powered mobility. GMFCS level V Children are transported in a manual wheelchair in all settings. Children are limited in their ability to maintain antigravity head and trunk postures and control leg and arm movements. GMFCS level I Children walk at home, school, outdoors and in the community. They can climb stairs without the use of a railing. Children perform gross motor skills such as running and jumping, but speed, balance and coordination are limited. Figure 1 | Gross Motor Function Classification System expanded and revised for children with cerebral palsy, 6–12 years of age. The Gross Motor Function Classification System (GMFCS) has become the gold standard to classify motor function in children with cerebral palsy. The GMFCS is an ordinal classification in which different descriptors are used according to the age of the child. The descriptors for children 6–12 years of age are shown. GMFCS has been shown to be valid, reliable, stable and predictive of long-term gross motor function. The descriptors were devised by Palisano et al.. Images are courtesy of B. Reid, A. Harvey and H.K.G., The Royal Children’s Hospital, Melbourne, Victoria, Australia. P R I M E R NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 3 © 2016 Macmillan Publishers Limited. All rights reserved expect that cerebral palsy shows a similar gradient, and it does seem to37,38. The prevalence of cerebral palsy seems to be higher in African­American infants in the United States, which may be explained by the higher rate of preterm birth in African­American women39. Of seven population­based studies of the epidemi­ ology of cerebral palsy in low­income and middle­income countries reviewed by Durkin40, one study showed much lower prevalence than in developing countries, two were in the same range and four showed higher prevalences, ranging from 4.4 to 10 per 1,000 live births or children. This observation hints to an increased risk of cerebral palsy in low­income and middle­income countries ver­ sus high­income countries despite the fact that many who experience perinatal brain­damaging events that might lead to cerebral palsy in developing countries do not survive infancy. In some regions of the world, chil­ dren may be born with a neurological syndrome that strongly resembles spastic diplegia — a type of cerebral palsy — due to severe iodine deficiency41. Neonatal jaun­ dice caused by high levels of bilirubin remains a major risk factor for cerebral palsy in developing countries, as is perinatal infection. Little is known of the distinct epidemiology of the different subtypes of cerebral palsy. Hemiplegic cere­ bral palsy, as noted above, at times represents the effects of a perinatal ischaemic stroke, but can occur in premature infants who have unilateral porencephalic cavities (or cysts in the cerebrum filled with cerebro­ spinal fluid) following white matter damage. Spastic diplegia, which is usually accompanied by periventri­ cular white matter loss, is linked to both preterm birth and fetal growth retardation at term. The combina­ tion of spastic quadriplegia with dyskinesia in term infants has been associated with severe birth asphyxia. Dyskinesia accompanied by sensorineural hearing loss is the form of cerebral palsy most often seen with kernicterus (a form of brain damage due to high levels of bilirubin). The rarest form of cerebral palsy, ataxic cerebral palsy, sometimes indicates the presence of a cerebellar malformation. Mechanisms/pathophysiology Cerebral palsy is a clinical entity that implies much hetero geneity in terms of aetiology and pathophysio­ logy1. Our understanding of the pathways leading to cerebral palsy has gained much from epidemiological, neuroimaging and post­mortem studies and animal models. However, a comprehensive understanding of the mechanisms that underlie the many features and profound phenotypic variations of cerebral palsy to enable specific strategies for management and primary and secondary prevention is yet to emerge. Brain lesions Characteristics. In approximately 90% of cases, cere­ bral palsy results from destructive processes that injure healthy brain tissue rather than from abnormalities in brain development42 (FIG. 4). Hypoxia and ischaemia have traditionally been proposed as causes of brain injury. Pathological and imaging studies of cerebral palsy have demonstrated varying combinations of lesions in the cerebral cortex, the hemispheric white matter, the basal ganglia and the cerebellum43. The stage of brain matur ation during which pathogenetic events occur defines the type and site of lesions, as well as the specific response to injury. Early in maturation (that is, in the fetus and the preterm infant) blood vessels in the brain have limited capacity for dilatation, which enhances ischaemia and Monoplegia Nature Reviews | Disease Primers Quadriplegia Diplegia Triplegia Hemiplegia Unilateral cerebral palsy Bilateral cerebral palsy Figure 2 | Topographical description in cerebral palsy: unilateral and bilateral cerebral palsy. In monoplegia, one limb is affected and it is more often the lower limb. In hemiplegia, one side of the body is affected and the upper limb is usually more affected than the lower limb. These topographical types are equivalent to the Surveillance of Cerebral Palsy Europe (SCPE) unilateral cerebral palsy. In diplegia, all limbs are affected, but the lower limbs are much more affected than the upper limbs, which frequently only show fine motor impairment. In triplegia, the usual pattern is unilateral upper limb involvement and bilateral (asymmetrical) lower limb involvement. The lower limb is invariably more affected on the same side as the upper limb involvement. In quadriplegia, all four limbs and the trunk are involved. Synonyms for quadriplegia include tetraplegia or ‘whole-body involvement’. Diplegia, triplegia and quadriplegia are covered by the term bilateral cerebral palsy according to SCPE terminology. P R I M E R 4 | 2016 | VOLUME 2 www.nature.com/nrdp © 2016 Macmillan Publishers Limited. All rights reserved leads to diffuse injury. Diffuse injury during the second trimester of pregnancy leads to liquefaction necrosis (a type of necrosis that transforms tissue into a viscous liquid mass), resulting in porencephalic cysts44. The astrocytic response to injury (including biochemical activity and morphological changes), which might lead to gliosis, is limited during the second trimester of preg­ nancy (<15% of the level observed in the mature brain) and gradually increases during development. Astrocytic response leads to cysts with increasing components of astroglial proliferation and septation observed for insults up to the neonatal period and astrogliosis without cysts for lesions sustained later44. The localization of brain lesions following diffuse insult markedly varies with gestational age. In preterm infants, deep periventricular white matter, which is a site of active proliferation of oligodendrocytes, is the most vulnerable. Maturation­dependent metabolic and molecular factors further enhance the susceptibil­ ity of the periventricular white matter in the preterm brain45,46. Consequently, periventricular leukomalacia (necrosis of white matter near the lateral ventricles) is the characteristic lesion pattern seen in cerebral palsy associated with preterm birth; it can be dif­ fuse, focal or multifocal, cystic or non­cystic. By con­ trast, insults occurring in full­term infants primarily affect the cerebral cortex and underlying subcortical and periventricular white matter as a result of other maturation­ dependent factors45 and probably factors affecting vascular supply with changes in intervascu­ lar boundary (watershed) zones (that is, border­zone regions in the brain supplied by major cerebral arteries where blood supply is slightly reduced). Phenotypical variability. Cerebral palsy is associated with various motor defects, which largely depend on the location of the brain lesion. Disruption of cortico– striatal–thalamic–cortical and cortico–cerebellar– cortical networks impairs motor planning, coordination, muscle strength regulation, motor learning and fine motor skills. Additional disruption of descending motor pathways that project to the brainstem and spinal relays, and retention of circuits that normally disappear with maturation result in persistent or poorly inhibited ‘primi tive’ reflexes, abnormal organization of movement and posture, hyperactive reflexes and abnormal muscle tone, including spasticity. The motor impairments, with poor motor repertoire, hypertonia, progressive muscle changes related to neuronal, nutritional and mechanical factors, lead to musculoskeletal deformities. Pathogenesis of brain lesions. The link between perinatal respiratory difficulties leading to hypoxia or ischaemia and cerebral palsy has been recognized clinically since the original description by Little5, and it has served to design various animal models since the 1950s. Given that birth asphyxia does not account for the majority of cases of cerebral palsy, other mechanisms must play a part. Brain injury in response to hypoxia or ischaemia is suggested to involve several events, including cellular energy depletion, excitotoxicity (that is, damage or death of nerve cells owing to excessive stimulation by neurotransmitters, particularly glutamate) and oxi­ dative stress; oxidative stress leads to mitochondrial failure that further exacerbates this energy depletion. Ultimately, neurons and glial cells undergo apoptosis or necrosis (FIG. 5). ATP depletion caused by mitochondrial failure dis­ rupts cellular ATP­dependent processes, which may result in cell death. Among ATP­dependent processes, Na+/K+­ATPase disruption alters neuronal membrane potential, contributing to glutamatergic N­methyl­ d­aspartate (NMDA) receptor­mediated excitotoxicity through massive Ca2+ influx into the cytoplasm, leading to necrosis and apoptosis43,47. Understanding this path­ way has led to the study of the potential neuroprotective effects of agents that block NMDA receptors, including magnesium sulfate23. Intracytoplasmic Ca2+ overload induces necrosis and apoptosis by inducing oxidative stress. Activation of Ca2+­dependent oxidases and inhibition of antioxidant activities48 generate excess reactive oxygen species that affect mitochondrial function, which further increases the rate of reactive oxygen species production, ultimately leading to cell death. This effect is particularly marked early in brain maturation (second trimester) owing to the limited efficiency of scavenging systems43. This notion has led to the development of neuro protective strategies based on free­radical­scavenging agents, such as melatonin49. In addition, the use of high oxygen concentrations in resuscitation approaches in neonatal asphyxia are contraindicated on the basis of studies in animals50 and those showing adverse clinical outcome in humans51. Various insults, not just hypoxia and ischaemia, can lead to necrosis and/or apoptosis. Necrosis occurs as an immediate response to injury and typically results in focal injury that involves nonspecific cell­type death. Conversely, apoptosis is more protracted, usually more diffuse and cell specific — preferentially targeting Nature Reviews | Disease Primers C er eb ra l p al sy c as es 100