Stroke & Vascular Disorders
Aug. 19, 2022
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Cerebral palsy describes a group of genetic and acquired childhood neurologic disorders characterized by abnormalities in tone, posture, and movement as a result of early injury to the developing brain. Cerebral palsy is often associated with language and intellectual disability, social impairment, epilepsy, other organ system involvement, and functional limitations. An appropriate diagnostic assessment and resource environment is important to ensure proper treatment and management. Neuroprotective strategies, including therapeutic hypothermia and adjuvant therapy, have been shown to reduce morbidity and mortality caused by hypoxic-ischemic encephalopathy, including cerebral palsy. In this article, the author discusses the many aspects of diagnosis and management of cerebral palsy.
• Cerebral palsy describes a group of nonprogressive genetic and acquired childhood neurologic disorders characterized by abnormalities in tone, posture, and movement as a result of injury to the developing brain.
• Although characterized by their motor dysfunction, children with cerebral palsy frequently have other associated impairments, which include language delay, seizures, strabismus, dysphagia, orthopedic deformities, and cognitive problems.
• Advances in neuroimaging and genetics promise to further the understanding of the pathogenesis and pathophysiology of cerebral palsy.
• Effective management of cerebral palsy requires a team with medical and rehabilitative specialists to provide careful, ongoing neurodiagnostic evaluation and rehabilitation to maximize functional capabilities.
• Neuroprotective strategies, chiefly therapeutic hypothermia, have demonstrated decreased death and disability related to cerebral palsy.
Cerebral palsy describes a group of nonprogressive genetic and acquired childhood neurologic disorders characterized by abnormalities in tone, posture, and movement as a result of injury to the developing brain (144; 86; 19).
Debates surrounding the nomenclature, definition, and etiology of cerebral palsy continue. In the mid-1800s, Sir William Little proposed that cerebral palsy was related to difficult childbirth (161). In recent decades, this view has had significant medical and legal implications (184). In the late 1800s Freud wrote, "Difficult birth, in certain cases, is merely a symptom of deeper effects that influence the development of the fetus" (80). This view suggested that cerebral palsy had a prenatal onset. The late 19th century brought further insight as Sir William Osler published his lectures, The Cerebral Palsies of Children, classifying the disorder by neuroanatomy, etiology, and extremity involvement (199).
The Collaborative Perinatal Project, a landmark American maternal and child health epidemiologic research study, demonstrated that the events of labor and delivery are not major contributors to the occurrence of cerebral palsy or most other neurodevelopmental disorders. Rather, most of these conditions have their origins before labor begins (189). Prenatal factors have emerged as the chief determinants of risk for cerebral palsy (28).
Clinical assessment allows classification by neurologic findings and topographical location. Although a number of classification systems exist (208; 274), categorization into specific phenotypes based on tone and limb involvement (Table 1) is of clinical benefit (113). Classification into a specific group may provide benefit when investigating etiology, determining medical and rehabilitative treatment, and determining recurrence risk. One should note, however, that (1) some individuals have signs of spasticity, rigidity, and dystonia and are often classified as “mixed” cerebral palsy; and (2) the motor manifestations of cerebral palsy may change over time (229).
• Spastic diplegia
• Spastic hemiplegia
Hypotonia and ataxia
Spastic diplegia. Spastic diplegia is a clinical syndrome with spasticity greater in legs than arms, seen most commonly in children born prematurely. Associated findings may include strabismus, orthopedic deformities, seizures, oromotor dysfunction, and disorders of cognitive function. It is primarily a disorder of developing white matter and is nearly always associated with neuropathological and neuroimaging findings of periventricular leukomalacia. As premature infants usually receive careful developmental follow-up after discharge from the neonatal intensive care unit, those with spastic diplegia are often identified during the first 6 to 12 months of life with signs of delayed motor development.
Spastic quadriplegia. Spastic quadriplegia represents bilateral spasticity affecting all extremities, with significant limitations in both mobility and hand use. Affected individuals commonly require a wheelchair for mobility. Associated deficits may be more severe, including intellectual disability, communication disorders, seizures, orthopedic deformities including scoliosis and hip dislocation, and visual impairment. Spastic quadriplegia is the result of a broader range of pathological insults than spastic diplegia, including genetic and developmental brain malformations, severe periventricular leukomalacia, pre- and postnatal infections, asphyxia, and nonaccidental trauma. As with other cerebral palsy syndromes, low birth weight, prematurity, and complicated neonatal course are important risk factors. Delayed motor development in the first year is usually more prominent than in spastic diplegia.
Spastic hemiplegia. Spastic hemiplegia represents unilateral spasticity, often with recognizable etiologies. Independent ambulation and normal intelligence are commonly seen. There is an increased risk of seizures, growth asymmetry, and sensory impairment of the hemiplegic side.
In children with extrapyramidal syndromes, clinical involvement is characteristically greater in the arms than the legs. Extrapyramidal syndromes are often associated with a marked reduction in speech production, but the child may have relatively preserved intelligence. Close clinical observation and examination facilitates categorization in the below groups.
Bradykinesia. This refers to a slowing of movement, with a paucity of facial movements. On examination there may be findings of hypertonic rigidity on passive limb movement.
Dystonia. This may be variably considered as twisting, repetitive movements with abnormal postures or as the production of 1 pattern of muscle activation when another is intended (233). At rest, muscle tone may be normal, with dystonic hypertonicity on volitional activity.
Choreoathetosis. This pattern of hyperkinetic movements may be seen individually as chorea (rapid, irregular, uncontrolled movements of the distal extremities) or as athetosis (slower, writhing movements) or in combination.
Hemiballismus. Hemiballismus refers to wild, uncontrolled movements of the extremities. This may be incapacitating for day-to-day activities and a source of great embarrassment.
Less commonly, children present with hypotonia or ataxia, or both, with delayed motor milestones (65). These patients are distinguished by the preservation of strength and reflexes, suggesting a disorder of upper motor neurons. This is a heterogeneous group of disorders, including recognized and presumptive static genetic or genetic-metabolic disorders, such as mitochondrial encephalomyopathies (90), Angelman syndrome, Prader-Willi (261), carbohydrate glycoprotein syndromes (97), childhood spinocerebellar atrophies (166), and chromosomal deletions and rearrangements.
Although characterized by their motor dysfunction, children with cerebral palsy frequently have other associated impairments (44; 241). Associated problems include language delay, seizures, strabismus, dysphagia, orthopedic deformities, and cognitive problems (44). Up to half of patients develop seizures, which commonly have their onset in the first years of life (03; 265). The incidence is greater in spastic quadriplegia and hemiplegia and lowest in mild spastic diplegia. About half of children with cerebral palsy have intellectual disability that can range from mild to severe. Intellectual disability is often closely associated with the presence of seizures, and patients with multiple seizure types are more likely to be severely delayed. Prolonged fixed primitive and postural reflexes are frequently mistaken for seizures. Impairments in hearing, vision, and speech are experienced in 15% to 20% of children with cerebral palsy. Abnormal speech and language may result from hearing loss, brain-based primary language problems, poor integration of motor mechanisms of the oropharynx, or poor coordination of breathing patterns.
Additional impairments include difficulties with swallowing and feeding, impaired growth, dental problems, respiratory disease, and emotional disorders. Swallowing and feeding disorders can develop with secondary esophagitis or aspiration (47; 222). Growth may be slow as a result of inadequate caloric intake, recurrent vomiting with aspiration secondary to gastroesophageal reflux, and pseudobulbar palsy.
Dental disease and chronic respiratory disease are both common. Respiratory problems can develop from severe reflux, palatopharyngeal dyscoordination, chest deformity, and poor coordination of respiratory muscles (122). Enuresis, frequency, urgency, and stress incontinence also occur in many children. These are related to neurogenic dysfunction, poor cognition and communication skills, limited mobility, and the expectations of caregivers (30).
Children with cerebral palsy may experience limitations in activities of daily living that contribute to behavioral and emotional difficulties (246; 20; 135). Problems in these areas should be promptly addressed by appropriate specialists to promote resolution and long-term success both socially and vocationally.
Depending on severity, the diagnosis of cerebral palsy may be established between 1 and 2 years of age, although in children with milder phenotypes it is often made after the age of 2 years. Normal motor development in infancy progresses from reflex-driven activity to adaptive postural reflexes to volitional activities. In 1 sense, cerebral palsy represents the persistence of reflex-driven activity, with the lack of emergence of cortical control. Many clinicians defer a diagnosis of cerebral palsy during early infancy unless profound motor delay is seen. Reasons for caution with regard to early diagnosis include the recognition that normal motor development can vary during infancy, and that evidence of motor dysfunction may not be noted until 6 to 12 months of age.
As the etiology of cerebral palsy is often related to prenatal factors, maternal perception of fetal movement can be an important clue to timing and cause. Children with genetic conditions, including Prader-Willi syndrome, mitochondrial disorders, congenital myotonic dystrophy, and other abnormalities in neural development, may have maternally perceived or externally measured decreased fetal movement (123; 78; 77; 264). Identifying the etiology may be difficult. A diagnostic approach for cerebral palsy in the genomic era has been published (152). This guide provides an approach that combines clinical assessment, MRI findings, and genomic testing to assist the provider in identifying the numerous genetic etiologies comprising cerebral palsy.
Increased fetal movement may represent fetal seizures and has been associated with congenital brain malformations including lissencephaly (203) and subsequent neonatal encephalopathy progressing to cerebral palsy (136).
Early postnatal motor signs include poor head or trunk control, persistent or asymmetric fisting, or obligatory extensor postures. Gross and fine motor development is not only delayed, but is also qualitatively abnormal. Neurobehavioral signs that should raise suspicion are excessive docility or irritability. Abnormal oromotor patterns may include tongue retraction and thrust, tonic bite, oral hypersensitivity, and grimacing.
The earliest indication of significant motor disability can be the delayed disappearance of a primitive reflex or the presence of one to an abnormal degree (43). For example, the tonic labyrinthine response occurs when the neck is extended when supine and leads to shoulder retraction, leg extension, and either elbow flexion or extension and pronation of the arms. Flexion of the neck causes flexion of the extremities. An excessive tonic labyrinthine response may manifest as "posturing" or apparent early "rolling over."
• Increased suspicion from obstetric and perinatal history
A comprehensive examination is essential to establishing a diagnosis of cerebral palsy. An important component of the examination is determination of muscle tone: normal, hypertonic, and hypotonic. Hypertonicity can be of spastic, rigid, or dystonic type (234). Spastic hypertonicity, which is velocity dependent, is a component of the upper motor neuron syndrome, which also includes clonus, hyperreflexia, a positive Babinski response, spastic weakness, and loss of manual dexterity. Rigidity is a type of hypertonicity with co-contractions of muscle groups. It is independent of velocity and does not cause fixed postures. Dystonic hypertonicity occurs when involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements and abnormal postures. When hypotonia is present and of central nervous system origin, strength is preserved; this is in contradistinction to neuromuscular hypotonia, in which strength and reflexes are depressed. The presence of ataxia, an uncommon sign in children with cerebral palsy, should focus the etiologic diagnosis on genetic disorders, including Angelman syndrome.
In addition to the formal neurologic examination, infant assessment includes observation in prone and supine positions, pull-to-sit, supported sitting, and in vertical and ventral suspension. Skill in propping on arms and hands and the ability to rotate around the body axis are noted as well as the emergence of protective postural reactions. Particular signs that are associated with an increased risk of cerebral palsy at 4 to 6 months are failure to support weight on the forearms in a prone position, to sit supported with head erect, or to show interest in surroundings or social responsiveness. Increased neck extensor and axial tone may give a false impression of good head control. Abnormalities in vertical suspension including scissoring and “sitting in air” merit close attention. Observation of abnormal general movements in the neonatal and infant period has been applied, primarily in the Netherlands, for the prediction of cerebral palsy (216; 95; 101). This method involves trained observation for the identification of patterns of spontaneous movements that result in cerebral palsy as an outcome.
Experienced clinicians include insights learned from the National Collaborative Perinatal Project, which highlighted the variable predictive capabilities of early neurologic evaluations in their diagnostic formulations. As a component of this large, multicenter study, 37,000 children were examined at the ages of 1 and 7 to determine the frequency of resolution of abnormal neurologic signs at the age of 1 and to investigate whether there was evidence at the age of 7 of other neurologic, sensory, cognitive, or behavioral problems (188). Only one half of the children diagnosed with cerebral palsy at the age of 1 carried that diagnosis at the age of 7. Of importance, however, is that children for whom a tentative early diagnosis of cerebral palsy does resolve are more likely to manifest other neurologic diagnoses including intellectual disability (27).
Prognosis is often dependent on severity of impairment and appropriate management of functional impairment. Occasionally, an etiologic evaluation is important in prognosis and recurrence risk, especially if the disease is determined to be of metabolic-genetic origin. Families as well as affected individuals often seek information about long-term prognosis so that preparations can be taken for appropriate medical, financial, and life care plans. Although comprehensive long-term studies are limited, the majority of children with cerebral palsy now survive into adulthood (56). However, children who are immobile and tube-fed may have a shorter life expectancy. Caution should be used in prognostication; physicians should encourage families to establish necessary plans but to not think of survival in a specific number of years.
Ongoing medical follow-up is necessary for the patient with cerebral palsy. Adolescents and adults with cerebral palsy are at risk for secondary conditions that cause a loss of musculoskeletal function and deterioration of quality of life (81). Increased hip flexion contracture from the physician's perspective is associated with deterioration in function from a patient and a therapist's perspective (212). The spine and joints of the lower extremities are especially vulnerable to deformities derived from muscle spasticity and contracture (34; 178). For example, some adults with extrapyramidal cerebral palsy are at risk for progressive cervical spine disease, which can lead to sudden quadriplegia if untreated (103). Others may develop progressive neurologic symptoms necessitating changes in medical management (237). A study of risk factors for hip pain in cerebral palsy found that hip displacement was associated with hip pain (164). However, hip displacement was not present in the majority of painful hips. In addition to hip displacement, decreased range of motion was found to be associated with hip pain.
Adolescents with neurodevelopmental disability are also at increased risk of premature pubertal changes when compared to the general population (243).
Lifestyle planning depends on multiple factors. Individual achievement is related to physical function, intelligence, ability to communicate, and personality attributes (172). Children with cerebral palsy benefit from a strong, continuing program of support services to facilitate their assimilation into the community. Social and environmental factors play an important role and accentuate the importance of early support and guidance; the availability of training, jobs, sheltered employment, and counseling contribute to the adjustment of adults with cerebral palsy. The presence of a supportive family and the availability of specialist medical care are also important factors. Long-term planning and preparation are imperative, particularly when all indications point toward the need for an ongoing support system.
Although the prognosis prediction for individuals with cerebral palsy continues to improve, the population retains higher mortality rates than the general population (248). There is an elevation in death from brain and breast cancer, respiratory, circulatory, and digestive disease as well as from external causes such as drowning or motor vehicle accidents (247). A systematic search and review identified 47 published studies of advanced MRI to predict neurodevelopmental outcome in preterm infants (201). Diffusion MRI and morphometry studies were the most commonly studied modalities. Extremely premature newborns are at higher risk of developing cerebral palsy. Progression of posthemorrhagic ventricular dilation as demonstrated by cranial ultrasound and the head circumference correlated with outcome. Measurements such as these may allow for additional studies comparing optimal treatment protocols (193).
Evidence suggests that 70% to 80% of cerebral palsy cases arise from antenatal factors and that birth asphyxia contributes approximately 10% of cases (124; 180). The majority of children (57%) are born at term (more than 37 gestational weeks) (09). In children with cerebral palsy who are born preterm, those born extremely preterm (before 26 weeks) have the highest risk (approximately 20%) of developing cerebral palsy (167). Prenatal disorders of genetic and environmental origin underlie the majority of cerebral palsy cases, with perinatal factors also playing an important role in children born preterm (96; 185). Mutations disrupting neuritogenesis genes confer risk for cerebral palsy (127).
Genetic disorders and acquired insults follow a pattern of selective vulnerability during early brain development. Cerebral malformations associated with cerebral palsy usually occur secondary to insults during the first 20 gestational weeks, and affected children are often born at term. Periventricular white matter is more susceptible to hypoxic and infectious insults during weeks 24 to 34 of gestation. At term, the basal ganglia, thalamus, and cortical gray matter are variably susceptible to hypoxia-ischemia. Perinatal stroke is a known risk factor for cerebral palsy and was detected in 12% of neonates having cardiopulmonary bypass (260). Those undergoing the Norwood procedure have a 3-fold risk of injury. In this study, stroke was associated with neurodevelopmental disability at 12 months of age (260).
Recognized causes include developmental brain malformations such as lissencephaly, schizencephaly, Dandy Walker syndrome, TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes) infections, and in utero vascular events. Important antecedents include prematurity, low birth weight, breech presentation, maternal chorioamnionitis, thrombophilic disorders (145), complicated neonatal course, asphyxia, and infection. In preterm infants, perinatal events including maternal chorioamnionitis, hypoxic-ischemia, and infection are important antecedents (198). Maternal risk factors include intellectual disability, epilepsy, diabetes, and thyroid disease (124). Only 10% to 20% of cases are acquired after the prenatal period and are usually related to central nervous system infection, trauma, strokes, and severe hypoxic events such as near-drowning. A publication by Chin and colleagues showed processes with direct central nervous system involvement (eg, perinatal hypoxic-ischemic encephalopathy or infectious encephalomalacia) carry greater than 10% absolute risk of cerebral palsy (46). Other acute perinatal processes including placental abruption, uterine rupture, and neonatal sepsis are also associated with increased risk of cerebral palsy but carry less than 3% absolute risk of cerebral palsy. Indirect markers of chronic placental insufficiency such as fetal and placental growth patterns are associated with increased risk of cerebral palsy, and risk of cerebral palsy in infants with growth abnormalities born extremely preterm exceeds 10%. Causal links remain incompletely understood, but genetic background, the intrauterine environment, general fetal health, and fetal neurologic health all appear to contribute (46).
Spastic diplegia. Spastic diplegia is most commonly a disorder of developing white matter and is nearly always associated with neuropathological and neuroimaging findings of periventricular leukomalacia (263), but may also be secondary to periventricular hemorrhagic infarction and posthemorrhagic hydrocephalus. Congenital HIV (174), familial spastic paraparesis (140; 57), structural cord lesions (68), as well as other uncommon disorders including Sjögren-Larsson syndrome (267) and arginase deficiency (215) may have similar clinical findings but distinctive imaging findings. If upper extremity neurologic examination is normal in a child with "spastic diplegia,” brain and spine imaging should both be obtained to exclude a cord lesion as the cause (227).
Spastic quadriplegia. Spastic quadriplegia is associated with a wider range of pathological insults than spastic diplegia, including severe periventricular leukomalacia or hypoxic-ischemic encephalopathy, genetic and developmental brain malformations, hydrocephalus of various causes, TORCH infections, meningitis, and non-accidental trauma (13; 263).
A number of children have relatively symmetric destructive lesions of the cerebral cortex. One important type of destructive lesion is multicystic encephalomalacia, which refers to multiple cystic cavities in the cortex separated by glial septations. It can be the end result of intrauterine infections, severe perinatal hypoxic-ischemic encephalopathy, perinatal herpes simplex virus, bacterial meningitis, or non-accidental trauma during infancy.
A second recognized subgroup includes patients with genetic and developmental brain malformations such as holoprosencephaly, agyria-pachygyria complex (including lissencephaly), bilateral schizencephaly, and agenesis of the corpus callosum, which commonly lead to microcephaly and spastic quadriplegia (154; 98). TORCH infections, especially cytomegalovirus, can also result in pachygyria, with similar clinical findings (106).
A third subgroup includes those with fetal or neonatal hydrocephalus, reflecting a variety of pathologies affecting the development and maintenance of CSF pathways, including aqueductal stenosis and Dandy Walker syndrome (92).
Spastic hemiplegia. A higher proportion of patients with hemiplegic cerebral palsy are born at term than those with diplegia or quadriplegia. Five groups of disorders are associated with spastic hemiplegia: (1) brain malformations such as unilateral schizencephaly, (2) in utero cortical-subcortical lesions, (3) abnormalities of periventricular white matter, (4) perinatal-stroke (151) as well as asymmetric grade 4 intraventricular hemorrhage, and (5) postnatal strokes (15; 49; 251; 74). Underlying genetic factors, including homeobox gene EMX2 in schizencephaly (35) as well as thrombophilic risk factors, including factor V Leiden (254; Harum and Hoon 1999), may be present. With the increased availability of imaging, cerebral infarction in term infants is more frequently diagnosed. The presence of multiple risk factors including infertility, preeclampsia, oligohydramnios, prolonged rupture of membranes, and chorioamnionitis significantly increases the risk of perinatal arterial stroke (151). The most common presentation is neonatal seizures. EEG and evaluation for associated prothrombotic disorders may refine prediction of prognosis (171).
The group of patients with extrapyramidal cerebral palsy demonstrates a heterogeneous etiology. A wide range of acquired and inherited disorders of the basal ganglia are responsible in some patients (116). Two recognizable newborn encephalopathies frequently resulting in extrapyramidal cerebral palsy include (1) perinatal hypoxic-ischemic encephalopathy, with areas of hyperintense signal in the putamen, thalamus, and motor strip, often leading to athetosis and dystonia; and (2) kernicterus, with hyperintense signal in the globus pallidus and the later development of choreoathetosis (129).
Inborn errors of metabolism may present as extrapyramidal cerebral palsy. Prominent lesions in the basal ganglia, present in glutaric aciduria type I (179) and juvenile Huntington disease (153), may have an extrapyramidal phenotype. Methylmalonic aciduria can present with prominent lesions of the globus pallidi after metabolic “strokes” (107). Patients with other more obscure disorders of intermediary or neurotransmitter metabolism, or of idiopathic or genetic dystonia, may present initially as extrapyramidal cerebral palsy.
Important treatable forms of extrapyramidal cerebral palsy include pediatric neurotransmitter diseases. These rare neurometabolic disorders cause severe, often progressive neurologic symptoms and are classified on the basis of alterations in neurotransmitter metabolic pathways. They include disorders of monoamine and gamma-aminobutyric acid (GABA) metabolism (205). Although individual disorders may be diagnosed with plasma amino acid or urinary organic acid analysis, carefully collected and analyzed CSF is the best method for diagnosis (10). The prototypic treatable pediatric neurotransmitter disorder is dopa-responsive dystonia, a defect in GTP cyclohydrolase (Segawa disease), which may present with severe idiopathic extrapyramidal cerebral palsy (or spastic diplegia) early in life (142) and a normal brain MRI. Treatment with levodopa can be beneficial, with returns in motor function (192).
Hypotonic and ataxic individuals represent a diverse group of both recognizable as well as currently undiagnosed genetic and metabolic disorders. Patients are usually term infants, so this group is probably the least likely of all the cerebral palsy syndromes to be caused by an acquired condition such as asphyxia. Recognized disorders include Angelman syndrome (268), ataxia-telangiectasia (39), congenital malformations of the cerebellar vermis with mega-cisterna magna, mitochondrial disorders, carbohydrate-deficient glycoprotein disorder (168), disorders of neurotransmitter metabolism, and Joubert syndrome.
Cerebral palsy results from disorders that disrupt developing neuronal networks in cortical and subcortical pathways controlling movement. The pathogenesis and pathophysiology of cerebral palsy are strongly linked to 3 important concepts: (1) etiology is often linked to specific disorders of genetic and environmental origin; (2) timing and severity of insults are related to clinical syndromes; and (3) during periods of active early development, vulnerability exists for specific cell populations, and brain regions are particularly susceptible to injury on the basis of age-dependent changes in cellular metabolism, neuronal connectivity, and circulation, termed “selective vulnerability” (59; 130; 187).
Early insults or genetic abnormalities affecting fetal brain development often affect the brain globally. By the late second or early third trimester, developing oligodendroglia in periventricular white matter are vulnerable to injury (196; 59), which can be triggered by hypoxia-ischemia, infection, or maternal metabolic abnormalities involving thyroid function and glucose homeostasis (129; 63). Neuropathology reflects focal components of complete necrosis deep in the cerebral white matter and diffuse injury to oligodendroglia precursors in the surrounding area (262). Pathogenesis of periventricular leukomalacia is related to 3 factors: (1) immaturity of cerebral blood vessels, (2) immaturity in the regulation of cerebral blood flow, and (3) selective vulnerability of developing oligodendroglial cells to infectious, hypoxic-ischemic, or possibly endocrinological insults. Glutamate released during ischemic episodes appears to trigger excitotoxic injury in immature oligodendroglia, in part because these cells are less protected from oxygen-free radical damage than more mature cells (196). Even for affected babies born at term, periventricular leukomalacia is commonly of prenatal origin (173).
As the fetus approaches term, the vulnerability shifts from the white matter to neuron populations in the cerebral cortex and basal ganglia. Characteristic patterns on MRI include hyperintense signal in the putamen and ventrolateral thalamus, parasagittal cortical infarction, and multicystic encephalomalacia (133).
Children born prematurely, in breech presentation, or with major and minor malformations (189; 53) have increased risk of cerebral palsy, as the difficulties probably reflect abnormal prenatal development. In particular, risk increases with increasing prematurity. Low birth weight makes preterm infants especially vulnerable to complications that can increase the risk of cerebral palsy. For instance, babies needing mechanical ventilation can develop bronchopulmonary dysplasia that can then lead to prolonged periods of hypoxemia.
An association exists between prenatal brain damage and multiple gestations; the prevalence of cerebral palsy is reported to be 6 times higher in twins than in singletons (183). Causes include low birth weight, congenital anomalies, cord entanglement, vascular shunts between twins, and abnormal vascular connections. If 1 twin dies in utero, a release of thromboplastins and emboli may occur. If the death occurs during early pregnancy, the surviving twin may develop cerebral dysgenesis (17). Twins are also more likely to develop antenatal periventricular leukomalacia, and the risk of cerebral palsy is greater in those that survive the fetal death of a co-twin. The risk also increases the higher the multiple gestation (210).
Other risk factors include male gender and older siblings with cerebral palsy. Preexisting maternal conditions that increase risk include stroke, autoimmune disorders, thrombophilic disorders such as factor V Leiden mutation, intrauterine growth restriction, and perinatal infection. Infection and inflammation are linked to a hypothesis implicating cytokines, including tumor necrosis factor, which are produced on microbial invasion of the amniotic fluid and can produce adverse effects on the developing brain (124). Research studying the placenta in preterm births suggests connective tissue inflammation of the umbilical cord is associated with cerebral palsy (156).
Advances in neuroimaging using diffusion imaging and diffusion tensor imaging promise to further the understanding of the pathogenesis and pathophysiology of cerebral palsy (242; 120; 176; 118; 245). For example, although cerebral palsy is believed to result from injury or maldevelopment in efferent motor pathways, it may also result from sensory tract dysfunction (23; 113). Hoon and coworkers mapped injured white matter pathways in 2 children with cerebral palsy associated with preterm birth (114). Three-dimensional reconstructions of white matter pathways in these 2 children show that the primary injury was in sensory pathways in the brain. Studies involving altered sensorimotor cortical activity demonstrate spinal cord microstructural changes may represent activity dependent plastic changes (256). Findings support the work of those who believe a component of rehabilitation involves activities such as hippotherapy (therapeutic horseback riding), which may be effective through activation of sensory pathways.
The overall prevalence of cerebral palsy is about 3.6 per 1000 live births (181; 96; 277). Despite dramatic improvements in obstetrical and neonatal intensive care, this figure has remained relatively constant over the last 2 decades. However, a nationwide study in Japan suggests the prevalence of periventricular leukomalacia has decreased significantly (249). There may be a trend in Europe toward decreasing prevalence of cerebral palsy. Data were collated from 20 population-based registers contributing to the Surveillance of Cerebral Palsy in Europe database; the overall prevalence of cerebral palsy decreased from 1.90 to 1.77 per 1000 live births. This was reported to be due to the decline in prevalence of cerebral palsy in children of very low birth weight (VLBW), and it confirmed what was previously reported (238). Rates of early neurodevelopmental impairment in extremely preterm infants have changed little despite significant improvements in overall survival (224). Efforts to provide family-centered medical, developmental, and social support systems can benefit patients and families for a lifetime after extreme preterm birth.
Prematurity is strongly associated with cerebral palsy (250), although 58% of cases are born at term (09). Despite the focus on prevention in industrialized countries including the United States (258), preterm birth has increased in the last decade. Subgroup studies of the 1980s and 1990s show that white women had a greater increase in medically indicated, rather than spontaneous, preterm birth, whereas black women saw increases in both. Both had decreases in preterm deliveries due to ruptured membranes (08).
The improved survival of very low birth weight infants has increased the absolute number of children with cerebral palsy (271). A related factor is the increase in multiple births, where infants are more likely to be of low birth weight and, therefore, at increased risk (89). Although most premature infants do develop normally, concerns have arisen that 1 undesirable effect of improved neonatal care is the increased survival of children with severe neurodevelopmental handicaps, such as cerebral palsy (93; 52). Furthermore, in some preterm children with normal intelligence at school age, a wide variety of more subtle motor and behavioral problems are seen (266).
From 2001 to 2013, NIH funding, averaging $30 million per year, supported clinical ($215 million), basic ($187 million), and translational ($26.3 million) cerebral palsy-related research (276). Clinical intervention studies comprised 19% of funding and focused on treatments ($60.3 million), early parent intervention ($2.7 million), and cerebral palsy prevention ($2.5 million). Among grants that specified gestational age, more funds were devoted to preterm ($166 million) than term infants ($15 million). Cerebral palsy in adulthood was the main focus of 4% of all funding. Annual NIH funding for cerebral palsy increased steadily over the study period from $3.6 to $66.7 million. However, funding for clinical intervention studies peaked in 2008, and it has since decreased (276).
The Danish Cerebral Palsy Follow-up Program is currently under development as a national clinical quality database in Denmark. The database holds potential for research in prevalence, clinical characteristics of the population, and the effects of prevention and treatment (220).
At present, the majority of cases of cerebral palsy are difficult to predict or prevent (172; 144). Individual events such as meconium-stained fluid, early low Apgar scores, delayed onset of respirations, and acidosis in the absence of neurologic abnormalities do not reliably predict cerebral palsy. Despite dramatic improvements in neonatal and obstetric medicine, there has been little change in the incidence of cerebral palsy over the last 2 decades. This suggests that neither sophisticated fetal monitoring, obstetrical interventions, nor increased rate of Caesarean section have had much impact in reducing the incidence of cerebral palsy (40; 235; 200; 50).
A number of identifiable causes of cerebral palsy are currently preventable or treatable. Vaccinations against infectious agents such as rubella and Haemophilus have decreased the incidence of these infectious disorders associated with cerebral palsy (226). Maternal treatment for Group B streptococcal colonization has been effective in decreasing neonatal sepsis and meningitis (24). Rhogam, phototherapy, and exchange transfusion can prevent kernicterus and the development of extrapyramidal cerebral palsy (64). Postnatal risk can be minimized through the prevention of accidental injury. Given the significant contribution of maternal and prenatal infection to the risk of cerebral palsy, this area holds great potential for risk prevention in the future (213; 236). This is supported in the reduction of vertical transmission of HIV by maternal administration of antiretrovirals (42).
Growth restriction may be a significant risk factor for cerebral palsy (28). The risk of cerebral palsy was found to be increased in antenatally growth-restricted singletons born at or near term to normotensive mothers. In growth-restricted singletons, a major birth defect was the dominant predictor, associated with a 30-fold increase in the odds of cerebral palsy. Identification of birth defects in the growth-restricted fetus or neonate may provide significant prognostic information (28).
Maternal thyroid hormone is important for fetal brain development (259). In regions of the world where there is severe endemic iodine deficiency with associated microcephaly, spasticity, and cognitive impairment, maternal supplementation during early pregnancy improved neurologic and cognitive function (41). Maternal thyroid hormone crosses the placenta and may affect fetal brain development by several mechanisms (02; 232).
A report using the Cochrane Pregnancy and Childbirth Group's Trials Register provides evidence for not giving antibiotics routinely to women in preterm labor with intact membranes in the absence of overt signs of infection (76). A large population-based study in Sweden showed of children born extremely preterm and receiving active perinatal care, 73% had mild or no disability, and neurodevelopmental outcome improved with each week of gestational age (239). These results are relevant for clinicians counseling families facing extremely preterm birth.
An exciting area of study is neuroprotection in term infants with hypoxic-ischemic encephalopathy (252; 70). Selective head cooling has been considered a neuroprotective therapy in term neonates with perinatal asphyxia due to its ability to slow the cascade of hypoxic-ischemic injury. Studies have investigated moderate hypothermia as a treatment for perinatal asphyxial encephalopathy. The TOBY Study group demonstrated moderate hypothermia does not reduce rate of death but does improve neurologic outcome, including cerebral palsy in survivors (11). A meta-analysis of 10 trials encompassing 1320 infants showed that in infants with hypoxic ischemic encephalopathy, moderate hypothermia is associated with reduction in death and neurologic impairment at 18 months (67). A National Institutes of Health outcomes study of 190 participants showed the rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors (240). Neonatal therapeutic hypothermia is expanding in many neonatal intensive care units. Overall, studies show that moderate hypothermia within 6 hours of asphyxia improves survival without cerebral palsy or other disability by about 40% and reduces death or neurologic disability by nearly 30% (131). Research is underway to discover adjuvant treatments such as xenon, topiramate, erythropoietin, melatonin, anti-inflammatory agents, growth factors, and molecular and cell-based therapy to enhance the effects of hypothermia (131; 223).
A randomized trial of erythropoietin for neuroprotection in preterm infants demonstrated that high-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age (134).
In high-risk extremely low birth weight infants, stress dose hydrocortisone therapy after 10 days of age had no statistically significant effect on the incidence of death or neurodevelopmental impairment at 18 to 22 months (202). Magnesium given prior to preterm delivery is associated with decreased risk of developing echodensities and echolucencies at less than 32 weeks gestation, which may partially explain the effect of magnesium decreasing the risk of cerebral palsy at 2 years of age (109). Systemic administration of a single dose of dendrimer-N-acetyl cysteine conjugate (D-NAC) at either subacute or delayed time points after injury results in sustained attenuation of the “detrimental” proinflammatory response up to 9 days after injury, while not impacting the “favorable” anti-inflammatory response. The D-NAC therapy also led to improvement in myelination, suggesting reduced white matter injury (182).
Morioka and colleagues demonstrated that periventricular leukomalacia-like brain injury in neonatal rats and human umbilical cord-derived mesenchymal stem cell infusion ameliorated dysmyelination in lipopolysaccharide-induced neonatal rat brain injury (177). Preconditioning of umbilical cord-derived mesenchymal stem cells improved neuroprotective effects.
Reviews have been published showing the emergent prophylactic, reparative, and restorative brain interventions for infants born preterm with cerebral palsy (75).
As the definition at the beginning of this article indicates, a wide range of genetic and acquired disorders are included as cerebral palsy. The primary distinction is from severe neurodegenerative disorders that usually lead to death, including progressive white matter disorders such as adrenoleukodystrophy and metachromatic leukodystrophy, and a wide range of storage disorders including the gangliosidoses and neuronal ceroid lipofuscinosis. Repeated examination is necessary to detect developmental changes that might be consistent with a progressive disorder. Rapidly evolving signs, in particular changes in muscle tone, suggest a neurodegenerative disorder. Patients with some progressive disorders, such as pantothenate kinase-associated neurodegeneration, may progress at such a slow rate initially that they appear to have idiopathic extrapyramidal cerebral palsy. Deterioration that appears to suggest a progressive disorder can also derive from an increase in contractures, anticonvulsant toxicity, and undiagnosed or intractable epilepsy. The differential diagnosis also includes developmental or traumatic lesions of the spinal cord, severe neuromuscular disorder, and neoplasm.
In the intellectual disability syndromes, primitive reflexes are usually appropriate, but the motor development and the appearance of postural reflexes may be delayed. Practically all children with severe intellectual handicap have some motor disorder that expresses itself in a pattern inappropriate to their chronological age. Cerebral palsy is present when, in addition to the intellectual impairment, a motor disorder as described above is seen.
As in other areas of medicine, the diagnostic workup of children with motor delay may require the input of a number of medical specialists as well as that of physical and occupational therapists. Those responsible for coordinating the evaluation should be experienced with the medical and rehabilitative needs of children with cerebral palsy. They should also be aware of the feelings of guilt and apprehension present in families. A marked delay in age at initial referral of children with cerebral palsy to medical and rehabilitation specialists was found by Boychuck and colleagues (31). A minority of referrals came from primary-care providers, which is of concern given their vital role in early detection of developmental disabilities. More than half of children with cerebral palsy do not have a complicated birth history, and referrals for diagnosis and management for these children were postponed, often beyond 3 years (31).
A careful history should include details of the prenatal, perinatal, and postnatal course. Maternal perception of decreased fetal movement is an important sign of prenatal onset. Early identification of cerebral palsy using neonatal MRI and the General Movements Assessment has been studied in a cohort of high-risk term neonates. Normal neonatal MRI and General Movements Assessment at the age of 3 months are reassuring that a high-risk term-born child is at low risk for moderate to severe cerebral palsy (84). Family history is important to identify potential genetic disorders. The systems review should include questions about vision, hearing, snoring, feeding, bowel, and bladder function, as well as any cardiac and pulmonary problems. The neurologic examination should be comprehensive, including careful observation for adventitious movements, including chorea, athetosis, hemiballismus, and dystonia. The functional assessment for children with cerebral palsy is best done in conjunction with skilled physical and occupational therapists. Children can be classified both by the extent of necessary mobility aids (from point canes to wheel chairs) as well as by their ability to ambulate independently in various settings.
There are limited data on cognition in childhood dystonia. Coenen and colleagues showed that primary dystonia showed intact cognition and IQ, but mild working memory and processing speed deficits (51). Secondary dystonia showed more pronounced deficits and lower IQ, with frequent intellectual disability. In combination with a thorough history and examination, neuroimaging techniques, including brain MRI, may provide benefit in recognition of etiologic disorders, management, prognosis, and assessment of recurrence risk (152). This is important because there are a number of treatable inborn errors of metabolism that mimic cerebral palsy (150). Neuroimaging techniques may uncover an underlying pathogenesis for many of the causes of cerebral palsy, including cerebral lesions, asphyxia, and genetic and metabolic disorders (191; 128; 118; 114). Imaging techniques should be selected based on the advantages and disadvantages of each technique as well as the sedation requirements for patients. MRI in particular has proved the greatest use in children with cerebral palsy as it can differentiate white and grey matter more clearly than CT scans (111). Seventy percent to 90% of affected individuals will have abnormalities on MRI (14; 115). Cranial ultrasound remains the most common technique for preterm neonates. Thirty-one articles met the inclusion criteria, 5 of which reported diagnostic accuracy and 5 reported data sufficient for calculation of diagnostic accuracy. Early structural MRI global scores detected a later diagnosis of cerebral palsy with a pooled sensitivity of 100% (95% confidence interval [CI] 86-100) and a specificity of 93% (95% CI 59-100). Global structural MRI scores determined adverse motor outcomes with a pooled sensitivity of 89% (95% CI 44-100) and a specificity of 98% (95% CI 90-100). White matter scores determined adverse motor outcomes with a pooled sensitivity of 33% (95% CI 20-48) and a specificity of 83% (95% CI 78-88).
Diffusion tensor imaging, which demonstrates preferential water diffusion along axonal tracts, is an area of great promise for identifying abnormalities of white-matter pathways, such as periventricular leukomalacia (111). Developmental abnormalities are being measured quantitatively using anatomic MRI and diffusion tensor imaging during multiple stages of brain development (195).
MRI findings can determine the need for additional testing (228). For example, in a child with extrapyramidal cerebral palsy and imaging abnormalities in the globus pallidus, a comprehensive evaluation for genetic-metabolic disorders should be conducted. In those with developmental brain malformations including neuronal migration disorders such as lissencephaly and schizencephaly, specific molecular testing may be important to identify an etiology and determine recurrence risk (85). If evidence is found in a clinical examination to suggest a genetic etiology, a karyotype as well as specific molecular probes should be obtained. In addition to brain MRI, the etiologic evaluation of extrapyramidal patients should include urine organic acids, plasma amino acids, lactate, and chromosomes. Evaluation of CSF biopterin, neurotransmitter, and amino acid metabolism is often indicated, especially in patients with idiopathic extrapyramidal cerebral palsy with normal MR scans. Careful follow-up is important because categories of disease continue to be established, such as the cholesterol synthesis abnormalities in Smith-Lemli-Opitz (197) and carbohydrate deficient glycoprotein disorders (91). Magnetic resonance spectroscopy assessment of the brain after moderate hypothermia in neonatal hypoxic ischemic encephalopathy is being studied by the MARBLE consortium (147).
Neurophysiologic studies show that motor performance errors of children with cerebral palsy are linked with neural synchronization within the somatosensory cortices (146).
In general, all children with cerebral palsy should receive an ophthalmological evaluation, both to detect ocular abnormalities suggestive of specific disorders and to treat the refractive errors frequently present.
Genetic studies have been a topic of interest to predict cerebral palsy and severity of disease. There is an expanding role for genetics in cerebral palsy (72). According to a large study of patients, the molecular diagnostic yield of exome sequencing in identifying a pathologic variant in patients with cerebral palsy is 32.7% in pediatric patients and 10.5% in adult patients (175). A study shows vasoactive intestinal polypeptide and GRIN3A SNPs may be associated with cerebral palsy at 2 years of age in children born preterm (55). Another study showed two IL18 loci SNPs (rs549908:A> C and rs1290349:C> A) had a protective effect against spastic cerebral palsy, and interestingly, both were associated to a decreased epidemiological expression of IL18 protein (110). These preliminary new data combining protein to genetic information also suggest IL18's involvement in the pathogenesis of spastic cerebral palsy. Pathogenic copy number variants may also impact the genomic burden in cerebral palsy (54).
Early markers of clinical phenotype and functional outcome have been studied (71). Aberrant general movements at 10 to 15 weeks' postterm are associated with adverse neurodevelopmental outcomes and specific white matter microstructure abnormalities for cognitive, language, and motor delays (211).
A multidisciplinary team approach is required to care for people with neurodevelopmental disorders such as cerebral palsy (255). Effective management of cerebral palsy requires a team with medical and rehabilitative specialists to provide careful, ongoing neurodiagnostic evaluation and rehabilitation to maximize functional capabilities. Coordination of the medical team with additional community support services is necessary to ensure that affected individuals receive full opportunities to learn in school and participate in society.
Management should aim to achieve maximal potential in all areas of development and to encourage independence. An understanding of where patient function is categorized on a spectrum of severity may be helpful when developing treatment plans. Early identification and intervention for neurodevelopmental disorders have age-dependent challenges and advantages (58; 94). Realistic, functional goals must be set and periodically re-evaluated by the rehabilitative team. Treatment plans should include the principal caregivers and teachers. A number of rehabilitative motor interventions exist for individuals with cerebral palsy. Rehabilitative goals will vary by patient depending on the clinical situation, including ease of care, prevention of orthopedic deformity, or facilitating function.
A range of oral pharmacological agents are also used to treat spasticity; these include diazepam, baclofen, dantrolene, and tizanidine (214; 36). Benzodiazepines, such as diazepam, reliably produce tone reduction safely but may produce drooling and sedation. Although no controlled studies exist comparing diazepam and baclofen, the lack of cognitive side effects with baclofen have led to preferential use over diazepam. Patients should be cautioned that abrupt discontinuation of baclofen use can precipitate hallucinations and seizures and that it may precipitate seizures in young children (102).
In 2009, the American Academy of Neurology published practice parameters for the pharmacologic treatment of spasticity in children and adolescents with cerebral palsy. Recommendations support the use of botulinum toxin A for treatment of localized or segmental spasticity that warrants treatment (21). The simultaneous use of BoNT-A and strength training is successful in spasticity reduction, improving strength and achieving functional goals, over and above treatment with BoNT-A alone (269). Neurophysiologic tests to evaluate reduced spasticity after botulinum toxin-A injection are being investigated; tendon reflex amplitude showed the highest correlation with severity of spasticity (125). For generalized spasticity, diazepam and tizanidine should be considered for short-term treatment. There are insufficient data to support or refute the use of phenol, alcohol, botulinum toxin B, dantrolene, oral baclofen, or continuous intrathecal baclofen (218).
For patients with extrapyramidal cerebral palsy, pharmacologic agents modulating dopamine action in the striatum have proved effective. For those with chorea, drugs to deplete dopamine have been used, including reserpine and tetrabenazine (126). Benzodiazepines, including clonazepam, which potentiate GABAergic action, may also be of benefit (207). For patients with dystonia, athetosis, or bradykinesia, drugs to increase dopamine flux have been used, including trihexyphenidyl, levodopa, and carbidopa (112). Gabapentin may significantly ameliorate dystonia severity and improve activities of daily living and quality of life in children with severe dystonia (159).
Surgical procedures are common for the progressive orthopedic deformities that arise in spastic patients. Surgeon-caregiver agreement is greater where literature support for a particular surgical indication is strong (ie, spinal fusion's known improvement of sitting posture in children with neuromuscular scoliosis). Stronger literature support may bolster surgeons' confidence in recommending a particular procedure, fostering greater communication, understanding, and agreement on surgical necessity between caregivers and surgeons (01). These operations have advanced from solo, sequential procedures to simultaneous, collective procedures including both soft tissue and bone work (73). Soft tissue procedures allow for muscle lengthening. Bone procedures are typically localized to the leg, hip, and spine. Videotaped gait analysis can be used to focus surgical intervention and to measure postoperative success (29). It is unclear at this time whether pharmacological interventions will lessen the need for orthopedic surgery in the future. Scoliosis is a common comorbidity in children with cerebral palsy. A multinational study identified truncal tone disorders, intractable epilepsy, and female gender as predictors of scoliosis in subjects with cerebral palsy (25). These data support increased frequency of spine and spine x-ray examinations in this population to identify candidates for treatment.
For children with severe cerebral palsy, refractory to standard interventions, neurosurgical procedures including intrathecal baclofen, selective dorsal rhizotomy, and deep brain stimulation should be considered (05). A prospective study confirms the benefit of single event multi-level surgery, showing clinically and statistically significant improvements in gait and function in children with bilateral spastic cerebral palsy, which were maintained at 5 years after surgery (253).
Intrathecal baclofen is an efficacious therapy for the treatment of hypertonicity. Intrathecal baclofen has been employed for patients with more severe degrees of spasticity of cerebral as well as spinal origin (206; 04). Drug dosages are delivered by a programmable pump placed in the abdomen and connected to a catheter that ends in the intrathecal space. Studies have indicated that intrathecal baclofen effectively reduces spasticity (83) and improves function (149; 244). The drug has also been reported to be of benefit in dystonic cerebral palsy (06). However, the determination of suitable candidates is ongoing (38). Complications of intrathecal therapy can include catheter kinking and infection, which can require replacement of either the catheter or pump. Dose-related side effects include confusion and lethargy. The presence of an intrathecal baclofen pump for spasticity appears to be associated with the increase in scoliosis progression, and these patients will likely have a more challenging spine fusion (158). Fortunately, the final outcome is not affected by intrathecal baclofen pump.
Interest has arisen in stereotactic neurosurgical procedures similar to those performed for Parkinson disease patients (62). Depending on the clinical setting, both ablative and neural stimulation procedures may be used. In carefully selected patients, the severity of dystonia and hemiballismus may be decreased. However, hardware complications are significant (194). Deep brain stimulation has been considered in patients with cerebral palsy and is being used on selective subgroups (137). The outcome is encouraging in the majority of dystonic cerebral palsy patients, with a stable outlook and a good safety profile (225). Further studies are required to elucidate the risk versus benefit in such neuroinvasive therapies.
Dorsal rhizotomy (transaction of selected sensory nerves entering the lower spinal cord) decreases spasticity in associated muscles but can have unwanted side effects on bowel and bladder function. The treatment should be performed in conjunction with physiotherapy and is only recommended for persons with severe lower extremity spasticity for whom other treatments have been unsuccessful (86). The ideal candidates are believed to be young children who were born prematurely and have good antigravity strength. Both medical and orthopedic surgical techniques can target symptoms at the musculoskeletal level, with goals of relaxing muscles and realigning the skeleton. One study confirms that the benefits of selective dorsal rhizotomy are long-lasting and positively alter the natural history of spastic cerebral palsy (66). Botulinum toxin can be injected into the neuromuscular junction of either dystonic or spastic muscles and has been effectively used on patients with localized spasticity to improve their gross and fine motor abilities (273; 141). Botox will relax muscles for a period of 4 to 6 months. Results improve if treatment is paired with splinting and physiotherapy. Children with greater motor involvement, as indexed by GMFCS level, may be at risk for increased pain (intensity, frequency, and duration) that interferes with activities of daily living (16).
Nanomedicine offers the opportunity to deliver agents that would promote repair and regeneration in the brain, resulting not only in attenuation of injury, but also enabling normal growth. Advances in nanotechnology for treatment of brain injury that results in cerebral palsy are being investigated to facilitate clinical translation in neonates and children (12). Other novel therapies such as stem cells have been studied for many years (204).
Physical, occupational, and speech therapies are employed as initial therapies or used in conjunction with medical and surgical treatments, focusing on improving the strength and motion of affected muscles. Language impairment is common in children with cerebral palsy, affecting 3 out of 5 children (170). These findings suggest most children would benefit from a clinical language assessment. Studies that evaluate dosing parameters of physical therapy for patients with cerebral palsy are a priority (82). Occupational and physical therapy play a fundamental role in children (18). Techniques serve to lessen the effects of inhibitory reflexes, facilitate the acquisition of gross and fine motor skills, and to encourage language and the promotion of confidence and self-esteem. Sophisticated technological aids may play an important role; these include motorized wheelchairs, voice-activated computers, and various switching devices that can be used to activate communication systems. Mobility aids should work in conjunction with physical therapy to progress toward maximum patient independence. Constraint-induced movement therapy (CIMT) has received attention as a therapeutic intervention for patients with stroke or hemiplegic cerebral palsy. Several randomized clinical trials have evaluated the impact of dosing frequency and intensity in children with cerebral palsy (32; 87; 231; 219). Constraint-induced movement therapy (CIMT) and repetitive transcranial magnetic stimulation (rTMS) are emerging as effective interventions in improving motor function in hemiplegic cerebral palsy (21; 121). Pediatric CIMT at both moderate and high dosages produce positive effects across multiple reliable, valid outcome measures (61). For school-aged children with unilateral cerebral palsy, a half dose (30 h) of either modified CIMT or bimanual therapy may not be sufficient to impact upper limb outcomes, but patients will have clinically meaningful gains in occupational performance (230). The Gross Motor Function Measure-88 can be reliably scored using video recordings (79). Robotic-assisted gait training (RAGT), using a device such as the Lokomat®Pro, may permit longer training duration and faster and more variable gait speeds as well as support walking pattern guidance more than overground/treadmill training to further capitalize on motor learning principles (108). Hilderley and colleagues reported the first randomized controlled trial comparing RAGT to an active gait-related physical therapy intervention in pediatric cerebral palsy that addresses gait-related gross motor, participation, and individualized outcomes (108). As such, the study is expected to provide comprehensive information as to the potential role of RAGT in clinical practice.
Treadmill training may improve the walking speed and gross motor function of adolescents with spastic cerebral palsy, without adverse effects on spasticity (48). A review of the utility of functional electrical stimulation in cerebral palsy shows promise for treatment benefit (275). Game systems such as the Nintendo Wii have shown potential for use as a rehabilitation tool in the management of children with cerebral palsy (88; 37). Clinical trials are being considered for these entertainment-related therapies. Cognitive studies suggest that the consequence of error making on future performance is intact youth with mild spastic cerebral palsy, but the study group was small, and replication is required (99). Novel mobility training methods are also showing promise for altering the motor disability trajectory in children with cerebral palsy (217). Electric stimulation has been studied as a potential treatment for reducing aspiration in cerebral palsy (162; 165). Interest in the outcomes of children with unilateral cerebral palsy has prompted a study by Klingels and colleagues (139). Over 5 years, children with unilateral cerebral palsy develop more limitations in premature rupture of membranes, and although capacity measures improve, the spontaneous use of the impaired limb in bimanual tasks becomes less effective after the age of 9 years.
Some patients and their families choose to supplement care with complementary therapies, and physicians should be aware of those that exist. Alternative medicine strategies for cerebral palsy include hyperbaric oxygen, the Adeli suit program, aquatherapy, hippotherapy, chiropractic, massage, and acupuncture sessions, conductive education, patterning, and prayer and music therapy. Uncontrolled and controlled trials of hippotherapy have shown beneficial effects on body structures and functioning. Studies of acupuncture are promising, but insufficient data exist to make specific recommendations. Most studies of patterning have been negative. Insufficient data exist to make specific recommendations on hyperbaric oxygen. There is growing interest in acupuncture intervention for cerebral palsy. One study from China shows that acupuncture with sitting training is better than sitting training intervention alone in improving cerebral palsy children with parafunctional sitting position, especially for the spastic and hypotonic cerebral palsy patients (278). In summary, limited literature exists on the effectiveness and safety of complementary and alternative medicine in pediatric populations, so physicians should use their best judgment in integrating medical treatments with alternative therapies (33; 160). More research based on high-quality studies focusing on functioning in all dimensions of the International Classification of Functioning, Disability, and Health perspective is necessary to clarify the impact of suit therapy (169). Auditory stimulation has been studied to improve motor function and caregiver burden (22).
Additional complications that may require management include feeding difficulties and psychosocial development. Feeding difficulties pose an additional complication for many children with cerebral palsy, particularly those with significant intellectual impairment. Coping with these difficulties can become a time-intensive part of patient management. A gastrostomy, usually in addition to a fundoplication, is often recommended. As a reliable route to the stomach, a g-tube can allow for improved nutrition, weight gain, reduced aspiration, and a safer route for medication. Focusing attention on improving nutrition early in the lives of children with cerebral palsy affords families and care providers with a unique opportunity for intervention that may result in better outcomes for the children (221). One study suggests that oculomotor function spontaneously improves in children with cerebral palsy (69).
Chronic pain in children with cerebral palsy is not commonly identified and may lead to detriments in physical, social, and mental well-being. A consensus among inter-professional working group members from Canada published 7 important chronic pain interference tools in the American Academy of Pediatrics. Not all tools have been validated with children with cerebral palsy nor is there 1 tool to meet the needs of all children experiencing chronic pain (138). Studies on chronic pain in children with cerebral palsy identify a need for nonpharmacologic interventions in addition to more studies on pharmacologic interventions (155).
Early social and psychological services are vital for both the parents and child. Psychosocial and environmental factors in school certainly impact the well-being of the family and individual with cerebral palsy (163). Physicians should discuss the diagnosis with parents honestly and sensitively, recognizing that parents must deal with large amounts of information and difficult or uncertain prognoses; they should be prepared to answer the child’s questions appropriately. With the increased responsibility of a handicapped child, parents themselves can become socially limited, putting stress on marital relationships and the nurturing of other children. Studies have shown mothers, in particular, feel the difficult implications of caregiver burden, family and social support, changing women's roles, and socioeconomic challenges that arise with caring for a child with cerebral palsy (100). Parents can express dissatisfaction and even resentment toward the physician, reacting with sorrow, as well as denial, guilt, frustration, anger, resentment, and embarrassment. It is important to try to alleviate any guilt that may be felt with regard to causation. Counseling is a continuous process, and ready availability of experienced professionals is important.
As the affected child grows older, prevocational assessment and training based on ongoing discussions becomes more important (45). Psychological development, communication, and education become the main priorities (172). Lifestyle management should provide a rational basis for communication and for daily living activities so that the affected individual can gain the maximal benefit from formal education. It is important for families to promote confidence and self-esteem in their children with therapeutic activities such as aquatherapy and horseback riding. Educational opportunities are available until the age of 21 years under the provisions of the Individuals with Disabilities Education Act, but services are less organized in adulthood. Despite the American with Disabilities Act, employment barriers continue to exist. Physicians and other health care providers who include adolescents with cerebral palsy in their practices should begin discussion and planning for transition to adult health care early in adolescence (26).
Chronic conditions occur more frequently in adults with cerebral palsy than without cerebral palsy and include hypertension, diabetes, stroke, joint pain, and respiratory diseases and heart diseases (209). The prevalence of sleep problems in children with cerebral palsy is high (117).
Medical doctor training in management of cerebral palsy is important; however, a significant proportion of child neurology and neurodevelopmental disabilities training programs felt that residents were not very well prepared to manage cerebral palsy. The development of cerebral palsy curricula and exposure to cerebral palsy clinics may improve training, translating to better care of individuals with cerebral palsy (270).
Participation of adolescents with cerebral palsy is predicted by early modifiable factors related to the child and family (60). Interventions for reduction of pain, psychological difficulties, and parenting stress in childhood are justified not only for their intrinsic value, but also for probable benefits to childhood and adolescent participation. Postmortem diagnostic overshadowing, which is defined as inaccurately reporting a disability as the underlying cause of death, occurs for over half of adults with cerebral palsy. Inaccurate reporting is associated with heightened contexts of clinical uncertainty, the false equivalence of disability and health, and potential racial-ethnic bias (148).
Little published data are known regarding pregnancy in women with cerebral palsy. (272; 257). Helpful resources addressing the health and reproductive possibilities for women with cerebral palsy include: (105; 143). It remains unknown whether assistive reproductive therapy increases the risk of cerebral palsy (119).
Special consideration should be used for anesthetizing patients with cerebral palsy in both surgical and neuroimaging situations. Anesthesiologists should be aware of particular perioperative problems including seizure control, respiratory function, and gastroesophageal reflux. Postoperative care should carefully address pain management and the prevention of muscle spasms (190). Anesthesia for dental care may also be required (07).
In neuroimaging studies, sufficient sedation is important for avoiding excess artifact. At Johns Hopkins Hospital, chloral hydrate is usually employed for infants and young children, intravenous sodium pentobarbital for older children, and general anesthesia for those who cannot remain still independently or for whom other types of sedation fail. Children with brain malformations and genetic and genetic-metabolic disorders like cerebral palsy may have atypical reactions to sedation and require longer periods of observation following a study (111).
Ryan W Y Lee MD
Dr. Lee of the John A Burns School of Medicine at the University of Hawaii has no relevant financial relationships to disclose.See Profile
Ann Tilton MD
Dr. Tilton has received honorariums from Allergan and Ipsen as an educator, advisor, and consultant.See Profile
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