REVIEWS Rehabilitation and neuroplasticity in children with unilateral cerebral palsy Lee B. Reid, Stephen E. Rose and Roslyn N. Boyd Abstract | Cerebral palsy is a childhood-onset, lifelong neurological disorder that primarily impairs motor function. Unilateral cerebral palsy (UCP), which impairs use of one hand and perturbs bimanual co-ordination, is the most common form of the condition. The main contemporary upper limb rehabilitation strategies for UCP are constraint-induced movement therapy and bimanual intensive therapy. In this Review, we outline the factors that are crucial to the success of motor rehabilitation in children with UCP, including the dose of training, the relevance of training to daily life, the suitability of training to the age and goals of the child, and the ability of the child to maintain close attention to the tasks. Emerging evidence suggests that the first 2 years of life are a critical period during which interventions for UCP could be more effective than in later life. Abnormal brain organization in UCP, and the effects of development on rehabilitation, must also be understood to develop new effective interventions. Therefore, we also consider neuroimaging methods that can provide insight into the neurobiology of UCP and how the condition responds to existing therapies. We discuss how these methods could shape future rehabilitative strategies based on the neurobiology of UCP and the therapy-induced changes seen in the brain. Reid, L. B. et al. Nat. Rev. Neurol. advance online publication 16 June 2015; doi.10.1038/nrneurol.2015.97
Introduction
The Australian e‑Health Research Centre, Level 5 UQ Health Sciences Building 901/16, Royal Brisbane and Women’s Hospital, Herston, QLD 4029, Australia (L.B.R., S.E.R.). Queensland Cerebral Palsy and Rehabilitation Research Centre, School of Medicine, The University of Queensland, Level 6, Children’s Health Research Centre, Lady Cilento Children’s Hospital, South Brisbane, QLD 4101, Australia (R.N.B.).
Cerebral palsy encompasses a heterogeneous group of neurodevelopmental conditions that primarily present as disorders of movement and posture, often accompanied by epilepsy, secondary musculoskeletal problems, and impaired sensation and cognition.1 Symptom onset occurs during early childhood, typically before 18 months of age;1 on average, diagnosis is confirmed at 13–19 months.2–4 The most common form of the condition is unilateral cerebral palsy (UCP), which impairs the use of one hand and consequently disrupts bimanual co-ordination. Cerebral palsy, by definition, results from abnormal brain development and/or brain damage that is nonprogressive and occurs during very early development. In most cases, the cause is periventricular white matter damage that is presumed to occur during the third trimester of pregnancy, but other abnormalities, such as diffuse grey matter injury, focal infarcts, lesions of the basal ganglia, and/or cerebral malformations, can underlie the condition.5–7 Early brain injury that can underlie cerebral palsy can lead to atypical brain development and reorganization, particularly during the first 2 years of life,8 which can complicate the understanding of the condition and the selection of appropriate rehabilitation. The current definition of cerebral palsy includes the word ‘permanent’, but notes that “initial disruption to normal brain structure and function … may be associated with changing or additional manifestations over time.”1 In children with UCP, the type and extent of
Correspondence to: R.N.B. [email protected]
Competing interests The authors declare no competing interests.
impairment is primarily determined by the location and size of the brain lesion. 9 The ability of patients to gain functionality with therapy might be influenced by comorbidities, such as impaired vision and concentration, learning difficulties, and epilepsy.10 We commence this Review by summarizing current evidence for the efficacy of existing rehabilitative therapies for children with UCP, and by discussing factors that can increase effectiveness, such as the mode, dose, context, relevance and timing of intervention, as well as the child’s motivation. We then discuss how future therapies for children with UCP could be informed by research into neuroplasticity in patients with the condition. We present imaging technologies that should be used in future studies to examine neuroplasticity, and the current knowledge that could direct future research that will ultimately shape the future of r ehabilitation for children with this lifelong condition. The appropriate rehabilitation for children with cere bral palsy depends on the motor subtype, the type and extent of brain damage or abnormalities, and other factors, such as age and cognitive ability. Current knowledge is largely limited to children with UCP, so we will concentrate on rehabilitation that targets the principal symptoms of this condition, that is, sensori motor deficits. The main focus of our discussion is upper limb rehabilitation.
Existing rehabilitative strategies
Rehabilitation for children with UCP should be evidence- based, activity-based (that is, the child performs the
NATURE REVIEWS | NEUROLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Activity-based therapy is the main clinical rehabilitation strategy for children with unilateral cerebral palsy (UCP) ■■ Therapies can be considered to be effective if they bring about improvements that transfer to daily activities and help children to meet their individual needs and goals ■■ Current research suggests that motor impairments in children with UCP result from damage to the corticospinal tract, as well as from impairments of sensorimotor pathways and motor planning ■■ A variety of tools and imaging modalities will enable the measurement of neuroplasticity in future clinical trials ■■ Future therapies for UCP are likely to be multimodal, and to be derived from research into the neurobiology of the condition
Box 1 | Contemporary rehabilitative therapies for unilateral cerebral palsy Constraint-induced movement therapy (CIMT) and bimanual intensive therapy (BIM) are two upper limb motor rehabilitative schemes that are being increasingly used in children with unilateral cerebral palsy (UCP). CIMT was originally designed to address ‘learned disuse’ of the impaired hand after stroke in adults, but has since been adapted to aid the development of motor skill in the impaired hand of children with UCP.26 A child-friendly protocol, called modified CIMT, involves constraint of the more functional upper limb for several hours per day over several days. During this period, the impaired arm is trained in an intensive and repetitive manner in activity-based practice. 27 Patients undergoing BIM intensively practice bimanual tasks that become progressively more difficult. This therapy is based on the premise that coordination of both hands is important for the improvement of performance in everyday tasks, as these tasks are predominantly bimanual in nature. BIM focuses on tasks that require use of both hands; the unimpaired hand acts as a template for learning motor control of the impaired hand.101,102 Robot-assisted therapy is an emerging modality for rehabilitation that uses robotics to aid and/or objectively record movement of limbs during repetitive exercises. Robot-assisted therapies can allow participants with moderate impairment to experience a wider range of motion (and, thus, sensory feedback) than other therapies, and can be linked to virtual reality environments that provide haptic feedback. The technique is in the very early experimental phase and is primarily used in adults after stroke; its potential for therapy in UCP is currently unclear.103
activity themselves), relevant to the environment and the child’s motivation, and goal-directed. The therapy should be delivered by the parents as a series of challenging but achievable activities, conducted in the appropriate environment and context, and designed to include specific learning goals for the child. The two most extensively investigated contemporary approaches to upper limb therapy in children with UCP are modified constraint-induced movement therapy (mCIMT) and bimanual intensive therapy (BIM; Box 1). Hybrid CIMT, in which the child trains with mCIMT before BIM, is another approach.11,12 mCIMT and BIM are increasingly being delivered to individuals and groups in real-life situations so as to provide context to motor skill learning.12 However, such therapy requires expertise, can be costly, and is not always accessible. For these reasons, the usual upper limb therapy for children with UCP includes occupational therapy together with adjunctive treatments— such as medications to reduce spasticity—that target secondary symptoms. Although occupational therapy can include mCIMT or BIM, the time devoted to these
therapies in these contexts is typically a lot less than the time allotted to them in clinical trials. In response to this multifactorial challenge, alternative modes of delivery, such as web-based training and virtual reality platforms, have been developed. Early studies of web-based multimodal training have shown that these approaches can improve motor and planning skills in children with UCP.13–15 In addition, robot-assisted virtual reality therapy (Box 1) has been tested in pilot trials16–18 and larger studies,19,20 which have provided preliminary evidence that highlights the potential of such therapy for rehabilitation in children with UCP. The efficacy of the current activity-based therapies, as determined by large systematic reviews and meta-analyses, can be used to gauge the optimal dose, environmental context and intensity of upper limb intervention for children with UCP.12,21 A meta-analysis of 42 randomized controlled trials assessed the efficacy of 14 approaches to upper limb therapy, and found moderate to strong evidence to support the use of intensive activity-b ased, goal-directed interventions (such as mCIMT and BIM) rather than usual care to improve the quality and efficiency of upper limb movement and to achieve individual goals.12 The conclusions drawn in this systematic review, in combination with knowledge of the factors that impede or enable implementation of therapy, have led to the current consensus on the essential elements of effective upper limb therapy. These elements are intensive structured task repetition, progressive incremental increases in difficulty, and goal-directed approaches that enhance the motivation and engagement of individuals receiving therapy.22 Current activity-based therapies are thought to provide both specific (unimanual or bimanual) and global (occupational performance) improvements in motor function. For example, when mCIMT and BIM, delivered in blocks of 60 h over 10 days, were compared in the randomized INCITE trial (n = 64),21 mCIMT was more effective at increasing the use of the impaired limb, whereas intensive BIM was more effective at improving bimanual co-ordination. This observation confirms that these training techniques have specific effects. Motor-evoked potential recruitment curves, which were measured by transcranial magnetic stimulation (TMS), were also changed more substantially by intensive group-based mCIMT than by BIM (R. N. Boyd et al., unpublished work). Delivery of intensive group-based therapy can, however, be costly, and many therapists have identified barriers to implementation.22 Another randomized trial made a direct comparison between intensive group-based hybrid CIMT over 2 weeks and a comparable amount of individual therapy distributed over 12 weeks.11,23 Improvements in bimanual co-ordination (evaluated with the Assisting Hand Assessment) and occupational performance (assessed with the Canadian Occupational Performance Measure) were similar between the two groups. These results show that with a constant total dose of activity-based therapy, similar results can be achieved despite vari ations in child:therapist ratios (1:2 or 1:1) and the way
2 | ADVANCE ONLINE PUBLICATION
www.nature.com/nrneurol © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS in which therapy is delivered (groups or individuals).23 The similar outcomes attained with the use of intensive group-based and individual therapy mean that therapists can choose to deliver upper limb therapy in the way that is best suited to family circumstances and characteristics of the child. In this trial, the willingness of children to independently persevere, solve problems, master challenging tasks, and use their impaired hand for bilateral activities contributed to occupational performance outcomes.24 Family ecology and the therapeutic context were also identified as critical factors that influenced the children’s mastery motivation and engagement in therapy.25 The long-term retention of functionality gained from upper limb therapies is not frequently assessed, but some evidence suggests that gains in functionality can last for at least 6–12 months after therapy in children with UCP.26–28 The majority of research into the effectiveness of rehabi litation and the mechanisms that underlie responses to therapy has been conducted with schoolaged children with UCP, but major brain growth and development occurs in the first 2 years of life. This period could represent a critical window during which rehabilitation might be most effective, but which is missed by modern rehabilitative approaches.29 Empirical evidence for the effectiveness of currently used therapies in infants with UCP is limited, but animal studies have provided evidence for a critical period.30–32 For example, in kittens, inactivation of the primary motor cortex in one hemisphere during postnatal weeks 5–7 results in seemingly permanent impairment of contra lateral motor skill, and a variety of abnormalities in neural organization.32 Motor training and limb restriction similar to CIMT can reverse these motor deficits when carried out during early development (8–13 weeks of age), but is much less effective when carried out at 20–24 weeks of age.32 Such critical periods of development might primarily reflect time windows during which abnormal neural organization can be prevented, rather than periods during which the brain is simply more able to repair existing damage.33 One pilot study (n = 5) of lower limb rehabilitation has indicated that intense rehabilitation is feasible and effective in children with UCP aged
Introduction
The Australian e‑Health Research Centre, Level 5 UQ Health Sciences Building 901/16, Royal Brisbane and Women’s Hospital, Herston, QLD 4029, Australia (L.B.R., S.E.R.). Queensland Cerebral Palsy and Rehabilitation Research Centre, School of Medicine, The University of Queensland, Level 6, Children’s Health Research Centre, Lady Cilento Children’s Hospital, South Brisbane, QLD 4101, Australia (R.N.B.).
Cerebral palsy encompasses a heterogeneous group of neurodevelopmental conditions that primarily present as disorders of movement and posture, often accompanied by epilepsy, secondary musculoskeletal problems, and impaired sensation and cognition.1 Symptom onset occurs during early childhood, typically before 18 months of age;1 on average, diagnosis is confirmed at 13–19 months.2–4 The most common form of the condition is unilateral cerebral palsy (UCP), which impairs the use of one hand and consequently disrupts bimanual co-ordination. Cerebral palsy, by definition, results from abnormal brain development and/or brain damage that is nonprogressive and occurs during very early development. In most cases, the cause is periventricular white matter damage that is presumed to occur during the third trimester of pregnancy, but other abnormalities, such as diffuse grey matter injury, focal infarcts, lesions of the basal ganglia, and/or cerebral malformations, can underlie the condition.5–7 Early brain injury that can underlie cerebral palsy can lead to atypical brain development and reorganization, particularly during the first 2 years of life,8 which can complicate the understanding of the condition and the selection of appropriate rehabilitation. The current definition of cerebral palsy includes the word ‘permanent’, but notes that “initial disruption to normal brain structure and function … may be associated with changing or additional manifestations over time.”1 In children with UCP, the type and extent of
Correspondence to: R.N.B. [email protected]
Competing interests The authors declare no competing interests.
impairment is primarily determined by the location and size of the brain lesion. 9 The ability of patients to gain functionality with therapy might be influenced by comorbidities, such as impaired vision and concentration, learning difficulties, and epilepsy.10 We commence this Review by summarizing current evidence for the efficacy of existing rehabilitative therapies for children with UCP, and by discussing factors that can increase effectiveness, such as the mode, dose, context, relevance and timing of intervention, as well as the child’s motivation. We then discuss how future therapies for children with UCP could be informed by research into neuroplasticity in patients with the condition. We present imaging technologies that should be used in future studies to examine neuroplasticity, and the current knowledge that could direct future research that will ultimately shape the future of r ehabilitation for children with this lifelong condition. The appropriate rehabilitation for children with cere bral palsy depends on the motor subtype, the type and extent of brain damage or abnormalities, and other factors, such as age and cognitive ability. Current knowledge is largely limited to children with UCP, so we will concentrate on rehabilitation that targets the principal symptoms of this condition, that is, sensori motor deficits. The main focus of our discussion is upper limb rehabilitation.
Existing rehabilitative strategies
Rehabilitation for children with UCP should be evidence- based, activity-based (that is, the child performs the
NATURE REVIEWS | NEUROLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Activity-based therapy is the main clinical rehabilitation strategy for children with unilateral cerebral palsy (UCP) ■■ Therapies can be considered to be effective if they bring about improvements that transfer to daily activities and help children to meet their individual needs and goals ■■ Current research suggests that motor impairments in children with UCP result from damage to the corticospinal tract, as well as from impairments of sensorimotor pathways and motor planning ■■ A variety of tools and imaging modalities will enable the measurement of neuroplasticity in future clinical trials ■■ Future therapies for UCP are likely to be multimodal, and to be derived from research into the neurobiology of the condition
Box 1 | Contemporary rehabilitative therapies for unilateral cerebral palsy Constraint-induced movement therapy (CIMT) and bimanual intensive therapy (BIM) are two upper limb motor rehabilitative schemes that are being increasingly used in children with unilateral cerebral palsy (UCP). CIMT was originally designed to address ‘learned disuse’ of the impaired hand after stroke in adults, but has since been adapted to aid the development of motor skill in the impaired hand of children with UCP.26 A child-friendly protocol, called modified CIMT, involves constraint of the more functional upper limb for several hours per day over several days. During this period, the impaired arm is trained in an intensive and repetitive manner in activity-based practice. 27 Patients undergoing BIM intensively practice bimanual tasks that become progressively more difficult. This therapy is based on the premise that coordination of both hands is important for the improvement of performance in everyday tasks, as these tasks are predominantly bimanual in nature. BIM focuses on tasks that require use of both hands; the unimpaired hand acts as a template for learning motor control of the impaired hand.101,102 Robot-assisted therapy is an emerging modality for rehabilitation that uses robotics to aid and/or objectively record movement of limbs during repetitive exercises. Robot-assisted therapies can allow participants with moderate impairment to experience a wider range of motion (and, thus, sensory feedback) than other therapies, and can be linked to virtual reality environments that provide haptic feedback. The technique is in the very early experimental phase and is primarily used in adults after stroke; its potential for therapy in UCP is currently unclear.103
activity themselves), relevant to the environment and the child’s motivation, and goal-directed. The therapy should be delivered by the parents as a series of challenging but achievable activities, conducted in the appropriate environment and context, and designed to include specific learning goals for the child. The two most extensively investigated contemporary approaches to upper limb therapy in children with UCP are modified constraint-induced movement therapy (mCIMT) and bimanual intensive therapy (BIM; Box 1). Hybrid CIMT, in which the child trains with mCIMT before BIM, is another approach.11,12 mCIMT and BIM are increasingly being delivered to individuals and groups in real-life situations so as to provide context to motor skill learning.12 However, such therapy requires expertise, can be costly, and is not always accessible. For these reasons, the usual upper limb therapy for children with UCP includes occupational therapy together with adjunctive treatments— such as medications to reduce spasticity—that target secondary symptoms. Although occupational therapy can include mCIMT or BIM, the time devoted to these
therapies in these contexts is typically a lot less than the time allotted to them in clinical trials. In response to this multifactorial challenge, alternative modes of delivery, such as web-based training and virtual reality platforms, have been developed. Early studies of web-based multimodal training have shown that these approaches can improve motor and planning skills in children with UCP.13–15 In addition, robot-assisted virtual reality therapy (Box 1) has been tested in pilot trials16–18 and larger studies,19,20 which have provided preliminary evidence that highlights the potential of such therapy for rehabilitation in children with UCP. The efficacy of the current activity-based therapies, as determined by large systematic reviews and meta-analyses, can be used to gauge the optimal dose, environmental context and intensity of upper limb intervention for children with UCP.12,21 A meta-analysis of 42 randomized controlled trials assessed the efficacy of 14 approaches to upper limb therapy, and found moderate to strong evidence to support the use of intensive activity-b ased, goal-directed interventions (such as mCIMT and BIM) rather than usual care to improve the quality and efficiency of upper limb movement and to achieve individual goals.12 The conclusions drawn in this systematic review, in combination with knowledge of the factors that impede or enable implementation of therapy, have led to the current consensus on the essential elements of effective upper limb therapy. These elements are intensive structured task repetition, progressive incremental increases in difficulty, and goal-directed approaches that enhance the motivation and engagement of individuals receiving therapy.22 Current activity-based therapies are thought to provide both specific (unimanual or bimanual) and global (occupational performance) improvements in motor function. For example, when mCIMT and BIM, delivered in blocks of 60 h over 10 days, were compared in the randomized INCITE trial (n = 64),21 mCIMT was more effective at increasing the use of the impaired limb, whereas intensive BIM was more effective at improving bimanual co-ordination. This observation confirms that these training techniques have specific effects. Motor-evoked potential recruitment curves, which were measured by transcranial magnetic stimulation (TMS), were also changed more substantially by intensive group-based mCIMT than by BIM (R. N. Boyd et al., unpublished work). Delivery of intensive group-based therapy can, however, be costly, and many therapists have identified barriers to implementation.22 Another randomized trial made a direct comparison between intensive group-based hybrid CIMT over 2 weeks and a comparable amount of individual therapy distributed over 12 weeks.11,23 Improvements in bimanual co-ordination (evaluated with the Assisting Hand Assessment) and occupational performance (assessed with the Canadian Occupational Performance Measure) were similar between the two groups. These results show that with a constant total dose of activity-based therapy, similar results can be achieved despite vari ations in child:therapist ratios (1:2 or 1:1) and the way
2 | ADVANCE ONLINE PUBLICATION
www.nature.com/nrneurol © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS in which therapy is delivered (groups or individuals).23 The similar outcomes attained with the use of intensive group-based and individual therapy mean that therapists can choose to deliver upper limb therapy in the way that is best suited to family circumstances and characteristics of the child. In this trial, the willingness of children to independently persevere, solve problems, master challenging tasks, and use their impaired hand for bilateral activities contributed to occupational performance outcomes.24 Family ecology and the therapeutic context were also identified as critical factors that influenced the children’s mastery motivation and engagement in therapy.25 The long-term retention of functionality gained from upper limb therapies is not frequently assessed, but some evidence suggests that gains in functionality can last for at least 6–12 months after therapy in children with UCP.26–28 The majority of research into the effectiveness of rehabi litation and the mechanisms that underlie responses to therapy has been conducted with schoolaged children with UCP, but major brain growth and development occurs in the first 2 years of life. This period could represent a critical window during which rehabilitation might be most effective, but which is missed by modern rehabilitative approaches.29 Empirical evidence for the effectiveness of currently used therapies in infants with UCP is limited, but animal studies have provided evidence for a critical period.30–32 For example, in kittens, inactivation of the primary motor cortex in one hemisphere during postnatal weeks 5–7 results in seemingly permanent impairment of contra lateral motor skill, and a variety of abnormalities in neural organization.32 Motor training and limb restriction similar to CIMT can reverse these motor deficits when carried out during early development (8–13 weeks of age), but is much less effective when carried out at 20–24 weeks of age.32 Such critical periods of development might primarily reflect time windows during which abnormal neural organization can be prevented, rather than periods during which the brain is simply more able to repair existing damage.33 One pilot study (n = 5) of lower limb rehabilitation has indicated that intense rehabilitation is feasible and effective in children with UCP aged
