Advisory Editor
H. Kerr Graham, MD, FRCS(Ed), FRACS
Professor of Orthopaedic Surgery
University of Melbourne
Associate Director, Clinical Research
Murdoch Children's Research Institute
Royal Children's Hospital
Victoria, Australia
The cerebral palsies (CP) are a group of disorders caused by a nonprogressive injury to the developing central nervous system (CNS) in children younger than 3 years, resulting in neurological and musculoskeletal abnormalities (Graham 2001). Impairments in movement and posture may lead to functional deficits and the inability to perform activities of daily living, which in turn may compromise the patients' functional independence and quality of life.
CP affects approximately 764,000 children and adults in the United States (Cerebral Palsy—Facts and Figures 2004) and is the most common cause of disability affecting children in developed countries, with an incidence of 1.7-2.0/1,000 live births (Winter S, et al. 2002). Based on 2003 estimates, the economic burden of CP includes $1.18 billion in direct medical costs, $1.05 billion in direct nonmedical costs, and an additional $9.24 billion in indirect costs, for a total cost of $11.5 billion or $921,000 average cost per person (Centers for Disease Control and Prevention 2004).
Effective clinical management of CP requires an appropriate understanding of the pathophysiology of the disorder, careful assessment of the patients' capabilities and limitations, and knowledge of the available treatment regimens and their appropriate applications and limitations.
The motor problems associated with CP can be classified according to three main criteria: type of motor disorder, topographical distribution, and gross motor function.
CP is part of a larger group of disorders in which injury to the motor pathways of the CNS is involved. Traditionally, motor disorders of central origin have been divided into "pyramidal" and "extrapyramidal" depending on the presumed anatomical location of the brain injury and its resulting symptoms (Sanger, et al. 2003). The pyramidal disorders, better known as the "upper motor neuron (UMN) syndrome," involve lesions in any part of the corticospinal tracts and their connections resulting in a disruption of the spinal motor centers and a net loss of inhibition of the "stretch" reflex. These tracts and their involvement in the reflex circuits associated with muscle movement are shown in Figure 1. Clinically, the UMN syndrome is manifested by muscle weakness with a typical distribution (extensors>flexors), loss of selective motor control, spasticity, hyperreflexia, and Babinski sign. Spasticity is characterized by muscle resistance at rest that is velocity dependent and associated with an increase in tonic stretch reflexes resulting from hyperexcitability of the stretch reflex (Lance 1980). Spasticity predominates in the antigravity muscles (flexors>extensors). Over the long term, patients with this disorder will develop bony deformities and musculoskeletal abnormalities that are the result of the muscle imbalance around the joint.
Figure 1: Neuronal Pathway (Dormans and Pellegrino 1998).
This diagram shows the neuronal pathways associated with response to a stretch reflex. In the UMN syndrome, lesions in any part of the corticospinal tracts or their connections result in a loss of inhibition of the stretch reflex. Reproduced with permission from Dormans JP, Pellegrino L. Caring for Children With Cerebral Palsy: A Team Approach. Baltimore, Md: Paul H. Brookes Publishing Co., Inc.; 1998.
The extrapyramidal motor syndrome results from injury to the basal ganglia and their connections. The motor symptoms associated with this type of disorder include dystonia, choreoathetosis, and other involuntary movements. Muscle tone may be decreased, normal, or increased. The hypertonia seen in patients with this disorder is not velocity dependent and affects both agonist and antagonist muscles. Dystonia is a hyperkinetic movement disorder characterized by sustained muscle contractions that cause twisting or repetitive movements and abnormal postures or positions; it is further characterized by an excessive co-contraction of antagonist muscles during voluntary movement, overflow of muscle contraction to remote muscles not normally employed for that particular movement, and spontaneous muscle spasms that are influenced by the patient's emotional and conscious state. Because of the variability in tone and movement, fixed contractures may take longer to develop in patients with extrapyramidal motor disorders. However, joint dislocations may occur at any stage. Tendon releases have a poor prognosis, and selective dorsal rhizotomies (SDR) do not improve the hypertonia seen in these patients because the hypertonia is not due to an exaggerated stretch reflex. Although more than 80% of patients with CP have spasticity, many have a mixed motor picture showing signs of spasticity and dystonia (Brunstrom 2001; Delgado and Albright 2003).
Proper identification and understanding of these motor disorders is essential to formulating a successful treatment strategy.
The symptoms of CP are not usually evident at birth but instead emerge as the child develops (Graham 2001; Rang, et al 1990). The symptoms that may be manifested in CP are highlighted in Box 1. Sanger et al (Sanger, et al. 2003) and Delgado and Albright (Delgado and Albright 2003) offer fuller discussions on classification of movement disorders associated with CP.
| Box 1. Clinical Manifestations of Cerebral Palsy |
| Movement disorders including: |
|
| Motor control difficulty |
| Difficulty with balance |
| Muscle weakness |
Many of the clinically significant phenomena associated with CP, such as dystonia and spasticity, result from a net imbalanceof dynamic and static forces that affect the position of the joints statically and the movement of limbs dynamically. These changes alter the functionality of the muscle, joint, and surrounding soft tissue.
Although the CNS damage in CP is not progressive, some evidence indicates that the secondary musculoskeletal pathology is progressive (Boyd and Graham 1997). Increased bone growth and increased muscle tone in the child with CP may lead to contractures and joint subluxation/dislocation, which can complicate movement. Therefore, it is important that these children are repeatedly screened for problems, such as silent hip subluxation, as they age (Graham 2001).As shown in Table 1, CP has a topographical distribution defined by the location of its musculoskeletal symptoms (although there is a substantial overlap of affected areas). Hemiplegia, diplegia, and quadriplegia are the common topographical types, with monoplegia and triplegia being relatively uncommon.
| Table 1. Topographical Distribution of Cerebral Palsy | |
| Topographical Descriptor | Area affected |
| Monoplegia | One limb involved |
| Hemiplegia | Involvement of one side of the body |
| Diplegia | Lower extremities more involved than the upper extremities |
| Triplegia | Three extremities involved |
| Quadriplegia or tetraplegia | All four extremities involved |
Most children with CP can be classified using a combination of movement disorder type with a topographic location—for example, spastic diplegia, spastic hemiplegia with athetosis, dystonia quadriplegia, etc. Perhaps the most common motor disorder is a mixed disorder—for example, spastic dystonia.
Gross motor function: The gross motor function classification system (GMFCS)
Gross motor function in children with CP can be easily classified using the Gross Motor Function Classification System (GMFCS). The GMFCS is a five-level grading system based on the assessment of self-initiated movement, with emphasis on function during sitting and walking. Distinctions between levels are based on functional limitations, the need for walking aids or wheeled mobility, and the quality of movement (Table 2). This system is a reliable and valid method for the classification and prediction of motor function in children with CP aged 2 to 12 years (Morris and Bartlett 2004).
| Table 2. The Gross Motor Function Classification System | |
| GMFCS Level | Definition |
| I | Children walk indoors and outdoors, and climb stairs without limitations. They perform gross motor skills, including running and jumping, but speed, balance, and coordination are reduced. |
| II | Children walk indoors and outdoors, and climb stairs holding onto a rail, but experience limitations walking on uneven surfaces and inclines, and walking in crowds and confined spaces. These children have at best only minimal ability to perform gross motor skills, such as running and jumping. |
| III | Children walk indoors or outdoors on a level surface with an assistive mobility device. They may climb stairs holding onto a rail. Depending on upper limb function, these children propel a wheelchair manually or are transported (pushed by another person) when traveling long distances or outdoors on uneven terrain. |
| IV | Children may maintain levels of function achieved when they were younger than 6 years or rely more on wheeled mobility when at home, or at school, or in the community. Children may achieve self-mobility using a powered wheelchair. |
| V | Physical impairments restrict voluntary control of movement and the ability to maintain antigravity head and trunk postures. All areas of motor function are limited. Functional limitations in sitting and standing are not fully compensated through the use of adaptive equipment and assistive technology. Children have no means of independent mobility and are transported (pushed by another person). Some children achieve self-mobility using a powered wheelchair with extensive modifications. |
Combining classification of the movement disorder and topographical distribution with grading of gross motor function results in a comprehensive description of the individual child with CP. This classification can be a useful aid to communication between physicians and allied health personnel in providing the right treatment for a child with CP. It is also helpful in clinical research. Presented here are two examples where this classification is effective.
Example 1: Ben is a 4-year-old boy with a right spastic hemiplegia. He is classified at GMFCS Level I. This classification describes a younger child with unilateral spasticity and a very high level of independent function. Such children often have a unilateral spastic equinus that can be effectively managed by intramuscular injection of botulinum neurotoxin type A (BoNT type A).
Example 2: Amy is a 12-year-old girl with spastic-dystonic quadriplegia. She is classified at GMFCS Level V. This classification describes a child with a generalized movement disorder and a very low level of function. Such children may benefit from complex interdisciplinary care, including physical therapy, communication aids, suitable seating, a wheelchair for mobility, and perhaps intrathecal baclofen (ITB) pump for the control of generalized spastic dystonia.
In children with CP, permanently shortened muscle fibers—contractures—develop primarily because bone growth outpaces muscle growth. Muscle weakness, which impedes voluntary activity and stretch, and the characteristic muscle stiffness of spasticity both inhibit muscle growth. In the younger child, muscle shortening is described as "dynamic" because it is the result of spasticity, is reversible, and is most easily observed during activity (Boyd and Graham 1997). As the child grows, the growth of muscle-tendon units falls progressively behind the growth of long bones. The resulting contractures cause permanent flexion or extension of joints in fixed postures, significantly reducing the range of motion around a joint. Much of the musculoskeletal management of CP is directed toward treating spasticity and maintaining or regaining muscle length.
The overall management of motor disorders in CP should address the following: spasticity, dystonia, muscle stiffness, contracture, joint deformity, muscle weakness, and other aspects of abnormal motor control.
Effective therapeutic management of CP should be specifically related to the neurological and motor impairments affecting the individual patient, and will most often require the efforts of a multidisciplinary healthcare professional team administering physical, pharmacological, and surgical treatments (Russman, et al. 1997). Traditionally, there has been a much greater emphasis on treating hypertonia symptoms than weakness and the lack of selective motor control, even though these last two symptoms may determine the level of disability and the long-term prognosis of children with CP. For example, muscle weakness may necessitate the need for a wheelchair, and a walking aid may be needed to cope with the effects of impaired balance (Tilton 2003). It is important that the relative contributions of the various symptoms form the basis of a rational treatment plan for the musculoskeletal disorders associated with CP. The most comprehensive, effective treatment plans will often require, if possible, multiple therapeutic targets using several treatment options administered by an interdisciplinary team, with the aim of optimizing functional outcomes. A broad-based treatment approach, therefore, enhances the potential to relieve symptoms, to improve motor performance, and to achieve functional restoration (Jackson 2001).
Effective assessment of the CP patient is the first step in determining the extent and nature of treatment (Russman, et al. 1997; Gormley, et al. 2001b). The patient should be evaluated to determine which symptoms significantly interfere with function, gait, activities of daily living, comfort, or caregiving, and whether the child is at risk for fixed musculoskeletal deformity. For example, if spasticity is interfering with function or is likely to lead to musculoskeletal deformity, such as fixed contractures, a thorough determination of reasonable treatment goals should be formulated
in collaboration with the patient and caregiver. Select treatment goals include reducing tone and/or pain, increasing functional capacity, and improving range of motion, gait, and hygiene. Relevant treatment strategies seek to balance muscle forces across joints, mechanically correct musculoskeletal deformity, correct neurological control, and/or modify motor power and control.
Nonpharmacologic and pharmacologic (via oral, parenteral, or intrathecal administration) treatment options are available for treating children with CP (Russman, et al. 1997; Gormley, et al. 2001b). Physical and occupational therapy, orthotics, and serial casting also constitute an important and well-documented part of an overall treatment program (Russman, et al. 1997; Gormley, et al. 2001b). Some patients may also require surgical treatments such as SDR or tendon lengthening.Chemodenervating agents—phenol, alcohol, and BoNT—have also become an important part of an effective treatment regimen, specifically for focal spasticity or dystonia associated with CP. These treatment options do not directly address the underlying CNS pathology responsible for spasticity or dystonia in disorders such as CP, but are designed to ameliorate the symptoms of motor dysfunction. Although it is not possible to completely eliminate a disorder such as spasticity, there are several treatment modalities with varying degrees of efficacy. Each treatment modality differs in its indications, limitations, and side effects, which should be considered when treating the patient with CP (Russman, et al. 1997).
An important treatment consideration is to first confirm whether a symptom such as spasticity is generalized, regional, or focal. For example, oral antispasticity medications act systemically and equally on all muscle groups, and are used primarily for generalized spasticity. SDR and ITB primarily target the lower limbs in the treatment of regional spasticity. BoNT is used to treat focal spasticity (Barnes 2003).
Sometimes it may be necessary to combine regional and focal treatments such as BoNT and SDR, or BoNT and ITB (Gormley, et al. 2001b). In some cases, combinations of other treatment modalities that include muscle strengthening, orthotic support, spasticity management, and correction of deformities through surgery along with physical therapy (PT) and occupational therapy (OT) may be necessary (Gormley 2001a). Muscle lengthening and BoNT injections may be used in some patients to prevent fixed contractures.
The choice of therapy in pediatric spasticity is influenced by a variety of other factors, including the age of the patient; drug dosing frequency, formulation, and delivery; compliance with treatment and commitment to follow up; side-effect profile; possible drug interactions; a patient's prior reaction to a given treatment; comorbid conditions, such as seizures; and cost (Tilton and Maria 2001).
It is evident that children with CP present with a variety of motor problems that change with growth and development. An optimal treatment plan evolves over the developmental years of the child, is specifically related to the spectrum of disorders that need to be treated, makes use of combinations of available therapeutic modalities, and is designed to improve functional outcomes if possible. A course of integrated treatment implementation in children with CP on the basis of age has been proposed (Boyd and Graham 1997; Pirpiris and Graham 2001). The following graph approximates the timeline of CP treatments commonly necessary at different ages in the child with CP (Figure 2).
Figure 2. Relative Frequency of Treatment Type in Cerebral Palsy Management Program (Pirpiris and Graham 2001).
Adapted from Pirpiris M, Graham HK. Management of spasticity in children. In: Barnes MP, Johnson GR, eds. Upper Motor Neuron Syndrome and Spasticity. Clinical Management and Neurophysiology. Cambridge, England: Cambridge University Press; 2001:266-305.
Spasticity is one of the most common symptoms associated with CP. An integrated treatment approach to ameliorate this symptom and its effects on the musculoskeletal system may include combinations of nonpharmacologic, pharmacologic, neurosurgical, and orthopedic surgical modalities, as shown in Box 2. The choice of treatment should be made on the basis of a variety of patient-related factors, including specific motor dysfunction and related disability, age, level of disability, dynamic or fixed nature of the deformities, and gait maturity.
| Box 2. Spasticity Treatment Options (Pirpiris and Graham 2001; Woo 2001) |
Nonpharmacologic
Pharmacologic
Neurosurgical
Orthopedic Surgery: Single-Level or Multilevel
|
PT and OT are often used in combination with oral medications or BoNT to help maintain muscle and soft tissue length, improve body symmetry, and facilitate functional activity (Albany 1997). PT and OT interventions include therapeutic exercise to improve range of motion, ambulation and gait training aimed at achieving a normal gait pattern and maximizing functional independence, and positioning to optimize posture and function and to inhibit spasticity patterns and facilitate movement. Weakness is a major determinant of gross motor function in CP, and the importance of progressive resistance strength training (PRST) has been confirmed in a recent clinical trial (Dodd, et al. 2003; McBurney, et al. 2003).
Orthoses or splints are often used as part of an overall rehabilitation program for both upper and lower limb spasticity. Certain types of ankle-foot orthoses (AFOs) have been found to improve heel-toe gait (Romkes and Brunner 2002). Orthoses are also used to help reduce energy expenditure and prevent secondary skeletal deformities (Woo 2001). Orthoses have been found to improve posture and to decrease involuntary movements of the upper and lower limbs (Blair, et al. 1995; Gracies, et al. 2000). There are many AFO designs available, and the choice to use a certain type may be determined by biomechanical alignment and gait pattern (Rodda, et al. 2004).
Serial casting is also used as part of an overall spasticity management program. The goal of casting is to stretch muscles, a process which provides a stimulus for growth (Woo 2001). Casting has been found to improve muscle tone, foot contact during gait, and passive range of motion (Cottalorda, et al. 2000; Watt, et al. 1986), although repeated casting is typically necessary to maintain benefit (Watt, et al. 1986). In many children, calf muscle spasticity and contracture co-exist; casting may then be used after injection of the calf with BoNT type A. Casting after injection of BoNT type A is better tolerated and more effective and is required for a shorter period compared with casting without prior injection of BoNT type A (Boyd and Graham 1997).
Several oral medications can be used to treat generalized spasticity. Oral agents are perhaps most useful for treating diffuse distribution of muscle overactivity involving many muscles throughout the body before the development of the fixed deformities and postures that occur from muscle imbalance between agonists and antagonists. Several medications—including diazepam (Valium ®) and baclofen (Lioresal ®)—operate at the brain and spinal cord level to agonize inhibitory neurotransmission at the GABA (gamma-aminobutyric acid) receptors (Abbruzzese 2002). Tizanidine (Zanaflex®), an a 2 -adrenergic agonist, is another commonly used antispasticity drug (Abbruzzese 2002). Additional secondary drugs include tiagabine, cyproheptadine, clonidine, lamotrigine, and gabapentin. These oral antispasticity medications are, in general, only marginally effective (Pirpiris and Graham 2001; Abbruzzese 2002). Often, by the time an effective dose is achieved, patients experience complications such as sedation, respiratory depression, hypotension, bradycardia, withdrawal syndrome, and increased oral secretions (Pirpiris and Graham 2001;.Gracies, et al. 1997b) Dantrolene (Dantrium ®) inhibits the release of calcium from the muscle fiber sarcoplasmic reticulum, thereby uncoupling excitation from contraction (Krause, et al. 2004). The potential side effects of this drug are hepatotoxicity, muscle weakness, diarrhea, mild drowsiness, paresthesias and, occasionally, dysphagia (Pirpiris and Graham 2001; Gracies, et al. 1997b).Trihexphenidyl (Artane ®) (Hoon, et al. 2001), levodopa (Sinemet ®) (Brunstrom, et al. 2000), and other drugs have demonstrated various degrees of efficacy for the treatment of dystonia in children with cerebral palsy.
Management of chronic spasticity or dystonia with oral medications in children with CP is rarely practical because of the generalized effects and associated safety and tolerability issues (Pirpiris and Graham 2001;.Gracies, et al. 1997b). However, management of acute exacerbations of hypertonia with oral agents is very useful, especially after orthopedic surgery (Pirpiris and Graham 2001).
Chemodenervation refers to the focal or multi-focal chemical interruption of the flow of nerve impulses to muscles. Phenol and alcohol operate neurolytically, while BoNT selectively prevents acetylcholine release from motor neurons. By reducing local spastic muscular contractions, these chemodenervating agents help improve limb position and/or function.
When injected at the motor end points, dehydrated ethyl alcohol (35% to 98%) and phenol (>3%) denature protein, causing necrosis of myelin, axons, and soft tissue proteins (Gracies, et al. 1997a). Phenol and alcohol can be injected percutaneously onto a peripheral nerve or its very distal motor branch, termed a motor point. Phenol causes nonselective neurolytic injury to axons of all sizes, effectively blocking transmission of nerve impulses to the target muscles. When phenol is dripped onto a nerve, the axons in the center of the nerve sheath are less affected and blocks are rarely complete. Interestingly, muscle strength is preserved more often than stretch reflexes. Since phenol has local anesthetic properties, the clinician will see an immediate reduction in muscle tone if the block has been performed well. The longer-term effect caused by protein denaturation develops several days later when Wallerian degeneration is initiated (Gracies, et al. 1997a). Regeneration will occur and, similar to other peripheral nerve injuries, its time course may depend, in part, on the length of nerve segment that has degenerated. An experienced injector can achieve desirable effects with phenol injection for 2 to 6 months (Gracies, et al. 1997a). The duration of alcohol-mediated chemodenervation ranges from 20 days (Carpenter and Seitz 1980) to more than 6 months (Chua and Kong 2000) and is largely a function of the alcohol concentration and route of injection. Tissue destruction may lead to soft tissue scarring and fibrosis, making repeat injections with phenol problematic. This, however, may contribute to long-term beneficial effects on muscle overactivity.
Chemodenervation with phenol or alcohol continues to be an especially appropriate choice for severe spasticity in the largest muscles, such as those of the thigh. Both can effectively weaken spastic muscle, reducing spasticity and improving range of motion.
Although ethyl alcohol and phenol are inexpensive, the injection procedure usually requires general anesthesia or deep conscious sedation to find the motor end points, and significant skill and experience in administering the medications. Side effects can be significant, including injection-site pain, chronic dysesthesia, tissue fibrosis, and permanent nerve palsy. These complications are particularly present when the alcohol or phenol is injected into a mixed motor and sensory nerve.
BoNT is produced by Clostridium botulinum as a complex of proteins containing the neurotoxin itself and other nontoxic proteins. BoNT consists of a 100-kDa heavy chain and a 50-kDa light chain linked by a single disulfide bond and noncovalent interactions. It is synthesized as a relatively inactive single-chain polypeptide with a molecular mass of approximately 150 kDa. Activation of the neurotoxin occurs upon proteolytic cleavage into the heavy and light chains (Dolly 2003) There are 7 BoNT serotypes (A, B, C1, D, E, F, and G), all of which inhibit acetylcholine release, although their intracellular target proteins and potencies vary substantially. When BoNT is injected into a target tissue, the heavy chain of the neurotoxin binds to glycoprotein structures specifically found on cholinergic nerve terminals. Specificity for these docking glycoproteins is the basis of BoNT's high selectivity for cholinergic synapses. After internalization, the neurotoxin light chain selectively cleaves one of several SNARE proteins required for the formation of the SNARE* complex that mediates the release of acetylcholine into the neuromuscular junction. The target proteins vary among the BoNT serotypes: BoNT type A cleaves synaptosomal-associated proteins of 25 kDa (SNAP-25) (Dolly 2003) and BoNT type B cleaves vesicle-associated membrane protein (VAMP) (Dolly 2003), thereby preventing the docking of the acetylcholine vesicle on the inner surface of the cellular membrane and acetylcholine exocytosis (Figure 3). The resulting temporary inhibition of muscle contraction forms the basis of the therapeutic application of BoNT.
BoNT chemodenervation is accompanied by sprouting of new nerve terminals that re-establish a functional neuromuscular junction and the return of neuromuscular activity, usually within 28 days (Dolly 2003). Gradually, functionality returns to the original nerve ending in about 90 days, and the newly formed sprouts regress. As muscle overactivity returns, reinjection is often necessary.*Soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein binds avidly to preformed ternary complex, which, in turn, allows the association of NSF, hence, the term SNAP receptors (SNAREs). The SNARE complex serves an essential role in exocytosis by bringing the vesicle membrane into close apposition to the plasma membrane.
Figure 3. BoNT Mechanism of Action (Rowland 2002).
Acetylcholine in nerve terminals is packaged in vesicles. To release the transmitter, vesicle membranes fuse with those of the nerve terminals, releasing the transmitter into the synaptic cleft. The process is mediated by a series of proteins collectively called the snare proteins. BoNT, taken up into the nerve terminals, cleaves the SNARE proteins, preventing assembly of the fusion complex and thus blocking the release of acetylcholine.
(© Copyright 2002 Massachusetts Medical Society. All rights reserved. Used with permission from Rowland LP. N Engl J Med. 2002;347:382-383.)
Only one BoNT type A (BOTOX ®) and one BoNT type B (MYOBLOC ®) preparation are available for clinical use in the United States. An additional BoNT type A (DYSPORT ®) preparation is approved for clinical use in Europe and elsewhere. BoNT serotypes are not interchangeable. Each requires different unit doses and has different biochemical, pharmacologic, and clinical properties. The BoNT type A products, although based on the same serotype, have different formulations, require different clinical doses, and have slightly different clinical profiles (Nussgens and Roggenkamper 1997; Aoki 2001). Controlled clinical trials are needed to determine BoNT type B dosing recommendations for the treatment of problematic muscle overactivity in children with CP (Berweck and Heinen 2004). Most of the clinical research and use of BoNT in CP and spasticity has involved BoNT type A (BOTOX ®). In the United States, BOTOX ® is approved by the Food and Drug Administration (FDA) for use in the treatment of blepharospasm, cervical dystonia, hyperhidrosis, strabismus, and glabellar lines. BoNT type B (MYOBLOC ®) is FDA approved for use in cervical dystonia to reduce the severity of abnormal head position and neck pain. Other potential therapeutic applications of BoNT include use in the treatment of spasticity, dystonia, spastic sphincters, tremors, myofascial pain syndromes, drooling, and other conditions in which altering the release of acetylcholine might be expected to improve function (Verheyden, et al. 2001). BoNT type A can also be effective in reducing pain by inhibiting the release of glutamate, substance P, and calcitonin gene-related peptide (Cui, et al. 2004)—all of which are neurotransmitters involved in the nociceptive response (Aoki 2002).
Although not labeled for therapeutic use in spasticity in the United States, BoNT type A is widely used to treat focal spasticity and dystonia in children with CP (Berweck and Heinen 2004) and is labeled in more than 40 countries, including Canada, for this indication (Koman, et al. 2003). BoNT type A can potentially be used as a primary therapy for focal spasticity (Russman, et al. 1997). Reduction of spasticity can facilitate retraining of the affected limb so that the child can adapt and develop skills to improve functional capacity and independence (Koman, et al. 2003).
Cosgrove and Graham investigated the effects of intramuscular injection of BoNT type A in an animal model of spasticity, the hereditary spastic mouse. Injection of the spastic gastrocsoleus in the spastic mouse promoted normal muscle growth and prevented contractures (Cosgrove and Graham 1994). Multiple studies have demonstrated a reduction in spasticity and an increase in function in children with CP treated with BoNT type A. Koman and colleagues assessed the effectiveness of intramuscularly injected BoNT type A on the muscular imbalances of CP in 27 pediatric patients, who experienced a reduction in lower-limb spasticity that lasted 3 to 6 months as a result of the BoNT type A treatment (Koman, et al. 1993). A subsequent prospective, 3-month, double-blind, randomized clinical trial that evaluated the short-term efficacy of BoNT type A injections in 114 children with CP and dynamic equinus foot deformity demonstrated that BoNT type A improves gait function (Koman, et al. 2000). The results of 2 randomized, placebo-controlled trials support the use of BoNT type A for reducing upper-limb spasticity and improving function in children with CP (Corry, et al. 1997; Fehlings, et al. 2000).
BoNT type A may also be used as an adjunctive treatment for regional or generalized spasticity (O'Brien 2002). It is used to achieve predetermined functional goals such as improved hygiene and gait. BoNT type A injections combined with occupational therapy significantly enhanced the improvement in function compared with occupational therapy alone (Boyd, et al. 2001). Graham and colleagues suggested that BoNT type A treatment during the dynamic phase of motor development may maximize the chance of disease modification and help postpone, simplify, or even avoid surgery. Treatment during later years may provide pain relief, improve ease of care, and facilitate sitting or standing (Graham, et al. 2000).
A comparison between BoNT type A and phenol, the two commonly used focal treatments, is shown in Table 3.
| Table 3. Comparison of BoNT Type A and Phenol (Gracies, et al. 1997a; Bell and Williams 2003; Brin 1997a; Brin, et al. 1997b) |
||
| BoNT type A | Phenol | |
| Titration effect | Dose dependent | Dependent on number of motor branches |
| Onset | 24-72 hours; peak at 21-28 days |
Immediate |
| Optimal location for injection |
Small muscles— fine control |
Large muscles such as lower limb |
| Local toxicity | No irritation | Potential edema, necrosis |
| Systemic toxicity | If total quantity > 800 U |
If intravascular or |
BoNT type A may be appropriate for use in children with focal spasticity who meet the criteria outlined in Box 3.
| Box 3. Criteria for BoNT Type A Treatment in Children With Focal Spasticity (Autti-Rämö, et al. 2001) |
Dynamic deformity interfering with function, producing pain,
Painful spasms Pain control
Symptomatic focal limb or cervical dystonia Diagnostic trial for surgery Drooling reduction |
The clinical contraindications for BoNT type A use in patients include the following (Klein 2004):
CP is caused by a nonprogressive injury to the developing central nervous system, resulting in a variety of motor dysfunctions including spasticity. Unlike the causal and nonprogressive CNS damage in CP, there is some evidence that the secondary musculoskeletal pathology is progressive. Optimal therapeutic management of CP should focus on the specific impairments affecting the individual patient and involve the efforts of a multidisciplinary healthcare professional team encompassing physical, pharmacological, and surgical treatment with the aim of improving the specific symptom(s) and, if possible, the functional capacity of CP patients. There are several clinical trials that demonstrate reduction in spasticity and increased function in children with CP treated with BoNT type A. BoNT type A may be an appropriate treatment for children with CP and focal spasticity who do not have fixed joint or muscle contractures. Further study is needed to evaluate the appropriate role of BoNT type A as part of the overall management of CP.
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